Hyporesponsiveness to gammac-chain cytokines in activated lymphocytes from patients with systemic lupus erythematosus leads to accelerated apoptosis.

Abstract

Pathogenesis of autoimmune diseases like systemic lupus erythematosus (SLE) is unresolved. Dysregulation of programmed cell death is discussed as a pathogenetic factor. We have previously shown that increased in vitro apoptosis of cultured peripheral blood mononuclear cells (PBMC) is nonspecific for SLE. Importantly, however, in recent experiments with SLE PBMC from patients with infections and fever in vitro apoptosis was strongly accelerated. We therefore hypothesized that regulation of apoptosis might be disturbed in activated SLE lymphocytes. Thus, we generated phytohemagglutinine (PHA)/IL-2 stimulated lymphoblasts in vitro. These lymphoblasts readily undergo apoptosis after culture in cytokine-free medium, and can be rescued by addition of gammac-chain cytokines IL-2, -4, -7, or -15. In lymphoblasts from 60 SLE patients tested in comparison to lymphoblasts from normal donors cultured in parallel, we found significant hyporesponsiveness to gammac-chain cytokines in SLE cells. Minor differences were also seen in lymphoblasts from patients with other systemic autoimmunopathies (mixed connective tissue disease, vasculitis, n=49)and in lymphoblasts from patients with other autoimmune diseases (mainly rheumatoid or reactive arthritis, myositis, n=44). In patients with high erythrocyte sedimentation rate (> 25 mm/h), TNF-alpha (> 6.5 pg/ml) or IL-12 (> 4.7 pg/ml) serum levels or detectable IFN-gamma concentrations hyporesponsiveness to gammac-chain cytokines was even more pronounced in SLE lymphoblasts, but not in lymphoblasts from the other groups. Moreover, increased apoptosis was seen in lymphoblasts from SLE patients with decreased complement (C)4 or elevated dsDNA antibody levels. In conclusion, these data suggest that in SLE patients with increased inflammatory activity and/or Th1 dominance signaling through gammac-chain cytokine receptors is deteriorated, leading to facilitated apoptosis of activated lymphocytes and enlarged onflow of apoptotic material.