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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
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
2006 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, 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.

Place, publisher, year, edition, pages
2006. Vol. 63, no 6, 420-429 p.
URN: urn:nbn:se:su:diva-25720DOI: 10.1111/j.1365-3083.2006.01758.xOAI: diva2:200368
Part of urn:nbn:se:su:diva-85Available from: 2004-03-31 Created: 2004-03-31 Last updated: 2010-01-18Bibliographically approved
In thesis
1. Maturation of humoral immune responses: Studies on the effects of antigen type, apoptosis and age
Open this publication in new window or tab >>Maturation of humoral immune responses: Studies on the effects of antigen type, apoptosis and age
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.
immunology, B cell, humoral immune response
National Category
Immunology in the medical area
urn:nbn:se:su:diva-85 (URN)91-7265-835-5 (ISBN)
Public defence
2004-04-21, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 8 C, Stockholm, 10:00
Available from: 2004-03-31 Created: 2004-03-31Bibliographically approved

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