Abstract This review focuses on the biology of T helper 17 (Th17) and regulatory T (Treg) cells and their role in inflammatory diseases, such as rheumatoid arthritis. Th17 cells represent a pro-inflammatory subset whereas Treg cells have an antagonist effect. Their developmental pathways are reciprocally interconnected and there is an important plasticity between Th17 and Treg cells. These features implicate that the Th17/Treg balance plays a major role in the development and the disease outcomes of animal model and human autoimmune/inflammatory diseases. During these diseases, this balance is disturbed and this promotes the maintenance of inflammation. Targeting the Th17/Treg imbalance can be performed at different levels such as inhibition of pro-inflammatory cytokines and their receptors, of pathogenic cells or their specific signaling pathways. Conversely, direct effects include administration or induction of protective cells, or stimulation of their specific pathways. Several clinical trials are underway and some positive results have been obtained.
Abstract Background Optimal vitamin D intake and its status are important not only for bone and calcium-phosphate metabolism, but also for overall health and well-being. Vitamin D deficiency and insufficiency as a global health problem are likely to be a risk for wide spectrum of acute and chronic illnesses. Methods A review of randomized controlled trials, meta-analyses, and other evidence of vitamin D action on various health outcomes. Results Adequate vitamin D status seems to be protective against musculoskeletal disorders (muscle weakness, falls, fractures), infectious diseases, autoimmune diseases, cardiovascular disease, type 1 and type 2 diabetes mellitus, several types of cancer, neurocognitive dysfunction and mental illness, and other diseases, as well as infertility and adverse pregnancy and birth outcomes. Vitamin D deficiency/insufficiency is associated with all-cause mortality. Conclusions Adequate vitamin D supplementation and sensible sunlight exposure to reach optimal vitamin D status are among the front line factors of prophylaxis for the spectrum of disorders. Supplementation guidance and population strategies for the eradication of vitamin D deficiency must be included in the priorities of physicians, medical professionals and healthcare policy-makers.
Abstract Autoimmune thyroid diseases (AITD) result from a dysregulation of the immune system leading to an immune attack on the thyroid. AITD are T cell-mediated organ-specific autoimmune disorders. The prevalence of AITD is estimated to be 5%; however, the prevalence of antithyroid antibodies may be even higher. The AITD comprise two main clinical presentations: Graves' disease (GD) and Hashimoto's thyroiditis (HT), both characterized by lymphocytic infiltration of the thyroid parenchyma. The clinical hallmarks of GD and HT are thyrotoxicosis and hypothyroidism, respectively. The mechanisms that trigger the autoimmune attack to the thyroid are still under investigation. Epidemiological data suggest an interaction among genetic susceptibility and environmental triggers as the key factor leading to the breakdown of tolerance and the development of disease. Recent studies have shown the importance of cytokines and chemokines in the pathogenesis of AT and GD. In thyroid tissue, recruited T helper 1 (Th1) lymphocytes may be responsible for enhanced IFN-γ and TNF-α production, which in turn stimulates CXCL10 (the prototype of the IFN-γ-inducible Th1 chemokines) secretion from the thyroid cells, therefore creating an amplification feedback loop, initiating and perpetuating the autoimmune process. Associations exist between AITD and other organ specific (polyglandular autoimmune syndromes), or systemic autoimmune disorders (Sjögren's syndrome, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, cryoglobulinemia, sarcoidosis, psoriatic arthritis). Moreover, several studies have shown an association of AITD and papillary thyroid cancer. These data suggest that AITD patients should be accurately monitored for thyroid dysfunctions, the appearance of thyroid nodules, and other autoimmune disorders.
