Autophagy in immunity: Implications in etiology of autoimmune/autoinflammatory diseases

Autophagy is now emerging as a spotlight in trafficking events that activate innate and adaptive immunity. It facilitates innate pathogen detection and antigen presentation, as well as pathogen clearance and lymphocyte homeostasis. In this review, we first summarize new insights into its functions in immunity, which underlie its associations with autoimmunity. As some lines of evidence are emerging to support its role in autoimmune and autoinflammatory diseases, we further discuss whether and how it affects autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, diabetes mellitus and multiple sclerosis, as well as autoinflammatory diseases, such as Crohn disease and vitiligo.     

Innate immunity functional gene polymorphisms and gout susceptibility

Gout is a common autoinflammatory disease characterized with elevated serum urate and recurrent attacks of intra-articular crystal deposition of monosodium urate. Accumulating evidence has demonstrated that MSU crystal-induced inflammation is a paradigm of innate immunity and the TLRs, NALP3 inflammasome and IL1R pathways are involved in gout development. Innate immunity components containing TLR2, TLR4, CD14, NALP3, ASC, Caspase-1 and CARD-8 are essential in the development of gouty inflammation. Recent studies suggest that innate immunity component gene functional mutations contribute to the development of autoinflammatory diseases including hereditary periodic fever syndrome, arthritis as well as inflammatory bowel disease. Taking into account these genetic findings, we would like to propose a novel hypothesis that the gene functional mutations might make innate immunity components as attractive susceptibility candidates and genetic markers for gout. Further clinical genetic studies need to be performed to confirm the role of innate immunity in the etiology of gout.     

病原DNA识别及其诱导天然免疫调节机制研究进展

机体天然免疫系统拥有一系列可以探测和抵制微生物侵袭的机制.目前,关于病原RNA的细胞内识别机制有了较为深入的研究和相关报道,但细胞内病原DNA的识别和相应的天然免疫应答机制仍未完全被揭示.阐明上述机制有助于了解和治疗一系列微生物感染相关的疾病,包括病毒和细菌感染类疾病、病毒相关的肿瘤、自身免疫性疾病等.近年来,细胞内多个充当"DNA传感器"的分子和干扰素调节分子被认为在细胞质DNA诱导宿主天然免疫反应过程中起着关键性调节作用.综述了对细胞内病原DNA的主要识别分子、信号通路以及相关的天然免疫调控机制.     

Secretory leukocyte protease inhibitor (SLPI), a multifunctional protein in the host defense response

Secretory leukocyte protease inhibitor (SLPI), a ∼12 kDa nonglycosylated cationic protein, is emerging as an important regulator of innate and adaptive immunity and as a component of tissue regenerative programs. First described as an inhibitor of serine proteases such as neutrophil elastase, this protein is increasingly recognized as a molecule that benefits the host via its anti-proteolytic, anti-microbial and immunomodulatory activities. Here, we discuss the diverse functions of SLPI. Moreover, we review several novel layers of SLPI-mediated control that protect the host from excessive/dysregulated inflammation typical of infectious, allergic and autoinflammatory diseases and that support healing responses through affecting cell proliferation, differentiation and apoptosis.     

Inflammasomes and autoimmunity

The NOD-like receptor (NLR) family members are cytosolic sensors of microbial components and danger signals. A subset of NLRs control inflammasome assembly that results in caspase-1 activation and, in turn, IL-1β and IL-18 production. Excessive inflammasome activation can cause autoinflammatory disorders, including the hereditary periodic fevers. Autoinflammatory and autoimmune diseases form a disease spectrum of aberrant, immune-mediated inflammation against self, through innate and adaptive immunity. However, the role of inflammasomes in autoimmune disease is less clear than in autoinflammation, despite the numerous effects IL-1β and IL-18 can have on shaping adaptive immunity. We summarize the role of inflammasomes in autoimmune disorders, highlight the need for a better understanding of inflammasomes in these conditions and offer suggestions for future research directions.     

