Immune tolerance to autoantibody-derived peptides delays development of autoimmunity in murine lupus.

Abstract

Mechanisms that initiate and maintain autoantibody (autoAb) production in individuals with autoimmune diseases like SLE are poorly understood. Inadequate suppression of autoreactive T cells and/or unusual activation of T and B cells may underlie the persistence of pathogenic autoAbs in lupus. Here, we examine the possibility that in mice with lupus, autoAb molecules may be upregulating their own production by activating self-reactive T cells via their own processed peptides; downregulation of this circuit may decrease autoAb production and delay the development of lupus. We found that before the onset of clinical disease, lupus-prone (NZB/NZW) F1 [BWF1] (but not MHCmatched nonautoimmune mice) developed spontaneous T cell autoimmunity to peptides from variable regions of heavy chains (V H) of syngeneic anti-DNA mAbs but not to peptides from the V H region of an mAb to an exogenous antigen. Tolerizing young BWF1 mice with intravenous injections of autoAb-derived determinants substantially delayed development of anti-DNA antibodies and nephritis and prolonged survival. Thus, in such an autoAb-mediated disease, the presence of autoreactive T cells against V H region determinants of autoAbs may represent an important mechanism involved in the regulation of autoimmunity. Our findings show that tolerizing such autoreactive T cells can postpone the development of an autoimmune disease like

Induction of Autoantibody Production Is Limited in Nonautoimmune Mice

“…Proteinuria and blood urea nitrogen were tested using Albustix and Azostix (range, 0 -4ϩ), respectively, and creatinine was estimated by reagents from Stanbio Laboratories (San Antonio, TX), as described previously (4,20).…”

“…Autoreactive, anti-V H , Th cells that recognize peptides processed from the V H of anti-DNA Ig molecules (4,20,(22)(23)(24)(25)(26)(27) arise spontaneously in humans and mice with systemic lupus erythematosus (6,20,28) and modulate the development and progression of disease in lupus mice (4,6,20,29,30). These MHC class II-restricted, anti-V H Th cells increase anti-DNA Ab production by BWF 1 B cells (15).…”

Self antigens and epitope spreading in systemic autoimmunity

“…Importantly, these latter T cells have functional consequences in vivo in SNF, mice, since they can drive pathogenic antinucleosome antibody synthesis with promotion of renal disease. Epitope spreading may also account for activation of diverse autoreactive T cells from lupus-prone (New Zealand black X New Zealand white)F, mice specific for several peptides derived from a single IgG anti-DNA antibody (71,72). In this example, an anti-DNA antibody can be processed into different peptide epitopes which can be presented to and can activate diverse autoreactive T cells, with subsequent stimulation of autoreactive B cells, perpetuation of anti-DNA production, and acceleration of nephritis.…”

Cerebrospinal fluid T cell clones from patients with multiple sclerosis: recognition of idiotopes on monoclonal IgG secreted by autologous cerebrospinal fluid B cells

“…This process seems to involve both epitope spreading and cross-reactivity [20,21]. Immunization with Id-bearing antibody in adjuvant accelerates development of the disease [22,23], while treatment with Id peptides in saline ameliorates disease [24][25][26][27]. The existence of Id-specific T cells has been suggested in rheumatoid arthritis and SLE [28][29][30][31][32].…”