IL‐6: Regulator of Treg/Th17 balance

IL‐6 is a pleiotropic cytokine involved in the physiology of virtually every organ system. Recent studies have demonstrated that IL‐6 has a very important role in regulating the balance between IL‐17‐producing Th17 cells and regulatory T cells (Treg). The two T‐cell subsets play prominent roles in immune functions: Th17 cell is a key player in the pathogenesis of autoimmune diseases and protection against bacterial infections, while Treg functions to restrain excessive effector T‐cell responses. IL‐6 induces the development of Th17 cells from naïve T cells together with TGF‐β; in contrast, IL‐6 inhibits TGF‐β‐induced Treg differentiation. Dysregulation or overproduction of IL‐6 leads to autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA), in which Th17 cells are considered to be the primary cause of pathology. Given the critical role of IL‐6 in altering the balance between Treg and Th17 cells, controlling IL‐6 activities is potentially an effective approach in the treatment of various autoimmune and inflammatory diseases. Here, we review the role of IL‐6 in regulating Th17/Treg balance and describe the critical functions of IL‐6 and Th17 in immunity and immune‐pathology.     

Selfie: Autoimmunity,boon or bane

The immune system provides protection to tissues damaged by infectious microrganisms or physical damage. In autoimmune diseases, the immune system recognizes and attacks its own tissues, i.e., self-destruction. Various agents such as genetic factors and environmental triggers are thought to play a major role in the development of autoimmune diseases. A common feature of all autoimmune diseases is the presence of autoantibodies and inflammation, including mononuclear phagocytes, autoreactive T lymphocytes, and autoantibody producing B cells (plasma cells). It has long been known that B cells produce autoantibodies and, thereby, contribute to the pathogenesis of many autoimmune diseases. Autoimmune diseases can be classified as organ-specific or non-organ specific depending on whether the autoimmune response is directed against a particular tissue or against widespread antigens as in chronic inflammatory autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Both SLE and RA are characterized by the presence of autoantibodies which play a major role in their etiopathogenesis. SLE is characterized by circulating antibodies and immune complex deposition that can trigger an inflammatory damage in organs. RA is a progressive inflammatory disease in which T cells, B cells, and pro-inflammatory cytokines play a key role in its pathophysiology.     

Breast milk – immunomodulatory signals against allergic diseases

Breastfeeding holds a key position with regard to the increasing burden of allergic diseases in the industrialized countries. Not only does it provide the infant with nutrients for growth and development, it also confers immunological protection during a critical period in life, when the infant's own defense mechanisms are immature. A delicate balance of stimulatory, even inflammatory, maturational signals, together with a myriad of anti-inflammatory compounds, is transferred from mother to infant via breastfeeding. Breastfeeding mothers, however, do not constitute a uniform group. The composition of breast milk shows marked individual variation and so, consequently, does the success of breastfeeding in reducing the risk of disease. Recent clinical studies indicate that the potential of breastfeeding to counteract allergic disease may be promoted by dietary means. While uncoordinated elimination diets result in a risk of general nutritional inadequacy or deficiency of essential single nutrients, a balanced diet following current dietary recommendations, specifically containing fresh fruits and vegetables (antioxidants) and fat of predominantly vegetable origin, may be associated with a lower incidence of atopy in the infant. As early nutrition appears to program the subsequent health of the child, the importance of the maternal dietary composition during breastfeeding should be emphasized. In future, an improved understanding of the mechanisms of this programming may offer specific therapeutic modalities for the prevention of allergic disease.     

Dendritic cells in tolerance induction for the treatment of autoimmune diseases

Autoimmune diseases are characterized by the loss of tolerance toward self‐antigens and the induction of destructive immune responses leading to tissue damage. Most patients with autoimmune diseases are treated with immunosuppressive drugs that suppress the immune response in a non‐specific fashion, which is inevitably accompanied by several side effects. Antigen‐specific immunomodulation and patient‐tailored therapies are likely to solve these issues and to elicit long‐term protection against disease flares. This Viewpoint analyzes the potential use of DC for induction of antigen‐specific tolerance in autoimmune disease settings.     

Helminths products directly modulate T cells that mediate experimental autoimmune encephalomyelitis

Infection with helminths can protect against the development of autoimmune diseases and this has been associated with induction of anti‐inflammatory innate immune responses and Tregs. Here, we demonstrate that helminth‐derived products can directly target T cells, especially IL‐17‐secreting γδ T cells that play a key pathogenic role in CNS autoimmune disease.     

