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  • 51.
    Hansson, Monika
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Mercury-induced autoimmunity: Genetics and immunoregulation2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The existence of immune self-tolerance allows the immune system to mount responses against infectious agents, but not against self-molecular constitutes. Although self-tolerance is a robust phenomenon, in some individuals as well as in experimental models, the self-tolerance breaks down and as a result, a self-destructive autoimmune disease emerges. The underlying mechanisms for the development of autoimmune diseases are not known, but genetic, environmental and immunological factors are suggested to be involved. In this thesis, we used murine mercury-induced autoimmunity to test this suggestion.

    In susceptible mice mercuric chloride induces a systemic autoimmune disease characterized by increased serum levels of IgG1 and IgE, production of anti-nucleolar autoantibodies (ANolA) and formation of renal IgG deposits. In contrast, in resistant DBA/2 (H-2d) mice, none of these characteristics develop after exposure to mercury. By crossing and backcrossing mercury-resistant DBA/2 mice to mercury susceptible strains, we found that the resistance was inherited as a dominant trait in F1 hybrids and that one gene or a cluster of genes located in the H-2 loci determined the resistance to ANolA production, whereas resistance to the other characteristics was found to be controlled by two or three non-H-2 genes.

    We further put forward the “cryptic peptide hypothesis” to investigate whether mercury and another xenobiotic metal use similar pathway(s) to induce the H-2 linked production of ANolA. We found that while mercury stimulated ANolA synthesis in all H-2 susceptible (H-2s, H-2q and H-2f) mouse strains, silver induced only ANolA responses in H-2s and H-2q mice, but not in H-2f mice. Further studies showed that the resistance to silver-induced ANolA production in H-2f mice was inherited as a dominant trait.

    We next tested the proposition that mercury induces more adverse immunological effects in mouse strains, which are genetically prone to develop autoimmune diseases, using tight-skin 1 mice, an animal model for human Scleroderma. It was found that in this strain, mercury induced a strong immune activation with autoimmune characteristics, but did not accelerate the development of dermal fibrosis, a characteristic in Tsk/1 mice.

    Finally we addressed the Th1/Th2 cross-regulation paradigm by examining if a Th1-type of response could interact with a Th2-type of response if simultaneous induced in susceptible mice. Our findings demonstrated that mercury-induced autoimmunity (Th2-type) and collagen-induced arthritis (CIA) (Th1-type) can interact in a synergistic, antagonistic or additive fashion, depending on at which stage of CIA mercury is administered.

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  • 52. Howard, Jennifer
    et al.
    Loizon, Séverine
    Tyler, Christopher J.
    Duluc, Dorothée
    Moser, Bernhard
    Mechain, Matthieu
    Duvignaud, Alexandre
    Malvy, Denis
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Moreau, Jean-Francois
    Eberl, Matthias
    Mercereau-Puijalon, Odile
    Déchanet-Merville, Julie
    Behr, Charlotte
    Mamani-Matsuda, Maria
    The Antigen-Presenting Potential of V gamma 9V delta 2 T Cells During Plasmodium falciparum Blood-Stage Infection2017In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 215, no 10, p. 1569-1579Article in journal (Refereed)
    Abstract [en]

    During Plasmodium falciparum infections, erythrocyte-stage parasites inhibit dendritic cell maturation and function, compromising effective antimalarial adaptive immunity. Human V gamma 9V delta 2 T cells can act in vitro as antigen-presenting cells (APCs) and induce alpha beta T-cell activation. However, the relevance of this activity in vivo has remained elusive. Because V gamma 9V delta 2 T cells are activated during the early immune response against P. falciparum infection, we investigated whether they could contribute to the instruction of adaptive immune responses toward malaria parasites. In P. falciparum-infected patients, V gamma 9V delta 2 T cells presented increased surface expression of APC-associated markers HLA-DR and CD86. In response to infected red blood cells in vitro, V gamma 9V delta 2 T cells upregulated surface expression of HLA-DR, HLA-ABC, CD40, CD80, CD83, and CD86, induced naive alpha beta T-cell responses, and cross-presented soluble prototypical protein to antigen-specific CD8(+) T cells. Our findings qualify V gamma 9V delta 2 T cells as alternative APCs, which could be harnessed for therapeutic interventions and vaccine design.

  • 53. Huang, Jenny
    et al.
    Ehrnfelt, Cecilia
    Paulie, Staffan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Mabtech AB, Sweden.
    Zuber, Bartek
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Mabtech AB, Sweden.
    ELISpot and ELISA analyses of human IL-21-secreting cells: Impact of blocking IL-21 interaction with cellular receptors2015In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 417, p. 60-66Article in journal (Refereed)
    Abstract [en]

    Interleukin (IL)-21 is crucial for the regulation of lymphocytes and is implicated in autoimmune and other diseases. The relevance of being able to measure human IL-21 prompted us to develop ELISA and ELISpot assays for analysis of IL-21 levels and IL-21-producing cells, respectively. Monoclonal antibodies (mAbs) to IL-21 were made and ELISA and ELISpot assays were developed. The selected detection mAb also neutralized IL-21-mediated activation of human cells. Peripheral blood mononuclear cells (PBMCs) from healthy donors (n = 24) were stimulated polyclonally (phytohemagglutinin; PHA) or with antigen (Candida albicans extract and tetanus toxoid). Using ELISpot, high numbers of IL-21-producing cells were detected after PHA activation; lower but positive responses to antigen were seen in approximately 50% of the donors. In contrast, the ELISA detected IL-21 in supernatants from PHA-activated cells but not from antigen-stimulated cells. When analyzing IL-17A in parallel, PHA and antigens induced detectable responses in ELISpot as well as in ELISA. Hypothesizing that the lack of detectable IL-21 levels after antigenic stimulation was due to a combination of low frequencies of IL-21-secreting cells and consumption of IL-21 by cellular receptors during cell culture, PBMCs (n = 18) were stimulated in the presence of the neutralizing detection mAb. When preventing IL-21 from interacting with its receptor, increased IL-21 levels were found by ELISA after PHA activation and IL-21 could also be measured after antigen stimulation. ELISpot results were unaffected by the addition of the neutralizing mAb. In conclusion, IL-21 secreted by low frequencies of antigen-specific ex vivo-stimulated PBMC can be difficult to detect by ELISA but prevention of IL-21 interaction with its receptor leads to detectable IL-21 levels. In ELISpot, where the cytokine is captured by mAbs on a solid phase immediately upon secretion, blocking the receptor interaction does not affect the detection of IL-21-secreting cells.

  • 54.
    Härfast, Bengt
    Stockholm University.
    The effect of virus on the cytotoxic effector function of normal human lymphocytes1979Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The cytotoxic effect of human peripheral blood lymphocytes (PBL) from healthy donors against mumps virus infected cells was studied by 5lCR-release assay. With several different cell fractionation techniques the effector cells were demonstrated to be undistinguishable from the lymphocytes responsible for antibody dependent cellular cytotoxicity (ADCC, K-cells) and from those responsible for natural cytotoxicity (NK cells). In these three cytolytic systems the effector cells have Fc receptors for IgG (FcR). While ADCC is dependent on antibody by definition, NK activity involves both antibody dependent and antibody independent mechanisms. To learn whether the killing of virus infected cells required antibody. Fab fragments of rabbit antibodies to human immunoglobulin were added to the PBL-target cell mixtures. This reagent failed to inhibit the virus dependent target cell lysis, implying that the; reaction was immunoglobulin independent. Binding of PBL to target cells by the virus did not seem to be sufficient to cause target cell lysis since a PBL subset which also adhered firmly to virus infected cells did not lyse those. However, a virus induced cross linking of effector cells and target cells may facilitate the expression of cytotoxicity. Exposure of PBL to small amounts of mumps virus results in an enhanced cytolytic activity against uninfected target cells. Also in this instance were the effector cells closely related to the K- and NK-cells. Virus dependent cytotoxicity was not due to an ADCC type of mechanism as it remained essentially unchanged when the FcR activity of the lymphocytes was experimentally modulated by exposure to antigen-antibody complexes. Mumps virions lacking both of their spike glycoproteins (HANA and F) failed to generate virus dependent cytotoxicity. Virions lacking only HANA also generated virus dependent cytotoxicity but their capacity to do so was markedly impaired. Solubilized preparations of viral spikes also enhanced cytotoxicity although to a lesser extent than intact virions. Anti-HANA antibodies, but not anti-F antibodies, abrogated cytotoxicity when incubated together with virus used for treatment of PBL. These experiments demonstrate that HANA was an essential component for the induction of cytotoxicity. The possible role of F remains to be established.

  • 55. Höglind, Ankie
    et al.
    Areström, Irene
    Ehrnfelt, Cecilia
    Masjedi, Khosro
    Zuber, Bartels
    Giavedoni, Luis
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Mabtech, Sweden.
    Systematic evaluation of monoclonal antibodies and immunoassays for the detection of Interferon-gamma and Interleukin-2 in old and new world non-human primates2017In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 441, p. 39-48Article in journal (Refereed)
    Abstract [en]

    Non-human primates (NHP) provide important animal models for studies on immune responses to infections and vaccines. When assessing cellular immunity in NHP, cytokines are almost exclusively analyzed utilizing cross-reactive anti-human antibodies. The functionality of antibodies has to be empirically established for each assay/application as well as NHP species.

    A rational approach was employed to identify monoclonal antibodies (mAb) cross-reactive with many NHP species. Panels of new and established mAbs against human Interferon (IFN)-gamma and Interleukin (IL)-2 were assessed for reactivity with eukaryotically expressed recombinant IFN-gamma and IL-2, respectively, from Old (rhesus, cynomolgus and pigtail macaques, African green monkey, sooty mangabey and baboon) and New World NHP (Ma's night monkey, squirrel monkey and common marmoset).

    Pan-reactive mAbs, recognizing cytokines from all NHP species, were further analyzed in capture assays and flow cytometry with NHP peripheral blood mononuclear cells (PBMC). Pan-reactive mAb pairs for IFN-gamma well as IL-2 were identified and used in ELISA to measure IFN-gamma and IL-2, respectively, in Old and New World NHP PBMC supernatants. The same mAb pairs displayed high functionality in ELISpot and FluoroSpot for the measurement of antigen-specific IFN-gamma and IL-2 responses using cynomolgus PBMC Functionality of pan-reactive mAbs in flow cytometry was also verified with cynomolgus PBMC.

    The development of well-defined immunoassays functional with a panel of NHP species facilitates improved analyses of cellular immunity and enables inclusion in multiplex cytokine assays intended for a variety of NHP.

  • 56.
    Högstrand, Kari
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Gene conversion of the mouse MHC class II1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The major histocompatibility complex (MHC) is the most polymorphic vertebrate gene loci known to exist. Gene products of the MHC are responsible for presentation of antigen derived peptides to T cells of the immune system, which thereby become activated and involved in the elimination of particles recognised as non-self. The mechanism of acquiring this extensive polymorphism is not known, but gene conversion has been suggested as one possible molecular genetic mechanism employed to generate new MHC alleles. A strict definition of gene conversion, based on the phenomenon in yeast, involves the transfer of a DNA fragment from a donor gene to a homologous acceptor gene without the donor gene being changed in the process. For practical reasons, the term gene conversion in higher organisms is rather used in the context of ìtemplated segmental mutationì.

