Increased plasma cell frequency and accumulation of abnormal syndecan-1plus T-cells in Igmu-deficient/lpr mice.
The expression of muH chain is an important checkpoint in B cell development. In mice deficient for IgM transmembrane tail exons (muMT mice) B cell development is blocked at the pro-B stage. However, we showed that Fas-deficient muMT mice (muMT/lpr) develop a very small population of isotype-switched B cells and produce high titers of self-reactive serum antibodies. In addition, muMT/lpr mice develop severe lymphoproliferation and both pathologic processes occur at young ages. This may suggest that lack of Fas-Fas ligand signaling exacerbates murine lupus in B cell lymphopenic mice. To test this we analyzed antibody and plasma cell formation, and accumulation of abnormal T cells in muMT/lpr mice. Our results show that the muMT/lpr mouse is particularly permissive for the development and accumulation of antibody-producing cells, thereby explaining the high titers of serum antibodies in these mice. In addition, we found that accumulating cells in spleen and lymph nodes of muMT/lpr mice are alphabeta T cells expressing the abnormal B220+/CD3+ surface markers, a phenotype also described for other Fas-deficient mouse models. Strikingly, we found that accumulating cells in muMT/lpr mice express the membrane proteoglycan syndecan-1, a known plasma cell marker. Development of these cells is blocked in mice deficient for TCRbeta and TCRdelta. We also found that both antibody production and lymphoproliferation in muMT/lpr mice are Th1 regulated. Our results, therefore, suggest that in the muMT/lpr mouse model a small population of isotype-switched B cells is sufficient for the initiation and propagation of Th1-regulated murine lupus.
Seagal
Jane
J
Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.
Leider
Nira
N
Wildbaum
Gizi
G
Karin
Nathan
N
Melamed
Doron
D
D000818:Animals; D000911:Antibodies, Monoclonal; D017252:CD3 Complex / Q000502:physiology; D002454:Cell Differentiation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007148:Immunoglobulin mu-Chains / Q000096:biosynthesis / Q000235:genetics*; D016130:Immunophenotyping; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000032:analysis*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010950:Plasma Cells / Q000276:immunology*; D011509:Proteoglycans / Q000032:analysis*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics; D013154:Spleen / Q000276:immunology; D053668:Syndecan-1; D053667:Syndecans; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D019014:fas Receptor / Q000502:physiology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007148:Immunoglobulin mu-Chains; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D011947:Receptors, Antigen, B-Cell; C508242:Sdc1 protein, mouse; D053668:Syndecan-1; D053667:Syndecans; D019014:fas Receptor