The association between the frequencies of T cells expressing IFN-gamma and IL-10 and clinical findings suggests a key role for these cells in the pathogenesis of lupus.

T cells that recognize nucleoproteins are required for the production of anti-dsDNA Abs involved in lupus development. SmD183–119 (a D1 protein of the Smith (Sm) proteins, part of small nuclear ribonucleoprotein) was recently shown to provide T cell help to anti-dsDNA Abs in the NZB/NZW model of lupus. Using this model in the present study, we showed that high dose tolerance to SmD1 (600–1000 μg i.v. of SmD183–119 peptide/mo) delays the production of autoantibodies, postpones the onset of lupus nephritis as confirmed by histology, and prolongs survival. Tolerance to SmD183–119 was adoptively transferred by CD90+ T cells, which also reduce T cell help for autoreactive B cells in vitro. One week after SmD183–119 tolerance induction in prenephritic mice, we detected cytokine changes in cultures of CD90+ T and B220+ B cells with decreased IFN-γ and IL-4 expression and an increase in TGFβ. Increased frequencies of regulatory IFN-γ+ and IL10+ CD4+ T cells were later detected. Such regulatory IL-10+/IFN-γ+ type 1 regulatory T cells prevented autoantibody generation and anti-CD3-induced proliferation of naive T cells. In conclusion, these results indicate that SmD183–119 peptide may play a dominant role in the activation of helper and regulatory T cells that influence autoantibody generation and murine lupus.

Objective. The C-terminal peptide of amino acids 83-119 of the SmD1 protein is a target of the autoimmune response in human and murine lupus. This study was undertaken to test the hypothesis that High-affinity antibodies against the Sm proteins as well as against double-stranded DNA (dsDNA) are a hallmark of the immune response in systemic lupus erythematosus (SLE) (1,2). Despite the importance of these antibodies as diagnostic and prognostic markers, the target structures and the mechanisms of autoantibody production are not well understood. The Sm antigens are part of the spliceosomal complex that plays an essential role in the generation of messenger RNA and DNA (for review, see

The SmD1(83-119) peptide is a main target of autoantibodies and T cells in human and murine lupus, but its role in autoimmunity induction remains elusive. Therefore, female Balb/c mice and (NZW x Balb/c)F1 [CWF1] mice with identical MHC haplotype as lupus prone NZB/W mice were immunized with SmD1(83-119). Immunizations of CWF1 mice with SmD1(83-119), but not with the controls (irrelevant peptide, HEL peptide, or saline), induced anti-SmD1(83-119) and anti-dsDNA antibodies and proteinuria not present in Balb/c mice. DsDNA-specific plasma cell induction after SmD1(83-119) immunizations was confirmed by ELISPOT assays showing that the generation of dsDNA-specific antibody forming cells (AFC) was mainly driven by increased T-cell help. T-cell help for the generation of dsDNA-specific AFC was also present in saline-treated CWF1 mice but was controlled on the levels of B cells preventing autoimmunity.