    This thesis describes the first direct evidence of gene conversion events between two endogenous MHC class II genes in a mouse system using sperm as a representative for future potential individuals. A PCR assay was developed using primers for the acceptor gene as well as the donor gene to obtain a detectable product only in cells where a gene conversion event had occurred. Interchromosomal gene conversion between a MHC class II Ab and Eb gene located on separate chromosomes was found to occur at a frequency of 1/500.000 sperm, whereas no gene conversion was detected in somatic liver cells. Intrachromosomal gene conversions between Ab and Eb genes located on the same chromosome were detected at frequencies ranging from 1/35.000 sperm to 1/830.000 sperm depending on the alleles in ves gat ed. This difference in frequency was found although the investigated alleles coexisted in the same cell, which indicates that there is sequence restraints acting on the genes involved in a gene conversion event. Both inter- and intra-chromosomal gene conversions transferred DNA fragments which varied in length, but the transfer breakpoints investigated were usually in regions where the donor and acceptor genes showed a high nucleotide similarity.

    Investigation of gene conversion during male gametogenesis showed that most gene conversion events detected between MHC class II genes were completed already in the premeiotic spermatogonia cell stage, which indicates that gene conversion relies on other molecular genetic mechanisms than normal meiotic recombination. Sequence analysis of several MHC mutants proposed to have been caused by gene conversion events revealed that both donor and acceptor sequences resided in regions where normal mammalian CpG suppression was absent. CpG dinucleotides have been shown to be relatively mutation prone, which accordingly suggests that regions with a high CpG content could be targeted for mutation events. Moreover, gene conversion could be induced and increased up to 15 times of the background level in a cell line by DNA damage, which indicates that the DNA repair system is involved in the gene conversion mechanism.

    From an evolutionary point of view, gene conversion thus is a very potent mechanism for creation of new MHC alleles by shuffling of already existing and functional parts of genes into new homologous locations. This mechanism can efficiently produce new functional MHC variants, which could give the population a selective advantage in terms of the ability to cope with various pathogens as well as being a mean to avoid inbreeding that could result in a reproductive loss.

  • 57.
    Iriemenam, Nnaemeka C.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Antibody responses and Fc gamma receptor IIa polymorphism in relation to Plasmodium falciparum malaria2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Immunity to asexual blood-stage of Plasmodium falciparum malaria is believed to be associated with protective antibodies of certain immunoglobulin classes and subclasses. This thesis addressed the importance of antibodies in relation to malaria infection and their effective interactions with Fc gamma receptor IIa (FcyRIIa) polymorphisms. Our data indicate that the frequency of FcyRIIa-R/R131 genotype was statistically significantly higher in Sudanese patients with severe malaria, while the FcyRIIa-H/H131 genotype showed a significant association with mild malaria. The levels of IgG1 and IgG3 subclass antibodies were statistically higher in the mild malaria patients.

    The Fulani ethnic group in West Africa has been shown to be relatively resistant to malaria. We investigated the possible impact of FcyRIIa polymorphisms in the Fulani and non-Fulani in Mali and Sudan, and analysed their malaria-reactive IgG subclass profiles. The FcyRIIa-H/H131 genotype and H131-allele were found to be prevalent in the Fulani while R131-allele was prevalent in non-Fulani. The Fulani had higher serum levels of IgG1-3, with higher proportion of IgG2 than the non-Fulani.

    Most clinico-epidemiology studies have been in areas with holo- and hyper-malaria endemicity. We have analysed antibody responses to a panel of six blood-stage antigens in relation to clinical malaria outcome in mesoendemic Sudan. Our results revealed a linear association with anti-AMA-1 IgG1 antibodies and reduced risk of severe malaria while a non-linear relationship with IgG3 antibodies was observed for MSP-2, MSP-3 and GLURP. In the combined final model, the highest levels of IgG1 subclass antibodies to AMA-1, GLURP-R0, and the highest levels of IgG3 subclass antibodies reactive to 3D7 MSP-2 were independently associated with a reduced risk of clinical malaria.

    Taken together, these data suggest a possible association between FcyRIIa-R/H131 and anti-malarial antibody responses in the clinical outcome of malaria.

     

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  • 58.
    Iriemenam, Nnaemeka C.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Khirelsied, Atif H.
    Nasr, Amre
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    ElGhazali, Gehad
    Giha, Haider A.
    Elhassan A-Elgadir, Thoraya
    Agab-Aldour, Ahmed A.
    Montgomery, Scott M.
    Anders, Robin F.
    Theisen, Michael
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Elbashir, Mustafa I.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Antibody responses to a panel of Plasmodium falciparum malaria blood-stage antigens in relation to clinical disease outcome in Sudan2009In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 27, no 1, p. 62-71Article in journal (Refereed)
    Abstract [en]

    Despite many intervention programmes aimed at curtailing the scourge, malaria remains a formidable problem of human health. Immunity to asexual blood-stage of Plasmodium falciparum malaria is thought to be associated with protective antibodies of certain immunoglobulin classes and subclasses. We have analysed immunoglobulin G profiles to six leading blood-stage antigens in relation to clinical malaria outcome in a hospital-based study in Sudan. Our results revealed a linear association with anti-AMA-1-IgG1 antibodies in children <5 years and reduced risk of severe malaria, while the responses of the IgG3 antibodies against MSP-2, MSP-3, GLURP in individuals above 5 years were bi-modal. A dominance of IgG3 antibodies in >5 years was also observed. In the final combined model, the highest levels of IgG1 antibodies to AMA-1, GLURP-R0, and the highest levels of IgG3 antibodies to 3D7 MSP-2 were independently associated with protection from clinical malaria. The study provides further support for the potential importance of the studied merozoite vaccine candidate antigens as targets for parasite neutralizing antibody responses of the IgG1 and IgG3 subclasses.

  • 59.
    Israelsson, Elisabeth
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Host genetic factors and antibody responses with potential involvement in the susceptibility to malaria2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The relatively lower susceptibility to malaria seen in the Fulani ethnic group in Africa, as compared to other sympatric ethnic groups, has been related to genetic regulation of the immune responses. This thesis aimed to describe important pathways related to the regulation of antibodies in the immune responses during a malaria infection. Our results suggest that the higher anti-malarial immune responses seen in the Fulani are not a general hyper-responsiveness in this group, but neither a malaria specific response. Fcγ receptors are important structures in the immune responses, and polymorphisms in these genes were associated with IgG subclass levels, P. falciparum parasitemia and haemoglobin levels, suggesting that these polymorphisms may be a contributing factor to the differential susceptibility to malaria. C-reactive protein levels rise immediately in response to inflammatory stimuli, and the -286 CRP polymorphism was indicated to influence parasite levels, suggesting a possible involvement in the lower susceptibility to malaria seen in the Fulani ethnic group. Several cytokines are important in maintaining the optimal parasite-neutralizing milieu in the host, and we investigated polymorphisms in some of these cytokine genes, in order to establish a possible influence of these on malaria susceptibility. Several of these polymorphisms showed associations with haemoglobin levels, IgG subclass antibody levels and parasitemia, suggesting that IL-1β, IL-6, IL-10 and TNF could affect the susceptibility to malaria and the severity of the malaria infection.

    Taken together, these data suggest that genetic factors have the ability to affect the antibody responses, and that several pathways can be affected. Moreover, the Fulani have a genetic predisposition for a higher inflammatory response during a malaria infection, which could lower their susceptibility to the disease. However, the control measures for this inflammation still have to be established and evaluated.

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  • 60.
    Israelsson, Elisabeth
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Ekström, Mattias
    Nasr, Amre
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Dolo, Amagana
    Kearsley, Susannah
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Arambepola, Gishanthi
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Homann, Manijeh V.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Maiga, Bakary
    Doumbo, Ogobara K.
    ElGhazali, Gehad
    Giha, Hayder A.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Tornvall, Per
    Marked differences in CRP genotype frequencies between the Fulani and sympatric ethnic groups in Africa2009In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, no 136Article in journal (Refereed)
    Abstract [en]

    Background

    C-reactive protein (CRP) is an acute phase protein that can activate various immune cells and bind to certain Fcγ receptors. The latter may compete with the binding of IgG antibodies to these receptors and could thereby interfere with the antigen-specific immune response. Polymorphisms in the promoter region of the CRP gene have been strongly associated with the plasma concentration of CRP. The known lower susceptibility to malaria in the Fulani ethnic group, as compared to their sympatric neighbours in Africa, has been linked to different genetic backgrounds. The present study was performed to investigate if polymorphisms in the CRP gene could contribute to the lower susceptibility to malaria seen in the Fulani ethnic group.

    Methods

    The CRP -717 T>C, -286 C>T>A, and +1444 C>T polymorphisms were analysed in asymptomatic Fulani and non-Fulani individuals from Mali and Sudan using Pyrosequencing T and TaqMan r MGB probes.

    Results

    The rare -286 A allele, previously shown to be associated with increased CRP expression and plasma levels, was shown to be more frequent in the non-Fulani ethnic groups as compared to the sympatric Fulani ethnic group both in Mali and Sudan. The common -717 T allele was more prevalent in the non-Fulani ethnic group compared to the sympatric Fulani ethnic group, but only in Mali. The parasite prevalence was increased for the -286 A allele, but not for the -717 T allele. No differences regarding genotype frequency or parasite prevalence were seen for +1444 C>T.

    Conclusion

    This study indicate that CRP may play an important role in the immune responses to malaria, and that the -286 C/T/A CRP polymorphism may be a contributing factor to the lower susceptibility to malaria seen in the Fulani.

  • 61. Jahnmatz, Peter
    et al.
    Bengtsson, Theresa
    Zuber, Bartek
    Farnert, Anna
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Mabtech AB, Sweden.
    An antigen-specific, four-color, B-cell FluoroSpot assay utilizing tagged antigens for detection2016In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 433, p. 23-30Article in journal (Refereed)
    Abstract [en]

    The FluoroSpot assay, a variant of ELISpot utilizing fluorescent detection, has so far been used primarily for assessment of T cells, where simultaneous detection of several cytokines has allowed a more qualitative analysis of functionally distinct T cells. The potential to measure multiple analytes also presents several advantages when analyzing B cells. Our aim was to develop a B-cell FluoroSpot assay adaptable to studies of a variety of antigens. The assay utilizes anti-IgG antibodies immobilized in 96-well filter membrane plates. During cell culture, IgG antibodies secreted by antibody-secreting cells (ASCs) are captured in the vicinity of each of these cells and the specificity of single ASCs is defined using antigens for detection. The antigens were labeled with biotin or peptide tags enabling secondary detection with fluorophore-conjugated streptavidin or tag-specific antibodies. The assay, utilizing up to four different tag systems and fluorophores simultaneously, was evaluated using hybridomas and immunized splenocytes as ASCs. Assay variants were developed that could: i) identify multiple ASCs with different antigen specificities; ii) detect ASCs showing cross-reactivity with different but related antigens; and iii) define the antigen-specificity and, by including anti-IgG subclass detection reagents, simultaneously determine the IgG subclass of antibodies secreted by ASCs. As demonstrated here, the B-cell FluoroSpot assay using tag-based detection systems provides a versatile and powerful tool to investigate antibody responses by individual cells that can be readily adapted to studies of a variety of antigen-specific ASCs.

