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Novel Immunoregulatory B Cell Pathways Revealed by lpr-+ Mixed Chimeras¹

Eric S. Sobel^2,*, Vellalore N. Kakkanaiah^3,, Joel Schiffenbauer^*, Elizabeth A. Reap, Philip L. Cohen and Robert A. Eisenberg^4,

^* Department of Medicine and Division of Rheumatology and Clinical Immunology, University of Florida, Gainesville, FL 32610; and Department of Medicine and Microbiology/Immunology, University of North Carolina, Chapel Hill, NC 27599

lpr, a murine mutation of the Fas apoptosis receptor, causes lymphadenopathy and autoantibody production, with lymphadenopathy primarily due to a population of CD4^-CD8^-B220⁺ T cells. Previous in vivo experiments, in which lpr and normal bone marrow cells were coinfused into lpr hosts, have demonstrated that only T cells of lpr origin accumulated abnormally and only B cells of lpr origin produced autoantibodies. Moreover, in these chimeras, B cells of normal origin were unable to respond to conventional, T cell-dependent exogenous Ag. To address the role of lpr B cells in regulation of lpr autoimmunity, we have prepared lpr-+ mixed chimeras and selectively eliminated lpr B cells using allele-specific, mAb treatment, thus allowing normal B cells to develop in an environment with lpr T cells. From these data, we arrived at four major conclusions: 1) Compared with control-treated chimeric mice, lpr B cell-depleted mice had greatly reduced total lymph node cell counts; 2) the T cells were derived equally from normal and lpr donors, and the percentage of lpr-derived CD4^-CD8^- T cells was greatly reduced; 3) despite the presence of the remaining lpr T cells, no autoantibodies were produced by the normal derived B cells; and 4) lpr T cells without lpr B cells were unable to prevent a normal B cell response to conventional Ag. These data demonstrate that B cells can play a critical and expansive regulatory role, not only for T cells, but for other B cells as well.

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