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  • 101. Minami, S. Sakura
    et al.
    Shen, Vivian
    Le, David
    Krabbe, Grietje
    Asgarov, Rustam
    Stockholm University, Faculty of Science, Department of Neurochemistry. Gladstone Institute of Neurological Diseases, United States.
    Perez-Celajes, Liberty
    Lee, Chih-Hung
    Li, Jinhe
    Donnelly-Roberts, Diana
    Gan, Li
    Reducing inflammation and rescuing FTD-related behavioral deficits in progranulin-deficient mice with alpha 7 nicotinic acetylcholine receptor agonists2015In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 97, no 4, p. 454-462Article in journal (Refereed)
    Abstract [en]

    Mutations in the progranulin gene cause frontotemporal dementia (FTD), a debilitating neurodegenerative disease that involves atrophy of the frontal and temporal lobes and affects personality, behavior, and language. Progranulin-deficient mouse models of FTD exhibit deficits in compulsive and social behaviors reminiscent of patients with FTD, and develop excessive microgliosis and increased release of inflammatory cytokines. Activation of nicotinic acetylcholine receptors (nAChRs) by nicotine or specific alpha 7 nAChR agonists reduces neuroinflammation. Here, we investigated whether activation of nAChRs by nicotine or alpha 7 agonists improved the excessive inflammatory and behavioral phenotypes of a progranulin-deficient FTD mouse model. We found that treatment with selective alpha 7 agonists, PHA-568487 or ABT-107, strongly suppressed the activation of NF-kappa B in progranulin-deficient cells. Treatment with ABT-107 also reduced microgliosis, decreased TNF alpha levels, and reduced compulsive behavior in progranulin-deficient mice. Collectively, these data suggest that targeting activation of the alpha 7 nAChR pathway may be beneficial in decreasing neuroinflammation and reversing some of the behavioral deficits observed in progranulin-deficient FTD.

  • 102. Mukherjee, Oindrilla
    et al.
    Singh, Birendra
    Bayrak, Burcu
    Jonsson, Ann-Beth
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Morgelin, Matthias
    Riesbeck, Kristian
    A fusion protein derived from Moraxella catarrhalis and Neisseria meningitidis aimed for immune modulation of human B cells2015In: Human Vaccines & Immunotherapeutics, ISSN 2164-5515, E-ISSN 2164-554X, Vol. 11, no 9, p. 2223-2227Article in journal (Refereed)
    Abstract [en]

    Moraxella IgD-binding protein (MID) is a well characterized trimeric autotransporter that specifically targets the IgD of B cells. We fused the membrane anchor of the meningococcal autotransporter NhhA with the IgD-binding region of MID (aa 962-1200) to create a chimeric protein designated as NID. The aim was to use this specific targeting to provide a better vaccine candidate against meningococci, in particular serogroup B by enhancing the immunogenicity of NhhA. NID was thereafter recombinantly expressed in E. coli. The NID-expressing E. coli bound to peripheral B lymphocytes that resulted in cellular activation. Furthermore, we also successfully expressed NID on outer membrane vesicles, nanoparticles that are commonly used in meningococcal vaccines. This study thus highlights the applicability of the menigococcal-Moraxella fusion protein NID to be used for specific targeting of vaccine components to the IgD B cell receptor.

  • 103. Mulas, Floriana
    et al.
    Wang, Xu
    Song, Shanshan
    Nishanth, Gopala
    Yi, Wenjing
    Brunn, Anna
    Larsen, Pia-Katharina
    Isermann, Berend
    Kalinke, Ulrich
    Barragan, Antonio
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Naumann, Michael
    Deckert, Martina
    Schlüter, Dirk
    The deubiquitinase OTUB1 augments NF-κB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC132021In: Cellular & Molecular Immunology, ISSN 1672-7681, E-ISSN 2042-0226, Vol. 18, p. 1512-1527Article in journal (Refereed)
    Abstract [en]

    Dendritic cells (DCs) are indispensable for defense against pathogens but may also contribute to immunopathology. Activation of DCs upon the sensing of pathogens by Toll-like receptors (TLRs) is largely mediated by pattern recognition receptor/nuclear factor-kappa B (NF-kappa B) signaling and depends on the appropriate ubiquitination of the respective signaling molecules. However, the ubiquitinating and deubiquitinating enzymes involved and their interactions are only incompletely understood. Here, we reveal that the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) is upregulated in DCs upon murine Toxoplasmagondii infection and lipopolysaccharide challenge. Stimulation of DCs with the TLR11/12 ligand T. gondii profilin and the TLR4 ligand lipopolysaccharide induced an increase in NF-kappa B activation in OTUB1-competent cells, resulting in elevated interleukin-6 (IL-6), IL-12, and tumor necrosis factor (TNF) production, which was also observed upon the specific stimulation of TLR2, TLR3, TLR7, and TLR9. Mechanistically, OTUB1 promoted NF-kappa B activity in DCs by K48-linked deubiquitination and stabilization of the E2-conjugating enzyme UBC13, resulting in increased K63-linked ubiquitination of IRAK1 (IL-1 receptor-associated kinase 1) and TRAF6 (TNF receptor-associated factor 6). Consequently, DC-specific deletion of OTUB1 impaired the production of cytokines, in particular IL-12, by DCs over the first 2 days of T. gondii infection, resulting in the diminished production of protective interferon-gamma (IFN-gamma) by natural killer cells, impaired control of parasite replication, and, finally, death from chronic T.encephalitis, all of which could be prevented by low-dose IL-12 treatment in the first 3 days of infection. In contrast, impaired OTUB1-deficient DC activation and cytokine production by OTUB1-deficient DCs protected mice from lipopolysaccharide-induced immunopathology. Collectively, these findings identify OTUB1 as a potent novel regulator of DCs during infectious and inflammatory diseases.

  • 104. Muus, Christoph
    et al.
    Luecken, Malte D.
    Eraslan, Gokcen
    Sikkema, Lisa
    Waghray, Avinash
    Heimberg, Graham
    Kobayashi, Yoshihiko
    Vaishnav, Eeshit Dhaval
    Subramanian, Ayshwarya
    Smillie, Christopher
    Jagadeesh, Karthik A.
    Duong, Elizabeth Thu
    Fiskin, Evgenij
    Triglia, Elena Torlai
    Ansari, Meshal
    Cai, Peiwen
    Lin, Brian
    Buchanan, Justin
    Chen, Sijia
    Shu, Jian
    Haber, Adam L.
    Chung, Hattie
    Montoro, Daniel T.
    Adams, Taylor
    Aliee, Hananeh
    Allon, Samuel J.
    Andrusivova, Zaneta
    Angelidis, Ilias
    Ashenberg, Orr
    Bassler, Kevin
    Becavin, Christophe
    Benhar, Inbal
    Bergenstrahle, Joseph
    Bergenstrahle, Ludvig
    Bolt, Liam
    Braun, Emelie
    Bui, Linh T.
    Callori, Steven
    Chaffin, Mark
    Chichelnitskiy, Evgeny
    Chiou, Joshua
    Conlon, Thomas M.
    Cuoco, Michael S.
    Cuomo, Anna S. E.
    Deprez, Marie
    Duclos, Grant
    Fine, Denise
    Fischer, David S.
    Ghazanfar, Shila
    Gillich, Astrid
    Giotti, Bruno
    Gould, Joshua
    Guo, Minzhe
    Gutierrez, Austin J.
    Habermann, Arun C.
    Harvey, Tyler
    He, Peng
    Hou, Xiaomeng
    Hu, Lijuan
    Hu, Yan
    Jaiswal, Alok
    Ji, Lu
    Jiang, Peiyong
    Kapellos, Theodoros S.
    Kuo, Christin S.
    Larsson, Ludvig
    Leney-Greene, Michael A.
    Lim, Kyungtae
    Litvinukova, Monika
    Ludwig, Leif S.
    Lukassen, Soeren
    Luo, Wendy
    Maatz, Henrike
    Madissoon, Elo
    Mamanova, Lira
    Manakongtreecheep, Kasidet
    Leroy, Sylvie
    Mayr, Christoph H.
    Mbano, Ian M.
    McAdams, Alexi M.
    Nabhan, Ahmad N.
    Nyquist, Sarah K.
    Penland, Lolita
    Poirion, Olivier B.
    Poli, Sergio
    Qi, CanCan
    Queen, Rachel
    Reichart, Daniel
    Rosas, Ivan
    Schupp, Jonas C.
    Shea, Conor
    Shi, Xingyi
    Sinha, Rahul
    Sit, Rene
    Slowikowski, Kamil
    Slyper, Michal
    Smith, Neal P.
    Sountoulidis, Alex
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Strunz, Maximilian
    Sullivan, Travis B.
    Sun, Dawei
    Talavera-Lopez, Carlos
    Tan, Peng
    Tantivit, Jessica
    Travaglini, Kyle J.
    Tucker, Nathan R.
    Vernon, Katherine A.
    Wadsworth, Marc H.
    Waldman, Julia
    Wang, Xiuting
    Xu, Ke
    Yan, Wenjun
    Zhao, William
    Ziegler, Carly G. K.
    Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics2021In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 27, no 3, p. 546-559Article in journal (Refereed)
    Abstract [en]

    Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2(+)TMPRSS2(+) cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention. An integrated analysis of over 100 single-cell and single-nucleus transcriptomics studies illustrates severe acute respiratory syndrome coronavirus 2 viral entry gene coexpression patterns across different human tissues, and shows association of age, smoking status and sex with viral entry gene expression in respiratory cell populations.

  • 105. Nasr, Amre
    et al.
    Iriemenam, Nnaemeka C.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Giha, Hayder
    Balogun, Halima A.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Anders, Robin F.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    ElGhazali, Gehad
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    FcgammaRIIa (CD32) polymorphism and anti-malarial IgG subclass pattern among Fulani and sympatric ethnic groups living in eastern Sudan2009In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, no 43, p. 1-10Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A SNP at position 131, in the FcgammaRIIa gene, affects the binding of the different IgG subclasses and may influence the clinical variation seen in patients with falciparum malaria. This study confirms and extends previous findings, analysing the FcgammaRIIa (CD32) polymorphism in relation to the IgG subclass distribution seen among two sympatric tribes living in eastern Sudan, characterized by marked differences in susceptibility to Plasmodium falciparum malaria. METHODS: Two hundred and fifty Fulani subjects living in an area of meso-endemic P. falciparum malaria infection were genotyped for the FcgammaRIIa-131 polymorphism. For comparison, 101 non-Fulani donors - (Masaleit, Hausa and Four) - living in the same study area, were genotyped. The levels of plasma antibodies (IgG and subclasses) to four malaria antigens (AMA-1, MSP 2 - 3D7 & FC27, Pf332-C231) were measured using indirect enzyme-linked immunosorbent assays. RESULTS: The FcgammaRIIa-H/H131 genotype was found to be significantly more prevalent in the Fulani as compared to the non-Fulani ethnic groups (36.0% for Fulani versus 17.8% for non-Fulani, adjusted OR 3.10, 95% CI 1.61-5.97, P value < 0.001). The Fulani showed lower anti-malarial IgG1 and IgG3 antibody levels as compared to the non-Fulani and higher levels of IgG2 antibodies. CONCLUSION: The FcgammaRIIa-H/H131 genotype and H131 allele is at higher frequency in the Fulani ethnic group. The H/H131 genotype was consistently associated with higher levels of anti-malarial IgG2 and IgG3 antibodies, while the R/R131 genotype was associated with higher levels of IgG1 antibodies.

