Hyporesponsiveness to γc‐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 γc‐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 γc‐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‐α (>6.5 pg/ml) or IL‐12 (>4.7 pg/ml) serum levels or detectable IFN‐γ concentrations hyporesponsiveness to γc‐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 γc‐chain cytokine receptors is deteriorated, leading to facilitated apoptosis of activated lymphocytes and enlarged onflow of apoptotic material.

Accumulation of apoptotic cells in the epidermis of patients with cutaneous lupus erythematosus after ultraviolet irradiation

“…1) Apoptosis may commence slower in the skin of patients with CLE, or 2) uptake and removal of apoptotic cells by macrophages might be less efficient. There are frequent reports of increased apoptosis in patients with SLE (6,60); in contrast, we are not aware of any reports describing delayed apoptosis in patients with SLE. Based on the clearance defects in apoptotic cells and the consecutive accumulation of apoptotic nuclei reported to occur in patients with SLE (20), we therefore favor the hypothesis that the clearance of apoptotic cells in the skin of ϳ45% of patients with CLE is impaired or delayed.…”

Autoantigens are translocated into small apoptotic bodies during early stages of apoptosis

“…Nevertheless, several publications released during the previous years point out that a dysregulation of apoptosis or an ineffective clearance of apoptotic cells contributes to the development of autoimmunity. [1][2][3][4] Our group and others have shown an increased rate of apoptosis in patients suffering from SLE. Further, we previously demonstrated that cells obtained from SLE patients show a hyporesponsiveness to survival factors and are therefore more susceptible to apoptosis than cells of healthy individuals.…”

“…Further, we previously demonstrated that cells obtained from SLE patients show a hyporesponsiveness to survival factors and are therefore more susceptible to apoptosis than cells of healthy individuals. 3,5,6 Furthermore, an impaired engulfment of apoptotic material by macrophages obtained from SLE patients has been described. 7,8 On the background of these data, it seems likely that an increased rate of apoptosis and an ineffective clearance of apoptotic material could result in a breakdown of self-tolerance and an autoimmune response against autoantigens contained in apoptotic particles.…”

Macrophages – Balancing Tolerance and Immunity

“…Some models of SLE invoke positive feedback loops between T and B cells, leading to epitope spread and autoantibody diversification, following an initial (B7 co-stimulation-independent) interaction between peripheral auto-reactive T cells and B cells, presenting autoimmunogenic peptides [514]. A specific hyposensitivity to certain (c-chain) cytokines, notably IL-15 and IL-2, may indicate a specific T cell defect in SLE, leading to enhanced T cell apoptosis, particularly evident under proinflammatory conditions, adding to the apoptotic load [515]. In the presence of increased IL-10, combined with increased proinflammatory cytokines, as in the uncompensated active phase of SLE, activation induced cell death of lymphocytes may be accelerated by IL-10 and by upregulated expression of Fas receptors on T and B cells.…”