Germinal centres

A lymph node consists of a cortex and an inner medulla. The cortex is composed of an outer cortex, which contains B-lymphocytes, within lymphoid follicles, and paracortical areas, which contain mainly T-lymphocytes and dendritic cells. The proliferation of B-cells occurs in central areas, called germinal centres. The medulla consists of strings of macrophages and the B-cells that secrete the antibodies (i.e. the effector cells) these are the medullary cords (Figure 17.42). Lymph carries immune cells (e.g. lymphocytes, antigen-presenting cells) and pathogens from the tissues to the lymph nodes, via the afferent lymphatics. 

Phan, R.T. and Dalla-Favera, R. (2004) The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature, 432, 635-639. 

Jacob, J., Kelsoe, G., Rajewsky, K., Weiss, U. (1991). Intraclonal generation of antibody mutants in germinal centres. Nature 354, 389-392. 

Kraal, G., Weissman, I.L., Butcher, E.C. (1982). Germinal centre B cells antigen specifrcity and changes in heavy chain class expression. Nature 298,377-379. 

Kiippers, R., Zhao, M., Hansmann, M.-L., Rajewsky, K. (1993). TracingB cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J. 12,4955-4967. 

P9. Pulendran, B., Kannourakis, G., Nouri, S., Smith, K. G., and Nossal, G. I., Soluble antigen can cause enhanced apoptosis of germinal-centre B cells. Nature 375, 331—334 (1995). 

Shokat, K. M., and Goodnow, C. C., Antigen-induced B-cell death and elimination during germinal-centre immune responses. Nature 375, 334-338 (1995). 

The final stage of B cell differentiation where the BCR repertoire is shaped is the germinal centre (GC) reaction. In the T cell dependent GC reaction, the BCR is adapted for its cognate antigen by somatic hypermutation (SMH) and class switch recombination (CSR), both of which are driven by activation induced cytidine deaminase (AID). Since AID induces targeted point mutations in the CDRs of the Ig HCs and Ig LCs, this can dramatically alter the BCR affinity or even its specificity. As AID activity may also result in the formation of an autoreactive BCR, a stringent counterselection of such self-reactive B cells is required. By analysis in human of the BCR repertoire of post-GC IgG+ memory B cells, it was demonstrated that indeed new auto-reactive B cells develop by SHM whereas 20% of naive B cells is self-reactive, up to 40% of the IgG+ memory B cells expressed a true de novo created self-reactive BCR. Apparently, lack of T cell help prevents activation of these self-... 

Gould HJ, Takhar P, Harries HE, Durham SR, Corrigan CJ Germinal-centre reactions in allergic inflammation. Trends Immunol 2006 27 446-452. 

A number of experiments performed thereafter were supportive for the immune-based etiology of zimeldine-induced adverse effects (Kristofferson Nilsson, 1989). Three individuals occupationally exposed to zimeldine developed allergy to the compound and showed positive patch and skin prick tests and positive response to zimeldine in the lymphocyte transformation test. Patients with a history of zimeldine-induced disease showed marked lymphocyte transformation test responses to zimeldine as well as two metabolites (norzimeldine and CPP200). These findings indicate that zimeldine may be immunogenic indeed, zimeldine has been shown to be positive in the popliteal lymph node assay, based on cell numbers and including germinal centre formation and production of IgM and IgG antibodies (Thomas et al., 1989). 

Vinuesa I guess we haven t looked early enough. The germinal centre phenotype is found even in mice that aren t weaned. One of the key issues for us is that when... 

Cyster This would be true in any germinal centre reactions. Do you think there is a defect here in apoptotic clearance ... 

Vinuesa No. There are likely other pathways to lupus that are not exclusively germinal centre driven. 

Cyster I am wondering why it would be restricted to those. You suggest the germinal centre as the rationale. It is really the lack of access to other tissue-specific autoantigens for which we know B cells are not tolerant to begin with. 

R. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat Genet 1997 16 161-170. 

In the human spleen, germinal centres with an epithelioid appearance may represent the early part of a normal primary immime reaction (Millikin... 

In addition to thymic involution, there are other important age-associated changes in the structure of the lymphoid tissues. The number of mature lymphocytes and plasma cells in the bone marrow markedly increases while the number of germinal centres in the lymph nodes and spleen is reduced with age (Benner et al. 1981, Gonzalez-Fernan-DEZ et al. 1994). 

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