Generation and selection of an IgG-driven autoimmune repertoire during B-lymphopoiesis in Igµ-deficient/lpr mice

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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 γ-heavy receptors, the nature of which is yet unknown. To study this γH-driven repertoire we used mice lacking IgM-transmembrane tail exon (µMT), 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 µMT mice deficient in Fas (µMT/lpr), thereby providing a mouse model allowing the assessment of γH-driven repertoire. Using a tissue array and phage display epitope library we report here that IgG repertoire in µMT/lpr mice is oligo-monoclonal, bearing self-tissue reactivity. This is supported by analysis of the Vκ utilization in peripheral B cells from µMT/lpr mice, which revealed a strikingly restricted repertoire. In contrast, µMT/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 γH-driven repertoire in vivo.

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