Mechanisms of anti-Sm B cell activation in autoimmune Fas-deficient mice Public Deposited

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  • March 21, 2019
  • Conway, Kara Lynne
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of anti-nuclear autoantibodies to Smith (Sm), a component of a ribonucleoprotein complex. Anti-Sm transgenic mice (2-12H) develop large numbers of anti-Sm B cells but do not develop elevated anti-Sm titers, indicating that anti-Sm B cells are regulated. However, 2-12H mice with the lpr mutation of the pro-apoptosis gene Fas (Faslpr) develop high anti-Sm titers and anti-Sm antibody secreting cells (ASCs) in multiple tissues. This loss of tolerance is coincident with an autoantigen-specific depletion of marginal zone (MZ) and B-1 B cells and a bypass in the early pre-plasma cell (PC) tolerance checkpoint. To demonstrate the involvement of each mature B cell subset in the anti-Sm response in Faslpr mice, I adoptively transferred sorted 2-12H splenic B cells to Faslpr or Faswt recipients. I demonstrate that both anti-Sm follicular (FO) and MZ B cells are precursors to early pre-PCs. In addition, MZ B cells and early pre-PCs give rise to immediate, short-lived ASC responses, while anti-Sm FO B cells give rise to a delayed, long-lived ASC response after transfer to Faslpr recipients. These findings indicate that all anti-Sm B cell subsets are activated in autoimmunity but follow different activation programs, paralleling their responses to foreign antigens. I also demonstrate that immature bone marrow-derived DCs (BMDCs) and ex vivo DCs that have phagocytized Sm-bearing apoptotic cells (ACs) induce anti-Sm MZ B cell differentiation to ASCs in vivo and in vitro. This MZ B cell activation is antigen-specific, T cell-dependent, cell-contact dependent, and dependent upon IL-1[beta], CD40L, and BAFF production. Interestingly, BMDCs and ex vivo DCs from Faslpr mice activate anti-Sm MZ B cells regardless of AC phagocytosis or maturation status. The restricted ability of immature, non-autoimmune DCs to activate anti-Sm MZ B cells after AC phagocytosis is likely to prevent concomitant T cell activation and to induce only a short-lived B cell response. In contrast, the loss of these restrictions by Faslpr DCs is likely to allow concomitant T cell activation, resulting in long-lived, T cell-dependent responses. These data provide a possible mechanism for long-lived, anti-self responses in SLE.
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  • Clarke, Stephen H.
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  • University of North Carolina at Chapel Hill
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