Abstract Inflammatory bowel disease (IBD) includes Crohn's disease (CD) and ulcerative colitis (UC). The exact cause of IBD remains unknown. Available evidence suggests that an abnormal immune response against the microorganisms of the intestinal flora is responsible for the disease in genetically susceptible individuals. The adaptive immune response has classically been considered to play a major role in the pathogenesis of IBD. However, recent advances in immunology and genetics have clarified that the innate immune response is equally as important in inducing gut inflammation in these patients. In particular, an altered epithelial barrier function contributes to intestinal inflammation in patients with UC, while aberrant innate immune responses, such as antimicrobial peptide production, innate microbial sensing and autophagy are particularly associated to CD pathogenesis. On the other hand, besides T helper cell type (Th)1 and Th2 immune responses, other subsets of T cells, namely Th17 and regulatory T (Treg) cells, are likely to play a role in IBD. However, given the complexity and probably the redundancy of pathways leading to IBD lesions, and the fact that Th17 cells may also have protective functions, neutralization of IL-17A failed to induce any improvement in CD. Studying the interactions between various constituents of the innate and adaptive immune systems will certainly open new horizons in the knowledge about the immunologic mechanisms implicated in gut inflammation.
Abstract (C–X–C motif) ligand (CXCL)10 (CXCL10) belongs to the ELR− CXC subfamily chemokine. CXCL10 exerts its function through binding to chemokine (C–X–C motif) receptor 3 (CXCR3), a seven trans-membrane receptor coupled to G proteins. CXCL10 and its receptor, CXCR3, appear to contribute to the pathogenesis of many autoimmune diseases, organ specific (such as type 1 diabetes, autoimmune thyroiditis, Graves' disease and ophthalmopathy), or systemic (such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, mixed cryoglobulinemia, Sjögren syndrome, or systemic sclerosis). The secretion of CXCL10 by cluster of differentiation (CD)4 +, CD8 +, natural killer (NK) and NK-T cells is dependent on interferon (IFN)-γ, which is itself mediated by the interleukin-12 cytokine family. Under the influence of IFN-γ, CXCL10 is secreted by several cell types including endothelial cells, fibroblasts, keratinocytes, thyrocytes, preadipocytes, etc. Determination of high level of CXCL10 in peripheral fluids is therefore a marker of host immune response, especially T helper (Th)1 orientated T-cells. In tissues, recruited Th1 lymphocytes may be responsible for enhanced IFN-γ and tumor necrosis factor-α production, which in turn stimulates CXCL10 secretion from a variety of cells, therefore creating an amplification feedback loop, and perpetuating the autoimmune process. Further studies are needed to investigate interactions between chemokines and cytokines in the pathogenesis of autoimmune diseases and to evaluate whether CXCL10 is a novel therapeutic target in various autoimmune diseases.
Abstract In the last decades, autoimmune diseases have experienced a dramatic increase in Western countries. The involvement of environmental factors is strongly suspected to explain this rise. Particularly, over the same period, obesity has followed the same outbreak. Since the exciting discovery of the secretory properties of adipose tissue, the relationship between obesity and autoimmunity and the understanding of the underlying mechanisms have become of major interest. Indeed, the fat tissue has been found to produce a wide variety of “adipokines”, involved in the regulation of numerous physiological functions, including the immune response. By conducting a systematic literature review, we extracted 329 articles regarding clinical, experimental and pathophysiological data on the relationship between obesity, adipokines – namely leptin, adiponectin, resistin, visfatin – and various immune-mediated conditions, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), multiple sclerosis (MS), type-1 diabetes (T1D), psoriasis and psoriatic arthritis (PsA), and thyroid autoimmunity (TAI), especially Hashimoto thyroiditis (HT). The strongest levels of evidence support an increased risk of RA (OR = 1.2–3.4), MS (OR = 2), psoriasis and PsA (OR = 1.48–6.46) in obese subjects. A higher risk of IBD, T1D and TAI is also suggested. Moreover, obesity worsens the course of RA, SLE, IBD, psoriasis and PsA, and impairs the treatment response of RA, IBD, psoriasis and PsA. Extensive clinical data and experimental models demonstrate the involvement of adipokines in the pathogenesis of these autoimmune diseases. Obesity appears to be a major environmental factor contributing to the onset and progression of autoimmune diseases.