  • 62. Jahnmatz, Peter
    et al.
    Nyabundi, Diana
    Sundling, Christopher
    Widman, Linnea
    Mwacharo, Jedidah
    Musyoki, Jennifer
    Otieno, Edward
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Mabtech AB, Sweden.
    Bejon, Philip
    Ndungu, Francis M.
    Färnert, Anna
    Plasmodium falciparum-Specific Memory B-Cell and Antibody Responses Are Associated With Immunity in Children Living in an Endemic Area of Kenya2022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 799306Article in journal (Refereed)
    Abstract [en]

    Identifying the mechanism of naturally acquired immunity against Plasmodium falciparum malaria could contribute to the design of effective malaria vaccines. Using a recently developed multiplexed FluoroSpot assay, we assessed cross-sectional pre-existing memory B-cells (MBCs) and antibody responses against six well known P. falciparum antigens (MSP-119, MSP-2 (3D7), MSP-2 (FC27), MSP-3, AMA-1 and CSP) and measured their associations with previous infections and time to clinical malaria in the ensuing malaria season in Kenyan children. These children were under active weekly surveillance for malaria as part of a long-term longitudinal malaria immunology cohort study, where they are recruited from birth. After performing Cox regression analysis, we found that children with a breadth of three or more antigen-specific MBC or antibody responses at the baseline had a reduced risk for malaria in the ensuing P. falciparum transmission season. Specifically, MBC responses against AMA-1, MSP-2 (3D7) and MSP-3, as well as antibody responses to MSP-2 (3D7) and MSP-3 were prospectively associated with a reduced risk for malaria. The magnitude or breadth of MBC responses were however not correlated with the cumulative number of malaria episodes since birth. We conclude that increased breadth for merozoite antigen-specific MBC and antibody responses is associated with protection against malaria.

     

  • 63. Jahnmatz, Peter
    et al.
    Sundling, Christopher
    Makower, Bartek
    Sondén, Klara
    Färnert, Anna
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Mabtech AB, Sweden.
    Multiplex analysis of antigen-specific memory B cells in humans using reversed B-cell FluoroSpot2020In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 478, article id 112715Article in journal (Refereed)
    Abstract [en]

    Analysis of B-cell specificities at the single cell level provides important information on how the B-cell compartment responds when challenged by infection or vaccination. We recently developed a reversed B-cell FluoroSpot assay and showed that it could be used to detect B cells specific for different antigens simultaneously in a mouse model. The aim of this study was to further develop the method to detect and quantify antigen-specific memory B cells (MBCs) in humans where circulating antigen-specific cells are less frequent. We show that MBCs specific for three antigens, tetanus toxoid, hepatitis B surface antigen and cytomegalovirus pp65, could be detected simultaneously in one well. In addition to enumerating antigen-specific MBCs, we also assessed the spot volume to estimate the intensity of the response in individual cells and found this to be a new and sensitive approach to study MBC responses after vaccination. This unique B-cell FluoroSpot approach provides a simple and sensitive multiplex analysis of MBCs and can be adapted to most antigens and host species.

  • 64. Jahnmatz, Peter
    et al.
    Sundling, Christopher
    Yman, Victor
    Widman, Linnea
    Asghar, Muhammad
    Sondén, Klara
    Stenström, Christine
    Smedman, Christian
    Ndungu, Francis
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Mabtech AB, Sweden.
    Färnert, Anna
    Memory B-Cell Responses Against Merozoite Antigens After Acute Plasmodium falciparum Malaria, Assessed Over One Year Using a Novel Multiplexed FluoroSpot Assay2021In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 11, article id 619398Article in journal (Refereed)
    Abstract [en]

    Memory B cells (MBCs) are believed to be important for the maintenance of immunity to malaria, and these cells need to be explored in the context of different parasite antigens and their breadth and kinetics after natural infections. However, frequencies of antigen-specific MBCs are low in peripheral blood, limiting the number of antigens that can be studied, especially when small blood volumes are available. Here, we developed a multiplexed reversed B-cell FluoroSpot assay capable of simultaneously detecting MBCs specific for the four Plasmodium falciparum blood-stage antigens, MSP-1(19), MSP-2, MSP-3 and AMA-1. We used the assay to study the kinetics of the MBC response after an acute episode of malaria and up to one year following treatment in travelers returning to Sweden from sub-Saharan Africa. We show that the FluoroSpot assay can detect MBCs to all four merozoite antigens in the same well, and that the breadth and kinetics varied between individuals. We further found that individuals experiencing a primary infection could mount and maintain parasite-specific MBCs to a similar extent as previously exposed adults, already after a single infection. We conclude that the multiplexed B-cell FluoroSpot is a powerful tool for assessing antigen-specific MBC responses to several antigens simultaneously, and that the kinetics of MBC responses against merozoite surface antigens differ over the course of one year. These findings contribute to the understanding of acquisition and maintenance of immune responses to malaria.

  • 65.
    Johansson, Maria
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Early gut microbiota in relation to cytokine responses and allergic disease2011Licentiate thesis, comprehensive summary (Other academic)
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  • 66.
    Johansson, Maria A.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Björkander, Sophia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mata Forsberg, Manuel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Qazi, Khaleda Rahman
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Salvany Celades, Maria
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Bittmann, Julia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Eberl, Matthias
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Probiotic Lactobacilli Modulate Staphylococcus aureus-Induced Activation of Conventional and Unconventional T cells and NK Cells2016In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 7, article id 273Article in journal (Refereed)
    Abstract [en]

    Lactobacilli are probiotic commensal bacteria and potent modulators of immunity. When present in the gut or supplemented as probiotics, they beneficially modulate ex vivo immune responsiveness. Further, factors derived from several lactobacilli strains act immune regulatory in vitro. In contrast, Staphylococcus aureus (S. aureus) is known to induce excessive T cell activation. In this study, we aimed to investigate S. aureus-induced activation of human mucosal-associated invariant T cells (MAIT cells), gamma delta T cells, NK cells, as well as of conventional CD4(+) and CD8(+) T cells in vitro. Further, we investigated if lactobacilli-derived factors could modulate their activation. PBMC were cultured with S. aureus 161: 2 cell-free supernatants (CFS), staphylococcal enterotoxin A or CD3/CD28-beads alone, or in combination with Lactobacillus rhamnosus GG-CFS or Lactobacillus reuteri DSM 17938-CFS and activation of T and NK cells was evaluated. S. aureus-CFS induced IFN-gamma and CD107a expression as well as proliferation. Costimulation with lactobacilli-CFS dampened lymphocyte-activation in all cell types analyzed. Preincubation with lactobacilli-CFS was enough to reduce subsequent activation, and the absence of APC or APC-derived IL-10 did not prevent lactobacilli-mediated dampening. Finally, lactate selectively dampened activation of unconventional T cells and NK cells. In summary, we show that molecules present in the lactobacilli-CFS are able to directly dampen in vitro activation of conventional and unconventional T cells and of NK cells. This study provides novel insights on the immune-modulatory nature of probiotic lactobacilli and suggests a role for lactobacilli in the modulation of induced T and NK cell activation.

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  • 67.
    Jonsjö, Martin A.
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute. Karolinska Institutet, Sweden.
    Olsson, Gunnar L.
    Wicksell, Rikard K.
    Alving, Kjell
    Holmstrom, Linda
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute. Karolinska Institutet, Sweden.
    The role of low-grade inflammation in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome): associations with symptoms2020In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 113, article id UNSP 104578Article in journal (Refereed)
    Abstract [en]

    Background: Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often present with a range of flu-like symptoms resembling sickness behavior as well as widespread pain and concentration deficits. The aim of this study was to explore the association between inflammatory markers previously shown to be related to fatigue severity in ME/CFS and common ME/CFS symptoms post-exertional fatigue, impaired cognitive processing, musculoskeletal pain and recurrent flu-like symptoms, and the moderating effect of sex on these associations. Methods: 53 adult patients diagnosed with ME/CFS at a specialist clinic were included in the study. Fasting blood plasma was analyzed using the Olink Proseek Multiplex Inflammation panel (beta-NGF, CCL11, CXCL1, CXCL10, IL-6, IL-7, IL-8, IL-10, IL-18, TGF-alpha, TGF-beta-1 and SCF) and BioRad Human Cytokine Type 1 assay (TNF-alpha). Participants rated the average severity of symptoms (0-10) based on the 2011 International Consensus Criteria of ME/CFS during a structured clinical interview. Associations between inflammatory markers and symptom severity were analyzed using bivariate correlations and moderated regression analyses bootstrapped with 5000 repetitions. Results and conclusions: Only beta-NGF was associated with the fatigue severity measure. However, higher levels of CCL11, CXCL10, IL-7, TNF-alpha and TGF-beta-1 were significantly associated with higher levels of impaired cognitive processing and musculoskeletal pain, and sex was a significant moderator for CXCL10, IL-7 and TGF-beta-1. Future studies should investigate the relationship between inflammatory markers and key symptoms in ME/CFS in a longitudinal design in order to explore if and for whom low-grade inflammation may contribute to illness development.

  • 68.
    Jönsson, Gun
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Apoptosis regulation in bladder cancer and multiple sclerosis2003Doctoral thesis, comprehensive summary (Other academic)
  • 69. Karshikoff, B.
    et al.
    Jensen, K. B.
    Ingvar, M.
    Kosek, E.
    Kalpouzos, G.
    Soop, A.
    Olgart Höglund, C.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Axelsson, J.
    LPS increases pain sensitivity by decreased pain inhibition and increased insular activation2015In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 49, p. e1-e1Article in journal (Refereed)
    Abstract [en]

    We have shown that women are more prone to developing LPS-induced pain sensitivity than men, and that the descending endogenous pain inhibition is disrupted in women during experimental systemic inflammation. The aim of the present study was to investigate some of the central neural mechanisms underlying our previous findings. 51 participants (29 women) were injected with 0.6 ng/kg LPS or saline and went through a thumb-pressure pain fMRI paradigm 2 h after injection. As hypothesized, the subjects injected with LPS had decreased activity in the ventromedial prefrontal cortex and rostral anterior cingulate cortex (rACC), areas involved in descending pain inhibition. In addition, the LPS group had higher activity in the anterior insula, an area involved in medial/affective pain processing and interoception. These effects were not sex dependent. However, the male participants had overall stronger descending pain inhibition, reflected as a stronger rACC activity compared to women. It is possible that the more robust activation of descending pain inhibition rendered the men more resistant to the immune provocation, which may explain previously seen sex differences in LPS-induced pain sensitivity. Our findings give an indication to how the pain matrix is affected during a sickness response. The results strengthen the proposed link between systemic inflammation and weakened pain regulation in chronic pain disorders, and offers a possible mechanism underlying the female predominance in chronic pain disorders.

