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A hallmark of immune responses is the ability to discriminate self versus non-self among the myriad antigens that can be present in different locations in an organism at various times throughout its lifetime. This discrimination is not a simple ‘no response versus response’ but rather an ability to mount appropriate responses that minimize damage to the host while allowing recognition of harmful host or foreign constituents. This delicate and shifting balance is, almost inevitably, vulnerable to disruption and there are about 80 recognized autoimmune diseases, which affect roughly 5% of the population. Autoimmune diseases are typically classified as systemic or organ specific, although intermediate features are frequently observed probably due to the complex of locations of antigens and ways of immune responses. Despite extensive and very long-established knowledge of the features and pathogenesis of these diseases, they have in general proved difficult to ameliorate.
Key features of autoimmune diseases are the wide variety of organs/systems targeted, the complexity of immune system components involved (innate, humoral and cellular) and the interplay of complex genetic and environmental elements. Thus, as is common with ‘experiments of nature’, they offer insights but shroud them in complexity. The pressing need for therapies that target autoimmune diseases nevertheless drives our search to understand how the immune system deals with self-antigens in health and what disturbances cause disease in so many people.
In this Special Issue, our first three Review articles discuss basic aspects of the immune response in autoimmunity, whereas the next two Reviews discuss therapeutic approaches that can target the disease. Finally, we include a research article that uses a model of autoimmunity to explore one potentially important mechanism whereby autoimmunity is just part of a complex interaction between the immune system and the general metabolism.
Genome-wide association studies (GWASs) have proved invaluable in identifying genetic loci associated with many autoimmune diseases and thus provided clues about the etiology of and inter-relationships of different phenotypes. As detailed by Yuta Kochi (p. 155), some loci are associated with many autoimmune diseases and combinations of loci may determine the risk of each disease in an individual (1). Most loci identified by GWAS are expression quantitative trait loci (eQTL) and it is thus the transcriptional activity that is important; this can be controlled by several neighboring or distant genes, and by epigenetic effects, in a cell-type-specific manner. The article focuses on risk-loci shared by different autoimmune diseases that affect important immune pathways: the MHC, TCR/BCR signaling, Th1/Th17/Treg cells and type I interferons.
Kiyoshi Hirahara and Toshinori Nakayama (p. 163) discuss the different CD4+ T-cell subsets that operate in autoimmunity and, indeed, in inflammatory diseases in general (2). They describe the ‘classical’ Th1/Th2 classification, which has proved to be a valuable paradigm in dissecting the contributions of specific T-helper cells in complex immune responses. Building on this, many other CD4+ T-cell subsets (e.g. Th9, Th17, Tfh and Treg cells) have been identified and all contribute to autoimmune diseases in different anatomical locations. The authors describe these, and detail the epigenetic mechanisms and transcription factors that regulate the plasticity now apparent in these various subsets. Finally, the authors detail a disease-induction model that expands beyond Th1/Th2 categorization and considers pathogenic T-helper cells (e.g. Tpath1, Tpath2 or Tpath17 cells) that contribute to type-1, type-2 or type-17 inflammatory responses.
Germinal centers are crucial sites for diversifying antibodies and increasing their affinity for antigens, including autoantigens, and Yangyang Zhu, Le Zou and Yun-Cai Liu (p. 173) discuss the roles of T follicular helper (Tfh) and T follicular regulatory (Tfr) cells in autoimmune diseases (3). As with all immune responses, the balance of stimulation versus inhibition determines the outcome and the authors provide a detailed update on the biology, differentiation and opposing functions of these specialized T-cell subsets. The authors describe the molecular interactions that allow Tfh and Tfr cells to regulate the generation of high-affinity antibodies and of memory responses. Finally, the authors discuss the evidence that these subsets have a role in human autoimmune diseases that feature pathogenic auto-antibodies.
Although antibodies clearly play a detrimental role in many autoimmune diseases, they can, conversely, be used therapeutically to target almost any extracellular molecule, including pathogenic cytokines. This has clear potential for treatment of autoimmune diseases, and Yuping Lai and Chen Dong (p. 181) discuss the present status and the future possibilities (4). They describe the role of cytokines in autoimmunity, then focus on four cytokines (TNFα, IL-6, IL-17 and IL-23) in particular. They detail the therapeutic antibodies that are currently approved for use in humans and the diseases that are known to be ameliorated. A feature of these antibodies, which target pleiotropic cytokines, is that they can modulate a wide range of diseases (autoimmune and non-autoimmune) but that predicting and fine-tuning the therapeutic benefit in specific conditions is complicated but has nevertheless proved rewarding.
As discussed above, both auto-antibodies and pathogenic cytokines are crucial for the development of many autoimmune diseases; however, the wide spectrum of diseases and the enormously varied contributions of different elements of the immune system in different circumstances make simplified treatment strategies difficult but attractive. Using cytokines that mediate general immunosuppression as therapeutic agents is a potentially fruitful approach and Keishi Fujio et al. (p. 189) describe the most likely candidates against pathogenic B cells (5). They focus on IL-10 and the TGF-β superfamily and start by detailing the variable effects of IL-10 in stimulating or suppressing T and B cells. They then comprehensively compare and contrast the effects of TGF-β1, TGF-β3 and BMPs, emphasizing the likely clinical implications. Finally, they update us about the currently available therapeutics and their potential future applications.
In their original research article, Kei Goto et al. (p. 197 examine the role of leptin in nephrotoxic serum nephritis (NTN) (6). Murine NTN is a model of Goodpasture’s syndrome, an autoimmune disease in humans that features inflammation triggered by immune complexes on the glomerular basement membrane. The authors show that leptin deficiency decreases mortality rates, attenuates kidney damage and decreases macrophage infiltration, MCP-1 expression and Th17 responses. Glomerular podocytes produce IL-23 in vivo and cultured podocytes make IL-23 in response to leptin. The authors discuss these molecular events in the context of leptin’s known effects on food intake, cell metabolism, adipose tissue and the immune system, and how leptin might function in autoimmune kidney disease.
I would like to express my sincere gratitude to the authors for their excellent contributions and we hope that readers of International Immunology find the articles interesting and that they offer insights that inspire further research in this important, intriguing but enigmatic topic.