  • 106. Norin, Ulrika
    et al.
    Rintisch, Carola
    Meng, Liesu
    Forster, Florian
    Ekman, Diana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Karolinska Institute, Sweden.
    Tuncel, Jonatan
    Klocke, Katrin
    Bäcklund, Johan
    Yang, Min
    Bonner, Michael Y.
    Lahore, Gonzalo Fernandez
    James, Jaime
    Shchetynsky, Klementy
    Bergquist, Maria
    Gjertsson, Inger
    Hubner, Norbert
    Bäckdahl, Liselotte
    Holmdahl, Rikard
    Endophilin A2 deficiency protects rodents from autoimmune arthritis by modulating T cell activation2021In: Nature Communications, E-ISSN 2041-1723, Vol. 12, no 1, article id 610Article in journal (Refereed)
    Abstract [en]

    The introduction of the CTLA-4 recombinant fusion protein has demonstrated therapeutic effects by selectively modulating T-cell activation in rheumatoid arthritis. Here we show, using a forward genetic approach, that a mutation in the SH3gl1 gene encoding the endocytic protein Endophilin A2 is associated with the development of arthritis in rodents. Defective expression of SH3gl1 affects T cell effector functions and alters the activation threshold of autoreactive T cells, thereby leading to complete protection from chronic autoimmune inflammatory disease in both mice and rats. We further show that SH3GL1 regulates human T cell signaling and T cell receptor internalization, and its expression is upregulated in rheumatoid arthritis patients. Collectively our data identify SH3GL1 as a key regulator of T cell activation, and as a potential target for treatment of autoimmune diseases.

  • 107.
    Nyakeriga, Alice
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Relation of nutritional status, immunity, hemoglobinopathy and falciparum malaria infection2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The interaction between nutritional status and malaria disease is complex and often controversial. Nutritional deficiencies (macro- or micro-nutrient) are thought to lead to malnutrition with subsequent susceptibility to malaria infection. On the other hand severe malaria or repeated malaria infections lead to malnutrition. While the cause and effect are difficult to attribute, micronutrient deficiencies such as iron deficiency and malaria infection often co-exist and show complex interactions leading to mutually reinforced detrimental clinical effects.

    That iron deficiency has adverse effects on human health is widely recognized. Iron plays a crucial role in processes of growth and cell division and in the transport of oxygen throughout the body. It is also important for the proliferation of cells of the immune system as well as for microorganisms including the malaria parasite. Iron deficiency results in a decrease in hemoglobin concentrations and subsequent anemia. However, the etiology of anemia is multi-factorial and may be affected, in addition, by several factors including malaria and host factors, especially hemoglobinopathies such as alpha-thalassemia and sickle cell trait. These hemoglobinopathies are also common in malaria endemic areas.

    In this thesis, we have investigated the relationship between nutritional status, immunity, hemoglobinopathies and falciparum malaria in a cohort of children less than 8 years old living on the coast of Kenya. We have found that malaria was associated with malnutrition in an age-dependent fashion. Malaria was associated with subsequent underweight or stunting in children under the age of 2 years, but this effect was not there in older children. Also, we observed that iron deficiency was associated with protection of children against clinical malaria. Children who were iron deficient had a lower incidence of malaria episodes as compared to those who were iron replete.

    While studies on the effects of single micronutrient deficiencies on components of the immune system are difficult to design and interpret, there is ample evidence that micronutrient deficiencies, in general, affect all components of immunity. In line with this, we found that nutritional iron status was associated with certain malaria-specific immunoglobulins and interleukin-4 mRNA levels. Iron deficient children had lower levels of malaria-specific IgG2 and IgG4 but higher expression levels of IL-4 mRNA as compared to the iron replete children. Finally, we observed a tendency towards a higher prevalence of iron deficiency in children carrying either alpha-thalassemia or sickle cell trait.

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  • 108.
    Nyakeriga, Alice
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Williams, Thomas
    Marsh, Kevin
    Wambua, Sammy
    Perlmann, Hedvig
    Perlmann, Peter
    Grandien, Alf
    Troye-Blomberg, Marita
    Cytokine mRNA expression and iron status in children in a malaria endemic area2005In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 61, no 4, p. 370-375Article in journal (Refereed)
    Abstract [en]

    Iron deficiency has been reported to affect both malaria pathogenesis and cell-mediated immune responses; however, it is unclear whether the protection afforded by iron deficiency is mediated through direct effects on the parasite, through immune effector functions or through both. We have determined cytokine mRNA expression levels in 59 children living in a malaria endemic area on the coast of Kenya who we selected on the basis of their biochemical iron status. Real-time quantitative reverse transcriptase polymerase chain reaction analysis of cytokine mRNA levels of peripheral blood mononuclear cells (PBMC) obtained from these children showed an association between interleukin-4 (IL-4) mRNA levels and all the biochemical indices of iron that we measured. Furthermore, IL-10 mRNA was higher in parasite blood smear-positive children than in blood smear-negative children irrespective of their iron status. This study suggests that IL-4 expression by PBMC may be affected by iron status.

  • 109. Ohm, Milou
    et al.
    van Rooijen, Debbie M.
    Bonačić Marinovic, Axel A.
    van Ravenhorst, Mariëtte B.
    van der Heiden, Marieke
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Buisman, Anne-Marie
    Sanders, Elisabeth A. M.
    Berbers, Guy A. M.
    Different Long-Term Duration of Seroprotection against Neisseria meningitidis in Adolescents and Middle-Aged Adults after a Single Meningococcal ACWY Conjugate Vaccination in The Netherlands2020In: Vaccines, E-ISSN 2076-393X, Vol. 8, no 4, article id 624Article in journal (Refereed)
    Abstract [en]

    Neisseria meningitidis is often asymptomatically carried in the nasopharynx but may cause invasive meningococcal disease, leading to morbidity and mortality. Meningococcal conjugate vaccinations induce functional protective antibodies against capsular antigens, but seroprotection wanes over time. We measured functional antibody titers five years after administration of a single dose of the meningococcal ACWY-polysaccharide-specific tetanus toxoid-conjugated (MenACWY-TT) vaccine in adolescents and middle-aged adults in the Netherlands, using the serum bactericidal antibody with baby rabbit complement (rSBA) assay. Protection was defined as rSBA titer >= 8. The meningococcal ACWY-specific serum IgG concentrations were measured with a multiplex immunoassay. Duration of protection was estimated by a bi-exponential decay model. Sufficient protection for MenC, MenW, and MenY was achieved in 94-96% of the adolescents five years postvaccination, but, in middle-aged adults, only in 32% for MenC, 65% for MenW and 71% for MenY. Median duration of protection for MenCWY was 4, 14, and 21 years, respectively, in middle-aged adults, while, in adolescents, it was 32, 98, and 33 years. Our findings suggest that adolescents, primed in early childhood with MenC conjugate vaccination, remain sufficiently protected after a single dose of MenACWY-TT vaccine. Middle-aged adults without priming vaccination show fast waning of antibodies, particularly MenC, for which protection is lost after four years.

  • 110. Olaniyan, Subulade A.
    et al.
    Amodu, Olukemi K.
    Bakare, Adekunle A.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Omotade, Olayemi O.
    Rockett, Kirk A.
    Tumour necrosis factor alpha promoter polymorphism, TNF-238 is associated with severe clinical outcome of falciparum malaria in Ibadan southwest Nigeria2016In: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 161, p. 62-67Article in journal (Refereed)
    Abstract [en]

    Tumour necrosis factor (TNF) - alpha has been shown to play an important role in the pathogenesis of falciparum malaria. Two TNF promoter polymorphisms, TNF-308 and TNF-238 have been associated with differential activity and production of TNF. In order to investigate the association between TNF-308 and TNF-238 and the clinical outcome of malaria in a Nigerian population, the two TNF polymorphisms were analysed using Sequenom iPLEX Platform. A total of 782 children; 283 children with uncomplicated malaria, 255 children with severe malaria and 244 children with asymptomatic infection (controls) were studied. The distribution of TNF-308 and TNF-238 genotypes were consistent with the Hardy-Weinberg equilibrium. Distribution of both TNF polymorphisms differed significantly across all clinical groups (TNF-308: p = 0.007; TNF-238: p=0.001). Further tests for association with severe malaria using genotype models controlling for age, parasitaemia and HbAS showed a significant association of the TNF-238 polymorphism with susceptibility to severe malaria (95% CI = 1.43-6.02, OR= 2.94, p = 0.003237) The GG genotype of TNF-238 significantly increased the risk of developing cerebral malaria from asymptomatic malaria and uncomplicated malaria (95% CI = 1.99-18.17, OR= 6.02, p <0.001 and 95% CI= 1.78-8.23, OR= 3.84, p <0.001 respectively). No significant association was found between TNF-308 and malaria outcome. These results show thegenetic association of TNF-238 in the clinical outcome of malaria in Ibadan, southwest Nigeria. These findings add support to the role of TNF in the outcome of malaria infection. Further large scale studies across multiple malaria endemic populations will be required to determine the specific roles of TNF-308 and TNF-238 in the outcome of falciparum malaria infection.

  • 111. Omokanye, Ajibola
    et al.
    Ong, Li Ching
    Lebrero-Fernandez, Cristina
    Bernasconi, Valentina
    Schön, Karin
    Strömberg, Anneli
    Bemark, Mats
    Saelens, Xavier
    Czarnewski, Paulo
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lycke, Nils
    Clonotypic analysis of protective influenza M2e-specific lung resident Th17 memory cells reveals extensive functional diversity2022In: Mucosal Immunology, ISSN 1933-0219, E-ISSN 1935-3456, Vol. 15, no 4, p. 717-729Article in journal (Refereed)
    Abstract [en]

    The fate of tissue-resident memory CD4 T cells (Trm) has been incompletely investigated. Here we show that intranasal, but not parenteral, immunization with CTA1-3M2e-DD stimulated M2e-specific Th17 Trm cells, which conferred strong protection against influenza virus infection in the lung. These cells rapidly expanded upon infection and effectively restricted virus replication as determined by CD4 T cell depletion studies. Single-cell RNAseq transcriptomic and TCR VDJ-analysis of M2e-tetramer-sorted CD4 T cells on day 3 and 8 post infection revealed complete Th17-lineage dominance (no Th1 or Tregs) with extensive functional diversity and expression of gene markers signifying mature resident Trm cells (Cd69, Nfkbid, Brd2, FosB). Unexpectedly, the same TCR clonotype hosted cells with different Th17 subcluster functions (IL-17, IL-22), regulatory and cytotoxic cells, suggesting a tissue and context-dependent differentiation of reactivated Th17 Trm cells. A gene set enrichment analysis demonstrated up-regulation of regulatory genes (Lag3, Tigit, Ctla4, Pdcd1) in M2e-specific Trm cells on day 8, indicating a tissue damage preventing function. Thus, contrary to current thinking, lung M2e-specific Th17 Trm cells are sufficient for controlling infection and for protecting against tissue injury. These findings will have strong implications for vaccine development against respiratory virus infections and influenza virus infections, in particular.

