Abstract
DNA-reactive B cells play a central role in systemic lupus erythematosus (SLE); DNA antibodies precede clinical disease and in established disease correlate with renal inflammation and contribute to dendritic cell activation and high levels of type 1 interferon. A number of central and peripheral B cell tolerance mechanisms designed to control the survival, differentiation and activation of autoreactive B cells are thought to be disturbed in patients with SLE. The characterization of DNA-reactive B cells has, however, been limited by their low frequency in peripheral blood. Using a tetrameric configuration of a peptide mimetope of DNA bound by pathogenic anti-DNA antibodies, we can identify B cells producing potentially pathogenic DNA-reactive antibodies. We, therefore, characterized the maturation and differentiation states of peptide, (ds) double stranded DNA cross-reactive B cells in the peripheral blood of lupus patients and correlated these with clinical disease activity. Flow cytometric analysis demonstrated a significantly higher frequency of tetramer-binding B cells in SLE patients compared to healthy controls. We demonstrated the existence of a novel tolerance checkpoint at the transition of antigen-naïve to antigen-experienced. We further demonstrate that patients with moderately active disease have more autoreactive B cells in both the antigen-naïve and antigen-experienced compartments consistent with greater impairment in B cell tolerance in both early and late checkpoints in these patients than in patients with quiescent disease. This methodology enables us to gain insight into the development and fate of DNA-reactive B cells in individual patients with SLE and paves the way ultimately to permit better and more customized therapies.
Highlights
A wide variety of autoantibodies can be detected in patients with systemic lupus erythematosus (SLE), a high percentage of which bind to nuclear antigens [1]
Tetramer-binding B cells in peripheral blood of lupus patients To determine the frequency of tetramer-binding B cells, peripheral blood cells of 22 patients with SLE (20 female, 2 male, 35.8610.7 years old) and 10 healthy donors (8 female, 2 male, 32.267.9 years old) were analyzed by flow cytometry
Both IgG anti-peptide antibody levels and IgG anti-dsDNA antibody levels determined by ELISA were significantly higher in SLE patients compared to healthy subjects (p,0.004, Figure 1A and p,0.0001, Figure 1B)
Summary
A wide variety of autoantibodies can be detected in patients with systemic lupus erythematosus (SLE), a high percentage of which bind to nuclear antigens [1]. Autoantibodies to dsDNA are essentially diagnostic of the disease They are considered to be pathogenic as changes in their titer correlate with disease activity, and in murine models they clearly contribute to lupus nephritis [2]. They help induce an ‘‘interferon signature’’ that results from activation of toll-like receptor (TLR) 9 in dendritic cells by DNA-containing immune complexes [3] elevated titers of anti-DNA antibodies can be seen in patients before the onset of clinical disease [4]. Defects in many of these checkpoints have been reported in murine models of lupus; each appears necessary to stave off pathogenic autoreactivity [10,11,12,13]
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