Induction of Autoantibody Production Is Limited in Nonautoimmune Mice

Abstract

Many individuals develop a single or a few brief episodes of autoimmunity from which they recover. Mechanisms that quell pathologic autoimmunity following such a breakdown of self-tolerance are not clearly understood. In this study, we show that in nonautoimmune mice, dsDNA-specific autoreactive B cells exist but remain inactive. This state of inactivation in dsDNA-specific B cells could be disrupted by autoreactive Th cells; in this case T cells that react with peptides from the VH region of anti-DNA Abs (hereafter called anti-VH T cells). Immunization with anti-DNA mAb, its γ-chain or peptides derived from its VH region induced anti-VH Th cells, IgG anti-dsDNA Ab, and proteinuria. The breakdown of B cell tolerance in nonautoimmune mice, however, was short-lived: anti-DNA Ab and nephritis subsided despite subsequent immunizations. The recovery from autoimmunity temporally correlated with the appearance of T cells that inhibited anti-DNA Ab production. Such inhibitory T cells secreted TGFβ; the inhibition of anti-DNA Ab production by these cells was partly abolished by anti-TGFβ Ab. Even without immunization, nonautoimmune mice possess T cells that can inhibit autoantibody production. Thus, inhibitory T cells in nonautoimmune mice may normally inhibit T-dependent activation of autoreactive B cells and/or reverse such activation following stimulation by Th cells. The induction of such inhibitory T cells may play a role in protecting nonautoimmune mice from developing chronic autoimmunity.

SLE: translating lessons from model systems to human disease

“…It is important to emphasize that a rigorous characterization of the exquisite T-cell epitopes that activate suppressor T cells, versus those that stimulate pathogenic Th cells, in humans is crucial to ensure that we do not run into premature disappointment, as seen in some other antigen therapy trials. Complicating the selection of peptides for treatment, our murine studies suggest that suppressor and Th-cell epitopes might colocalize or overlap [20], as if nature has done a fine Most T-cell lines generated from immunized BWF1 mice are CD4 C Th cells that promote anti-DNA antibody formation in vitro [9]. By contrast, although CWF1 mice develop CD4 C Th cells during initial immunizations, most T-cell lines, including CD8 C cells, CD4 C CD25 C Treg cells and NKT cells, generated from CWF1 mice recovering from disease suppress anti-DNA antibody production by lupus (BWF1) B cells [9,19,20].…”

“…Serendipitous discoveries or deliberate attempts have led to the identification of animal models that appear to recapitulate these various steps or stages of disease ( Figure 2). For example, BALB/c mice immunized with a DNA surrogate peptide develop autoantibodies and extensive immune deposition but have no renal inflammation [7], whereas BALB/c mice injected with the hydrocarbon oil pristane develop immune deposition and a limited kidney inflammation but no kidney failure [8,9]. However, genetically lupus-prone mouse strains develop lethal renal disease spontaneously, with strain-dependent variation in disease patterns and severity [4,10].…”

“…Step 1: insufficient immune regulation in SLEharnessing the capacity of inhibitory or suppressor T cells to suppress lupus Otherwise healthy, non-autoimmune mice can be induced to develop antibodies to DNA and mild nephritis by in vivo stimulation of the Th cells that are capable of promoting autoantibody production [9]. These animals, however, completely recover from such an episode of autoimmunity, despite persistent exposure to autoreactive Th cells.…”

“…This suggests that self-reactive B and Th cells exist in the normal immune repertoire but are kept in control to avoid pathological autoimmunity. These control mechanisms are defective in lupus mice, which have impaired activation of such inhibitory, suppressor and regulatory T (Treg) cells [9]. Impairments in CD8 C T-cell suppressor functions have also been described in human SLE [18].…”

Regulation of autoreactive B cells: checkpoints and activation

“…These studies provide a rationale to develop "universally tolerogenic" epitopes for antigen-specific lupus treatment [8]. Recent studies from Erikson and Singh's laboratories also showed that the anergy of anti--dsDNA B cells in non-autoimmune mice could be reversed by the provision of T cell help [58,61], although the induction of autoAb synthesis and renal pathology appears to be mild and transitory. Our previous studies have indicated that T cells from lupus-prone MRL lpr/lpr 2-12 Tg mice can help B cells of non-autoimmune origin to initiate an anti-snRNP response [73].…”