  • 112. O'Toole, M. S.
    et al.
    Bovbjerg, D. H.
    Renna, M. E.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Mennin, D. S.
    Zachariae, R.
    Effects of psychological interventions on systemic levels of inflammatory biomarkers in humans: A systematic review and meta-analysis2018In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 74, p. 68-78Article, review/survey (Refereed)
    Abstract [en]

    The purpose of the present investigation was to systematically review randomized controlled trials examining the effects of psychological interventions on inflammatory biomarkers in adult populations and to quantitatively analyze those effects by meta-analysis. Two researchers independently searched key electronic databases, selected eligible publications, extracted data, and evaluated methodological quality. Nineteen randomized controlled trials examining a total of 1510 participants were included. The overall combined effect size from pre to post psychological intervention on pro-inflammatory biomarker levels was statistically significant, showing an attenuating effect, although of a small magnitude (s’ g = 0.15, p = .008, CI [0.04–0.26]). However, this effect was not maintained into the follow-up period (g < −0.01, p = .964, CI [−0.19–0.18]). Looking at the individual biomarkers assessed across studies, only C-reactive protein (CRP) was found to significantly decrease following psychological intervention. A number of moderation analyses were conducted, none of which reached statistical significance. However, the numerically largest – and significant – within-group effect size was obtained for the group of studies that had preselected participants based on elevated psychological distress (g = 0.29, p = .047). In conclusion, psychological interventions appear efficacious in reducing pro-inflammatory biomarker levels. Future studies are recommended to carefully select individuals based on inflammatory (e.g., the presence of low-grade inflammation) and/or psychological (e.g., psychological distress) criteria.

  • 113.
    Pilström, Björn
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Murine insulin-dependent diabetes mellitus: a model for disease development and protection1997Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease caused by destruction of the insulin-producing beta cells in the pancreatic Langerhans' islets. This destruction is preceded by an infiltration of mononuclear leukocytes called insulitis. This study aims at determining the cellular mechanisms for the autoimmune reaction associated with diabetes development by using transgenic animal models as well as the spontaneously diabetic non-obese diabetic (NOD) mice.

    MHC class II expression on beta cells has been proposed to be a mechanism for the development of insulitis and diabetes. Transgenic mice expressing physiological levels of allogeneic MHC class II on beta cells do not display any sign of neither insulitis nor diabetes, although they are functionally intolerant to the allogeneic MHC. We demonstrate that this inability to react to the allogeneic MHC class II on beta cells is due to a functional inability of the beta cells to act as antigen-presenting cells. The MHC class II transgenic mice were mated to mice expressing the costimulatory molecule B7-1 on beta cells. Mice expressing both MHC class II and B7-1 on beta cells develop a severe insulitis and diabetes, while mice lacking either transgene reveal no sign of autoimmunity. This demonstrates that expression of costimulatory molecules can overcome immunological non-recognition.

    E alpha-transgenic NOD mice are almost completely protected against insulitis and diabetes. This effect can be modulated by mutating the Ea promoter to give a restricted expression of the transgene. These mice are only partially protected against the development of insulitis. By comparing the different degrees of insulitis in three promoter-mutated transgenic lines, and relating them to the different patterns of I-E expression, we demonstrate the requirements for I-E expression on primary antigen-presenting cells in order to alleviate NOD insulitis. By mating the promoter-mutated lines to one another we got double-transgenic lines with an expression pattern very close to normal wildtype expression. In spite of this, none out of three double-transgenic lines were completely protected from insulitis.We therefore conclude that minute differences in I-E expression account for the susceptibility to insulitis seen in the double-transgenic lines.

    By intracellular immunofluorescence staining for eight different cytokines we demonstrate a biphasic cytokine pattern with early monokine production correlated to an increasing infiltration of the Langerhans' islets, and Th1 lymphokines produced prior to the development of diabetes, thus characterising the effector phase with beta-cell destruction. In addition, we could find abundant production of IL-6 by endocrine cells, probably as a stress response to the ongoing tissue damage

  • 114.
    Poux, Candice
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Dondalska, Aleksandra
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Bergenstrahle, Joseph
    Pålsson, Sandra
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Contreras, Vanessa
    Arasa, Claudia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Järver, Peter
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Albert, Jan
    Busse, David C.
    LeGrand, Roger
    Lundeberg, Joakim
    Tregoning, John S.
    Spetz, Anna-Lena
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    A Single-Stranded Oligonucleotide Inhibits Toll-Like Receptor 3 Activation and Reduces Influenza A (H1N1) Infection2019In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 10, article id 2161Article in journal (Refereed)
    Abstract [en]

    The initiation of an immune response is dependent on the activation and maturation of dendritic cells after sensing pathogen associated molecular patterns by pattern recognition receptors. However, the response needs to be balanced as excessive pro-inflammatory cytokine production in response to viral or stress-induced pattern recognition receptor signaling has been associated with severe influenza A virus (IAV) infection. Here, we use an inhibitor of Toll-like receptor (TLR)3, a single-stranded oligonucleotide (ssON) with the capacity to inhibit certain endocytic routes, or a TLR3 agonist (synthetic double-stranded RNA Polyl:C), to evaluate modulation of innate responses during H1N1 IAV infection. Since IAV utilizes cellular endocytic machinery for viral entry, we also assessed ssON's capacity to affect IAV infection. We first show that IAV infected human monocyte-derived dendritic cells (MoDC) were unable to up-regulate the co-stimulatory molecules CD80 and CD86 required for T cell activation. Exogenous TLR3 stimulation did not overcome the IAV-mediated inhibition of co-stimulatory molecule expression in MoDC. However, TLR3 stimulation using Polyl:C led to an augmented pro-inflammatory cytokine response. We reveal that ssON effectively inhibited Polyl:C-mediated pro-inflammatory cytokine production in MoDC, notably, ssON treatment maintained an interferon response induced by IAV infection. Accordingly, RNAseq analyses revealed robust up-regulation of interferon-stimulated genes in IAV cultures treated with ssON. We next measured reduced IAV production in MoDC treated with ssON and found a length requirement for its anti-viral activity, which overlapped with its capacity to inhibit uptake of Polyl:C. Hence, in cases wherein an overreacting TLR3 activation contributes to IAV pathogenesis, ssON can reduce this signaling pathway. Furthermore, concomitant treatment with ssON and IAV infection in mice resulted in maintained weight and reduced viral load in the lungs. Therefore, extracellular ssON provides a mechanism for immune regulation of TLR3-mediated responses and suppression of IAV infection in vitro and in vivo in mice.

  • 115.
    Qazi, Khaleda Rahman
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Heat shock proteins as vaccine adjuvants2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    New efficient vaccines against infectious diseases are in demand. Some important factors impeding the vaccine development are the poor immunogenicity and the MHC restriction of the immune responses to a number of antigens. The use of novel vaccine adjuvants or carrier proteins, which are known to enhance the immunogenicity of the subunit antigens and provide T-cell help, can circumvent these problems. The potential of heat shock proteins (HSPs) to function as adjuvants when fused to or co-delivered with protein antigens, make them attractive vaccine candidates. In this thesis we have evaluated the potency of heat shock protein 70 (HSP70) as a possible vaccine adjuvant and studied the mechanisms behind the adjuvanticity.

    The first article aims to evaluate the carrier effect of glutathione-S-transferase (GST) on a malarial antigen EB200 that induces a MHC restricted response in mice. Immunization of CBA and C57BL/6 mice, high and low responders to EB200, respectively, with the GST-EB200 fusion protein elicited EB200 specific antibody responses in both strains of mice, which indicated that MHC restriction was broken in C57BL/6 mice. However, the antibody affinity and the magnitude of the response were lower in the C57BL/6 mice compared with that in CBA. To improve the response, the efficacy of various adjuvants like alum, HSP70 from Trypanosoma cruzi, and the adjuvant combination (HSP70 and cholera toxin) was evaluated. The results indicated that cholera toxin and HSP70 act synergistically and improve the immunogenicity of EB200 antigen by increasing the affinity and magnitude of the response.

    HSP belongs to a family of conserved molecules and the maximum homology lies on the N-terminal region of the protein, therefore there is a risk that use of a complete molecule would give rise to autoimmunity. Thus, in our second study we first evaluated the adjuvant effect of the less conserved portion of HSP70 derived from Plasmodium falciparum (Pf70C). We found that the Pf70C exhibited similar adjuvant properties as the whole molecule. We further analyzed the adjuvant potential of Pf70C against EB200 formulated as a chimeric DNA vaccine construct. These constructs alone failed to generate substantial levels of EB200 specific antibodies in mice. However, the DNA immunization efficiently primed the immune system. This was evident as the subsequent boosting with the corresponding recombinant fusion proteins Pf70C-EB200 elicited strong EB200 specific Th-1 antibody responses. In contrast, no such priming effect was observed for ex vivo IFN-γ production, however stimulation with the Pf70C-EB200 fusion protein induced an enhanced secretion of IFN-γ in vitro.

    During the infection process, the synthesis of bacterial HSP is up-regulated, which is known to sensitize T cells in the infected host. Since a high degree of homology exists within the phylogenetic families of HSPs, we postulated that exposure of mice to microorganisms could prime the immune system for evolutionary diverse HSPs and for any antigen coupled to them. We tested this hypothesis by priming mice with different microorganisms such as BCG, Mycobacterium vaccae or Chlamydia pneumoniae and boosted with a recombinant fusion protein Pf70C-EB200 or with a panel of HSPs. We found that BCG and M. vaccae but not C. pneumoniae could provide priming of the immune system to induce secondary IgG responses to Pf70C as well as to other HSPs tested. The priming effect was also observed when the EB200 antigen was coupled to Pf70C. Analysis of the IgG1 and IgG2a profiles and IFN-g production induced against the HSPs revealed a mixture of Th1/Th2 type of responses. We also observed that HSP70 specific sera cross-reacted some extent with certain autoreactive antigens. However, no deposits were observed in the kidneys of HSP treated animals.

    Finally, we investigated the role of TLR2 and TLR4 on HSP70-mediated adjuvanticity. We found that HSPs displayed different degrees of adjuvanticity regarding both the strength and the profile of the induced immune response. Also, they possessed different requirements for signaling through TLRs. While HSP70 from T. cruzi induced antigen-specific humoral responses in wild type as well as in both the TLR2 and TLR4 knockout mice, the response was diminished in the TLR4 knockout mice when both the whole and C-terminal fragment of HSP70 from Mycobacterium tuberculosis was used. However, the C-terminal fragment of P. falciparum HSP70 elicited responses only in wild type mice but not in TLR2 or TLR4 knockout mice indicating that the adjuvant function differ for phylogenetically related HSPs. Taken together our data suggest that HSPs can be promising candidates in future vaccines.

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  • 116.
    Qazi, Khaleda Rahman
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Bach Jensen, Georg
    van der Heiden, Marieke
    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.
    Holmlund, Ulrika
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Haileselassie, Yeneneh
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kokkinou, Efthymia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Marchini, Giovanna
    Jenmalm, Maria C.
    Abrahamsson, Thomas
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Extremely Preterm Infants Have Significant Alterations in Their Conventional T Cell Compartment during the First Weeks of Life2020In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 204, no 1, p. 68-77Article in journal (Refereed)
    Abstract [en]

    Extremely preterm neonates are particularly susceptible to infections, likely because of severely impaired immune function. However, little is known on the composition of the T cell compartment in early life in this vulnerable population. We conducted a comprehensive phenotypic flow cytometry-based longitudinal analysis of the peripheral conventional T cell compartment of human extremely low gestational age neonates (ELGAN) with extremely low birth weight (ELBW; <1000 g) participating in a randomized placebo-controlled study of probiotic supplementation. PBMCs from ELGAN/ELBW neonates were collected at day 14, day 28, and postmenstrual week 36. Comparisons were made with full-term 14-d-old neonates. Total CD4(+) and CD8(+) T cell frequencies were markedly lower in the preterm neonates. The reduction was more pronounced among the CD8(+) population, resulting in an increased CD4/CD8 ratio. The preterm infants were also more Th2 skewed than the full-term infants. Although the frequency of regulatory T cells seemed normal in the ELGAN/ELBW preterm neonates, their expression of the homing receptors alpha 4 beta 7, CCR4, and CCR9 was altered. Notably, ELGAN/ELBW infants developing necrotizing enterocolitis before day 14 had higher expression of CCR9 in CD4(+)T cells at day 14. Chorioamnionitis clearly associated with reduced T regulatory cell frequencies and functional characteristics within the preterm group. Finally, probiotic supplementation with Lactobacillus reuteri did not impose any phenotypic changes of the conventional T cell compartment. In conclusion, notable immaturities of the T cell compartment in ELGAN/ELBW neonates may at least partially explain their increased susceptibility to severe immune-mediated morbidities.