  • 70. Karshikoff, B.
    et al.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Olgart Höglund, C.
    Axelsson, J.
    Pain sensitivity during experimentally induced systemic inflammation in humans2013In: Brain, Behavior, and Immunity, 2013, Vol. 32, p. e32-Conference paper (Refereed)
  • 71.
    Karshikoff, Bianka
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska University Hospital, Sweden; Karolinska Institutet, Sweden.
    Jensen, K. B.
    Kosek, E.
    Kalpouzos, Grégoria
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Soop, A.
    Ingvar, M.
    Olgart Höglund, C.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska University Hospital, Sweden; Karolinska Institutet, Sweden.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska University Hospital, Sweden; Karolinska Institutet, Sweden.
    Why sickness hurts: A central mechanism for pain induced by peripheral inflammation2016In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 57, p. 38-46Article in journal (Refereed)
    Abstract [en]

    Low-grade systemic inflammation has been implicated in chronic pain, as well as in comorbid diseases like depression and fatigue. We have previously shown that women's pain perception and regulation is more affected by systemic inflammation than that of men. Here we investigated the neural substrates underlying these effects using an fMRI paradigm previously employed in a clinical population. Fifty-one participants (29 women) were injected with 0.6ng/kg lipopolysaccharide (LPS) or saline to induce a peripheral inflammatory response. The subjects were then tested with a pressure pain fMRI paradigm designed to capture descending pain inhibitory activity 2h after injection, and blood was sampled for cytokine analysis. The subjects injected with LPS became more pain sensitive compared to the placebo group, and the heightened pain sensitivity was paralleled by decreased activity in the ventrolateral prefrontal cortex and the rostral anterior cingulate cortex (rACC) compared to placebo; areas involved in descending pain regulation. The LPS group also had higher activity in the anterior insular cortex, an area underpinning affective and interoceptive pain processing. Women displayed overall less pain-evoked rACC activity compared to men, which may have rendered women less resilient to immune provocation, possibly explaining sex differences in LPS-induced pain sensitivity. Our findings elucidate the pain-related brain circuits affected by experimental peripheral inflammation, strengthening the theoretical link between systemic inflammation and weakened pain regulation in chronic pain disorders. The results further suggest a possible mechanism underlying the female predominance in many chronic pain disorders.

  • 72.
    Karshikoff, Bianka
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Sundelin, Tina
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Sweden.
    Lasselin, Julie
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; University Hospital Essen, Germany.
    Role of inflammation in Human Fatigue: Relevance of Multidimensional Assessments and Potential Neuronal Mechanisms2017In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 8, article id 21Article, review/survey (Refereed)
    Abstract [en]

    Fatigue is a highly disabling symptom in various medical conditions. While inflammation has been suggested as a potential contributor to the development of fatigue, underlying mechanisms remain poorly understood. In this review, we propose that a better assessment of central fatigue, taking into account its multidimensional features, could help elucidate the role and mechanisms of inflammation in fatigue development. A description of the features of central fatigue is provided, and the current evidence describing the association between inflammation and fatigue in various medical conditions is reviewed. Additionally, the effect of inflammation on specific neuronal processes that may be involved in distinct fatigue dimensions is described. We suggest that the multidimensional aspects of fatigue should be assessed in future studies of inflammation-induced fatigue and that this would benefit the development of effective therapeutic interventions.

  • 73. Kokkinou, Efthymia
    et al.
    Soini, Tea
    Pandey, Ram Vinay
    van Acker, Aline
    Theorell, Jakob
    Czarnewski, Paulo
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Kvedaraite, Egle
    Vandamme, Niels
    Lourda, Magda
    Sorini, Chiara
    Weigel, Whitney
    Carrasco, Anna
    Tibbitt, Christopher Andrew
    Schlums, Heinrich
    Lindforss, Ulrik
    Nordenvall, Caroline
    Ljunggren, Malin
    Idestrom, Maja
    Svensson, Mattias
    Henter, Jan-Inge
    Villablanca, Eduardo J.
    Bryceson, Yenan T.
    Rolandsdotter, Helena
    Mjosberg, Jenny
    The single-cell transcriptional landscape of innate and adaptive lymphocytes in pediatric-onset colitis2023In: Cell reports medicine, ISSN 2666-3791, Vol. 4, no 5, article id 101038Article in journal (Refereed)
    Abstract [en]

    Innate lymphoid cells (ILCs) are considered innate counterparts of adaptive T cells; however, their common and unique transcriptional signatures in pediatric inflammatory bowel disease (pIBD) are largely unknown. Here, we report a dysregulated colonic ILC composition in pIBD colitis that correlates with inflammatory ac-tivity, including accumulation of naive-like CD45RA+CD62L- ILCs. Weighted gene co-expression network analysis (WGCNA) reveals modules of genes that are shared or unique across innate and adaptive lympho-cytes. Shared modules include genes associated with activation/tissue residency, naivety/quiescence, and antigen presentation. Lastly, nearest-neighbor-based analysis facilitates the identification of most in-flamedand least inflamedlymphocytes in pIBD colon with unique transcriptional signatures. Our study reveals shared and unique transcriptional signatures of colonic ILCs and T cells in pIBD. We also provide insight into the transcriptional regulation of colonic inflammation, deepening our understanding of the poten-tial mechanisms involved in pIBD.

  • 74. Kumsiri, Ratchanok
    et al.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Pattanapanyasat, Kovit
    Krudsood, Srivicha
    Maneerat, Yaowapa
    IgE low affinity receptor (CD23) expression, Plasmodium falciparum specific IgE and tumor necrosis factor-alpha production in Thai uncomplicated and severe falciparum malaria patients2016In: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 154, p. 25-33Article in journal (Refereed)
    Abstract [en]

    Previous studies have suggested that Plasmodium falciparum (P. falciparum) specific IgE in the form of immune complexes crosslinking the low-affinity receptor (CD23) on monocyte results in tumor necrosis factor (TNF)-alpha and nitric oxide (NO) production. However, the roles of these parameters in severity and immune protection are still unclear. This study aimed to determine the association between CD23 expression on monocytes, plasma soluble CD23 (sCD23), total IgE, malaria-specific IgE and IgG, and TNF-alpha levels in P. falciparum infected patients. We evaluated 64 uncomplicated (UC) and 25 severe patients (S), admitted at the Hospital for Tropical Diseases, Mahidol University, and 34 healthy controls (C) enrolled in 2001. Flow cytometry and enzyme linked immunosorbent assays (ELISA) demonstrated that trends of the CD23 expression, levels of sCD23 and specific IgE were higher in the S group as compared to those in the UC and C groups. Plasma levels of P. falciparum specific IgE in the UC (p = 0.011) and S groups (p = 0.025) were significantly higher than those in C group. In contrast the TNF-alpha levels tended to be higher in the UC than those in the S (p = 0343) and significantly higher than those in C (p = 0.004) groups. The specific IgG levels in UC were significantly higher than those in S and C (p < 0.001) groups. At admission, a strong significant negative correlation was found between specific IgG and sCD23 (r = -0.762, p = 0.028), and TNF-alpha and IgE-IgG complexes (r=-0.715, p = 0.002). Significant positive correlations between levels of specific IgE and TNF-alpha (r=0.575, p = 0.010); and sCD23 (r=0.597, p = 0.000) were also observed. In conclusion, our data suggest that CD23 expression and malaria-specific IgE levels may be involved in the severity of the disease while TNF-alpha and the malaria-specific IgG may correlate with protection against falciparum malaria.

  • 75. Kurioka, Ayako
    et al.
    Cosgrove, Cormac
    Simoni, Yannick
    van Wilgenburg, Bonnie
    Geremia, Alessandra
    Björkander, Sophia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Thurnheer, Christine
    Günthard, Huldrych F.
    Khanna, Nina
    Walker, Lucy Jane
    Arancibia-Cárcamo, Carolina V.
    Newell, Evan W.
    Willberg, Christian B.
    Klenerman, Paul
    CD161 Defines a Functionally Distinct Subset of Pro-Inflammatory Natural Killer Cells2018In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 9, article id 486Article in journal (Refereed)
    Abstract [en]

    CD161 is a C-type lectin-like receptor expressed on the majority of natural killer (NK) cells; however, the significance of CD161 expression on NK cells has not been comprehensively investigated. Recently, we found that CD161 expression identifies a transcriptional and innate functional phenotype that is shared across various T cell populations. Using mass cytometry and microarray experiments, we demonstrate that this functional phenotype extends to NK cells. CD161 marks NK cells that have retained the ability to respond to innate cytokines during their differentiation, and is lost upon cytomegalovirus-induced maturation in both healthy and human immunodeficiency virus (HIV)-infected patients. These pro-inflammatory NK cells are present in the inflamed lamina propria where they are enriched for integrin CD103 expression. Thus, CD161 expression identifies NK cells that may contribute to inflammatory disease pathogenesis and correlates with an innate responsiveness to cytokines in both T and NK cells.

  • 76. Kurioka, Ayako
    et al.
    Jahun, Aminu S.
    Hannaway, Rachel F.
    Walker, Lucy J.
    Fergusson, Joannah R.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Corbett, Alexandra J.
    Ussher, James E.
    Willberg, Christian B.
    Klenerman, Paul
    Shared and Distinct Phenotypes and Functions of Human CD161++ V alpha 7.2+T Cell Subsets2017In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 8, article id 1031Article in journal (Refereed)
    Abstract [en]

    Human mucosal-associated invariant T (MAIT) cells are an important T cell subset that are enriched in tissues and possess potent effector functions. Typically such cells are marked by their expression of V alpha 7.2-J alpha 33/J alpha 20/J alpha 12 T cell receptors, and functionally they are major histocompatibility complex class I-related protein 1 (MR1)-restricted, responding to bacterially derived riboflavin synthesis intermediates. MAIT cells are contained within the CD161++ V alpha 7.2+ T cell population, the majority of which express the CD8 receptor (CD8+), while a smaller fraction expresses neither CD8 or CD4 coreceptor (double negative; DN) and a further minority are CD4+. Whether these cells have distinct homing patterns, phenotype and functions have not been examined in detail. We used a combination of phenotypic staining and functional assays to address the similarities and differences between these CD161++ V alpha 7.2+ T cell subsets. We find that most features are shared between CD8+ and DN CD161++ V alpha 7.2+ T cells, with a small but detectable role evident for CD8 binding in tuning functional responsiveness. By contrast, the CD4+ CD161++ V alpha 7.2+ T cell population, although showing MR1-dependent responsiveness to bacterial stimuli, display reduced T helper 1 effector functions, including cytolytic machinery, while retaining the capacity to secrete interleukin-4 (IL-4) and IL-13. This was consistent with underlying changes in transcription factor (TF) expression. Although we found that only a proportion of CD4+ CD161++ V alpha 7.2+ T cells stained for the MR1-tetramer, explaining some of the heterogeneity of CD4+ CD161++ V alpha 7.2+ T cells, these differences in TF expression were shared with CD4+ CD161++ MR1-tetramer+ cells. These data reveal the functional diversity of human CD161++ V alpha 7.2+ T cells and indicate potentially distinct roles for the different subsets in vivo.

  • 77.
    Lasaviciute, Gintare
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Barz, Myriam
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    van Der Heiden, Marieke
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Arasa, Claudia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Tariq, Kanwal
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Quin, Jaclyn
    Östlund Farrants, Ann-Kristin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Gut commensal Limosilactobacillus reuteri induces atypical memory-like phenotype in human dendritic cells in vitro2022In: Gut microbes, ISSN 1949-0976, E-ISSN 1949-0984, Vol. 14, no 1, article id 2045046Article in journal (Refereed)
    Abstract [en]

    Memory-like responses in innate immune cells confer nonspecific protection against secondary exposures. A number of microbial agents have been found to induce enhanced or diminished recall responses in innate cells, however, studies investigating the ability of probiotic bacteria to trigger such effects are lacking. Here, we show that priming of human monocytes with a secretome from the gut probiotic bacterium Limosilactobacillus (L.) reuteri induces a mixed secondary response phenotype in monocyte-derived dendritic cells (mo-DCs), with a strong IL-6 and IL-1β response but low TNFα, IL-23 and IL-27 secretion. Instead, blood DC priming with L. reuteri-secretome resembles a tolerant state upon secondary exposure. A similar pattern was found in conventional and gut-like (retinoic acid exposed) DCs, although retinoic acid hampered TNFα and IL-6 production and enrichment of histone modifications in L. reuteri-secretome primed mo-DC cultures. Further, we show that the memory-like phenotype of mo-DCs, induced by priming stimuli, is important for subsequent T helper (Th) cell differentiation pathways and might determine the inflammatory nature of Th cells. We also show enhanced recall responses characterized by robust inflammatory cytokines and lactate production in the gut-like mo-DCs derived from β-glucan primed monocytes. Such responses were accompanied with enriched histone modifications at the promoter of genes associated with a trained phenotype in myeloid cells. Altogether, we demonstrate that a gut commensal-derived secretome prompts recall responses in human DCs which differ from that induced by classical training agents such as β-glucan. Our results could be beneficial for future therapeutic interventions where T cell responses are needed to be modulated.