Abstract Zinc (Zn) nutritional importance has been known for a long time, but in the last decades its importance in immune modulation has arisen. This review aims at describing the mechanisms involved in the regulation of Zn homeostasis and their effects on the immune response focusing on those which are implicated in the physiopathology of rheumatoid arthritis. Zn functions as a modulator of the immune response through its availability, which is tightly regulated by several transporters and regulators. When this mechanism is disturbed, Zn availability is reduced, altering survival, proliferation and differentiation of the cells of different organs and systems and, in particular, cells of the immune system. Zn deficiency affects cells involved in both innate and adaptive immunity at the survival, proliferation and maturation levels. These cells include monocytes, polymorphonuclear-, natural killer-, T-, and B-cells. T cell functions and the balance between the different T helper cell subsets are particularly susceptible to changes in Zn status. While acute Zn deficiency causes a decrease in innate and adaptive immunity, chronic deficiency increases inflammation. During chronic deficiency, the production of pro-inflammatory cytokines increases, influencing the outcome of a large number of inflammatory diseases, including rheumatoid arthritis.
Abstract Hashimoto thyroiditis (HT), now considered the most common autoimmune disease, was described over a century ago as a pronounced lymphoid goiter affecting predominantly women. In addition to this classic form, several other clinico-pathologic entities are now included under the term HT: fibrous variant, IgG4-related variant, juvenile form, Hashitoxicosis, and painless thyroiditis (sporadic or post-partum). All forms are characterized pathologically by the infiltration of hematopoietic mononuclear cells, mainly lymphocytes, in the interstitium among the thyroid follicles, although specific features can be recognized in each variant. Thyroid cells undergo atrophy or transform into a bolder type of follicular cell rich in mitochondria called Hürthle cell. Most HT forms ultimately evolve into hypothyroidism, although at presentation patients can be euthyroid or even hyperthyroid. The diagnosis of HT relies on the demonstration of circulating antibodies to thyroid antigens (mainly thyroperoxidase and thyroglobulin) and reduced echogenicity on thyroid sonogram in a patient with proper clinical features. The treatment remains symptomatic and based on the administration of synthetic thyroid hormones to correct the hypothyroidism as needed. Surgery is performed when the goiter is large enough to cause significant compression of the surrounding cervical structures, or when some areas of the thyroid gland mimic the features of a nodule whose cytology cannot be ascertained as benign. HT remains a complex and ever expanding disease of unknown pathogenesis that awaits prevention or novel forms of treatment.
Abstract Antiphospholipid Syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity occurring in patients with persistent antiphospholipid antibodies (aPL). The primary objective of the APS Treatment Trends Task Force, created as part of the 14th International Congress on aPL, was to systematically review the potential future treatment strategies for aPL-positive patients. The task force chose as future clinical research directions: a) determining the necessity for controlled clinical trials in venous thromboembolism with the new oral direct thrombin or anti-factor Xa inhibitors pending the results of the ongoing rivaroxaban in APS (RAPS) trial, and designing controlled clinical trials in other forms of thrombotic APS; b) systematically analyzing the literature as well as aPL/APS registries, and creating specific registries for non-warfarin/heparin anticoagulants ; c) increasing recruitment for an ongoing primary thrombosis prevention trial, and designing secondary thrombosis and pregnancy morbidity prevention trials with hydroxychloroquine ; d) determining surrogate markers to select patients for statin trials; e) designing controlled studies with rituximab and other anti-B-cell agents; f) designing mechanistic and clinical studies with eculizumab and other complement inhibitors ; and g) chemically modifying peptide therapy to improve the half-life and minimize immunogenicity. The report also includes recommendations for clinicians who consider using these agents in difficult-to-manage aPL-positive patients.
Abstract First described in 1971, adult-onset Still's disease (AOSD) is a rare multisystemic disorder considered as a complex (multigenic) autoinflammatory syndrome. A genetic background would confer susceptibility to the development of autoinflammatory reactions to environmental triggers. Macrophage and neutrophil activation is a hallmark of AOSD which can lead to a reactive hemophagocytic lymphohistiocytosis. As in the latter disease, the cytotoxic function of natural killer cells is decreased in patients with active AOSD. IL-18 and IL-1β, two proinflammatory cytokines processed through the inflammasome machinery, are key factors in the pathogenesis of AOSD; they cause IL-6 and Th1 cytokine secretion as well as NK cell dysregulation leading to macrophage activation. The clinico-biological picture of AOSD usually includes high spiking fever with joint symptoms, evanescent skin rash, sore throat, striking neutrophilic leukocytosis, hyperferritinemia with collapsed glycosylated ferritin (< 20%), and abnormal liver function tests. According to the clinical presentation of the disease at diagnosis, two AOSD phenotypes may be distinguished: i) a highly symptomatic, systemic and feverish one, which would evolve into a systemic (mono- or polycyclic) pattern; ii) a more indolent one with arthritis in the foreground and poor systemic symptomatology, which would evolve into a chronic articular pattern. Steroid- and methotrexate-refractory AOSD cases benefit now from recent insights into autoinflammatory disorders: anakinra seems to be an efficient, well tolerated, steroid-sparing treatment in systemic patterns; tocilizumab seems efficient in AOSD with active arthritis and systemic symptoms while TNFα-blockers could be interesting in chronic polyarticular refractory AOSD.