  • 117.
    Rahman, Muhammad Jubayer
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Mucosal immunity against mycobacterial infection2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis aimed to the identification of immune biomarkers of mycobacterial infection for better diagnosis of tuberculosis (TB) and also focused on new vaccination strategies with a particular emphasis on the immune responses in the respiratory tract using murine models.

    Since the lung is the natural habitat for the M. tuberculosis, we reasoned that immune responses detected locally in the lungs would be good correlates of infection (Paper I). Likewise, immune responses induced in the respiratory tract following immunization would be more effective against mycobacterial infection. We showed that cytokines (IL-12, TNF, and IFN-γ) and cytokine receptors (sTNFR1 and sTNFR2) together with specific antibodies in the respiratory tract correlated better with the bacterial burden in the organs. In Paper II, we investigated the role of the BCG vaccination as a priming vaccine in a heterologous prime-boost immunization protocol. The results showed that the neonatal BCG vaccination primed the immune system for a relevant antigen and showed a generalized adjuvant effect. Using this immunization protocol, protective immune responses in the lungs were generated independently of the route used for the booster immunization. In Paper III, We showed that exposure to mycobacterial antigens during the gestational period led to antigen transportation from the mother to the fetus and this resulted in an early priming of the fetal immune system. Immunization with the same antigen during the postnatal life increased antigen-specific recall IFN-γ responses and protection against infection. We examined the role of innate immunity for the induction of acquired immune responses upon immunization with mycobacterial antigens using TLR2 deficient mice (Paper IV). Our data indicated that suboptimal innate immune responses in the TLR2-/- mice might compromise the induction of acquired immune responses.

    Overall, the current findings suggested that a better understanding of the mucosal immunity would be useful for the improvement of diagnostic procedures and the development of efficient vaccines against TB.

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  • 118.
    Rahman Qazi, Khaleda
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jensen, Georg B.
    van Der Heiden, Marieke
    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.
    Marchini, Giovanna
    Jenmalm, Maria C.
    Abrahamsson, Thomas
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Extreme prematurity and sepsis strongly influence frequencies and functional characteristics of circulating gamma delta T and natural killer cells2021In: Clinical & Translational Immunology (CTI), E-ISSN 2050-0068, Vol. 10, no 6, article id e1294Article in journal (Refereed)
    Abstract [en]

    Objectives. Extremely low gestational age neonates with extremely low birthweight (ELGAN/ELBW) are highly susceptible to infection. This is linked to their relatively immature immune system which is not yet fully compatible with an extra-uterine environment. Here, we performed a longitudinal characterisation of unconventional T and natural killer (NK) cells in ELGAN/ELBW during their first months of life. Methods. Peripheral blood mononuclear cells were collected from 97 ELGAN/ELBW at 14 and 28 days of life and at a time point corresponding to postmenstrual week 36 + 0. gamma delta T-cell, NKT-cell, mucosa-associated invariant T-cell and NK cell frequencies and characteristics were analysed by flow cytometry. As control, cells from 14-day-old full-term (FT) infants were included. Results. Extreme prematurity had significant bearing on gamma delta T-cell and NK cell frequencies and characteristics. ELGAN/ELBW had significantly higher proportions of gamma delta T cells that were skewed towards effector and effector memory phenotypes, characteristics that were maintained throughout the study period. Expression of the gut homing receptor CCR9 was also more common in gamma delta T cells from ELGAN/ELBW. Conversely, NK cell frequencies were markedly lower and skewed towards a cytotoxic phenotype in the ELGAN/ELBW group at 14 days of age. Culture-proven sepsis with an onset during the first 14 days after birth further manifested these differences in the gamma delta T- and NK cell populations at 14 days of age. Conclusion. Prematurity strongly influences the levels of gamma delta T and NK cells, in particular in cases where sepsis debuts during the first 2 weeks of life.

  • 119. Rey, N.
    et al.
    Ebrahimian, T.
    Gloaguen, C.
    Kereselidze, D.
    Magneron, V.
    Bontemps, C. A.
    Demarquay, C.
    Olsson, G.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Caen Normandie, France.
    Lehoux, S.
    Ebrahimian, Teni G.
    Exposure to Low to Moderate Doses of Ionizing Radiation Induces A Reduction of Pro-Inflammatory Ly6chigh Monocytes and a U-Curved Response of T Cells in APOE -/- Mice2021In: Dose-Response, E-ISSN 1559-3258, Vol. 19, no 2, article id 15593258211016237Article in journal (Refereed)
    Abstract [en]

    Low dose ionizing radiation (LDIR) is known to have a protective effect on atherosclerosis in rodent studies, but how it impacts different cells types involved in lesion formation remains incompletely understood. We investigated the immunomodulatory response of different doses and dose-rates of irradiation in ApoE-/- mice. Mice were exposed to external γ rays at very low (1.4 mGy.h-1) or low (50 mGy.h-1) dose-rates, with cumulative doses spanning 50 to 1000 mGy. Flow cytometry of circulating cells revealed a significant decrease in pro-inflammatory Ly6CHi monocytes at all cumulative doses at low dose-rate, but more disparate effects at very low dose-rate with reductions in Ly6CHi cells at doses of 50, 100 and 750 mGy only. In contrast, Ly6CLo monocytes were not affected by LDIR. Similarly, proportions of CD4+ T cell subsets in the spleen did not differ between irradiated mice and non-irradiated controls, whether assessing CD25+FoxP3+ regulatory or CD69+ activated lymphocytes. In the aorta, gene expression of cytokines such as IL-1 and TGF-ß and adhesion molecules such as E-Selectin, ICAM-1, and VCAM-1 were reduced at the intermediate dose of 200 mGy. These results suggest that LDIR may reduce atherosclerotic plaque formation by selectively reducing blood pro-inflammatory monocytes and by impairing adhesion molecule expression and inflammatory processes in the vessel wall. In contrast, splenic T lymphocytes were not affected by LDIR. Furthermore, some responses to irradiation were nonlinear; reductions in aortic gene expression were significant at intermediate doses, but not at either highest or lowest doses. This work furthers our understanding of the impact of LDIR with different dose-rates on immune system response in the context of atherosclerosis. 

  • 120.
    Rodríguez, Ariane
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Mucosal immunity in the respiratory tract: The role of IgA in protection against intracellular pathogens2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The lungs and upper airways are mucosal surfaces that are common site for infection with an enormous variety of inhaled pathogens. Therefore, induction of immune responses in the respiratory tract is crucial for protection against respiratory diseases.

    One of the pathogens infecting the host via the respiratory tract is Mycobacterium Tuberculosis. The reported efficacy of the currently used Bacillus Calmette-Guérin (BCG) vaccine against tuberculosis is highly variable, ranging from 50% against pulmonary tuberculosis to 80% against disseminated tuberculosis. Recently, the current route of vaccination (intradermal) has been considered as a possible factor influencing the protective capacity of the BCG vaccine. In this regard, intradermal route most likely induces protective systemic responses while it fails to induce optimal responses in the lungs. Therefore, our working hypothesis is that vaccination should be directed towards the respiratory mucosal immunity in order to improve the degree of host protection in the lungs.

    In this thesis we studied the effect of the route of immunization as well as of different mucosal adjuvants on the induction of mucosal immune responses against the mycobacterial surface antigen PstS-1. We found that, the intranasal (i.n.) route of immunization was a more favorable route inducing strong local immune responses, than intraperitoneal (i.p.) route. Indeed, i.n. route immunization, unlike the i.p. route, elicited strong IgA responses in the lungs accompanied by a major influx of CD4+ T cells and a significant local production of IFN-gamma.

    IgA, being the predominant Ig isotype at mucosal tissues, is considered a major effector molecule involved in defense mechanisms against viral and bacterial pathogens at these sites. Therefore, we investigated the possible role of IgA in the protection of the respiratory mucosa against mycobacterial infections, using mice deficient in IgA and in the polymeric Ig receptor. We show that, deficient mice are more susceptible to mycobacterial infections than wild type mice, thereby demonstrating a role for IgA in protection against mycobacteria. Importantly, our studies revealed a reduced production of protective factors, such as INF-gamma and TNF-alpha in the lungs of deficient mice that was associated with the higher susceptibility seen in these mice compared to wild-type mice. We also conducted challenge experiments against another respiratory pathogen, Chlamydia pneumoniae, using IgA deficient mice. Likewise to mycobacteria, our data support a role for IgA in the protection of the respiratory tract against C. pneumoniae infection.

    Finally, we investigated the possible mechanisms explaining the reduced pro-inflammatory responses in IgA deficient mice. Our data indicated that IgA deficient mice present a defective response to stimulation with LPS or 19kDa which appears to be both, essentially due to suboptimal stimulation of macrophages and restricted to the lungs.

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  • 121.
    Saghafian Hedengren, Shanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Microbial and maternal influences on allergic sensitization during childhood: defining a role for monocytes2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Allergic diseases are influenced by genetics and the environment. Maternal allergy appears to confer a higher risk for allergic sensitization than paternal allergy, suggesting an in utero influence. A decrease in particular infections or a lower exposure to microbial components during infancy is suggested to contribute to the high allergy prevalence in affluent societies. Toll-like receptors (TLR) 2 and 4 recognize peptidoglycan (PGN) and LPS respectively, are expressed on e.g. monocytes, and have been implicated in modulating the risk of IgE-sensitization. This thesis aimed to study the influence of maternal allergy and early microbial exposure on monocyte function and allergic sensitization during childhood.

    Blood samples from children participating in a prospective allergy cohort were used. Two-year old infants with allergic mothers had lower IL-6 production and reduced activation of the TLR-signalling intermediate p38-MAPK in response to PGN than children with non-allergic mothers. In 5-year old children, allergic disease and not maternal allergy influenced monocytic TLR2-regulation. Five-year olds who were seropositive for Epstein-Barr virus (EBV) at 2-years of age had a lower risk of persistent IgE-sensitization while EBV contraction after 2-years of age related to a higher risk of IgE-sensitization. Upon in vitro stimulation, NK cells from EBV+ 2-year olds produced lower IFN-g levels. EBV+ 2-year olds had also lower systemic IFN-g. In comparison to CD14++CD16- monocytes, CD14+CD16+ cells induced NK-cell IFN-g more potently in vitro, and EBV+ infants tended to have lower proportions of these CD14+CD16+ monocytes.

    This thesis highlights the importance of early-life microbial (EBV) exposure for a proper allergy-protective immunity. Also, maternal allergic heredity appears to influence monocytic microbial responses in early infancy. All these aspects relate to altered monocyte functionality, which suggest that they could have a role in allergic sensitization.

