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Humoral Autoimmunity to Basement Membrane Antigens Is Regulated in C57BL/6 and MRL/MpJ Mice Transgenic for Anti-Laminin Ig Receptors¹

Earl H. Rudolph^*, Kendra L. Congdon^*, Faustina N. A. Sackey^*, Muriel M. Fitzsimons and Mary H. Foster^2,*

^* Department of Medicine, Duke University Medical Center and Veterans Affairs Medical Center, Durham, NC 27710; and Department of Medicine, St. Louis University and Veterans Affairs Medical Center, St. Louis, MO 63106

Basement membrane proteins are targeted in organ-limited and systemic autoimmune nephritis, yet little is known about the origin or regulation of immunity to these complex extracellular matrices. We used mice transgenic for a nephrotropic systemic lupus erythematosus (SLE) Ig H chain to test the hypothesis that humoral immunity to basement membrane is actively regulated. The LamH-Cµ Ig H chain transgene combines with diverse L chains to produce nephrotropic Ig reactive with murine laminin 1. To determine the fate of transgene-bearing B cells in vivo, transgenic mice were outcrossed onto nonautoimmune B6 and SLE-prone MRL backgrounds and exposed to potent mitogen or Ag in adjuvant. In this work we demonstrate that transgenic autoantibodies are absent in serum from M6 and M29 lineage transgenic mice and transgenic B cells hypoproliferate and fail to increase Ig production upon exposure to endotoxin or when subjected to B cell receptor cross-linking. Administration of LPS or immunization with autologous or heterologous laminin, maneuvers that induce nonoverlapping endogenous anti-laminin IgG responses, fails to induce a transgenic anti-laminin response. The marked reduction in splenic B cell number suggests that selected LamH-Cµ H chain and endogenous L chain combinations generate autospecificities that lead to B cell deletion. It thus appears that SLE-like anti-laminin B cells have access to and engage a tolerizing self-Ag in vivo. Failure to induce autoimmunity by global perturbations in immune regulation introduced by the MRL autoimmune background and exposure to potent environmental challenge suggests that humoral immunity to nephritogenic basement membrane epitopes targeted in systemic autoimmunity is tightly regulated.

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