Immunological function of familial Mediterranean fever disease protein Pyrin

Pyrin,encoded by MEFV gene,is conserved in humans and mice.Mutations in the MEFV gene are associated with the human autoinflammatory disease familial Mediterranean fever(FMF).Pyrin can interact with the inflammasome adaptor ASC and induce inflammatory caspase-1 activation in monocytic cells,but the physiological function of Pyrin has been unknown for many years.Here we summarize previous studies of Pyrin function under the context of FMF and immunity,and discuss a recent study demonstrating that Pyrin forms an inflammasome complex for caspase-1 activation in innate immunity.Pyrin inflammasome detects inactivating modifications of host Rho GTPases by diverse bacterial toxins and infections,including Clostridium difficile glucosylating cytotoxin Tcd B,FIC-domain adenylyltransferase effectors from Vibrio parahaemolyticus and Histophilus somni,ADP-ribosylating Clostridium botulinum C3 toxin as well as Burkholderia cenocepacia infection.The mode of Pyrin action,i.e.,sensing pathogen virulence activity rather than directly recognizing a microbial molecule,represents a new paradigm in innate immunity.     

Host responses from innate to adaptive immunity after vaccination: Molecular and cellular events

The availability of effective vaccines has had the most profound positive effect on improving the quality of public health by preventing infectious diseases. Despite many successful vaccines, there are still old and new emerging pathogens against which there is no vaccine available. A better understanding of how vaccines work for providing protection will help to improve current vaccines as well as to develop effective vaccines against pathogens for which we do not have a proper means to control. Recent studies have focused on innate immunity as the first line of host defense and its role in inducing adaptive immunity; such studies have been an intense area of research, which will reveal the immunological mechanisms how vaccines work for protection. Toll-like receptors (TLRs), a family of receptors for pathogen-associated molecular patterns on cells of the innate immune system, play a critical role in detecting and responding to microbial infections. Importantly, the innate immune system modulates the quantity and quality of longterm T and B cell memory and protective immune responses to pathogens. Limited studies suggest that vaccines which mimic natural infection and/or the structure of pathogens seem to be effective in inducing long-term protective immunity. A better understanding of the similarities and differences of the molecular and cellular events in host responses to vaccination and pathogen infection would enable the rationale for design of novel preventive measures against many challenging pathogens.     

H. pylori exploits and manipulates innate and adaptive immune cell signaling pathways to establish persistent infection

Persistent infection with the gastric bacterial pathogen Helicobacter pylori causes gastritis and predisposes carriers to a high gastric cancer risk, but has also been linked to protection from allergic, chronic inflammatory and autoimmune diseases. In the course of tens of thousands of years of co-existence with its human host, H. pylori has evolved elaborate adaptations that allow it to persist in the hostile environment of the stomach in the face of a vigorous innate and adaptive immune response. For this review, we have identified several key immune cell types and signaling pathways that appear to be preferentially targeted by the bacteria to establish and maintain persistent infection. We explore the mechanisms that allow the bacteria to avoid detection by innate immune cells via their pattern recognition receptors, to escape T-cell mediated adaptive immunity, and to reprogram the immune system towards tolerance rather than immunity. The implications of the immunomodulatory properties of the bacteria for the prevention of allergic and auto-immune diseases in chronically infected individuals are also discussed.     

Developments in the scientific and clinical understanding of autoinflammatory disorders

The autoinflammatory diseases, also known as periodic fever syndromes, are disorders of innate immunity which can be inherited or acquired and which cause recurrent, self-limiting, seemingly spontaneous episodes of systemic inflammation and fever in the absence of autoantibody production or infection. There has been much recent progress in elucidating their aetiologies and treatment. With the exception of familial Mediterranean fever, which is common in certain populations, autoinflammatory diseases are mostly rare but should not be overlooked in the differential diagnosis of recurrent fevers since DNA diagnosis and effective therapies are available for many of them.     

