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Maturation of humoral immune responses: Studies on the effects of antigen type, apoptosis and age
Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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

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

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

Place, publisher, year, edition, pages
Stockholm: Wenner-Grens institut för experimentell biologi , 2004. , 60 p.
Keyword [en]
immunology, B cell, humoral immune response
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:su:diva-85ISBN: 91-7265-835-5 (print)OAI: oai:DiVA.org:su-85DiVA: diva2:200369
Public defence
2004-04-21, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 8 C, Stockholm, 10:00
Opponent
Supervisors
Available from: 2004-03-31 Created: 2004-03-31Bibliographically approved
List of papers
1. The response in old mice: positive and negative immune memory after priming in early age
Open this publication in new window or tab >>The response in old mice: positive and negative immune memory after priming in early age
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2001 In: International Immunology, ISSN 0953-8178, Vol. 13, no 10, 1213-1221 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25717 (URN)
Note
Part of urn:nbn:se:su:diva-85Available from: 2004-03-31 Created: 2004-03-31Bibliographically approved
2. Understanding thymus independent antigen induced reduction of thymus dependent immune responses
Open this publication in new window or tab >>Understanding thymus independent antigen induced reduction of thymus dependent immune responses
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2004 (English)In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 112, no 3, 413-419 p.Article in journal (Refereed) Published
Abstract [en]

Deficiencies in immune responses against polysaccharides can have direct consequences for patients, and therefore, a better understanding of these immune reactions is crucial. We have studied the immune response against the polysaccharide dextran B512 (Dx). Administration of immunogenic doses of thymus-independent (TI) Dx reduces the immunoglobulin G1 response to later challenges with a thymus-dependent (TD) form of Dx. We investigated if this suppression is a general phenomenon caused not only by Dx but also by other TI antigens, and examined possible mechanisms contributing to this unresponsiveness. We show that clonal exhaustion is not involved in modulating subsequent responses, nor is signalling via FcgammaRIIB or other antibody mediated pathways. The reduced TD response is not an exclusive Dx phenomenon; it is also induced by TI antigen oxazolone (Ox). However, responses against the hapten dinitrophenyl (DNP) are not affected, indicating that the TI priming negative effect is not a general process. This may be explained by the restricted immune response to both Dx and Ox, in contrast to the unrestricted DNP response. Our conclusion from these experiments is that the underlying mechanism for the TI-induced reduction of latter TD responses is a property of the TI activation itself.

Keyword
antibody responses; B cells; affinity maturation/somatic hypermutation; isotypes/isotype switching
Identifiers
urn:nbn:se:su:diva-25718 (URN)
Note
Part of urn:nbn:se:su:diva-85Available from: 2004-03-31 Created: 2004-03-31 Last updated: 2017-12-13Bibliographically approved
3. The role of Blimp-1 in the GC reaction: Differential expression of Blimp-1 upon immunization with TD and TI antigens
Open this publication in new window or tab >>The role of Blimp-1 in the GC reaction: Differential expression of Blimp-1 upon immunization with TD and TI antigens
2007 (English)In: Immunology Letters, ISSN 0165-2478, E-ISSN 1879-0542, Vol. 113, no 2, 70-75 p.Article in journal (Refereed) Published
Abstract [en]

Humoral responses against thymus-dependent (TD) antigens are characterized by Ig class switch, somatic hypermutations (SHM) and generation of memory. These processes are thought to occur in the specialized environment of the germinal center (GC). Some thymus-independent (TI) antigens, such as native dextran B512 (Dx) can also induce formation of GCs, but the responses do not undergo substantial affinity maturation or induction of memory. Immunization with TI Dx affects later TD responses against the same epitope, reducing Dx specific IgG 1. We have studied if the different outcome of the TI- and TD-induced GC reaction is due to differences in plasma cell differentiation. The transcriptional repressor B lymphocyte-induced maturation protein, Blimp- 1, was used as a marker for differentiation of plasma cells. We show that TI GCs contain Blimp- I in early and mature GCs, in contrast to TD-induced GCs which strongly express Blimp- I only in established GCs. Furthermore, the intensity of the Blimp- I staining is stronger in TI GCs. In addition, we demonstrate that in TD responses after TI priming the pattern of Blimp- I expression is a mixture of both TI and TD responses. This is novel evidence since these TD Immoral responses against Dx display a TI isotype pattern.

Identifiers
urn:nbn:se:su:diva-25719 (URN)10.1016/j.imlet.2007.07.018 (DOI)000250852500002 ()
Note
Part of urn:nbn:se:su:diva-85Available from: 2004-03-31 Created: 2004-03-31 Last updated: 2017-12-13Bibliographically approved
4. Somatic hypermutation of Ig genes is affected differently by failures in apoptosis caused by disruption of Fas (lpr mutation) or by over-expression of Bcl-2
Open this publication in new window or tab >>Somatic hypermutation of Ig genes is affected differently by failures in apoptosis caused by disruption of Fas (lpr mutation) or by over-expression of Bcl-2
2006 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 63, no 6, 420-429 p.Article in journal (Refereed) Published
Abstract [en]

The effects of the two main apoptotic pathways on the somatic hypermutation process were analysed. Transgenic mice carrying the V(kappa)Ox1-J(kappa)5 rat transgene were crossed with Fas-deficient lpr mice or with mice overexpressing the Bcl-2 protein. The transgenic V(kappa)Ox1 segment and the endogenous J(H)4-C-mu Ig intron from Peyer's patches germinal centre B cells were sequenced to study the intrinsic somatic hypermutation process without the skewing effects of specific antigen selection. The lpr/ox mice displayed, in both regions, a high level of mutations with a normal pattern of substitutions. On the contrary, the bcl-2/ox mice displayed a lower level of mutations with an altered pattern, showing a decreased mutational rate in the intrinsic hotspots of the V(kappa)Ox1 gene. Our results suggest that the lpr mutation does not have a direct effect on the somatic hypermutation process, but rather on the negative selection of B cells in the germinal centres, leading to the accumulation of recurrent mutations. In contrast, Bcl-2 overexpression might influence the somatic hypermutational process either by altering the incorporation of mutations or by enhancing the repair mechanism(s). The present work supports the hypothesis that both apoptotic pathways, Fas and Bcl-2, play distinct roles in the germinal centre reactions.

Identifiers
urn:nbn:se:su:diva-25720 (URN)10.1111/j.1365-3083.2006.01758.x (DOI)
Note
Part of urn:nbn:se:su:diva-85Available from: 2004-03-31 Created: 2004-03-31 Last updated: 2017-12-13Bibliographically approved

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