Generation and selection of an IgG-driven autoimmune repertoire during B-lymphopoiesis in Igμ-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 (muMT), 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 muMT mice deficient in Fas (muMT/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 muMT/lpr mice is oligo-monoclonal, bearing self-tissue reactivity. This is supported by analysis of the Vkappa utilization in peripheral B cells from muMT/lpr mice, which revealed a strikingly restricted repertoire. In contrast, muMT/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.