I kappa B kinase alpha (IKKα) activity is required for functional maturation of dendritic cells and acquired immunity to infection

Dendritic cells (DC) are required for priming antigen‐specific T cells and acquired immunity to many important human pathogens, including Mycobacteriuim tuberculosis (TB) and influenza. However, inappropriate priming of auto‐reactive T cells is linked with autoimmune disease. Understanding the molecular mechanisms that regulate the priming and activation of naïve T cells is critical for development of new improved vaccines and understanding the pathogenesis of autoimmune diseases. The serine/threonine kinase IKKα (CHUK) has previously been shown to have anti‐inflammatory activity and inhibit innate immunity. Here, we show that IKKα is required in DC for priming antigen‐specific T cells and acquired immunity to the human pathogen Listeria monocytogenes. We describe a new role for IKKα in regulation of IRF3 activity and the functional maturation of DC. This presents a unique role for IKKα in dampening inflammation while simultaneously promoting adaptive immunity that could have important implications for the development of new vaccine adjuvants and treatment of autoimmune diseases.     

E3 ubiquitin ligase Cbl-b in innate and adaptive immunity

Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b), a RING finger E3 ubiquitin-protein ligase, has been demonstrated to play a crucial role in establishing the threshold for T-cell activation and controlling peripheral T-cell tolerance via multiple mechanisms. Accumulating evidence suggests that Cbl-b also regulates innate immune responses and plays an important role in host defense to pathogens. Understanding the signaling pathways regulated by Cbl-b in innate and adaptive immune cells is therefore essential for efficient manipulation of Cbl-b in emerging immunotherapies for human disorders such as autoimmune diseases, allergic inflammation, infections, and cancer. In this article, we review the latest developments in the molecular structural basis of Cbl-b function, the regulation of Cbl-b expression, the signaling mechanisms of Cbl-b in immune cells, as well as the biological function of Cbl-b in physiological and pathological immune responses in animal models and human diseases.     

IL-18 in autoimmunity: review

IL-18 is among the cytokines responsible for immune-mediated pathologies and is probably one of the factors that contribute to the pathogenesis of autoimmune diseases. Identification of the causes of uncontrolled IL-18 production and activity in autoimmunity would allow for novel therapeutic targets to effectively block autoimmune activation and inhibit concomitant tissue damage. IL-18 is produced mainly by monocytes/macrophages in response to stimuli of viral/bacterial origin, its production being therefore one of the effects of innate immunity initiated by host-pathogen interaction. In this review, we summarise the evidence supporting both the effector and the pathogenic role of IL-18 in autoimmunity, and propose that the disturbed mechanism of innate immunity, resulting from macrophage activation through innate immunity receptors (TLR/IL-1R family), may be the basis of pathologically high levels of IL-18 production and activation. Unravelling the mechanisms of IL-18 production and activity in autoimmune diseases will allow the identification of targets for more effective therapeutic intervention.     

Toll-like receptors in autoimmunity with special reference to systemic lupus erythematosus

The Toll-like receptor (TLR) family plays a fundamental role in host innate immunity by mounting a rapid and potent inflammatory response to pathogen infection. TLRs recognize distinct microbial components and activate intracellular signaling pathways that induce expression of host inflammatory genes. Several studies have indicated that TLRs are implicated in many inflammatory and immune disorders. Extensive research in the past decade to understand TLR-mediated mechanisms of innate immunity has enabled pharmaceutical companies to begin to develop novel therapeutics for the purpose of controlling an inflammatory disease. The roles of TLRs in the development of autoimmune diseases have been studied. TLR7 and TLR9 have key roles in production of autoantibodies and/or in development of systemic autoimmune disease. It remains to be determined their role in apoptosis, in the pathogenesis of RNA containing immune complexes, differential expression of TLRs by T regulatory cells.     