  • 78.
    Lasaviciute, Gintare
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Björkander, Sophia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Carvalho-Queiroz, Claudia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hed Myrberg, Ida
    Nussbaum, Bianca
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nilsson, Caroline
    Bemark, Mats
    Nilsson, Anna
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Saghafian-Hedengren, Shanie
    Epstein-Barr Virus, but Not Cytomegalovirus, Latency Accelerates the Decay of Childhood Measles and Rubella Vaccine Responses-A 10-Year Follow-up of a Swedish Birth Cohort2017In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 8, article id 1865Article in journal (Refereed)
    Abstract [en]

    Background: Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are ubiquitous and persistent herpesviruses commonly acquired during childhood. Both viruses have a significant impact on the immune system, especially through mediating the establishment of cellular immunity, which keeps these viruses under control for life. Far less is known about how these viruses influence B-cell responses. Objectives: To evaluate the impact of latent EBV and CMV infection on rubella- and measles-specific antibody responses as well as on the B-cell compartment in a prospective birth cohort followed during the first 10 years of life. Methods: IgG titers against rubella and measles vaccines were measured in plasma obtained from the same donors at 2, 5, and 10 years of age. Peripheral B-cell subsets were evaluated ex vivo at 2 and 5 years of age. Factors related to optimal B-cell responses including IL-21 and CXCL13 levels in plasma were measured at all-time points. Results: EBV carriage in the absence of CMV associated with an accelerated decline of rubella and measles-specific IgG levels (p = 0.003 and p = 0.019, respectively, linear mixed model analysis), while CMV carriage in the absence of EBV associated with delayed IgG decay over time for rubella (p = 0.034). At 5 years of age, EBV but not CMV latency associated with a lower percentage of plasmablasts, but higher IL-21 levels in the circulation. Conclusion: Our findings suggest that EBV carriage in the absence of CMV influences the B-cell compartment and the dynamics of antibody responses over time during steady state in the otherwise healthy host.

  • 79.
    Lasaviciute, Gintare
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Bricaud, Andreas L.
    Hellgren, Fredrika
    Ingelman-Sundberg, Hanna M.
    Eksborg, Staffan
    Jonker, Margreet
    Haanstra, Krista G.
    Hed Myrberg, Ida
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Loré, Karin
    Saghafian-Hedengren, Shanie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Karolinska Institutet, Sweden.
    Nilsson, Anna
    Deficits in the IgG+ memory B‐cell recovery after anthracycline treatment is confined to the spleen of rhesus macaques2020In: Clinical & Translational Immunology (CTI), E-ISSN 2050-0068, Vol. 9, no 7, article id e1150Article in journal (Refereed)
    Abstract [en]

    Objectives. Loss of vaccine-induced antibodies (Abs) after chemotherapy against paediatric acute lymphoblastic leukaemia (ALL) is common and often necessitates re-immunisation after cessation of treatment. Even so, some ALL survivors fail to mount or to maintain protective Abs. Germinal centres (GCs) are clusters of proliferating B cells in follicles of secondary lymphoid tissues (SLTs) formed during adaptive immune responses and the origins of long-lived memory B and plasma cells that are the source of Abs. Furthermore, productive GC reactions depend on T follicular helper (TFH) cells. To understand why chemotherapy induces deficits in Ab responses, we examined how SLTs were affected by chemotherapy. Methods. Rhesus macaques were infused with either three cycles of the anthracycline doxorubicin or saline, followed by immunisation with a de novo and booster antigen. Spleen and lymph nodes were removed, and memory B, bulk T and TFH cells were examined. Results. Despite adequate GC morphology, a diminished memory and IgG+ B-cell population along with diminished total and booster vaccine-specific IgGproducing memory B cells were noted in the spleens of macaques with past doxorubicin exposure compared to the saline-treated controls (P < 0.05). Intact bulk T and TFH cells were found in the SLTs of treated macaques, which displayed higher CD40L upregulation capacity by their splenic CXCR5+ helper T cells (P < 0.01). In contrast to the spleen, the immune cell populations studied were comparable between the lymph nodes of both saline- and doxorubicin-treated macaques. Conclusion. Our findings suggest that the splenic memory B-cell subset, compared to its lymph node counterpart, is more severely altered by anthracycline treatment.

  • 80.
    Lasselin, Julie
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. University of Duisburg-Essen, Germany; Karolinska Institutet, Sweden.
    Karshikoff, Bianka
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Åkerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Benson, Sven
    Engler, Harald
    Schedlowski, Manfred
    Jones, Mike
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Macquarie University, Australia.
    Fatigue and sleepiness responses to experimental inflammation and exploratory analysis of the effect of baseline inflammation in healthy humans2020In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 83, p. 309-314Article in journal (Refereed)
    Abstract [en]

    Inflammation is believed to be a central mechanism in the pathophysiology of fatigue. While it is likely that dynamic of the fatigue response after an immune challenge relates to the corresponding cytokine release, this lacks evidence. Although both fatigue and sleepiness are strong signals to rest, they constitute distinct symptoms which are not necessarily associated, and sleepiness in relation to inflammation has been rarely investigated. Here, we have assessed the effect of an experimental immune challenge (administration of lipopolysaccharide, LPS) on the development of both fatigue and sleepiness, and the associations between increases in cytokine concentrations, fatigue and sleepiness, in healthy volunteers. In addition, because chronic-low grade inflammation may represent a risk factor for fatigue, we tested whether higher baseline levels of inflammation result in a more pronounced development of cytokine-induced fatigue and sleepiness. Data from four experimental studies was combined, giving a total of 120 subjects (LPS N = 79, 18 (23%) women; Placebo N = 69, 12 (17%) women). Administration of LPS resulted in a stronger increase in fatigue and sleepiness compared to the placebo condition, and the development of both fatigue and sleepiness closely paralleled the cytokine responses. Individuals with stronger increases in cytokine concentrations after LPS administration also suffered more from fatigue and sleepiness (N = 75), independent of gender. However, there was no support for the hypothesis that higher baseline inflammatory markers moderated the responses in fatigue or sleepiness after an inflammatory challenge. The results demonstrate a tight connection between the acute inflammatory response and development of both fatigue and sleepiness, and motivates further investigation of the involvement of inflammation in the pathophysiology of central fatigue.

  • 81.
    Lasselin, Julie
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; University of Bordeaux, France; Universitätsklinikum Essen, Germany.
    Magne, Eric
    Beau, Cedric
    Aubert, Agnes
    Dexpert, Sandra
    Carrez, Julie
    Laye, Sophie
    Forestier, Damien
    Ledaguenel, Patrick
    Capuron, Lucile
    Low-grade inflammation is a major contributor of impaired attentional set shifting in obese subjects2016In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 58, p. 63-68Article in journal (Refereed)
    Abstract [en]

    Impairment in cognitive flexibility and set shifting abilities has been described in obesity. This alteration is critical as it can interfere with obesity management strategies. Recent evidences suggest that chronic low-grade inflammation may be involved in cognitive deficits associated with obesity, but the potential involvement in reduced flexibility remains unknown. The objective of this study was to assess the contribution of low-grade inflammation, determined by circulating levels of high-sensitivity C-reactive protein (hsCRP), in reduced cognitive flexibility and shifting abilities of obese subjects relatively to a group of non-obese participants. Performance in the intra/extra-dimensional set shift (IED) test, extracted from the CANTAB, was assessed in 66 obese subjects and 20 non-obese participants. Obese subjects with concentrations of hsCRP above 5 mg/L exhibited reduced performance on the IED test in comparison to obese subjects with lower levels of hsCRP and non-obese participants. This difference was particularly manifest in the number of errors made during the extra-dimensional shift (EDS errors). In contrast, performance before the extra-dimensional shift was spared. Linear regression analyses revealed that the association between obesity and IED alterations was significant only when the condition hsCRP >5 mg/L was entered in the model. These findings are important as they indicate that, rather than obesity itself, low-grade inflammation represents a major contributor of IED performance in obese subjects.

  • 82.
    Lekander, Mats
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Karshikoff, Bianka
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Johansson, Emilia
    Soop, Anne
    Fransson, Peter
    Lundström, Johan N.
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Ingvar, Martin
    Petrovic, Predrag
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Nilsonne, Gustav
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Intrinsic functional connectivity of insular cortex and symptoms of sickness during acute experimental inflammation2016In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 56, p. 34-41Article in journal (Refereed)
    Abstract [en]

    Task-based fMRI has been used to study the effects of experimental inflammation on the human brain, but it remains unknown whether intrinsic connectivity in the brain at rest changes during a sickness response. Here, we investigated the effect of experimental inflammation on connectivity between areas relevant for monitoring of bodily states, motivation, and subjective symptoms of sickness. In a double blind randomized controlled trial, 52 healthy volunteers were injected with 0.6 ng/kg LPS (lipopolysaccharide) or placebo, and participated in a resting state fMRI experiment after approximately 2h 45 minutes. Resting state fMRI data were available from 48 participants, of which 28 received LPS and 20 received placebo. Bilateral anterior and bilateral posterior insula sections were used as seed regions and connectivity with bilateral orbitofrontal and cingulate (anterior and middle) cortices was investigated. Back pain, headache and global sickness increased significantly after as compared to before LPS, while a non-significant trend was shown for increased nausea. Compared to placebo, LPS was followed by increased connectivity between left anterior insula and left midcingulate cortex. This connectivity was significantly correlated to increase in back pain after LPS and tended to be related to increased global sickness, but was not related to increased headache or nausea. LPS did not affect the connectivity from other insular seeds. In conclusion, the finding of increased functional connectivity between left anterior insula and middle cingulate cortex suggests a potential neurophysiological mechanism that can be further tested to understand the subjective feeling of malaise and discomfort during a sickness response.

  • 83. Lepzien, Rico
    et al.
    Liu, Sang
    Czarnewski, Paulo
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Nie, Mu
    Österberg, Björn
    Baharom, Faezzah
    Pourazar, Jamshid
    Rankin, Gregory
    Eklund, Anders
    Bottai, Matteo
    Kullberg, Susanna
    Blomberg, Anders
    Grunewald, Johan
    Smed-Sörensen, Anna
    Monocytes in sarcoidosis are potent tumour necrosis factor producers and predict disease outcome2021In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 58, no 1, article id 2003468Article in journal (Refereed)
    Abstract [en]

    Background Pulmonary sarcoidosis is an inflammatory disease characterised by granuloma formation and heterogeneous clinical outcome. Tumour necrosis factor (TNF) is a pro-inflammatory cytokine contributing to granuloma formation and high levels of TNF have been shown to associate with progressive disease. Mononuclear phagocytes (MNPs) are potent producers of TNF and highly responsive to inflammation. In sarcoidosis, alveolar macrophages have been well studied. However, MNPs also include monocytes/monocyte-derived cells and dendritic cells, which are poorly studied in sarcoidosis, despite their central role in inflammation.