Abstract Background There is increasing evidence that, in addition to the well-known effects on musculoskeletal health, vitamin D status may be related to a number of non-skeletal diseases. An international expert panel formulated recommendations on vitamin D for clinical practice, taking into consideration the best evidence available based on published literature today. In addition, where data were limited to smaller clinical trials or epidemiologic studies, the panel made expert-opinion based recommendations. Methods Twenty-five experts from various disciplines (classical clinical applications, cardiology, autoimmunity, and cancer) established draft recommendations during a 2-day meeting. Thereafter, representatives of all disciplines refined the recommendations and related texts, subsequently reviewed by all panelists. For all recommendations, panelists expressed the extent of agreement using a 5-point scale. Results and conclusion Recommendations were restricted to clinical practice and concern adult patients with or at risk for fractures, falls, cardiovascular or autoimmune diseases, and cancer. The panel reached substantial agreement about the need for vitamin D supplementation in specific groups of patients in these clinical areas and the need for assessing their 25-hydroxyvitamin D (25(OH)D) serum levels for optimal clinical care. A target range of at least 30 to 40 ng/mL was recommended. As response to treatment varies by environmental factors and starting levels of 25(OH)D, testing may be warranted after at least 3 months of supplementation. An assay measuring both 25(OH)D2 and 25(OH)D3 is recommended. Dark-skinned or veiled individuals not exposed much to the sun, elderly and institutionalized individuals may be supplemented (800 IU/day) without baseline testing.
Abstract Myelin oligodendrocyte glycoprotein (MOG) is a protein exclusively expressed on the surface of oligodendrocytes and myelin in the central nervous system. MOG has been identified as a putative candidate autoantigen and autoantibody target in demyelination for almost three decades, with extensive literature validating its role in murine models of experimental autoimmune encephalomyelitis. Seminal studies using murine anti-MOG antibodies have highlighted the fact that antibodies that target epitopes of native MOG in its conformational state, rather than linearized or denature`d MOG, are biologically relevant. However, the relevance of anti-MOG antibodies in humans has been difficult to decipher over the years due to varying methods of detection as well as the fact that it was assumed that these antibodies would be clinically associated with multiple sclerosis. There is now international consensus that anti-MOG antibodies are important in both pediatric and adult demyelination, and the clinical association of MOG antibody-associated demyelination has been refined to include acute disseminated encephalomyelitis, relapsing and bilateral optic neuritis, and transverse myelitis. Anti-MOG antibodies are now thought not to be associated with multiple sclerosis in adults. Patients with MOG antibody-associated demyelination appear to have a unique clinical, radiological, and therapeutic profile, which represents a major advance in their diagnosis and management. It is imperative to understand whether anti-MOG antibodies are indeed pathogenic, and if so, their mechanisms of action. As it has become apparent that there are differences in MOG epitope binding between species, translation of animal studies to human demyelination should be analyzed in this context. Further work is required to identify the specific epitope binding sites in human disease and pathogenic mechanisms of anti-MOG antibodies, as well optimal therapeutic strategies to improve prognosis and minimize disability in these patients.
