The cellular requirements for B cell hyperactivity in systemic lupus erythematosus (SLE) were studied. Removal of either CD8+ or CD4+ lymphocyte markedly decreased the spontaneous in vitro production of polyclonal IgG and of antigen-specific (anti-double-stranded DNA and antinucleoprotein) antibodies by SLE peripheral blood mononuclear cells (PBMC). The CD8+ lymphocytes that sustained IgG production were CD3+, HLA-DR+, and their activity was abrogated by preincubation with anti-HLA-DR monoclonal antibody. When both CD4+ and CD8+ cells were removed, the readdition of either subset partially restored polyclonal IgG production, but both cell subsets were required to reconstitute autoantibody production. Purified SLE B cell cultures, which generated only 15% of the IgG produced by unseparated PBMC, were fully reconstituted only by mixtures of CD4+ with CD8+ cells, and with CD8-, CD4-, CD16+ cells. At least part of the support for spontaneous IgG production can be attributed to endogenous interleukin-2 and interleukin-6.

CD8+ lymphocytes from patients with systemic lupus erythematosus sustain, rather than suppress, spontaneous polyclonal IgG production and synergize with CD4+ cells to support autoantibody synthesis.

Fas antigen (CD95) is a membrane-associated molecule that mediates apoptotic cell death and may play a role in the induction and maintenance of T cell tolerance. To elucidate the involvement of Fas antigen in human autoimmune diseases, we analysed Fas antigen expression by peripheral T cells from patients with SLE and rheumatoid arthritis (RA), using three-colour flow cytometry. Both CD4+ and CD8+ T cells from SLE patients expressed Fas antigen in a higher density than did these cells from healthy donors and from RA patients. Enhancement of Fas antigen density was noted in Fas+CD45RO+ memory T cells from SLE patients. More remarkably, a significant expression of Fas antigen was observed in CD45RO- naive T cells from SLE patients. CD4+CD45RO- T cells from SLE patients co-expressed Fas antigen and early to intermediate activation antigens such as CD25 and CD71, and late activation antigen HLA-DR in only FashiCD4+ naive T cells. Such up-regulation of Fas antigen expression in SLE patients seems to be clinically meaningful, because mean fluorescence intensity (MFI) of Fas antigen on CD4+ T cell subsets inversely correlates with the absolute size of CD4+ T cell subsets in peripheral blood of SLE patients. These results suggest that T cells with increased Fas antigen expression may be highly susceptible to apoptotic cell death, in vivo. A putative mechanism for lymphopenia in SLE patients is discussed.

Up-regulated expression of Fas antigen (CD95) by peripheral naive and memory T cell subsets in patients with systemic lupus erythematosus (SLE): a possible mechanism for lymphopenia.

Surface antigens of T lymphocytes in peripheral blood mononuclear cells from 19 patients with systemic lupus erythematosus (SLE), 14 patients with Sjogren's syndrome (SS), and 14 healthy control subjects were studied by 2-color analysis. The proportion of CD4+2H4+ cells, which correspond to a suppressor/inducer subset, was decreased significantly in both SLE and SS. In contrast, the percentage of CD4+4B4+ cells, which define a helper/inducer subset, showed no significant difference among the patient groups. These data suggest that quantitative defect of suppressor/inducer cells may play an important role in the immunoregulatory disturbance in SLE and SS.

Quantitative defect of CD4+2H4+ cells in systemic lupus erythematosus and Sjögren's syndrome.

Objective. To determine whether impaired generation of polyclonal T cell cytolytic activity is over-represented in systemic lupus erythematosus (SLE) compared with other rheumatologic diseases and whether such impaired generation of cytolytic activity waxes and wanes with disease activity and/or changes in medications.



Methods. Peripheral blood mononuclear cells from 84 SLE patients, 55 rheumatologic disease (RD) controls, and 44 normal subjects were stimulated with anti-CD3 monoclonal antibody, maintained in interleukin-2, and assayed for cytolytic activity against 51Cr-labeled Daudi target cells.



Results. Generation of cytolytic activity was significantly lower in SLE patients than in either RD or normal controls. Abnormal cytolytic responses in SLE could not be attributed to the patient's sex, race, age, disease activity, or antirheumatic medications (including corticosteroids and cytotoxics), although both SLE and RD patients taking azathioprine (AZA) manifested lower responses than did corresponding patients not taking AZA. Abnormal cytolytic activity reflected, in large measure, impaired cytolytic activity of CD8+ T cells. No significant difference in the generation of cytolytic activity between RD and normal controls was detected.



Conclusion. Impaired generation of polyclonal T cell cytolytic activity may be a predisposing factor in the development of SLE.

Impaired polyclonal T cell cytolytic activity. A possible risk factor for systemic lupus erythematosus.

Increasing data suggest that human and murine lupus are heterogeneous diseases and that, in genetically susceptible individuals, lupus may be the final common pathway of a number of etiological agents and/or immunological processes. This review has discussed a number of cytokines which appear to be involved in lupus pathogenesis. The models that we have put forward illustrate several possible mechanisms which may lead to lupus. During the next several years, the exact role of these cytokine in the pathogenesis of lupus should become more fully elucidated. Hopefully, this knowledge will provide the framework for newer, highly specific immunotherapeutic approaches to the treatment of this fascinating, complex, and potentially devastating disease.

The role of cytokines in the immunopathogenesis of lupus

Activated T cells in the peripheral blood of patients with systemic lupus erythematosus (SLE) were determined using monoclonal antibodies against activation antigens. Elevated percentages of HLA-DR+ T cells were found in association with active disease. In contrast, we observed an increase in IL-2, receptor-bearing T cells in only six out of 16 patients with active disease. In vitro assays, like spontaneous proliferation, response to IL-2, production of IL-2, and immunoglobulin synthesis have shown that the different patterns of activation antigens are related to different functional stages of T-cell activation. The possible therapeutic consequences are discussed.

I. J. Körner

Papers

Correlation between the phenotype and the functional capacity of activated T cells in patients with active systemic lupus erythematosus.