    Objective To determine the role of pulmonary monocyte-derived cells and dendritic cells during sarcoidosis.

    Methods We performed in-depth phenotypic, functional and transcriptomic analysis of MNP subsets from blood and bronchoalveolar lavage (BAL) fluid from 108 sarcoidosis patients and 30 healthy controls. We followed the clinical development of patients and assessed how the repertoire and function of MNP subsets at diagnosis correlated with 2-year disease outcome.

    Results Monocytes/monocyte-derived cells were increased in blood and BAL of sarcoidosis patients compared to healthy controls. Interestingly, high frequencies of blood intermediate monocytes at time of diagnosis associated with chronic disease development. RNA sequencing analysis showed highly inflammatory MNPs in BAL of sarcoidosis patients. Furthermore, frequencies of BAL monocytes/ monocyte-derived cells producing TNF without exogenous stimulation at time of diagnosis increased in patients that were followed longitudinally. In contrast to alveolar macrophages, the frequency of TNFproducing BAL monocytes/monocyte-derived cells at time of diagnosis was highest in sarcoidosis patients that developed progressive disease.

    Conclusion Our data show that pulmonary monocytes/monocyte-derived cells are highly inflammatory and can be used as a predictor of disease outcome in sarcoidosis patients.

  • 84. Lepzien, Rico
    et al.
    Nie, Mu
    Czarnewski, Paulo
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Liu, Sang
    Yu, Meng
    Ravindran, Avinash
    Kullberg, Susanna
    Eklund, Anders
    Grunewald, Johan
    Smed-Sörensen, Anna
    Pulmonary and blood dendritic cells from sarcoidosis patients more potently induce IFNγ-producing Th1 cells compared with monocytes2022In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 111, no 4, p. 857-866Article in journal (Refereed)
    Abstract [en]

    Sarcoidosis is a systemic inflammatory disease mainly affecting the lungs. The hallmark of sarcoidosis are granulomas that are surrounded by activated T cells, likely targeting the disease-inducing antigen. IFNγ-producing Th1 and Th17.1 T cells are elevated in sarcoidosis and associate with disease progression. Monocytes and dendritic cells (DCs) are antigen-presenting cells (APCs) and required for T cell activation. Several subsets of monocytes and DCs with different functions were identified in sarcoidosis. However, to what extent different monocyte and DC subsets can support activation and skewing of T cells in sarcoidosis is still unclear. In this study, we performed a transcriptional and functional side-by-side comparison of sorted monocytes and DCs from matched blood and bronchoalveolar lavage (BAL) fluid of sarcoidosis patients. Transcriptomic analysis of all subsets showed upregulation of genes related to T cell activation and antigen presentation in DCs compared with monocytes. Allogeneic T cell proliferation was higher after coculture with monocytes and DCs from blood compared with BAL and DCs induced more T cell proliferation compared with monocytes. After coculture, proliferating T cells showed high expression of the transcription factor Tbet and IFNγ production. We also identified Tbet and RORγt coexpressing T cells that mainly produced IFNγ. Our data show that DCs rather than monocytes from sarcoidosis patients have the ability to activate and polarize T cells towards Th1 and Th17.1 cells. This study provides a useful in vitro tool to better understand the contribution of monocytes and DCs to T cell activation and immunopathology in sarcoidosis.

  • 85.
    Lettesjö, Helene
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Immunoregulatory factors in synovial fluid of rheumatoid arthritis patients1998Doctoral thesis, comprehensive summary (Other academic)
  • 86.
    Lindroth, Karin
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Maturation of humoral immune responses: Studies on the effects of antigen type, apoptosis and age2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The humoral immune response is dependent on the formation of antibodies. Antibodies are produced by terminally differentiated B cells, plasma cells. Plasma cells are generated either directly from antigen challenged B cells, memory cells or from cells that have undergone the germinal center (GC) reaction. The GC is the main site for class switch, somatic hypermutation and generation of memory cells.

    Different factors, both internal and external, shape the outcome of the immune response. In this thesis, we have studied a few factors that influence the maturation of the humoral response. We have studied how age affects the response, and we show that responses against thymus dependent antigens (TD) are more affected than responses to thymus independent (TI) antigens, in concordance with the view that the T cell compartment is more affected by age than the B cell compartment. Furthermore, we demonstrate that priming early in life have a big influence on the immune response in the aged individual. Priming with a TI form of the carbohydrate dextran B512 (Dx) induces a reduction of IgG levels in later TD responses against Dx. We have evaluated possible mechanisms for this reduction. The reduction does not seem to be caused by clonal exhaustion or antibody mediated mechanisms. We also showed that the reduced TD response after TI priming can be induced against another molecule than Dx. With the hypothesis that TI antigens induce a plasma cell biased maturation of the responding B cells, we examined the presence of Blimp-1, a master regulator of plasma cell differentiation, in GCs induced by TD and TI antigen. Blimp-1 was found earlier in GCs induced by TI antigen and the staining intensity in these GCs was stronger than in TD antigen induced GCs, indicating that plasma cells might be continuously recruited from these GCs.

    B cells undergoing the GC reaction are thought to be under a strict selection pressure that removes cells with low affinity for the antigen and also cells that have acquired self-reactivity. We investigated the effect of apoptotic deficiencies on the accumulation of somatic mutations in GC B cells. In mice lacking the death receptor Fas, lpr mice, the frequency of mutations was increased but the pattern of the mutations did not differ from wild type mice. In contrast, mice over-expressing the anti-apoptotic protein Bcl-2, had a lowered frequency of mutations and the mutations introduced had other characteristics.

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  • 87.
    Ljungström, Inger
    Stockholm University.
    Trichinella spiralis: formation of specific antibodies and modulation of the immune response1979Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The present study showed that Trichinella spiralis infection in human induced a specific antibody response including antibodies of IgM, IgA and IgG classes. Reactive sera were demonstrated from day 10 up to 2 years after onset of clinical symtoms. Experimental trichinosis resulted in cortical depletion of thymus and increased cell proliferation in T cell dependent and independent areas of spleen and lymph nodes during the early stage of infection. The capacity of the host to respond to an unrelated T cell dependent antigen given orally during the intestinal stage, was almost abolished at the local level in intestine, whereas the systemic response was depressed. Parenteral administration or oral immunization with unrelated T cell dependent antigens during the extraintestinal stage resulted in a depressed systemic antibody response. The humoral response to an unrelated T cell independent antigen was increased. Cellular immunity, measured as split heart allograft rejection, was depressed and the prolonged survival time was most pronounced during the intestinal stage. Spleen cell reactivity to polyclonal T cell activators and allogeneic stimulation was decreased and again the depression was most marked during the intestinal stage. Thus, T.spiralis infection profoundly affected the T cells during the intestinal stage and some depressive effects were observed also during the extraintestinal stage. T.spiralis infection enhanced the cholera toxin induced diarrhoea during the intestinal stage. This could probably be explained by the decreased absorption observed during the same period of infection. During the migration stage the intestinal secretory response to the enterotoxin was decreased. As the intestinal absorption was normal at this time the reduced fluid accumulation probably reflected a true inhibition of the secretory response. 

  • 88.
    Lodin, Karin
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Syk, J.
    Undén, K.
    Alving, K.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Nixon Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Self-rated health is associated with fatigue, but not inflammatory cytokines or fraction of exhaled nitric oxide in men and women with allergic asthma2013In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 32, no Suppl., p. e31-e31Article in journal (Other academic)
    Abstract [en]

    Allergic asthma is a chronic inflammatory disorder with both local and systemic inflammation and is associated with elevated levels of cytokines as well as exhaled fraction of nitric oxide (FeNO). Fatigue is a prominent symptom. Poor self-rated health has previously been associated to fatigue and inflammatory markers. However, it is not known if self-rated health is associated with fatigue and inflammation also in patients with asthma. Here, we investigated the associations between self-rated health, fatigue, inflammatory cytokines and FeNO in patients with asthma. Self-rated health, fatigue, levels of cytokines and FeNO were assessed in 184 (93 men, 91 women) non-smoking patients with allergic asthma aged 18–64 years in a one-year longitudinal study with five repeated measurements, two for cytokine levels. Analyses of associations between repeated measurements were performed using mixed regression models. More fatigue was associated with poor self-rated health in both men and women (p < 0.001). Fatigue was also associated to elevated levels of IL-1beta and TNF-alpha in women (p < 0.01). However, no association between self-rated health, inflammatory cytokines and FeNO were found. In conclusion, fatigue is an important determinant of self-rated health also in patients with asthma. In addition, fatigue was associated to elevated levels of inflammatory cytokines in women. Possibly, variance in inflammation may be of less importance in a chronic inflammatory condition such as asthma in relation to how subjective health is appraised.

  • 89. Lundberg, Mathias
    et al.
    Bohman, Hannes
    Curbo, Sophie
    Mansouri, Shiva
    Agartz, Ingrid
    Arestrom, Irene
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Mabtech, Sweden.
    Development of an ELISA displaying similar reactivity with reduced and oxidized human Thioredoxin-1 (Trx1): The plasma level of Trx1 in early onset psychosis disorders2022In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 510, article id 113347Article in journal (Refereed)
    Abstract [en]

    The plasma level of human thioredoxin-1 (Trx1) has been shown to be increased in various somatic diseases and psychiatric disorders. However, when comparing the reported plasma levels of Trx1, a great inter-study variability, as well as variability in study outcomes of differences between patients and control subjects has been observed, ultimately limiting the possibility to make comparative analyses. Trx1 is a highly redox active protein prone to form various redox forms, e.g. dimers, oligomers or Trx1-protein complexes. We have recently shown that ELISA systems may vary in reactivity to various Trx1 redox forms. The primary aim of the present study was to develop an ELISA system with similar reactivity to various Trx1 redox forms. By evaluating a panel of novel monoclonal antibodies (mAbs), in various paired combinations, three ELISA systems were generated, with observed large variability in reactivity to various Trx1 redox forms. Importantly, an ELISA system (capture mAb MT17R6 and detection mAb MT13X3-biotin), was identified that displayed similar reactivity to oxidized and DTT reduced Trx1. The ELISA system (MT17R6/MT13X3-biotin), was subsequently used to analyze the level of Trx1 in plasma from patients (<18 years) with early onset psychosis disorders (EOP). However, no significant (p > 0.7) difference in plasma Trx1 levels between patients with EOP (n = 23) and healthy age matched controls (HC) (n = 20) were observed. Furthermore, reliable measurement was shown to be dependent on the establishment of platelet poor plasma samples, enabled by rigorous blood sample centrifugation and by efficient blocking of potentially interfering heterophilic antibodies. In conclusion, we report the design and characterization of a Trx1 ELISA system with similar reactivity to various Trx1 redox forms. Importantly, data indicated that generated ELISA systems show large variability in reactivity to various redox forms with ultimate impact on measured levels of Trx1. Overall, results from this study suggests that future studies may be strongly improved by the use of Trx1 ELISA systems with characterized specificity to various redox forms.

