The role of cytokines in the pathogenesis and treatment of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by a defect in immune tolerance and exacerbated by both the innate and adaptive arms of the immune response. SLE-associated immune hyperactivity can be detected systemically as elevations in levels of cytokines along with their upregulated receptors expressed by hematopoietic cells. Importantly, increased levels of cytokines and their receptors can be observed in target organs, and it is clear that they have important roles in disease pathogenesis. Recent therapeutic strategies have focused on proximal cytokines, such as interferon-α, interleukin (IL)-1, IL-6, and tumor necrosis factor as a result of the efficacious use of biologic agents for intervention in rheumatoid arthritis and other autoimmune diseases. Despite the recent advances in understanding the cytokine networks involved in autoimmune diseases and more specifically in SLE, the diagnosis and prognosis of lupus remain a challenge. Lupus is heterogeneous and unpredictable; moreover, the frequency and severity of flares can be difficult to determine and treat. A better understanding of the regulation of expression of key cytokines and their receptors can likely provide important clues to the pathogenic mechanisms underlying specific forms of SLE, and pave the way toward more effective therapeutics.

FIG. 1.

The role of cytokines in systemic and end-organ autoimmune-initiated interactions in lupus. Increased IFN-α produced by pDC initiates a cascade of events that result in the activation of silent autoreactive lymphocytes in the periphery (upper panel). Although autoreactive B cells and T cells are central players driving the systemic component of lupus (upper panel), myeloid cells, and the cytokines, they elaborate constitute key determinants in shaping the autoimmune response. Autoreactive B cells interact with IFN-α-induced myeloid dendritic cells (not shown) and Th1 cells to elaborate both cytokines and autoreactive antibodies. The antibodies can form immune complexes with products released from apoptotic cells and directly stimulate pDC to propagate the immune response. Antibodies and immune complexes deposited in target organs can induce the production of chemokines, cytokines, and cytotoxic mediators from the target tissue (lower panel). Infiltrating Th cells support the local inflammatory response by producing cytokines and chemokines that further accelerate inflammation. Although there is evidence for Th2 cytokines promoting some elements of chronic nephritis, the overwhelming contribution of T cells in systemic lupus erythematosus appears to be Th1-skewed. Macrophages also contribute a number of key mediators that induce apoptosis and necrosis of target tissues, ultimately resulting in fibrosis and end-stage disease. IFN, interferon; pDC, plasmacytoid dendritic cells; IL, interleukin; TNF-α, tumor necrosis factor-α; TGF-β, transforming growth factor-β; BAFF, B cell activating factor.