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  • 122. Saghafian-Hedengren, Shanie
    et al.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nilsson, Anna
    T Cell Subsets During Early Life and Their Implication in the Treatment of Childhood Acute Lymphoblastic Leukemia2021In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 12, article id 582539Article, review/survey (Refereed)
    Abstract [en]

    The immune system plays a major role in recognizing and eliminating malignant cells, and this has been exploited in the development of immunotherapies aimed at either activating or reactivating the anti-tumor activity of a patient's immune system. A wide range of therapeutic approaches involving T lymphocytes, such as programmed cell death protein ligand-1 (PDL-1) inhibitors, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) blockers, and CD19-targeted T-cell therapy through chimeric antigen receptor (CAR)-T cells or CD19/CD3 bi-specific T-cell engagers, have been introduced to the field of oncology, leading to significant improvements in overall survival of adult cancer patients. During the past few years, the availability and approval of T-cell based immunotherapies have become a reality also for the treatment of childhood cancers. However, the distribution, ratio of regulatory to effector cells and the quality of T-cell responses early in life are distinct from those during adolescence and adulthood, raising the possibility that these differences impact the efficacy of immunotherapy. Herein we provide a brief overview of the properties of conventional T cell subsets during early life. Focusing on the most common cancer type during childhood, acute lymphoblastic leukemia (ALL), we describe how current conventional therapies used against ALL influence the T-cell compartment of small children. We describe early life T-cell responses in relation to immunotherapies engaging T-cell anticancer reactivity and present our opinion that it is not only immaturity of the adaptive immune system, but also the impact of an immunosuppressive environment that may prove disadvantageous in the setting of immunotherapies targeting pediatric cancer cells.

  • 123. Savolainen, Johannes
    et al.
    Mascialino, Barbara
    Pensamo, Elina
    Åberg, K. Magnus
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. Thermo Fisher Scientific, Sweden.
    Silvan, Maija
    Borres, Magnus P.
    Korhonen, Krista
    Structured intervention plan including component-resolved diagnostics helps reducing the burden of food allergy among school-aged children2019In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 30, no 1, p. 99-106Article in journal (Refereed)
    Abstract [en]

    Background: Food allergies can substantially burden patients and families by negatively affecting finances, social relationships, and personal perceptions of health. This study was performed under the Finnish Allergy Programme aimed at reducing avoidance diets to foods in schoolchildren by 50%. The main goal of this study was to investigate how many children could be freed from diet restrictions in a Finnish school district through a diagnostic algorithm including component-resolved diagnostics and food challenge. The secondary aim was to provide a crude estimate of the burden of the elimination food diets in the region, and the savings associated with the proposed intervention.

    Methods: A total of 205 children on a food avoidance diet according to the school register because of food allergy were invited into the study. One hundred and fifty-seven children were interviewed, tested for IgE to extracts and allergen components and food challenged in respective order.

    Results: After two years, 12 children still had an avoidance diet and three of them were treated successfully with sOTI; the rest suspended their avoidance diet (n = 134) or dropped out of the study (n = 11). The cost of the elimination diets was estimated in 172 700euro per year at start and 13 200euro per year at the end of the study; total savings were 128 400euro yearly.

    Conclusions: The results demonstrate a 65% reduction of avoidance diets to foods in school-aged children, exceeding the 50% aim of the Finnish Allergy Programme. Therefore, it is possible to actively reduce the number of food allergy diagnoses that remain unmonitored in the society through a tailored diagnostic work-up.

  • 124. Schlüter, Dirk
    et al.
    Barragan, Antonio
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Advances and Challenges in Understanding Cerebral Toxoplasmosis2019In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 10, article id 242Article, review/survey (Refereed)
    Abstract [en]

    Toxoplasma gondii is a widespread parasitic pathogen that infects over one third of the global human population. The parasite invades and chronically persists in the central nervous system (CNS) of the infected host. Parasite spread and persistence is intimately linked to an ensuing immune response, which does not only limit parasite-induced damage but also may facilitate dissemination and induce parasite-associated immunopathology. Here, we discuss various aspects of toxoplasmosis where knowledge is scarce or controversial and, the recent advances in the understanding of the delicate interplay of T. gondii with the immune system in experimental and clinical settings. This includes mechanisms for parasite passage from the circulation into the brain parenchyma across the blood-brain barrier during primary acute infection. Later, as chronic latent infection sets in with control of the parasite in the brain parenchyma, the roles of the inflammatory response and of immune cell responses in this phase of the disease are discussed. Additionally, the function of brain resident cell populations is delineated, i.e., how neurons, astrocytes and microglia serve both as target cells for the parasite but also actively contribute to the immune response. As the infection can reactivate in the CNS of immune-compromised individuals, we bring up the immunopathogenesis of reactivated toxoplasmosis, including the special case of congenital CNS manifestations. The relevance, advantages and limitations of rodent infection models for the understanding of human cerebral toxoplasmosis are discussed. Finally, this review pinpoints questions that may represent challenges to experimental and clinical science with respect to improved diagnostics, pharmacological treatments and immunotherapies.

  • 125. Sherina, Natalia
    et al.
    Piralla, Antonio
    Du, Likun
    Wan, Hui
    Kumagai-Braesch, Makiko
    Andréll, Juni
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Braesch-Andersen, Sten
    Cassaniti, Irene
    Percivalle, Elena
    Sarasini, Antonella
    Bergami, Federica
    Di Martino, Raffaella
    Colaneri, Marta
    Vecchia, Marco
    Sambo, Margherita
    Zuccaro, Valentina
    Bruno, Raffaele
    Sachs, Michele
    Oggionni, Tiberio
    Meloni, Federica
    Abolhassani, Hassan
    Bertoglio, Federico
    Schubert, Maren
    Byrne-Steele, Miranda
    Han, Jian
    Hust, Michael
    Xue, Yintong
    Hammarström, Lennart
    Baldanti, Fausto
    Marcotte, Harold
    Pan-Hammarström, Qiang
    Persistence of SARS-CoV-2-specific B and T cell responses in convalescent COVID-19 patients 6-8 months after the infection2021In: Med, ISSN 2666-6340, Vol. 2, no 3, p. 281-295Article in journal (Refereed)
    Abstract [en]

    Background: Monitoring the adaptive immune responses during the natural course of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection provides useful information for the development of vaccination strategies against this virus and its emerging variants. We thus profiled the serum anti-SARS-CoV-2 antibody (Ab) levels and specific memory B and T cell responses in convalescent coronavirus disease 2019 (COVID-19) patients.

    Methods: A total of 119 samples from 88 convalescent donors who experienced mild to critical disease were tested for the presence of elevated anti-spike and anti-receptor binding domain Ab levels over a period of 8 months. In addition, the levels of SARS-CoV-2 neutralizing Abs and specific memory B and T cell responses were tested in a subset of samples.

    Findings: Anti-SARS-CoV-2 Abs were present in 85% of the samples collected within 4 weeks after the onset of symptoms in COVID-19 patients. Levels of specific immunoglobulin M (IgM)/IgA Abs declined after 1 month, while levels of specific IgG Abs and plasma neutralizing activities remained relatively stable up to 6 months after diagnosis. Anti-SARS-CoV-2 IgG Abs were still present, although at a significantly lower level, in 80% of the samples collected at 6-8 months after symptom onset. SARS-CoV-2-specific memory B and T cell responses developed with time and were persistent in all of the patients followed up for 6-8 months.

    Conclusions: Our data suggest that protective adaptive immunity following natural infection of SARS-CoV-2 may persist for at least 6-8 months, regardless of disease severity. Development of medium- or long-term protective immunity through vaccination may thus be possible.

  • 126.
    Simone, Olivia
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Bejarano, Maria Teresa
    Pierce, Susan K
    Antonaci, Salvatore
    Wahlgren, Mats
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Donati, Daria
    TLRs innate immunereceptors and Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) CIDR1α-driven human polyclonal B-cell activation.2011In: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 119, no 2-3, p. 144-150Article in journal (Refereed)
    Abstract [en]

    Chronic malaria severely affects the immune system and causes polyclonal B-cell activation, as evidenced by the presence of hypergammaglobulinemia, elevated levels of autoantibodies, loss of B-cell memory and the frequent occurrence of Burkitt's lymphomas (BL) in children living in malaria endemic areas. Previous studies have shown that the cysteine-rich interdomain region 1α (CIDR1α) of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) of the FCR3S1.2 strain, subsequently named CIDR1α, interacts with B cells partially through the binding to the B-cell receptor (BCR). This interaction leads to an activated phenotype, increased survival, and a low degree of proliferation. CIDR1α preferentially activates the memory B-cell compartment, therefore PfEMP1 is considered to act as a polyclonal B-cell activator and its role in memory maintenance has been suggested. In this report, we extend the analysis of the PfEMP1-CIDR1α B-cell interaction and demonstrate that PfEMP1-CIDR1α increases the expression of TLR7 and TLR10 mRNA transcripts and sensitizes B cells to TLR9 signalling via the MyD88 adaptor molecule. Furthermore, despite its ability to bind to surface Igs, PfEMP1-CIDR1α-induced B-cell activation does not seem to proceed through the BCR, since it does not induce Lyn and/or phospho-tyrosine mediated signalling pathways. Rather PfEMP1-CIDR1α induces the phosphorylation of downstream kinases, such as ERK1/2, p38 and IKBα, in human B cells. These findings indicate that PfEMP1-CIDR1α induces a persistent activation of B cells, which in turn can contribute to the exhaustion and impairment of B-cell functions during chronic malaria infection.

  • 127.
    Stejskal, Vera
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Metals as a Common Trigger of Inflammation Resulting in Non-Specific Symptoms: Diagnosis and Treatment2014In: Israel Medical Association Journal, ISSN 1565-1088, Vol. 16, no 12, p. 753-758Article in journal (Refereed)
    Abstract [en]

    Background: The multiple symptoms of chronic fatigue syndrome (CFS) and fibromyalgia resemble those described in patients suffering from autoimmune/inflammatory syndrome induced by adjuvants (ASIA). It has been suggested that chronic metal-induced inflammation might play a role both in CFS and fibromyalgia as well as in ASIA. Humans are exposed to metal Mainly through the release of metal ions from corroding dental restorations and orthopedic implants, food, Vaccines and jewelry. Metals readily bind to sulphur and other groups in the mitochondria, enzymes and cell proteins. Metal-bound proteins are recognized by the immune system of susceptible subjects and might trigger an abnormal immune response, including allergy and autoimmunity. Objectives: To study three subjects with CFS and two with fibromyalgia, all cif whom suspected metal exposure as a trigger for their ill health. Methods: We measured delayed-type hypersensitivity to metals (metal allergy) using a validated lymphocyte transformation test, LTT-MELISA (R). All patients except one were sensitized to metals present in their dental restorations. The remaining patient reacted to metals in his Skull implant. The removal a sensitizing metals resulted in long-term health improvement. Nine healthy controls matched for gender and age showed only marginal reactivity to the metals tested. Conclusions: Patients with CFS and fibromyalgia are frequently sensitized to metals found in the environment or used in dentistry and surgery. This allergy to metals Might initiate or aggravate non-specific symptoms in metal-sensitized patients.