Therapeutic effect of omega-3 fatty acids on T cell-mediated autoimmune diseases

The present study was to demonstrate that the G protein coupled receptors serve as targets for the treatment of autoimmune disease such as rheumatoid arthritis and multiple sclerosis. Rats received pristane at the base of the tail. Affected joints were counted daily. The T cell mediated autoimmune diseases such as pristine-induced arthritis (PIA) and autoimmune encephalomyelitis (EAE) in a rat model were profoundly ameliorated by treatment with the specific G protein couple receptors 120 (GPR120) stimuli omega-3 fatty acids (ω-3 FAs). Our study further revealed that the activation of GPR120 by ω-3 FAs can result in a decrease of phosphorylated transforming growth factor-β activated kinase 1 (TAK1), and further inhibit the downstream IKKβ/I-κB pathway and the terminal NF-κB activation which serves as a mediator of T cell activation. ω-3 Fatty acids exhibited an inhibitory effect on TAK1 by enhancing the association of β-arrestin2 and TAK1 binding protein 1 (TAB1), thus the disassociation of TAB1 from the TAB1/TAK1 complex renders a limited effect on β-arrestin2 signaling as an innate immunity regulation. GPR120 is a functional receptor of ω-3 fatty acids in T cell-mediated autoimmune disease compared with its effect on innate immunity.     

A special issue on ＂Interferons, Cytokines, and Immunity＂

Vertebrates including human employ both innate and adaptive immune responses to defend against pathogen infections and malignancy. Interferons and cytokines play pivotal roles in mediating and coordinating diverse aspects of the host immune response responsible for the clearance of infection and elimination of malignant cells. In addition, abnormal immune and/or inflammatory responses are closely linked to the pathogenesis of various human diseases such as infections, autoimmune diseases and cancer. Thus, a better understanding of these signaling pathways is essential to our efforts in developing more effective regimes to prevent and treat infectious diseases as well as to combat autoimmune diseases and cancer.     

Antiviral TRIMs: friend or foe in autoimmune and autoinflammatory disease?

The concept that viral sensing systems, via their ability to drive pro-inflammatory cytokine and interferon production, contribute to the development of autoimmune and autoinflammatory disease is supported by a wide range of clinical and experimental observations. Recently, the tripartite motif-containing proteins (TRIMs) have emerged as having key roles in antiviral immunity - either as viral restriction factors or as regulators of pathways downstream of viral RNA and DNA sensors, and the inflammasome. Given their involvement in these pathways, we propose that TRIM proteins contribute to the development and pathology of autoimmune and autoinflammatory conditions, thus making them potential novel targets for therapeutic manipulation.     

Mitochondrial DNA in the regulation of innate immune responses

Mitochondrion is known as the energy factory of the cell, which is also a unique mammalian organelle and considered to be evolved from aerobic prokaryotes more than a billion years ago. Mitochondrial DNA, similar to that of its bacterial ancestor’s, consists of a circular loop and contains significant number of unmethylated DNA as CpG islands. The innate immune system plays an important role in the mammalian immune response. Recent research has demonstrated that mitochondrial DNA (mtDNA) activates several innate immune pathways involving TLR9, NLRP3 and STING signaling, which contributes to the signaling platforms and results in effector responses. In addition to facilitating antibacterial immunity and regulating antiviral signaling, mounting evidence suggests that mtDNA contributes to inflammatory diseases following cellular damage and stress. Therefore, in addition to its well-appreciated roles in cellular metabolism and energy production, mtDNA appears to function as a key member in the innate immune system. Here, we highlight the emerging roles of mtDNA in innate immunity.     

From inflammasomes to fevers, crystals and hypertension: how basic research explains inflammatory diseases

Pattern-recognition receptors, such as Toll-like receptors and NOD-like receptors (NLRs), are able through the recognition of pathogen-associated molecular patterns and danger-associated molecular patterns to sense microbe-dependent and microbe-independent danger and thereby initiate innate immune responses. In some autoinflammatory conditions, abnormalities in NLR signaling pathways are involved in pathogenesis, as exemplified by NOD2 mutations associated with Crohn's disease. Some other NLRs are components of the inflammasome, a caspase-1- and prointerleukin-1beta-activating complex. Clinical and experimental studies are beginning to reveal the central role of the inflammasome in innate immunity. Here, we focus on monogenic hereditary inflammatory diseases, such as Muckle-Wells syndrome, which are associated with mutations in proteins that modulate the activity of the inflammasome, and on some multifactorial disorders, such as Type 2 diabetes and hypertension.