Abstract The incidence of autoimmune diseases is increasing along with the expansion of industrial food processing and food additive consumption. The intestinal epithelial barrier, with its intercellular tight junction, controls the equilibrium between tolerance and immunity to non-self-antigens. As a result, particular attention is being placed on the role of tight junction dysfunction in the pathogenesis of AD. Tight junction leakage is enhanced by many luminal components, commonly used industrial food additives being some of them. Glucose, salt, emulsifiers, organic solvents, gluten, microbial transglutaminase, and nanoparticles are extensively and increasingly used by the food industry, claim the manufacturers, to improve the qualities of food. However, all of the aforementioned additives increase intestinal permeability by breaching the integrity of tight junction paracellular transfer. In fact, tight junction dysfunction is common in multiple autoimmune diseases and the central part played by the tight junction in autoimmune diseases pathogenesis is extensively described. It is hypothesized that commonly used industrial food additives abrogate human epithelial barrier function, thus, increasing intestinal permeability through the opened tight junction, resulting in entry of foreign immunogenic antigens and activation of the autoimmune cascade. Future research on food additives exposure-intestinal permeability–autoimmunity interplay will enhance our knowledge of the common mechanisms associated with autoimmune progression.
Abstract MicroRNAs (miRNAs) are single-stranded, endogenous non-coding small RNAs, ranging from 18 to 25 nucleotides in length. Growing evidence suggests that miRNAs are essential in regulating gene expression, cell development, differentiation and function. Autoimmune diseases are a family of chronic systemic inflammatory diseases. Recent findings on miRNA expression profiles have been suggesting their role as biomarkers in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis and Sjögren's syndrome. In this review, we summarize the characteristics of miRNAs and their functional role in the immune system and autoimmune diseases including systemic lupus erythematosus, primary Sjögren's syndrome, rheumatoid arthritis, systemic sclerosis, multiple sclerosis and psoriasis; moreover, we depict the advantages of miRNAs in modern diagnostics.
Abstract Background Failure of anti-TNF treatment in inflammatory bowel disease (IBD) patients can take on several forms, each posing distinct etio-pathogenic considerations and management dilemmas. Aim The aim of this study is to review the mechanisms responsible for the various forms of anti-TNF failures in IBD and to elucidate strategies for optimizing clinical efficacy. Results Primary failures of anti-TNF induction therapy occur in up to 40% of patients in clinical trials and in 10–20% in clinical series. Longer disease duration, smoking and several genetic mutations are predisposing factors for primary failures. Curiously, primary non-response is probably not a class-effect phenomenon since switching to another anti-TNF is effective in over 50% of such patients. Secondary loss of response is also a common clinical problem with incidence ranging between 23 and 46% at 12 months after anti-TNF initiation. Underlying mechanisms are often related to increased anti-TNF clearance by anti-drug antibodies, but may also include other causes for recalcitrant IBD activity as well as disorders that are unrelated to IBD itself. Astute management begins with verifying the presence of uncontrolled inflammatory IBD activity as a cause for patient's symptoms. Next, it is prudent to consider a trial of wait-and-see approach, since in some patients with mild-moderate symptoms, loss of response may resolve without alteration of therapy. If it does not, measuring anti-TNF trough levels and anti-drug antibodies may clarify the underlying mechanism in individual patients although there are still limited and conflicting data regarding the role of these measurements in guiding the choice between dose-intensification, switch to another anti-TNF or to another immuno-modulator, and the addition of an immuno-modulator as a combination therapy with the failing anti-TNF. Anti-TNF re-induction after prior drug-holiday is a distinct clinical scenario and scarce evidence suggests re-induction outcome to be dependent on the circumstances when drug-holiday was commenced. Finally, discontinuation of anti-TNF in patients with stable deep clinico-biologic and mucosal remission may be a viable option, as in these carefully selected patients the majority may enjoy long-term remission without the need for continued anti-TNF treatment.
Abstract Recent research in systemic lupus erythematosus (SLE) yielded new antigens and antibodies in SLE patients. We describe the various autoantibodies that can be detected in patients with SLE. A literature review, using the terms “autoantibody” and “systemic lupus erythematosus”, was conducted to search for articles on autoantibodies in SLE, their target antigens, association with disease activity and other clinical manifestations. One hundred and eighty autoantibodies were so far described in SLE patients. These include autoantibodies that target nuclear antigens, cytoplasmic antigens, cell membrane antigens, phospholipid-associated antigens, blood cells, endothelial cells, and nervous system antigens, plasma proteins, matrix proteins, and miscellaneous antigens. The target of an autoantibody, the autoantigen properties, autoantibody frequencies in SLE, as well as clinical associations, and correlation with disease activity are described for all 180 autoantibodies. SLE is so far the autoimmune disease with the largest number of detectable autoantibodies. Their production could be antigen-driven, the result of a polyclonal B cell activation, impaired apoptotic pathways, or the outcome of an idiotypic network dysregulation.
