B Cell Tolerance to SLE Antigens and Innate Immunity

Immune Disease Institute, Inc., Boston MA

Investigators

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Abstract

Systemic lupus erythematodes (SLE) is a frequent, multigenic autoimmune disease, characterized by the appearance of high-affinity antibodies to DNA, histones and ribonuclear proteins. There is evidence from human SLE and mouse models of it that components of the innate immune system such as complement and natural antibodies contribute to keeping autoantibody production under control. This control may operate at the level of clearance of autoantigens and/or their presentation to newly generated autoreactive cells, interfering with tolerance induction. There is also evidence that Fas-mediated apoptosis is of critical importance for the control of SLE-type auto-antibodies. The present application explores the in vivo interplay of innate immunity, Fas- mediated apoptosis and receptor editing in the control of autoantibody production, using mouse models of SLE-like disease and approaches of cell type-specific or inducible gene targeting. Specifically, we will analyze whether and to which extent the contribution of Fas deficiency to the spontaneous generation of anti-DNA antibodies on various autoimmune-prone genetic backgrounds depends upon Fas inactivation in B cells, at which stage of B cell differentiation Fas inactivation is required in this context. This will be achieved by the selective inactivation of the fas gene in T or B cells, or at various stages of B cell maturation, including germinal center B cells. Further, we will assess a possible in vivo contribution of receptor editing at the immunoglobulin heavy chain (IgH) locus to the control of autoreactive B cells. For this purpose we use mice genetically engineered to carry an IgH variable region in its physiological position, with unrearranged VH (but not DH elements) upstream. If VH gene replacement turns out to be a potential mechanism of induced receptor editing, its contribution to the control of autoreactive B cells in the context of components of the innate immune system will be determined. Finally, we will establish a transgenic system that allows the induction, in bone marrow or germinal centers, of anti- DNA reactive B cells in the presence or absence of natural antibodies, or, eventually, other components of innate immunity. Following the fate of those cells under the various conditions should allow us to determine the impact of natural immunity on the control of autoreactive B cells in a setting mimicking that of acquired autoantibody production in a previously healthy organism.