99th Dahlem Conference on Infection,Inflammation and Chronic Inflammatory Disorders: Triggering of autoimmune diseases by infections

Human autoimmune diseases, such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus (SLE), are linked genetically to distinct major histocompatibility complex (MHC) class II molecules and other immune modulators. However, genetic predisposition is only one risk factor for the development of these diseases, and low concordance rates in monozygotic twins as well as geographical distribution of disease risk suggest a critical role for environmental factors in the triggering of these autoimmune diseases. Among potential environmental factors, infections have been implicated in the onset and/or promotion of autoimmunity. This review will discuss human autoimmune diseases with a potential viral cause, and outline potential mechanisms by which pathogens can trigger autoimmune disease as discerned from various animal models of infection‐induced autoimmune disease.     

Autoimmune priming,tissue attack and chronic inflammation — The three stages of rheumatoid arthritis

Extensive genome‐wide association studies have recently shed some light on the causes of chronic autoimmune diseases and have confirmed a central role of the adaptive immune system. Moreover, better diagnostics using disease‐associated autoantibodies have been developed, and treatment has improved through the development of biologicals with precise molecular targets. Here, we use rheumatoid arthritis (RA) as a prototype for chronic autoimmune disease to propose that the pathogenesis of autoimmune diseases could be divided into three discrete stages. First, yet unknown environmental challenges seem to activate innate immunity thereby providing an adjuvant signal for the induction of adaptive immune responses that lead to the production of autoantibodies and determine the subsequent disease development. Second, a joint‐specific inflammatory reaction occurs. This inflammatory reaction might be clinically diagnosed as the earliest signs of the disease. Third, inflammation is converted to a chronic process leading to tissue destruction and remodeling. In this review, we discuss the stages involved in RA pathogenesis and the experimental approaches, mainly involving animal models that can be used to investigate each disease stage. Although we focus on RA, it is possible that a similar stepwise development of disease also occurs in other chronic autoimmune settings such as multiple sclerosis (MS), type 1 diabetes, and systemic lupus erythematosus.     

Macrophage‐derived reactive oxygen species protects against autoimmune priming with a defined polymeric adjuvant

Understanding the nature of adjuvants and the immune priming events in autoimmune diseases, such as rheumatoid arthritis, is a key challenge to identify their aetiology. Adjuvants are, however, complex structures with inflammatory and immune priming properties. Synthetic polymers provide a possibility to separate these functions and allow studies of the priming mechanisms in vivo. A well‐balanced polymer, poly‐N‐isopropyl acrylamide (PNiPAAm) mixed with collagen type II (CII) induced relatively stronger autoimmunity and arthritis compared with more hydrophilic (polyacrylamide) or hydrophobic (poly‐N‐isopropylacrylamide‐co‐poly‐N‐tertbutylacrylamide and poly‐N‐tertbutylacrylamide) polymers. Clearly, all the synthesized polymers except the more hydrophobic poly‐N‐tertbutylacrylamide induced arthritis, especially in Ncf1‐deficient mice, which are deficient in reactive oxygen species (ROS) production. We identified macrophages as the major infiltrating cells present at PNiPAAm‐CII injection sites and demonstrate that ROS produced by the macrophages attenuated the immune response and the development of arthritis. Our results reveal that thermo‐responsive polymers with high immune priming capacity could trigger an autoimmune response to CII and the subsequent arthritis development, in particular in the absence of NOX2 derived ROS. Importantly, ROS from macrophages protected against the autoimmune priming, demonstrating a critical regulatory role of macrophages in immune priming events.     

Lessons from helminth infections: ES‐62 highlights new interventional approaches in rheumatoid arthritis

Parasitic worms are able to survive in their mammalian host for many years due to their ability to manipulate the immune response by secreting immunomodulatory products. It is increasingly clear that, reflecting the anti‐inflammatory actions of such worm‐derived immunomodulators, there is an inverse correlation between helminth infection and autoimmune diseases in the developing world. As the decrease in helminth infections due to increased sanitation has correlated with an alarming increase in prevalence of such disorders in industrialized countries, this ‘hygiene hypothesis’ has led to the proposal that worms and their secreted products offer a novel platform for the development of safe and effective strategies for the treatment of autoimmune disorders. In this study we review the anti‐inflammatory effects of one such immunomodulator, ES‐62 on innate and adaptive immune responses and the mechanisms it exploits to afford protection in the murine collagen‐induced arthritis (CIA) model of rheumatoid arthritis (RA). As its core mechanism involves targeting of interleukin (IL)‐17 responses, which despite being pathogenic in RA are important for combating infection, we discuss how its selective targeting of IL‐17 production by T helper type 17 (Th17) and γδ T cells, while leaving that of CD49b⁺ natural killer (NK and NK T) cells intact, reflects the ability of helminths to modulate the immune system without immunocompromising the host. Exploiting helminth immunomodulatory mechanisms therefore offers the potential for safer therapies than current biologicals, such as ‘IL‐17 blockers’, that are not able to discriminate sources of IL‐17 and hence present adverse effects that limit their therapeutic potential.     

