Background/Purpose: Systemic lupus erythematosus (SLE) is an autoimmune disease in which various organs and tissues are damaged through abnormal immune responses mediated by tissue-binding autoantibodies and immune complex deposition. As the majority of SLE patients are women of child-bearing age, estrogen has been suggested to play an important role in the pathogenesis of SLE. One of the proposed roles of estrogen is to induce B cell activation culminating in increased autoantibody production. IL-21, a common-γ chain cytokine, has been shown to be crucial in the differentiation of activated B cells into plasma cells. Based on these concepts, we hypothesized that estrogen contributes to pathogenesis of SLE via IL-21 dependent pathway and investigated the effect of estrogen on the production of IL-21 by T cells and subsequent B cell activation in SLE patients.   

Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from peripheral blood of 23 SLE patients and 16 healthy controls. CD4+ T cells, non CD4+ T cells and B cells were isolated using microbeads. Isolated cells were treated with 17-β estradiol at various concentrations for 48hrs (up to 72hrs in some experiments). The expression of IL-21 and its receptor was assessed by measuring the level of protein and mRNA using ELISA and RT-PCR, respectively. The level of immunoglobulin G secreted by activated B cells were measured with specific ELISA.

Results: The expression of IL-21 and its receptor in serum, PBMCs, and CD4+ T cells were higher in the patients with SLE compared to healthy controls. Exposure of CD4+ T cells from SLE patients to 17-β estradiol leads to a dose-and time-dependent increase in the IL-21 expression. The increase was abolished in the presence of MAP kinase (MEK, p38, JNK) inhibitors. B cells of healthy controls showed an increased antibody production when they were co-cultured with estrogen treated CD4+ T cells of patients with SLE. Treatment with anti-IL-21 antibody abrogated the increased antibody production of the co-culture systems, suggesting the increase was mediated by IL-21 dependent manner.

Conclusion: This study revealed the association of estrogen and IL-21 in the pathogenesis of SLE. Estrogen upregulates IL-21 expression of CD4+ T cells via MAPK dependent pathways in SLE patients, which in turn induces increased antibody production by B cells.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/estrogen-upregulates-interleukin-21-production-of-clusters-of-differentiation-4-positive-t-lymphocytes-in-patients-with-systemic-lupus-erythematosus/