  • 128. Sun, Peifang
    et al.
    Ramos, Irene
    Coelho, Camila H.
    Grifoni, Alba
    Balinsky, Corey A.
    Vangeti, Sindhu
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Icahn School of Medicine at Mount Sinai, USA.
    Tarke, Alison
    Bloom, Nathaniel I.
    Jani, Vihasi
    Jakubski, Silvia J.
    Boulifard, David A.
    Cooper, Elizabeth
    Goforth, Carl W.
    Marayag, Jan
    Marrone, Amethyst
    Nunez, Edgar
    White, Lindsey
    Porter, Chad K.
    Sugiharto, Victor A.
    Schilling, Megan
    Mahajan, Avinash S.
    Beckett, Charmagne
    Sette, Alessandro
    Sealfon, Stuart C.
    Crotty, Shane
    Letizia, Andrew G.
    Asymptomatic or symptomatic SARS-CoV-2 infection plus vaccination confers increased adaptive immunity to variants of concern2022In: iScience, E-ISSN 2589-0042 , Vol. 25, no 10, article id 105202Article in journal (Refereed)
    Abstract [en]

    The ongoing evolution of SARS-CoV-2 requires monitoring the capability of immune responses to cross-recognize Variants of Concern (VOC). In this cross-sectional study, we examined serological and cell-mediated immune memory to SARS-CoV-2 variants, including Omicron, among a cohort of 18-21-year-old Marines with a history of either asymptomatic or mild SARS-CoV-2 infection 6 to 14 months earlier. Among the 210 participants in the study, 169 were unvaccinated while 41 received 2 doses of mRNA-based COVID-19 vaccines. Vaccination of previously infected participants strongly boosted neutralizing and binding activity and memory B and T cell responses including the recognition of Omicron, compared to infected but unvaccinated participants. Additionally, no measurable differences were observed in immune memory in healthy young adults with previous symptomatic or asymptomatic infections, for ancestral or variant strains. These results provide mechanistic immunological insights into population-based differences observed in immunity against Omicron and other variants among individuals with different clinical histories.

  • 129.
    Sverremark-Ekström, Eva
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Hultgren, E. H.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Borres, M. P.
    Nilsson, C.
    Peanut sensitization during the first five years of life is associated with elevated levels of peanut-specific IgG2012In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 23, no 3, p. 224-229Article in journal (Refereed)
    Abstract [en]

    Background: Allergen-specific IgE antibodies are implicated in allergic diseases while allergen-specific IgG antibodies have been proposed to prevent allergic reactions. The objective for this study was to study if the immune response (IgG and IgG4) to peanut differs in IgE sensitized and non-sensitized young children.

    Methods: A total of 239 children have been followed prospectively from birth to 5 years of age. Levels of IgG and IgG4 to peanut, Ara h 2 and Ara h 8 were analyzed at 2 and 5 years of age and related to IgE-sensitization and peanut consumption.

    Results:  Levels of peanut-specific IgG and IgG4 were significantly higher in peanut-sensitized children at 2 and 5 years of age when compared to non-sensitized children and children sensitized to other food/inhalant allergens. A strong correlation was seen between levels of peanut-specific IgG/IgG4-ratios and peanut-specific IgE at 5 years of age. Children avoiding peanuts, a subgroup of the peanut sensitized, had statistically significant higher levels of IgE to peanut and a tendency of higher IgG and IgG4 levels to peanut. In the avoidance-group significant correlations between IgE and IgG/IgG4 to peanut was found compared to children eating peanuts. 

    Conclusion: Peanut-specific IgG or IgG4 levels were elevated in peanut-sensitized children especially those avoiding peanuts. In our study, IgG and IgG4 do not seem to indicate tolerance or protection from sensitization.

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    PAI 2012
  • 130. Swartz, Jackie
    et al.
    Lindblad, Frank
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Arinell, Hans
    Theorell, Töres
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Alm, Johan
    Anthroposophic lifestyle and salivary cortisol are associated with a lower risk of sensitization during childhood2015In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 26, no 2, p. 153-160Article in journal (Refereed)
    Abstract [en]

    Background Infants from anthroposophic families have low cortisol levels and low risk of IgE-sensitization during first 2years of life. Our aim was to study the impact of an anthroposophic lifestyle and cortisol levels at 6months on allergy sensitization up to age 5years.

    Methods A total of 507 families participated from maternal healthcare centers. Parental lifestyle was categorized as anthroposophic, partly anthroposophic, or non-anthroposophic. Blood samples for analyzes of sensitization were obtained from parents at inclusion and from children at 6, 12, 24, and 60months. Salivary samples were collected at home at 6months.

    Results Sensitization increased from 2.9% to 26.0% in the anthroposophic group, from 8.4% to 26.8% in the partly anthroposophic group, and from 19.1% to 44.1% in the non-anthroposophic group. Children from anthroposophic families had lower cortisol levels in the morning, afternoon, and evening. The odds ratio (OR) for anthroposophic lifestyle was always <1 and lowest at 12months (OR, 0.10; 95% CI, 0.03-0.36). Adjusting for cortisol levels at 6 months increased these ORs at 12 and 24months. At the same ages, ORs for sensitization were elevated also for cortisol levels at 6months. Analyzes in children not sensitized at 6months confirmed the cortisol-related risk of sensitization.

    Conclusions Children from families with an anthroposophic lifestyle have lower risk than comparisons of developing sensitization up to 5years. This risk is partially explained by low cortisol levels during infancy. High cortisol levels at 6months predict sensitization up to 24months.

  • 131. Szulkin, Adam
    et al.
    Nilsonne, Gustav
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Mundt, Filip
    Wasik, Agata M.
    Souri, Pega
    Hjerpe, Anders
    Dobra, Katalin
    Variation in Drug Sensitivity of Malignant Mesothelioma Cell Lines with Substantial Effects of Selenite and Bortezomib, Highlights Need for Individualized Therapy2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 6, article id e65903Article in journal (Refereed)
    Abstract [en]

    Background: Malignant mesothelioma cells have an epithelioid or sarcomatoid morphology, both of which may be present in the same tumor. The sarcomatoid phenotype is associated with worse prognosis and heterogeneity of mesothelioma cells may contribute to therapy resistance, which is often seen in mesothelioma. This study aimed to investigate differences in sensitivity between mesothelioma cell lines to anti-cancer drugs. We studied two novel drugs, selenite and bortezomib and compared their effect to four conventional drugs. We also investigated the immunoreactivity of potential predictive markers for drug sensitivity; Pgp, MRP-1, ERCC1, RRM1, TS, xCT and proteasome 20S subunit. Materials and methods: We treated six mesothelioma cell lines with selenite, bortezomib, carboplatin, pemetrexed, doxorubicin or gemcitabine as single agents and in combinations. Viability was measured after 24 and 48 hours. Immunocytochemistry was used to detect predictive markers. Results: As a single agent, selenite was effective on four out of six cell lines, and in combination with bortezomib yielded the greatest response in the studied mesothelioma cell lines. Cells with an epithelioid phenotype were generally more sensitive to the different drugs than the sarcomatoid cells. Extensive S-phase arrest was seen in pemetrexed-sensitive cell lines. MRP-1 predicted sensitivity of cell lines to treatment with carboplatin and xCT predicted pemetrexed effect. Conclusions: The observed heterogeneity in sensitivity of mesothelioma cell lines with different morphology highlights the need for more individualized therapy, requiring development of methods to predict drug sensitivity of individual tumors. Selenite and bortezomib showed a superior effect compared to conventional drugs, motivating clinical testing of these agents as future treatment regime components for patients with malignant mesothelioma.

  • 132. Thålin, Charlotte
    et al.
    Daleskog, Maud
    Paues Göransson, Sophie
    Schatzberg, Daphne
    Lasselin, Julie
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Laska, Ann-Charlotte
    Kallner, Anders
    Helleday, Thomas
    Wallén, Håkan
    Demers, Mélanie
    Validation of an enzyme-linked immunosorbent assay for the quantification of citrullinated histone H3 as a marker for neutrophil extracellular traps in human plasma2017In: Immunologic research, ISSN 0257-277X, E-ISSN 1559-0755, Vol. 65, no 3, p. 706-712Article in journal (Refereed)
    Abstract [en]

    There is an emerging interest in the diverse functions of neutrophil extracellular traps (NETs) in a variety of disease settings. However, data on circulating NETs rely largely upon surrogate NET markers such as cell-free DNA, nucleosomes, and NET-associated enzymes. Citrullination of histone H3 by peptidyl arginine deiminase 4 (PAD4) is central for NET formation, and citrullinated histone H3 (H3Cit) is considered a NET-specific biomarker. We therefore aimed to optimize and validate a new enzyme-linked immunosorbent assay (ELISA) to quantify the levels of H3Cit in human plasma. A standard curve made of in vitro PAD4-citrullinated histones H3 allows for the quantification of H3Cit in plasma using an anti-histone antibody as capture antibody and an anti-histone H3 citrulline antibody for detection. The assay was evaluated for linearity, stability, specificity, and precision on plasma samples obtained from a human model of inflammation before and after lipopolysaccharide injection. The results revealed linearity and high specificity demonstrated by the inability of detecting non-citrullinated histone H3. Coefficients of variation for intra- and inter-assay variability ranged from 2.1 to 5.1% and from 5.8 to 13.5%, respectively, allowing for a high precision. Furthermore, our results support an inflammatory induction of a systemic NET burden by showing, for the first time, clear intra-individual elevations of plasma H3Cit in a human model of lipopolysaccharide-induced inflammation. Taken together, our work demonstrates the development of a new method for the quantification of H3Cit by ELISA that can reliably be used for the detection of NETs in human plasma.

  • 133.
    Tjärnlund, Anna
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Does IgA play a role in protection against pulmonary tuberculosis?2005Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    More than a century after the identification of the tubercle bacillus and the first attempts at vaccination, tuberculosis (TB) still remains one of the world’s most serious infectious diseases. TB is typically a disease of the lung, which serves both as port of entry and as the major site of disease manifestation. The currently used vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), is administered parentally and induces a systemic immune response. However, it fails to protect against pulmonary TB, thereby raising the question whether vaccination targeting the mucosal immunity in the lungs could be favourable.

    The respiratory mucosal surfaces represent the first line of defence against a multitude of pathogens. Secretory IgA (sIgA) in mucosal secretions has an important function by blocking entrance of pathogenic organisms and preventing infections. Yet, another role for IgA in protection against intracellular pathogens has lately been appreciated, when sIgA was demonstrated to neutralize viruses intracellulary. We aimed to investigate the relevance of sIgA in protection against mycobacterial infections using mice deficient for IgA and the polymeric Ig receptor. Mice were immunized intranasally with a mycobacterial antigen which elicited, in wild-type mice, a strong IgA response in mucosal secretions in the respiratory tract. Gene-targeted mice failed to induce the same response and more importantly, were more susceptible to mycobacterial infections in the respiratory tract, as demonstrated by higher bacterial loads in the lungs than wild-type mice. Analysis of immune responses after infection revealed reduced production of proinflammatory, and protective, factors such as IFN-γ and TNF-α in the lungs of deficient mice, which was in concordance with the higher bacterial burden seen in the lungs of these mice. The mechanisms explaining the defective proinflammatory responses in the lungs of deficient mice are not clear but might involve impaired signalling through Fcα receptors, or homologous receptors, which could lead to inadequate activation of pulmonary macrophages. This could subsequently result in suboptimal induction and production of cytokines and chemokines important for attraction and migration of cells to sites of infection in the lungs.

    Our results demonstrate a role for IgA in protection against mycobacterial infection in the respiratory tract by blocking the entrance of the mycobacterium into the lungs, and/or by modulating the locally induced proinflammatory immune responses.