Germ‐free mice deficient of reactive oxygen species have increased arthritis susceptibility

The NADPH oxidase 2 (NOX2) complex is responsible for the production of ROS in phagocytic cells. Genetic defects in NOX2 lead to opportunistic infections and inflammatory manifestations such as granulomas in humans, also known as chronic granulomatous disease (CGD). This condition is mirrored in mice with defective ROS production and interestingly both species are predisposed to autoimmune diseases. An unresolved question is whether the hyper‐inflammation and tendency to develop autoimmunity are secondary to the increased infections, or whether these are parallel phenomena. We generated germ‐free ROS deficient Ncf1 mutant mice that when reared in specific pathogen‐free condition, are highly susceptible to collagen‐induced arthritis compared with wild‐type mice. Strikingly, arthritis incidence and severity was almost identical in germ‐free and specific pathogen‐free ROS‐deficient mice. In addition, partial reduction of the microbial flora by antibiotics treatment did not alter the disease course. Taken together, this shows that ROS has a clear immune regulatory function that is decoupled from its function in host defence.     

The Th17 Pathway as a Therapeutic Target in Rheumatoid Arthritis and Other Autoimmune and Inflammatory Disorders

Production of the pro-inflammatory cytokine interleukin (IL)-17 by Th17 cells and other cells of the immune system protects the host against bacterial and fungal infections, but also promotes the development of rheumatoid arthritis (RA) and other autoimmune and inflammatory disorders. Several biologicals targeting IL-17, the IL-17 receptor, or IL-17-related pathways are being tested in clinical trials, and might ultimately lead to better treatment for patients suffering from various IL-17-mediated disorders. In this review, we provide a clear overview of current knowledge on Th17 cell regulation and the main Th17 effector cytokines in relation to IL-17-mediated conditions, as well as on recent IL-17-related drug developments. We demonstrate that targeting the Th17 pathway is a promising treatment for rheumatoid arthritis and various other autoimmune and inflammatory diseases. However, improvements in technical developments assisting in the identification of patients suffering from IL-17-driven disease are needed to enable the application of tailor-made, personalized medicine.     

Breast-feeding in 1991

The author discusses support for the benefits of breastfeeding during the 1st 3-6 months of an infant's life, raises the issues of potentially deleterious and detrimental maternal-infant exchange of infectious diseases and alcohol, and comments on demands faced by working mothers hoping to breastfeed. For developing countries, breastfeeding is an inexpensive, nutritious feeding method, which may be used instead of other potentially contaminated or inadequate substances. Rich in immune components, studies suggest that breast milk reduces infant morbidity and mortality from infectious diseases, and may increase the chances of survival of low-birth-weight infants in both developed and developing countries. Concerns over available feeding alternatives and sanitation being less important in the United States, most physicians still encourage mothers to breastfeed on the basis of its cost-effectiveness, the potential effects on the clinical severity of gastrointestinal infections, the presumed beneficial effects on maternal-infant interactions, the mother's perception of that interaction, and its contributions to the mother's confidence in her maternal capabilities. The author acknowledges the need for concern over HIV and alcohol transmission from mother to child through breast milk, and discusses the ongoing debate while pointing out caveats and qualifications to conclusions. Breastfeeding may be impossible for constrained by the obligations of work. Accordingly, physicians should recognize these limitations, and support political and legislative initiatives to make breastfeeding a practical possibility for all mothers.     

Human dendritic cells — stars in the skin

“A properly functioning adaptive immune system signifies the best features of life. It is diverse beyond compare, tolerant without fail, and capable of behaving appropriately with a myriad of infections and other challenges. Dendritic cells (DCs) are required to explain how this remarkable system is energized and directed.” This is a quote by one of the greatest immunologists our community has ever known, and the father of dendritic cells, Ralph Steinman. Steinman's discovery of DCs in 1973 and his subsequent research opened a new field of study within immunology: DC biology and in particular the role of DCs in immune regulation in health and disease. Here, I review themes from our work and others on the complex network of dendritic cells in the skin and discuss the significance of skin DCs in understanding aspects of host defense against infections, the pathology of inflammatory skin diseases, and speculate on the future effective immune‐based therapies.     

Rheumatoid arthritis: the role of reactive oxygen species in disease development and therapeutic strategies

Autoimmune diseases such as rheumatoid arthritis (RA) are chronic diseases that cannot be prevented or cured If the pathologic basis of such disease would be known, it might be easier to develop new drugs interfering with critical pathway. Genetic analysis of animal models for autoimmune diseases can result in discovery of proteins and pathways that play key function in pathogenesis, which may provide rationales for new therapeutic strategies. Currently, only the MHC class II is clearly associated with human RA and animal models for RA. However, recent data from rats and mice with a polymorphism in Ncf1, a member of the NADPH oxidase complex, indicate a role for oxidative burst in protection from arthritis. Oxidative burst-activating substances can treat and prevent arthritis in rats, as efficiently as clinically applied drugs, suggesting a novel pathway to a therapeutic target in human RA. Here, the authors discuss the role of oxygen radicals in regulating the immune system and autoimmune disease. It is proposed that reactive oxygen species set the threshold for T cell activation and thereby regulate chronic autoimmune inflammatory diseases like RA. In the light of this new hypothesis, new possibilities for preventive and therapeutic treatment of chronic inflammatory diseases are discussed.     