  • 90.
    López-González, Moisés
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Av. IPN, México.
    Meza-Sanchez, David
    Garcia-Cordero, Julio
    Bustos-Arriaga, Jose
    Velez-Del Valle, Cristina
    Marsch-Moreno, Meytha
    Castro-Jimenez, Tannya
    Flores-Romo, Leopoldo
    Santos-Argumedo, Leopoldo
    Gutierrez-Castaneda, Benito
    Cedillo-Barróna, Leticia
    Human keratinocyte cultures (HaCaT) can be infected by DENV, triggering innate immune responses that include IFN lambda and LL372018In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 223, no 11, p. 608-617Article in journal (Refereed)
    Abstract [en]

    The skin is the first anatomical region that dengue virus (DENV) encounters during the natural infection. Although the role of some skin resident cells like dendritic cells and fibroblasts has been demonstrated to be crucial to elucidate the role of resident cells and molecules participating during the early events of the innate immune response, the participation of keratinocytes during DENV infection has not been fully elucidated. In this paper we aimed to evaluate the use of the HaCaT cell line as a model to study the immune responses of skin keratinocytes to DENV infection. We demonstrated productive DENV-2 infection of HaCaT cells and their capability to establish an antiviral response through production of type I and type III interferons (IFN-beta and IFN-lambda). The production of these cytokines by HaCaT cells correlated with upregulation of IFN-inducible transmembrane protein-3 (IFITM3) and viperin in bystander, uninfected cells. We also observed an increase in secretion of IL-6 and IL-8. Skin keratinocytes are known to secrete antimicrobial peptides (AMPs) during viral infections. In our model, DENV-2 infected HaCaT cells upregulate the production of cytoplasmic LL-37. We evaluated the dual role of LL-37, HBD2, and HBD3 antiviral activity and immunoregulation during DENV-2 infection of HaCaT cells and found that LL-37 significantly reduced DENV-2 replication. This indicates that the HaCaT cell line can be used as a model for studying the innate response of keratinocytes to DENV infection. Our results also suggest that skin keratinocytes play an important role in the skin microenvironment after DENV infection by secreting molecules like type I and type III IFNs, pro-inflammatory molecules, and LL-37, which may contribute to the protection against arboviral infections.

  • 91.
    Magoulopoulou, Anastasia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Qian, Xiaoyan
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Setiabudiawan, Todia Pediatama
    Marco Salas, Sergio
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Yokota, Chika
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Rottenberg, Martin E.
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Carow, Berit
    Spatial Resolution of Mycobacterium tuberculosis Bacteria and Their Surrounding Immune Environments Based on Selected Key Transcripts in Mouse Lungs2022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 876321Article in journal (Refereed)
    Abstract [en]

    Mycobacterium tuberculosis (Mtb) bacilli are the causative agent of tuberculosis (TB), a major killer of mankind. Although it is widely accepted that local interactions between Mtb and the immune system in the tuberculous granuloma determine whether the outcome of infection is controlled or disseminated, these have been poorly studied due to methodological constraints. We have recently used a spatial transcriptomic technique, in situ sequencing (ISS), to define the spatial distribution of immune transcripts in TB mouse lungs. To further contribute to the understanding of the immune microenvironments of Mtb and their local diversity, we here present two complementary automated bacteria-guided analysis pipelines. These position 33 ISS-identified immune transcripts in relation to single bacteria and bacteria clusters. The analysis was applied on new ISS data from lung sections of Mtb-infected C57BL/6 and C3HeB/FeJ mice. In lungs from C57BL/6 mice early and late post infection, transcripts that define inflammatory macrophages were enriched at subcellular distances to bacteria, indicating the activation of infected macrophages. In contrast, expression patterns associated to antigen presentation were enriched in non-infected cells at 12 weeks post infection. T-cell transcripts were evenly distributed in the tissue. In Mtb-infected C3HeB/FeJ mice, transcripts characterizing activated macrophages localized in apposition to small bacteria clusters, but not in organized granulomas. Despite differences in the susceptibility to Mtb, the transcript patterns found around small bacteria clusters of C3HeB/FeJ and C57BL/6 mice were similar. Altogether, the presented tools allow us to characterize in depth the immune cell populations and their activation that interact with Mtb in the infected lung.

  • 92.
    Maiga, Bakary
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Science, Technique and Technologies of Bamako (USTTB), Mali.
    Dolo, Amagana
    Toure, Ousmane
    Dara, Victor
    Tapily, Amadou
    Campino, Susana
    Sepulveda, Nuno
    Risley, Paul
    Silva, Nipula
    Corran, Patrick
    Rockett, Kirk A.
    Kwiatkowski, Dominic
    Clark, Taane G.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Doumbo, Ogobara K.
    Human Candidate Polymorphisms in Sympatric Ethnic Groups Differing in Malaria Susceptibility in Mali2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 10, article id e75675Article in journal (Refereed)
    Abstract [en]

    Malaria still remains a major public health problem in Mali, although disease susceptibility varies between ethnic groups, particularly between the Fulani and Dogon. These two sympatric groups share similar socio-cultural factors and malaria transmission rates, but Fulani individuals tend to show significantly higher spleen enlargement scores, lower parasite prevalence, and seem less affected by the disease than their Dogon neighbours. We have used genetic polymorphisms from malaria-associated genes to investigate associations with various malaria metrics between the Fulanai and Dogon groups. Two cross sectional surveys (transmission season 2006, dry season 2007) were performed. Healthy volunteers from the both ethnic groups (n=939) were recruited in a rural setting. In each survey, clinical (spleen enlargement, axillary temperature, weight) and parasitological data (malaria parasite densities and species) were collected, as well as blood samples. One hundred and sixty six SNPs were genotyped and 5 immunoassays (AMA1, CSP, MSP1, MSP2, total IgE) were performed on the DNA and serum samples respectively. The data confirm the reduced malaria susceptibility in the Fulani, with a higher level of the protective O-blood group, and increased circulating antibody levels to several malaria antigens (p<10(-15)). We identified SNP allele frequency differences between the 2 ethnic groups in CD36, IL4, RTN3 and ADCY9. Moreover, polymorphisms in FCER1A, RAD50, TNF, SLC22A4, and IL13 genes were correlated with antibody production (p-value<0.003). Further work is required to understand the mechanisms underpinning these genetic factors.

  • 93.
    Mangano, Valentina D
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Dissecting the complexity of human susceptibility to Plasmodium falciparum malaria: genetic approaches2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    There are many aspects of the immunology of P. falciparum infection that are not understood. Genetic approaches are of great value for dissecting the complexity of immune responses to malaria in natura by providing new insights into molecular interactions between the parasite and the host. The work presented in this thesis had two major aims: to investigate the role of IFN-γ signalling in susceptibility to malaria; and to understand the biological basis of the low susceptibility to malaria shown by the Fula people of West Africa. We conducted genetic association studies to investigate the role of four candidate loci: IFNG, IFNGR1, IFNGR2 and IRF1. We observed significant associations between common genetic variation at the IRF1 locus and the ability to control P. falciparum infection. Our studies did not provide evidence for a major role of this gene in determining susceptibility to severe malaria. Using allele-specific expression assays we obtained preliminary results suggesting the existence of a regulatory element(s) in the 5’ upstream region of the IRF1 locus. IRF1 polymorphisms regulating gene expression could affect the production of inflammatory cytokines and the control of infection, but not the immune-based pathogenesis of severe disease. To understand the biological basis of the resistance to malaria shown by the Fula, we analysed HLA class II polymorphism and confirmed previous data showing that the Fula from Burkina Faso are genetically distinct from sympatric Mossi and Rimaibé. We then compared the expression profiles of PBMCs and CD4+CD25+ cells isolated from healthy adults of Fula and Mossi ethnicity. In the Fula we observed higher expression of several genes related to Th1 and Th2 function and reduced expression of important genes related to immune tolerance: FOXP3, CTLA4, TGFB and TGFBRs. These results suggest a functional deficit of T regulatory cells in the Fula and identify key genes as good candidates for future genetic association studies.

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  • 94. Mansouri, Larry
    et al.
    Sutton, Lesley-Ann
    Ljungström, Viktor
    Bondza, Sina
    Arngården, Linda
    Bhoi, Sujata
    Larsson, Jimmy
    Cortese, Diego
    Kalushkova, Antonia
    Plevova, Karla
    Young, Emma
    Gunnarsson, Rebeqa
    Falk-Sörqvist, Elin
    Lönn, Peter
    Muggen, Alice F.
    Yan, Xiao-Jie
    Sander, Birgitta
    Enblad, Gunilla
    Smedby, Karin E.
    Juliusson, Gunnar
    Belessi, Chrysoula
    Rung, Johan
    Chiorazzi, Nicholas
    Strefford, Jonathan C.
    Langerak, Anton W.
    Pospisilova, Sarka
    Davi, Frederic
    Hellström, Mats
    Jernberg-Wiklund, Helena
    Ghia, Paolo
    Söderberg, Ola
    Stamatopoulos, Kostas
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Uppsala University, Sweden.
    Rosenquist, Richard
    Functional loss of I kappa B epsilon leads to NF-kappa B deregulation in aggressive chronic lymphocytic leukemia2015In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 212, no 6, p. 833-843Article in journal (Refereed)
    Abstract [en]

    NF-kappa B is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-kappa B pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes I kappa B epsilon, a negative regulator of NF-kappa B in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced I kappa B epsilon protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that I kappa B epsilon loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-kappa B deregulation during lymphomagenesis.

  • 95. Marcotte, Harold
    et al.
    Piralla, Antonio
    Zuo, Fanglei
    Du, Likun
    Cassaniti, Irene
    Wan, Hui
    Kumagai-Braesh, Makiko
    Andréll, Juni
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Percivalle, Elena
    Sammartino, Josè Camilla
    Wang, Yating
    Vlachiotis, Stelios
    Attevall, Janine
    Bergami, Federica
    Ferrari, Alessandro
    Colaneri, Marta
    Vecchia, Marco
    Sambo, Margherita
    Zuccaro, Valentina
    Asperges, Erika
    Bruno, Raffaele
    Oggionni, Tiberio
    Meloni, Federica
    Abolhassani, Hassan
    Bertoglio, Federico
    Schubert, Maren
    Calzolai, Luigi
    Varani, Luca
    Hust, Michael
    Xue, Yintong
    Hammarström, Lennart
    Baldanti, Fausto
    Pan-Hammarström, Qiang
    Immunity to SARS-CoV-2 up to 15 months after infection2022In: iScience, E-ISSN 2589-0042 , Vol. 25, no 2, article id 103743Article in journal (Refereed)
    Abstract [en]

    Information concerning the longevity of immunity to SARS-CoV-2 following natural infection may have considerable implications for durability of immunity induced by vaccines. Here, we monitored the SARS-CoV-2 specific immune response in COVID-19 patients followed up to 15 months after symptoms onset. Following a peak at day 15-28 postinfection, the IgG antibody response and plasma neutralizing titers gradually decreased over time but stabilized after 6 months. Compared to G614, plasma neutralizing titers were more than 8-fold lower against variants Beta, Gamma, and Delta. SARS-CoV-2-specific memory B and T cells persisted in the majority of patients up to 15 months although a significant decrease in specific T cells, but not B cells, was observed between 6 and 15 months. Antiviral specific immunity, especially memory B cells in COVID-19 convalescent patients, is long-lasting, but some variants of concern may at least partially escape the neutralizing activity of plasma antibodies.