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    FULLTEXT01
  • 134.
    Tjärnlund, Anna
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Rodriguez, Ariane
    Cardona, Pere-Joan
    Guirado, Evelyn
    Ivanyi, Juraj
    Singh, Mahavir
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Fernandez, Carmen
    Polymeric Ig receptor knockout mice are more susceptible to mycobacteria infection in the respiratory tract2006In: International Immunology, ISSN 0953-8178, E-ISSN 1460-2377, Vol. 18, no 5, p. 807-816Article in journal (Refereed)
    Abstract [en]

    It is generally accepted that cellular, and not humoral immunity, plays the crucial role in defense against intracellular bacteria. However, accumulating data indicate the importance of humoral immunity for the defense against a number of intracellular bacteria, including mycobacteria. We have investigated the role of secretory IgA, the main isotype found in mucosal tissues, in protection against mycobacterial infection, using polymeric IgR (pIgR)-deficient mice. Characterization of the humoral response induced after intra-nasal immunizations with the mycobacterial antigen PstS-1 revealed a loss of antigen-specific IgA response in saliva from the knockout mice. IgA level in the bronchoalveolar lavage of knockout mice was similar to wild-type level, although the IgA antibodies must have reached the lumen by other means than pIgR-mediated transport. Infection with Mycobacterium bovis bacillus Calmette–Guérin (BCG) demonstrated that the immunized pIgR−/− mice were more susceptible to BCG infection than immunized wild-type mice, based on higher bacterial loads in the lungs. This was accompanied by a reduced production of both IFN-γ and tumor necrosis factor-alpha (TNF-α) in the lungs. Additionally, the pIgR−/− mice displayed reduced natural resistance to mycobacterial infection proved by significantly higher bacterial growth in their lungs compared with wild-type mice after infection with virulent Mycobacterium tuberculosis. The knockout mice appeared to have a delayed mycobacteria-induced immune response with reduced expression of protective mediators, such as IFN-γ, TNF-α, inducible nitric oxide synthase and regulated upon activation normal T cell sequence, during early infection. Collectively, our results show that actively secreted IgA plays a role in protection against mycobacterial infections in the respiratory tract, by blocking entrance of bacilli into the lungs, in addition to modulation of the mycobacteria-induced pro-inflammatory response.

  • 135.
    Vangeti, Sindhu
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Icahn School of Medicine at Mount Sinai, USA.
    Periasamy, Sivakumar
    Sun, Peifang
    Balinsky, Corey A.
    Mahajan, Avinash S.
    Kuzmina, Natalia A.
    Soares-Schanoski, Alessandra
    Cooper, Elizabeth
    Beckett, Charmagne
    Marayag, Jan
    Marrone, Amethyst
    Nunez, Edgar
    Ge, Yongchao
    Porter, Chad K.
    Goforth, Carl W.
    Lizewski, Stephen E.
    Lizewski, Rhonda
    Jani, Vihasi
    Sugiharto, Victor A.
    Schilling, Megan
    Yu, Xuechen B.
    Marjanovic, Nada
    George, Mary Catherine
    Bukreyev, Alexander
    Sealfon, Stuart C.
    Letizia, Andrew G.
    Ramos, Irene
    Serum Fc-Mediated Monocyte Phagocytosis Activity Is Stable for Several Months after SARS-CoV-2 Asymptomatic and Mildly Symptomatic Infection2022In: Microbiology Spectrum, E-ISSN 2165-0497, Vol. 10, no 6, article id e01837-22Article in journal (Refereed)
    Abstract [en]

    We investigated the temporal profile of multiple components of the serological response after asymptomatic or mildly symptomatic SARS-CoV-2 infection, in a cohort of 67 previously SARS-CoV-2 naive young adults, up to 8.5 months after infection. We found a significant decrease of spike IgG and neutralization antibody titers from early (11 to 56 days) to late (4 to 8.5 months) time points postinfection. Over the study period, S1-specific IgG levels declined significantly faster than that of the S2-specific IgG. Further, serum antibodies from PCR-confirmed participants cross-recognized S2, but not S1, of the betacoronaviruses HKU1 and OC43, suggesting a greater degree of cross-reactivity of S2 among betacoronaviruses. Antibody-Dependent Natural Killer cell Activation (ADNKA) was detected at the early time point but significantly decreased at the late time point. Induction of serum Antibody-Dependent Monocyte Phagocytosis (ADMP) was detected in all the infected participants, and its levels remained stable over time. Additionally, a reduced percentage of participants had detectable neutralizing activity against the Beta (50%), Gamma (61 to 67%), and Delta (90 to 94%) variants, both early and late postinfection, compared to the ancestral strain (100%). Antibody binding to S1 and RBD of Beta, Gamma, Delta (1.7 to 2.3-fold decrease), and Omicron (10 to 16-fold decrease) variants was also significantly reduced compared to the ancestral SARS-CoV-2 strain. Overall, we found variable temporal profiles of specific components and functionality of the serological response to SARS-CoV-2 in young adults, which is characterized by lasting, but decreased, neutralizing activity and antibody binding to S1, stable ADMP activity, and relatively stable S2-specific IgG levels.

  • 136. Ventayol, Pilar Samperio
    et al.
    Geiser, Petra
    Di Martino, Maria Letizia
    Florbrant, Alexandra
    Fattinger, Stefan A.
    Walder, Naemi
    Sima, Eduardo
    Shao, Feng
    Gekara, Nelson O.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sundbom, Magnus
    Hardt, Wolf-Dietrich
    Webb, Dominic-Luc
    Hellström, Per M.
    Eriksson, Jens
    Sellin, Mikael E.
    Bacterial detection by NAIP/NLRC4 elicits prompt contractions of intestinal epithelial cell layers2021In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, no 16, article id e2013963118Article in journal (Refereed)
    Abstract [en]

    The gut epithelium serves to maximize the surface for nutrient and fluid uptake, but at the same time must provide a tight barrier to pathogens and remove damaged intestinal epithelial cells (IECs) without jeopardizing barrier integrity. How the epithelium coordinates these tasks remains a question of significant interest. We used imaging and an optical flow analysis pipeline to study the dynamicity of untransformed murine and human intestinal epithelia, cultured atop flexible hydrogel supports. Infection with the pathogen Salmonella Typhimurium (S.Tm) within minutes elicited focal contractions with inward movements of up to similar to 1,000 IECs. Genetics approaches and chimeric epithelial monolayers revealed contractions to be triggered by the NAIP/NLRC4 inflammasome, which sensed type-III secretion system and flagellar ligands upon bacterial invasion, converting the local tissue into a contraction epicenter. Execution of the response required swift sublytic Gasdermin D pore formation, ion fluxes, and the propagation of a myosin contraction pulse across the tissue. Importantly, focal contractions preceded, and could be uncoupled from, the death and expulsion of infected IECs. In both two-dimensional monolayers and three-dimensional enteroids, multiple infection-elicited contractions coalesced to produce shrinkage of the epithelium as a whole. Monolayers deficient for Caspase-1(-11) or Gasdermin D failed to elicit focal contractions but were still capable of infected IEC death and expulsion. Strikingly, these monolayers lost their integrity to a markedly higher extent than wild-type counterparts. We propose that prompt NAIP/NLRC4/Caspase-1/Gasdermin D/myosin-dependent contractions allow the epithelium to densify its cell packing in infected regions, thereby preventing tissue disintegration due to the subsequent IEC death and expulsion process.

  • 137.
    Vetrano, Davide L.
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Fondazione Policlinico “A- Gemelli” IRCCS and Catholic University of Rome, Italy.
    Triolo, Federico
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Maggi, Stefania
    Malley, Richard
    Jackson, Thomas A.
    Poscia, Andrea
    Bernabei, Roberto
    Ferrucci, Luigi
    Fratiglioni, Laura
    Fostering healthy aging: The interdependency of infections, immunity and frailty2021In: Ageing Research Reviews, ISSN 1568-1637, E-ISSN 1872-9649, Vol. 69, article id 101351Article, review/survey (Refereed)
    Abstract [en]

    Untangling the interdependency of infections, immunity and frailty may help to clarify their roles in the maintenance of health in aging individuals, and the recent COVID-19 pandemic has further highlighted such priority. In this scoping review we aimed to systematically collect the evidence on 1) the impact of common infections such as influenza, pneumonia and varicella zoster on frailty development, and 2) the role played by frailty in the response to immunization of older adults. Findings are discussed under a unifying framework to identify knowledge gaps and outline their clinical and public health implications to foster a healthier aging. Twenty-nine studies (113,863 participants) selected to answer the first question provided a moderately strong evidence of an association between infections and physical as well as cognitive decline – two essential dimensions of frailty. Thirteen studies (34,520 participants) investigating the second aim, showed that frailty was associated with an impaired immune response in older ages, likely due to immunosenescence. However, the paucity of studies, the absence of tools to predict vaccine efficacy, and the lack of studies investigating the efficacy of newer vaccines in presence of frailty, strongly limit the formulation of more personalized immunization strategies for older adults. The current evidence suggests that infections and frailty repeatedly cross each other pathophysiological paths and accelerate the aging process in a vicious circle. Such evidence opens to several considerations. First, the prevention of both conditions pass through a life course approach, which includes several individual and societal aspects. Second, the maintenance of a well-functioning immune system may be accomplished by preventing frailty, and vice versa. Third, increasing the adherence to immunization may delay the onset of frailty and maintain the immune system homeostasis, beyond preventing infections.

  • 138.
    Wallin, Cecilia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kulkarni, Yashraj S.
    Abelein, Axel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Karolinska Institutet, Sweden.
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. The National Institute of Chemical Physics and Biophysics, Estonia.
    Liao, Qinghua
    Strodel, Birgit
    Olsson, Lisa
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Luo, Jinghui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. University of Oxford, UK.
    Abrahams, Jan Pieter
    Sholts, Sabrina B.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. National Museum of Natural History, USA.
    Roos, Per M.
    Kamerlin, Shina C. L.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Characterization of Mn(II) ion binding to the amyloid-beta peptide in Alzheimer's disease2016In: Journal of Trace Elements in Medicine and Biology, ISSN 0946-672X, E-ISSN 1878-3252, Vol. 38, p. 183-193Article in journal (Refereed)
    Abstract [en]

    Growing evidence links neurodegenerative diseases to metal exposure. Aberrant metal ion concentrations have been noted in Alzheimer's disease (AD) brains, yet the role of metals in AD pathogenesis remains unresolved. A major factor in AD pathogenesis is considered to be aggregation of and amyloid formation by amyloid-beta (A beta) peptides. Previous studies have shown that A beta displays specific binding to Cu(II) and Zn(II) ions, and such binding has been shown to modulate A beta aggregation. Here, we use nuclear magnetic resonance (NMR) spectroscopy to show that Mn(II) ions also bind to the N-terminal part of the A beta(1-40) peptide, with a weak binding affinity in the milli- to micromolar range. Circular dichroism (CD) spectroscopy, solid state atomic force microscopy (AFM), fluorescence spectroscopy, and molecular modeling suggest that the weak binding of Mn(II) to A beta may not have a large effect on the peptide's aggregation into amyloid fibrils. However, identification of an additional metal ion displaying A beta binding reveals more complex AD metal chemistry than has been previously considered in the literature.

  • 139.
    Wang, Xiao
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Zhang, Ding
    Sjölinder, Mikael
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wan, Yi
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sjölinder, Hong
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Mälar Hospital, Sweden.
    CD46 accelerates macrophage-mediated host susceptibility to meningococcal sepsis in a murine model2017In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 47, no 1, p. 119-130Article in journal (Refereed)
    Abstract [en]

    CD46, a membrane cofactor expressed on all nucleated human cells, plays an essential role in suppressing autoimmune reactions and protecting host cells from complement-mediated attack. Human transgenic CD46 homozygousmice (CD46(+/+)) are prone to lethal sepsis upon infection with Neisseria meningitidis (N. meningitidis). However, the underlying mechanisms are poorly understood. Here, we determined thatCD46(+/+) mice produce large numbers of M1 type macrophages with enhanced surface expression of MHC II and production of pro-inflammatory mediators such as IL-6, TNF, IL-12, and IL-1 beta In the presence of M-CSF or GM-CSF, CD46 signaling enhances monocyte-macrophage differentiation. Additionally, CD46(+/+) macrophages rapidly undergo apoptosis upon LPS challenge or meningococcal infection, which could contribute to uncontrolled bacterial dissemination in vivo. Adoptive transfer of CD46(+/+) peritoneal macrophages aggravated septic responses in wild-type mice, but the depletion of macrophages partially alleviated septic reactions in CD46(+/+) mice after N. meningitidis infection. Our findings reveal a novel role of CD46 in accelerating inflammatory responses upon meningococcal infection or LPS stimulation by regulating the functional polarization and survival of macrophages.

