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Autoimmune reactions reflect an imbalance between effector and regulatory immune responses, typically develop through stages of initiation and propagation, and often show phases of resolution (indicated by clinical remissions) and exacerbations (indicated by symptomatic flares). The fundamental underlying mechanism of autoimmunity is defective elimination and/or control of self-reactive lymphocytes. Studies in humans and experimental animal models are revealing the genetic and environmental factors that contribute to autoimmunity. A major goal of research in this area is to exploit this knowledge to better understand the pathogenesis of autoimmune diseases and to develop strategies for reestablishing the normal balance between effector and regulatory immune responses.
Autoimmune diseases are a significant clinical problem because of their chronic nature, the associated healthcare cost, and their prevalence in young populations during the prime of their working and peak reproductive years. Current therapies, such as cytokine antagonists, have shown great promise in treating many of these diseases. TNF-α antagonists have changed the course of rheumatoid arthritis, and other cytokine antagonists are showing impressive efficacy in various other diseases (1, 2). However, most of the current therapeutic agents target the terminal phase of inflammation and do not address the fundamental problems that are responsible for the initiation and progression of the autoimmune process. In most cases, this necessitates continued and sometimes life-long therapy, resulting in an increased risk of malignant and infectious complications. Tackling these diseases at their source will require an understanding of how the abnormal immune reactions arise, how they are sustained, and the intrinsic mechanisms used to suppress these responses in healthy individuals.
Autoimmune diseases vary greatly in the organs they affect and in their clinical manifestations, with some being limited to particular tissues and others being systemic or disseminated. Despite these variations, all autoimmune diseases are believed to go through sequential phases of initiation, propagation, and resolution (Figure 1). All stages of autoimmune disease are thought to be associated with a failure of regulatory mechanisms, with the resolution phase defined by a partial, and in most cases, short-term ability to restore the balance of effector and regulatory responses. Augmenting regulatory mechanisms and establishing robust and long-lived disease resolution is a goal of new therapeutic strategies.
Cuba has mobilized its medical corps around the world to distribute a new "wonder drug" that officials there say is capable of treating the new coronavirus despite the United States' strict sanctions that continue to pressure the communist-run island.
The drug, called Interferon Alpha-2B Recombinant (IFNrec),
The type I interferon system plays a critical role in host defense in health, and a growing body of literature suggests that type I interferon is a critical mediator of human autoimmune disease (1). Type I interferons function as a bridge between the innate and adaptive immune systems, and as such play an important role in setting thresholds for response against self antigens. Many investigators have focused on the role type I interferons play in autoimmune disease. This fascinating and rapidly growing body of literature encompasses many different autoimmune diseases, including systemic lupus erythematosus, type I diabetes, multiple sclerosis, and others. Type I interferons play differing roles in human autoimmune conditions.
For example, in the autoimmune diseases, systemic lupus erythematosus and Sjogren’s syndrome, increased interferon alpha signaling plays a pathogenic role (2, 3). Interestingly, interferon beta is used as a therapeutic in multiple sclerosis, an autoimmune disease of the central nervous system (4). Both interferon alpha and beta signal through the same type I interferon receptor and share many similarities in downstream signaling, suggesting that the disparate activities of type I interferons in lupus and multiple sclerosis relate to differences in the underlying disease processes and immunoregulation in these two diseases. In this Research Topic, a series of articles provides a comprehensive overview of the various roles type I interferons play in autoimmune diseases, with a focus on human immunology.
This Research Topic features a number of Original Research Articles, including a study by Mavragani et al. examining type I interferon levels in the organ-specific autoimmune disorders type I diabetes and autoimmune thyroid disease (5). They demonstrate high type I interferon levels in both of these autoimmune conditions, supporting the idea that high levels of type I interferon are detectable in organ-specific autoimmune conditions in addition to systemic autoimmune disorders. Clark et al. investigate genetic polymorphisms in the interferon regulatory factor 5 (IRF5) gene (6).
This gene has been associated with susceptibility to systemic lupus erythematosus (7), and they demonstrate four distinct promoter regions have differential activity. Ko et al. study type I interferon-induced gene expression in patients with systemic lupus erythematosus (8). They demonstrate that the expression of type I interferon-induced genes in lupus immune cells differs significantly between ancestral backgrounds, which corresponds to clinical differences in the disease between ancestral backgrounds. A Methods article by Feng et al. examines public domain gene expression data to document patterns of type I interferon-induced gene expression and infer both positive and negative regulation by transcription factors
The Research Topic also features a number of Review Articles focusing on various disease states. Liu et al. review murine models of systemic lupus erythematosus that are interferon-inducible, providing model systems of autoimmunity related to type I interferon (10). Wu et al. review the role of type I interferon in systemic sclerosis, a distinct autoimmune disease characterized by thickening and fibrosis of the skin, which shares a type I interferon signature with other autoimmune conditions (11). Li et al. review the evidence supporting a role for type I interferon in the pathogenesis of Sjogren’s syndrome, spanning genetic associations, gene expression studies, and clinical features of the disease (12). Reder et al. review the contrasting role of type I interferon in multiple sclerosis and systemic lupus erythematosus and other autoimmune conditions (13).
In multiple sclerosis, type I interferon levels are low (14), and administration of recombinant type I interferon is an effective treatment. They review the evidence supporting multiple sclerosis as a low interferon autoimmune disease, and speculate on immunological features that might underlie this striking difference. Shrivastav et al. review the role of nucleic acid receptors in type I interferon generation in systemic lupus erythematosus (15), a disease characterized by pathological activation of the type I interferon pathway. These articles taken together provide an overview of many of the ways type I interferons have been implicated in human autoimmune disease, providing a fascinating window into the biology of the human immune system gone wrong.
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