  • 96. Martínez-Pérez, Amparo
    et al.
    Igea, Ana
    Estévez, Olivia
    Ferreira, Catarina M.
    Torrado, Egídio
    Castro, António Gil
    Fernández, Carmen
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Spetz, Anna-Lena
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Adam, Lucille
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    López González, Moisés
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Singh, Mahavir
    Reljic, Rajko
    González-Fernández, África
    Changes in the Immune Phenotype and Gene Expression Profile Driven by a Novel Tuberculosis Nanovaccine: Short and Long-Term Post-immunization2021In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 11, article id 589863Article in journal (Refereed)
    Abstract [en]

    Deciphering protection mechanisms against Mycobacterium tuberculosis (Mtb) remains a critical challenge for the development of new vaccines and therapies. We analyze the phenotypic and transcriptomic profile in lung of a novel tuberculosis (TB) nanoparticle-based boosting mucosal vaccine Nano-FP1, which combined to BCG priming conferred enhanced protection in mice challenged with low-dose Mtb. We analyzed the vaccine profile and efficacy at short (2 weeks), medium (7 weeks) and long term (11 weeks) post-vaccination, and compared it to ineffective Nano-FP2 vaccine. We observed several changes in the mouse lung environment by both nanovaccines, which are lost shortly after boosting. Additional boosting at long-term (14 weeks) recovered partially cell populations and transcriptomic profile, but not enough to enhance protection to infection. An increase in both total and resident memory CD4 and CD8 T cells, but no pro-inflammatory cytokine levels, were correlated with better protection. A unique gene expression pattern with differentially expressed genes revealed potential pathways associated to the immune defense against Mtb. Our findings provide an insight into the critical immune responses that need to be considered when assessing the effectiveness of a novel TB vaccine.

  • 97.
    Masjedi, Khosro
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    In vitro analyses of immune responses to metal and organic haptens in humans with contact allergy2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Contact allergy is one of the most common skin diseases with great social and economical impact. The origin and nature of contact allergens (haptens) capable of inducing T-cell mediated allergic reactions are diverse, ranging from organic molecules to metal ions. Most of the current knowledge on T-cell responses to haptens in humans with contact allergy have been established by studies on the metal ion nickel (Ni), the most common cause of contact allergy, whereas reactivity to the large group of organic haptens has been less studied.

    Haptens are not immunogenic by themselves but must bind carrier molecules prior to their presentation on MHC class I or II molecules and subsequent recognition by T cells. Due to differences in their chemical nature, haptens interact with host molecules by different mechanisms and differences in their solubility can influence their access to different antigen-presenting pathways.

    The aim of the present study was to define immune responses elicited by haptens of different chemical nature including Ni (hydrophilic metal ion), methylisothiazolinones (hydrophilic organic molecule) and parthenolide (lipophilic organic molecule). The immune response displayed by subjects with allergy to these substances, and non-allergic control subjects, was assessed by measuring hapten-induced cytokine production in peripheral blood mononuclear cells (PBMC) with a focus on ELISpot analysis of T-cell type 1 (e.g. IFN-g and IL-2) and type 2 (e.g. IL-4, IL-5 and IL-13) cytokines. For Ni and parthenolide, the phenotype of the hapten-reactive T cells was determined. The allergic status of subjects was defined by clinical history and patch testing. The latter is the established diagnostic method for contact allergy, based on applying various haptens to the subjects’ back and grading the skin reaction after 2-3 days.

    All three haptens elicited a concomitant T-cell type 1 and 2 response in subjects with contact allergy to the corresponding hapten, suggesting the induction of a functionally related cytokine profile, irrespective of the chemical character of the hapten. The cytokine response was related to the degree of the subjects’ patch test reactivity; PBMC from a vast majority of subjects with strong and moderate patch test reactivity displayed detectable cytokine responses to the corresponding haptens, whereas subjects with weak or no (controls) patch test reactivity did not. Despite the similar cytokine profile induced, the phenotype of the reactive T cells was found to differ between haptens with Ni eliciting CD4+ T cells and parthenolide eliciting CD8+ T cells. This difference may be explained by a better ability of a lipophilic hapten to gain access to the MHC class I-restricted antigen-presentation pathway. Moreover, the data suggest that analysis of cytokine responses to haptens may facilitate future development of in vitro-based diagnostics assay for contact allergy.

    Finally, the relationship between the variation over time in patch test reactivity and systemic reactivity to Ni, in terms of cytokine responses to Ni in vitro, was investigated. The degree of patch test reactivity is known to vary over time, in particular in subjects with weak reactivity. Ni-allergic subjects were patch tested three times with three month intervals and PBMC obtained at the same time points were assessed for in vitro reactivity to Ni. The overall reactivity in the patch test and the in vitro test was well correlated confirming that both methods provide a good and comparable estimate of the systemic reactivity to Ni. However, fluctuations in the patch test reactivity over time were not well correlated with variations in the cytokine response elicited in vitro suggesting that other parameters besides changes in the systemic reactivity could significantly contribute to the variation in patch test reaction over time.

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  • 98. Masjedi, Khosro
    et al.
    Bruze, Magnus
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    T-Helper 22 Cell Type Responses to Nickel in Contact Allergic Subjects Are Associated with T-Helper 1, T-Helper 2, and T-Helper 17 Cell Cytokine Profile Responses and Patch Test Reactivity2023In: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097Article in journal (Refereed)
    Abstract [en]

    Introduction: Contact allergy to nickel (Ni) is a delayed-type hypersensitivity reaction mediated by Ni-reactive T cells producing the hallmark cytokines of several T-helper cell (Th) populations including IFN-gamma (Th1), IL-4, IL-5 and IL-13 (Th2), and IL-17A (Th17). IL-22-expressing CD4+ cells, which could be either Th17 co-expressing IL-22 or Th22, expressing IL-22 in the absence of IL-17A, have also been found in Ni-provoked skin of allergic subjects. It has been unclear if Ni-reactive T cells consist of distinct Th cell type populations or if they secrete a mix of Th cell hallmark cytokines. The aim herein was to assess if cellular cytokine responses to Ni, in ex vivo-stimulated peripheral blood mononuclear cells (PBMCs) from Ni-allergic subjects, include not only Th1, Th2, and Th17 but also Th22 hallmark cytokines and to define if the cytokines are produced by distinct cell populations representing different Th profiles. Methods: PBMC from Ni-allergic subjects (n = 15) with different degrees of patch test reactivity and non-allergic controls (n = 5) were in vitro stimulated with Ni. Cytokine levels in PBMC supernatants were analyzed by enzyme-linked immunosorbent assay (ELISA) (IFN-gamma, IL-2, IL-3, IL-5, IL-6, IL-13, IL-17A, IL-22, and IL-31). FluoroSpot was used to assess if individual Ni-reactive cells produced single, or combinations of, cytokines representing different Th profiles. Cytokine combinations analyzed were IL-17A/IL-22/IFN-gamma, IL-5/IL-17A/IFN-gamma, IL-13/IL-22/IFN-gamma, and IL-5/IL-13. Results: IL-22 as well as all other cytokines measured by ELISA were induced by Ni at higher levels in PBMC from allergic versus non-allergic subjects, with higher levels being associated with stronger patch test reactivity. The levels of most Ni-induced cytokines were positively correlated with each other; IL-2 displayed the highest correlation with other cytokines and IL-6 the lowest. FluoroSpot analysis showed that Th signature cytokines, IFN-gamma (Th1), IL-5 and IL-13 (Th2), IL-17A (Th17), and IL-22 (Th22), were almost exclusively produced by distinct cell populations. Conclusion: Distinct Th cell populations, including Ni-reactive cells displaying Th1, Th2, Th17, and Th22 cytokine profiles, are all increased in PBMC from Ni-allergic subjects and positively associated with patch test reactivity. The relevance of these different Th profile populations for the up- or down-regulation of inflammatory reactions in the skin of Ni-allergic subjects remains to be clarified.

  • 99.
    Mata Forsberg, Manuel
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Arasa, Claudia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    van Zwol, Willemien
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Uzunçayır, Sibel
    Schönbichler, Anna
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Regenthal, Paulina
    Schelin, Jenny
    Lindkvist-Petersson, Karin
    Björkander, Sophia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Activation of human γδ T cells and NK cells by Staphylococcal enterotoxins requires both monocytes and conventional T cells2022In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 111, no 3, p. 597-609Article in journal (Refereed)
    Abstract [en]

    Staphylococcal enterotoxins (SE) pose a great threat to human health due to their ability to bypass antigen presentation and activate large amounts of conventional T cells resulting in a cytokine storm potentially leading to toxic shock syndrome. Unconventional T- and NK cells are also activated by SE but the mechanisms remain poorly understood. In this study, the authors aimed to explore the underlying mechanism behind SE-mediated activation of MAIT-, γδ T-, and NK cells in vitro. CBMC or PBMC were stimulated with the toxins SEA, SEH, and TSST-1, and cytokine and cytotoxic responses were analyzed with ELISA and flow cytometry. All toxins induced a broad range of cytokines, perforin and granzyme B, although SEH was not as potent as SEA and TSST-1. SE-induced IFN-γ expression in MAIT-, γδ T-, and NK cells was clearly reduced by neutralization of IL-12, while cytotoxic compounds were not affected at all. Kinetic assays showed that unconventional T cell and NK cell-responses are secondary to the response in conventional T cells. Furthermore, co-cultures of isolated cell populations revealed that the ability of SEA to activate γδ T- and NK cells was fully dependent on the presence of both monocytes and αβ T cells. Lastly, it was found that SE provoked a reduced and delayed cytokine response in infants, particularly within the unconventional T and NK cell populations. This study provides novel insights regarding the activation of unconventional T- and NK cells by SE, which contribute to understanding the vulnerability of young children towards Staphylococcus aureus infections.

  • 100.
    Mata Forsberg, Manuel
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Björkander, Sophia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Pang, Yanhong
    Lundqvist, Ludwig
    Ndi, Mama
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ott, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Escribá, Irene Buesa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jaeger, Marie-Charlotte
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Roos, Stefan
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Extracellular Membrane Vesicles from Lactobacilli Dampen IFN-gamma Responses in a Monocyte-Dependent Manner2019In: Scientific Reports, E-ISSN 2045-2322, Vol. 9, article id 17109Article in journal (Refereed)
    Abstract [en]

    Secreted factors derived from Lactobacillus are able to dampen pro-inflammatory cytokine responses. Still, the nature of these components and the underlying mechanisms remain elusive. Here, we aimed to identify the components and the mechanism involved in the Lactobacillus-mediated modulation of immune cell activation. PBMC were stimulated in the presence of the cell free supernatants (CFS) of cultured Lactobacillus rhamnosus GG and Lactobacillus reuteri DSM 17938, followed by evaluation of cytokine responses. We show that lactobacilli-CFS effectively dampen induced IFN-gamma and IL-17A responses from T- and NK cells in a monocyte dependent manner by a soluble factor. A proteomic array analysis highlighted Lactobacillus-induced IL-1 receptor antagonist (ra) as a potential candidate responsible for the IFN-gamma dampening activity. Indeed, addition of recombinant IL-1ra to stimulated PBMC resulted in reduced IFN-gamma production. Further characterization of the lactobacilli-CFS revealed the presence of extracellular membrane vesicles with a similar immune regulatory activity to that observed with the lactobacilli-CFS. In conclusion, we have shown that lactobacilli produce extracellular MVs, which are able to dampen pro-inflammatory cytokine responses in a monocyte-dependent manner.

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