Emerging role of interleukin‐33 in autoimmune diseases

Interleukin‐33 (IL‐33) is a member of the IL‐1 cytokine family. It predominantly induces type 2 immune responses and thus is protective against atherosclerosis and nematode infections but contributes to allergic airway inflammation. Interleukin‐33 also plays a pivotal role in the development of many autoimmune diseases through mechanisms that are still not fully understood. In this review, we focus on the recent advances in understanding of the expression and function of IL‐33 in some autoimmune disorders, aiming to provide insight into its potential role in disease development.     

The role of B cells and their interactions with stromal cells in the context of inflammatory autoimmune diseases

Interactions between B cells and stromal cells have essential functions in immune cell development and responses. During chronic inflammation, the pro-inflammatory microenvironment leads to changes in stromal cells, which acquire a pathogenic phenotype specific to each organ and disease. B cells are recruited to the site of inflammation and interact with these pathogenic stromal cells contributing to the disease’s severity. In addition to producing autoantibodies, B cells contribute to the pathogenesis of autoimmune inflammatory diseases by serving as professional antigen-presenting cells, producing cytokines, and through additional mechanisms. This review describes the role of B cells and their interactions with stromal cells in chronic inflammation, with a focus on human disease, using three selected autoimmune inflammatory diseases: rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis. Understanding B cells roles and their interaction with stromal cells will help develop new therapeutic options for the treatment of autoimmune diseases.     

P38丝裂原活化蛋白激酶信号转导通路在免疫性疾病中的研究进展

P38丝裂原活化蛋白激酶(P38 mitogen activated protein kinase,P38MAPK)信号转导通路在机体的免疫应答反应中发挥着重要作用,包括与类风湿性关节炎、原发性干燥综合征、寻常型天疱疮、炎症性肠病、系统性红斑狼疮、骨关节病、银屑病、自身免疫性脑脊髓炎等疾病密切相关.其不仅参与免疫性疾病炎性介质的调节,还参与其发生发展相关基因的调控,因此探讨P38MAPK信号转导通路在免疫性疾病中的作用可为免疫性疾病在临床中的治疗研究提供新的思路.     

The Hygiene Theory Harnessing Helminths and Their Ova to Treat Autoimmunity

The incidence of autoimmune diseases is increasing in Western countries, possibly due to the improved sanitary conditions and reduced exposure to infections in childhood (the hygiene hypothesis). There is an ongoing debate whether infection prevents or precipitates autoimmune diseases. Various helminths species used in several animal models were shown to limit inflammatory activity in a variety of diseases including inflammatory bowel disease, multiple sclerosis, type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. At present the scientific data is based mostly on experimental animal models; however, there is an increasing body of evidence in a number of clinical trials being conducted. Herein we review several clinical trials evaluating the anti-inflammatory effects of helminths and assessing their association with different autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, and autoimmune liver diseases. We also describe the common pathways by which helminths induce immune modulation and the key changes observed in the host immune system following exposure to helminths. These common pathways include the inhibition of IFN-γ and IL-17 production, promotion of IL-4, IL-10 and TGF-β release, induction of CD4(+) T cell FoxP3⁺ expression, and generation of regulatory macrophages, dendritic cells, and B cells. Helminths products are becoming significant candidates for anti-inflammatory agents in this context. However, further research is needed for synthetic analogues of helminths' potent products that mimic the parasite-mediated immunomodulation effect.     

Prolactin and Autoimmunity

The relationship between prolactin and the immune system has been demonstrated in the last two decades, opening new windows in the field of the immunoendocrinology. Prolactin has an important role in the innate and adaptive immune response. Increased prolactin levels have been described in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, and systemic sclerosis among others. Hyperprolactinemia is associated with active disease and organ involvement in systemic lupus erythematosus. Therefore, prolactin is an integral member of the immunoneuroendocrinology network and seems to have a role in pathogenesis of autoimmune diseases. Few controlled studies of dopamine agonist treatment in humans with autoimmune disease have been conducted only in systemic lupus erythematosus patients, which support the potential efficacy of such agents even during pregnancy and postpartum. Further studies are necessary to elucidate the mechanisms by which prolactin affects autoimmune disease activity, increase the inflammatory mechanism, and determine the role of anti-prolactinemic drugs to regulate the immune/inflammatory process.