Generation and selection of an IgG-driven autoimmune repertoire during B-lymphopoiesis in Igmicro-deficient/lpr mice.
Class switch recombination (CSR) is a well-regulated process that occurs in peripheral lymphoid tissue, and is thought of as an important factor constructing the memory repertoire. We have recently shown that CSR normally occurs during bone marrow (BM) development, and these isotype-switched B cells are negatively selected by Fas signaling. This novel pathway of B cell development may generate a primary repertoire driven by gamma-heavy receptors, the nature of which is yet unknown. To study this gammaH-driven repertoire we used mice lacking IgM-transmembrane tail exon ( micro MT), where B cell development is limited by their ability to undergo CSR. We already showed that lack of Fas signaling rescues development of a significant population of isotype-switched B cells and production of high titers of non-IgM serum antibodies in micro MT mice deficient in Fas ( micro MT/lpr), thereby providing a mouse model allowing the assessment of gammaH-driven repertoire. Using a tissue array and phage display epitope library we report here that IgG repertoire in micro MT/lpr mice is oligo-monoclonal, bearing self-tissue reactivity. This is supported by analysis of the Vkappa utilization in peripheral B cells from micro MT/lpr mice, which revealed a strikingly restricted repertoire. In contrast, micro MT/lpr B cells that are grown in non-selective BM cultures utilize a wide repertoire. These results suggest that the Fas pathway is an important regulator in the generation and selection of an autoimmune gammaH-driven repertoire in vivo.
Seagal
Jane
J
Department of Immunology, Bruce Rappaport Faculty of Medicine and Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa, Israel.
Edry
Efrat
E
Naftali
Hadas
H
Melamed
Doron
D
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D007142:Immunoglobulin gamma-Chains / Q000235:genetics / Q000276:immunology*; D007145:Immunoglobulin kappa-Chains / Q000235:genetics / Q000276:immunology; D007148:Immunoglobulin mu-Chains / Q000235:genetics / Q000276:immunology*; D038041:Lymphopoiesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011995:Recombination, Genetic / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology*
D001324:Autoantigens; D007142:Immunoglobulin gamma-Chains; D007145:Immunoglobulin kappa-Chains; D007148:Immunoglobulin mu-Chains; D019014:fas Receptor