The many faces of type I interferon in systemic lupus erythematosus

Abstract

C o m m e n t a r y 2 5 6 2 jci.org Volume 125 Number 7July 2015 The many faces of type I interferon in systemic lupus erythematosus Claudia Mauri and Madhvi MenonCentre for Rheumatology, Division of Medicine, University College London, London, United Kingdom. Systemic lupus erythematosus: a heterogeneous diseaseSystemic lupus erythematosus (SLE) is a systemic autoimmune disease with diverse clinical presentations that can affect multiple organ systems (1). The multiplicity of symptoms and pathologies are a result of the heterogeneous immunological abnormalities that contribute to disease pathogenesis. While the precise etiology of SLE is unknown, it is hypothesized to be a combination of genetic and environmental factors (1). The onset of clinical symptoms and subsequent diagnosis of SLE occur long after the initiation of disease, making it difficult to identify the causative factor(s). Defective apoptotic cell clearance by marginal zone macrophagesAn abnormal response to autoantigens is considered an important driving force in the development of human SLE (2) and is thought to be due to a defect in clearance of apoptotic cells (ACs), resulting in increased exposure of lymphocytes to internal cellular antigens (3). Lupus-associated autoantigens, including nucleosomal DNA and small nuclear ribonucleoproteins, have been identified on the blebs of ACs (3). The lack of AC clearance has been shown to be pivotal in the production of anti-nuclear antibodies (ANAs) against these antigens, and the presence of circulating ANAs is a diagnostic criterion for lupus. Immune complexes formed by autoantibodies and self-antigens accumulate in multiple organs, cause tissue damage, and promote a systemic inflammatory response (4). Although it is widely accepted that ACs contribute to SLE pathogenesis, the mechanisms responsible for the defective clearance of ACs remain poorly understood. Recently, it has become apparent that, in addition to B cells, several other cells of the immune system are defective in patients with SLE. These include cells of the innate immune system, such as macrophages and monocytes, which contribute to impaired phagocytosis and defective AC clearance (5). In particular, marginal zone macrophages (MZMs) surrounding the splenic follicles have been reported to play a crucial role in the efficient clearance of ACs and in the induction of tolerance to AC autoantigens (AC-Ags) (6). MZM dysfunction results in a loss of tolerance to self-antigens and a decrease in AC clearance (7). Type I IFNs in SLE

Association Between a History of Nontyphoidal Salmonella and the Risk of Systemic Lupus Erythematosus: A Population-Based, Case-Control Study

“…Both autoantigens and immune complexes promote the production of IFN-I by activating plasmacytoid dendritic cell signaling via amyloid/DNA complexes ( 42 , 43 ). IFN-I hampers the clearance of apoptotic cells by macrophages and induces B cells to produce autoantibodies ( 44 ). In addition, the immune complexes containing antinuclear autoantibodies could provoke plasmacytoid dendritic cells to produce more IFN-I, leading to SLE ( 45 , 46 ).…”

JAK inhibitors: a potential treatment for JDM in the context of the role of interferon-driven pathology

“…The release of IFN type I leads to immune cell activation and vasculopathy. A major source of IFN type I is from plasmacytoid dendritic cells (pDC) after activation by either self-DNA or viral nucleic acid [ 70 , 71 ]. Plasmacytoid dendritic cells (pDC) have been identified in JDM muscle, but IFN type I is difficult to detect in serum due to limits of sensitivity of existing assays until recently [ 11 , 72 ].…”

Effects of type I interferons in malaria

“…Type I IFNs are a cytokine family that includes 13 different isoforms of IFN‐ α in humans (14 in mice) and a single IFN‐ β , as well as others, for example, IFN‐ ε , which appears to function predominantly in the female reproductive tract . Although type I IFNs can play important roles in immunity to viral and bacterial infections, excessive signalling may also contribute to autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis . In addition, type I IFN‐signalling can impede immunity to pathogens such as Mycobacterium tuberculosis and Leishmania .…”