Abstract Toll-like receptors (TLRs) constitute an important mechanism in the activation of innate immune cells including monocytes, macrophages and dendritic cells. Macrophage activation by TLRs is pivotal in the initiation of the rapid expression of pro-inflammatory cytokines TNF, IL-1β and IL-6 while promoting Th17 responses, all of which play critical roles in autoimmunity. Surprisingly, in inflammatory arthritis, activation of specific TLRs can not only induce but also inhibit cellular processes associated with bone destruction. The intercellular and intracellular orchestration of signals from different TLRs, their endogenous or microbial ligands and accessory molecules determine the activating or inhibitory responses. Herein, we review the TLR-mediated activation of innate immune cells in their activation and differentiation to osteoclasts and the capacity of these signals to contribute to bone destruction in arthritis. Detailed understanding of the opposing mechanisms of TLRs in the induction and suppression of cellular processes in arthritis may pave the way to develop novel therapies to treat autoimmunity.
Abstract Regulatory T cells (Tregs) are central to the maintenance of self-tolerance and tissue homeostasis. Markers commonly used to define human Tregs in the research setting include high expression of CD25, FOXP3 positivity and low expression/negativity for CD127. Many other markers have been proposed, but none unequivocally identifies bona fide Tregs. Tregs are equipped with an array of mechanisms of suppression, including the modulation of antigen presenting cell maturation and function, the killing of target cells, the disruption of metabolic pathways and the production of anti-inflammatory cytokines. Treg impairment has been reported in a number of human autoimmune conditions and includes Treg numerical and functional defects and conversion into effector cells in response to inflammation. In addition to intrinsic Treg impairment, resistance of effector T cells to Treg control has been described. Discrepancies in the literature are common, reflecting differences in the choice of study participants and the technical challenges associated with investigating this cell population. Studies differ in terms of the methodology used to define and isolate putative regulatory cells and to assess their suppressive function. In this review we outline studies describing Treg frequency and suppressive function in systemic and organ specific autoimmune diseases, with a specific focus on the challenges faced when investigating Tregs in these conditions.
Abstract Rheumatoid arthritis (RA) is a polygenic disease characterized by autoimmunity and systemic inflammation with progressive impairment of joints that results in lifelong disability and increased mortality. Early diagnosis and therapeutic intervention or treatment can prevent severe disease manifestations in patients suffering from RA. The use of appropriate predictive biomarkers may improve the efficiency of RA therapy. The general aim of this review is to highlight the most recent findings on miRNAs expression profiles in RA patients and to discuss their potential as new biomarkers for diagnostic purposes. The current literature demonstrates that a variety of miRNAs is frequently dysregulated in RA patients. To date, the majority of miRNAs have been found to be overexpressed during the natural course of RA. MiR-16, miR-146a/b, miR-150, miR-155, and miR-223 described here were shown to be overexpressed at the systemic level: in both the periphery and RA joints. Circulating peripheral blood miRNAs, especially miR-16, miR-21, miR-24, miR-26a, miR-125a-5p, miR-125b, miR-126-3p, miR-223, and miR-451, which are elevated in the plasma or serum, are considered to be the most promising non-invasive biomarkers for the detection of RA.
Abstract Current classification criteria for definite Antiphospholipid Syndrome (APS) require the use of three laboratory assays to detect antiphospholipid antibodies (aCL, anti-β2GPI and LA) in the presence of at least one of the two major clinical manifestations (i.e. thrombosis or pregnancy morbidity) of the syndrome. However, several other autoantibodies shown to be directed to other proteins or their complex with phospholipids have been proposed to be relevant to APS but their clinical utility and their diagnostic value remains elusive. This report summarizes the findings, conclusions and recommendations of the “APS Task Force 3—Laboratory Diagnostics and Trends” meeting that took place during the 14th International Congress on Antiphospholipid Antibodies (APLA 2013, September 18–21, Rio de Janeiro, RJ, Brazil).