  • 140.
    Wassing, Gabriela M.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ilehag, Nathalie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Frey, Jonas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jonsson, Ann-Beth
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Modulation of Human Beta-Defensin 2 Expression by Pathogenic Neisseria meningitidis and Commensal Lactobacilli2021In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 65, no 4, article id e02002-20Article in journal (Refereed)
    Abstract [en]

    Antimicrobial peptides (AMPs) play an important role in the defense against pathogens by targeting and killing invading microbes. Some pathogenic bacteria have been shown to negatively regulate AMP expression, while several commensals may induce AMP expression. The expression of certain AMPs, such as human betadefensin 2 (hBD2), can be induced via nuclear factor NF-kappa B, which, in turn, is negatively controlled by tumor necrosis factor alpha-induced protein 3 (TNFAIP3, or A20). In this work, we examined the expression of hBD1 and hBD2 during coincubation of pharyngeal epithelial cells with pathogenic Neisseria meningitidis and commensal lactobacilli. The Lactobacillus strains induced hBD2 expression in human pharyngeal cells, while the pathogen N. meningitidis did not. In coincubation experiments, meningococci were able to dampen the AMP expression induced by lactobacilli. We found that N. meningitidis induced the NF-kappa B inhibitor A20. Further, RNA silencing of A20 resulted in increased hBD2 expression after meningococcal infection. Since it is known that induction of A20 reduces NF-kappa B activity and thus hBD2 levels, meningococcal-mediated A20 induction could be a way for the pathogen to dampen AMP expression. Finally, treatment of N. meningitidis and lactobacilli with synthetic hBD2 reduced N. meningitidis viability more efficiently than Lactobacillus reuteri, explaining why maintaining low AMP levels is important for the survival of the pathogen.

  • 141. Weidemann, Felix
    et al.
    Dehnert, Manuel
    Koch, Judith
    Wichmann, Ole
    Höhle, Michael
    Stockholm University, Faculty of Science, Department of Mathematics.
    Modelling the epidemiological impact of rotavirus vaccination in Germany - A Bayesian approach2014In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 32, no 40, p. 5250-5257Article in journal (Refereed)
    Abstract [en]

    Background: Rotavirus (RV) infection is the primary cause of severe gastroenteritis in children aged <5 years in Germany and worldwide. In 2013 the German Standing Committee on Vaccination (STIKO) developed a national recommendation for routine RV-immunization of infants. To support informed decision-making we predicted the epidemiological impact of routine RV-vaccination in Germany using statistical modelling. Methods: We developed a population-based model for the dynamic transmission of RV-infection in a vaccination setting. Using data from the communicable disease reporting system and survey records on the vaccination coverage from the eastern federal states, where the vaccine was widely used before recommended at national level, we first estimated RV vaccine effectiveness (VE) within a Bayesian framework utilizing adaptive Markov Chain Monte Carlo inference. The calibrated model was then used to compute the predictive distribution of RV-incidence after achieving high vaccination coverage with the introduction of routine vaccination. Results: Our model estimated that RV-vaccination provides high protection against symptomatic RV-infection (VE=96%; 95% credibility interval (CI): 91-99%) that remains at its maximum level for three years (95% CI: 1.43-5.80 years) and is fully waned after twelve years. At population level, routine vaccination at 90% coverage is predicted to reduce symptomatic RV-incidence among children aged <5 years by 84% (95% prediction interval (PI): 71-90%) including a 2.5% decrease due to herd protection. Ten years after vaccine introduction an increase in RV incidences of 12% (95% PI: -16 to 85%) among persons aged 5-59 years and 14% (95% PI: -6 to 109%) within the age-group >60 years was predicted. Conclusion: Routine infant RV-vaccination is predicted to considerably reduce RV-incidence in Germany among children <5 years. Outwork generated estimates of RV VE in the field and predicted the population-level impact, while adequately addressing the role of model and prediction uncertainty when making statements about the future.

  • 142. Yu, Meng
    et al.
    Charles, Afandi
    Cagigi, Alberto
    Christ, Wanda
    Österberg, Björn
    Falck-Jones, Sara
    Azizmohammadi, Lida
    Åhlberg, Eric
    Falck-Jones, Ryan
    Svensson, Julia
    Nie, Mu
    Warnqvist, Anna
    Hellgren, Fredrika
    Lenart, Klara
    Arcoverde Cerveira, Rodrigo
    Ols, Sebastian
    Lindgren, Gustaf
    Lin, Ang
    Maecker, Holden
    Bell, Max
    Johansson, Niclas
    Albert, Jan
    Sundling, Christopher
    Czarnewski, Paulo
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Klingström, Jonas
    Färnert, Anna
    Loré, Karin
    Smed-Sörensen, Anna
    Delayed generation of functional virus-specific circulating T follicular helper cells correlates with severe COVID-192023In: Nature Communications, E-ISSN 2041-1723, Vol. 14, article id 2164Article in journal (Refereed)
    Abstract [en]

    Effective humoral immune responses require well-orchestrated B and T follicular helper (Tfh) cell interactions. Whether these interactions are impaired and associated with COVID-19 disease severity is unclear. Here, longitudinal blood samples across COVID-19 disease severity are analysed. We find that during acute infection SARS-CoV-2-specific circulating Tfh (cTfh) cells expand with disease severity. SARS-CoV-2-specific cTfh cell frequencies correlate with plasmablast frequencies and SARS-CoV-2 antibody titers, avidity and neutralization. Furthermore, cTfh cells but not other memory CD4 T cells, from severe patients better induce plasmablast differentiation and antibody production compared to cTfh cells from mild patients. However, virus-specific cTfh cell development is delayed in patients that display or later develop severe disease compared to those with mild disease, which correlates with delayed induction of high-avidity neutralizing antibodies. Our study suggests that impaired generation of functional virus-specific cTfh cells delays high-quality antibody production at an early stage, potentially enabling progression to severe disease.

  • 143. Zheleznyakova, Galina Yurevna
    et al.
    Piket, Eliane
    Needhamsen, Maria
    Hagemann-Jensen, Michael
    Ekman, Diana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Han, Yanan
    James, Tojo
    Khademi, Mohsen
    Al Nimer, Faiez
    Scicluna, Patrick
    Huang, Jesse
    Kockum, Ingrid
    Faridani, Omid R.
    Olsson, Tomas
    Piehl, Fredrik
    Jagodic, Maja
    Small noncoding RNA profiling across cellular and biofluid compartments and their implications for multiple sclerosis immunopathology2021In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, no 17, article id e2011574118Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease affecting the central nervous system (CNS). Small non-coding RNAs (sncRNAs) and, in particular, microRNAs (miRNAs) have frequently been associated with MS. Here, we performed a comprehensive analysis of all classes of sncRNAs in matching samples of peripheral blood mononuclear cells (PBMCs), plasma, cerebrospinal fluid (CSF) cells, and cell-free CSF from relapsing-remitting (RRMS, n = 12 in relapse and n = 11 in remission) patients, secondary progressive (SPMS, n = 6) MS patients, and noninflammatory and inflammatory neurological disease controls (NINDC, n = 11; INDC, n = 5). We show widespread changes in miRNAs and sncRNA-derived fragments of small nuclear, nucleolar, and transfer RNAs. In CSF cells, 133 out of 133 and 115 out of 117 differentially expressed sncRNAs were increased in RRMS relapse compared to remission and RRMS compared to NINDC, respectively. In contrast, 65 out of 67 differentially expressed PBMC sncRNAs were decreased in RRMS compared to NINDC. The striking contrast between the periphery and CNS suggests that sncRNA-mediated mechanisms, including alternative splicing, RNA degradation, and mRNA translation, regulate the transcriptome of pathogenic cells primarily in the CNS target organ.

  • 144. Zouikr, Ihssane
    et al.
    Karshikoff, Bianka
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Lifetime Modulation of the Pain System via Neuroimmune and Neuroendocrine interactions2017In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 8, article id 276Article, review/survey (Refereed)
    Abstract [en]

    Chronic pain is a debilitating condition that still is challenging both clinicians and researchers. Despite intense research, it is still not clear why some individuals develop chronic pain while others do not or how to heal this disease. In this review, we argue for a multisystem approach to understand chronic pain. Pain is not only to be viewed simply as a result of aberrant neuronal activity but also as a result of adverse early-life experiences that impact an individual's endocrine, immune, and nervous systems and changes which in turn program the pain system. First, we give an overview of the ontogeny of the central nervous system, endocrine, and immune systems and their windows of vulnerability. Thereafter, we summarize human and animal findings from our laboratories and others that point to an important role of the endocrine and immune systems in modulating pain sensitivity. Taking early-life history into account, together with the past and current immunological and endocrine status of chronic pain patients, is a necessary step to understand chronic pain pathophysiology and assist clinicians in tailoring the best therapeutic approach.

  • 145.
    Öhlander, Christer
    Stockholm University.
    Immunoglobulin-Fc receptor interactions in cytotoxicity and phagocytosis mediated by lymphocytes and monocytes1981Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Antibody dependent cellular cytotoxicity (ADCC) and phagocytosis mediated by lymphocytes and monocytes depend on IgG-binding Fc receptors on the effector cells. Properties of the immunoglobulin-Fc receptor interactions of human lymphocytes and monocytes were investigated using 51Cr release assays for detection of cytolysis or phagocytosis of target erythrocytes. The specificity of Fc receptors for different antibody isotypes was studied with guinea pig IgGl and IgG2 subclasses. While lymphocyte-mediated ADCC was induced by IgG2 only, both subclasses induced monocyte-mediated ADCC and phagocytosis, indicating that the Fc receptors on these two types of effector cells are different. Cross-subclass inhibition of monocyte-mediated phagocytosis by immune complexes suggested that the same monocytic Fc receptor binds all IgG isotypes. Similar results as in the human system were also obtained with guinea pig effector cells.

    Human lymphocytes have also Fc receptors for IgM (Fcp receptors) that do not trigger ADCC by themselves but are able to improve the binding between effector and target cells coated with both IgG and IgM and thereby enhance IgG dependent ADCC. As demonstrated by studies of binding of 125I-labelled IgG antibodies to target erythrocytes this cooperation between antibody isotypes resulted in a 50-fold reduction of the number of IgG molecules/ target cell required for ADCC. When IgG and IgM antibodies bound to different antigenic sites on the target cells, enhanced ADCC was easily obtained with high concentrations of IgM. When the antibodies competed for the same antigenic determinants, excessive amounts of IgM were inhibitory or gave no enhancement despite the fact that the number of IgG molecules bound was unaltered. Thus, IgM seemed to abrogate triggering of ADCC by steric hindrance of multivalent IgG-Fc receptor interactions which appeared to be essential for induction of ADCC. Human monocytes lacked detectable Fcp receptors and were consequently unable to exert destruction of IgM-coated target cells.

    The importance of multivalent IgG-Fc receptor interactions in effector functions mediated by human lymphocytes and monocytes was further studied by varying the antigenic density on the target cells. Both effector cell types required at least 500 antigenic determinants/target cell, suggesting that several, but not necessarily closely contiguous, IgG-Fc receptor interactions are essential for ADCC and phagocytosis.

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