Autophagy in immunity

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.     

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.     

Immunological pathomechanisms in vitiligo

Vitiligo is a depigmenting disorder characterised by the loss of melanocytes from the cutaneous epidermis. Although the exact aetiology of vitiligo has not yet been established, the abnormal immune responses frequently observed in vitiligo patients have led to the suggestion that, in some cases, the condition has an autoimmune component. Briefly, circulating autoantibodies and autoreactive T cells that recognise pigment cell antigens have been detected in the sera of a significant proportion of vitiligo patients compared with healthy individuals. In addition, vitiligo is often associated with other disorders that have an autoimmune origin, including Hashimoto's thyroiditis, Graves' disease, type 1 insulin-dependent diabetes mellitus and Addison's disease. Furthermore, effective use of immunosuppressive therapies to treat vitiligo, the association of vitiligo with certain major histocompatibility complex antigens, and evidence from animal models of the disease have all added credence to the hypothesis that immune reactions play a role in vitiligo pathogenesis. This review presents and discusses the evidence for immunological pathomechanisms in vitiligo.     

Mercury-induced inflammation and autoimmunity

BackgroundHuman exposure to mercury leads to a variety of pathologies involving numerous organ systems including the immune system. A paucity of epidemiological studies and suitable diagnostic criteria, however, has hampered collection of sufficient data to support a causative role for mercury in autoimmune diseases. Nevertheless, there is evidence that mercury exposure in humans is linked to markers of inflammation and autoimmunity. This is supported by experimental animal model studies, which convincingly demonstrate the biological plausibility of mercury as a factor in the pathogenesis of autoimmune disease.Scope of the reviewIn this review, we focus on ability of mercury to elicit inflammatory and autoimmune responses in both humans and experimental animal models.Major conclusionsAlthough subtle differences exist, the inflammatory and autoimmune responses elicited by mercury exposure in humans and experimental animal models show many similarities. Proinflammatory cytokine expression, lymphoproliferation, autoantibody production, and nephropathy are common outcomes. Animal studies have revealed significant strain dependent differences in inflammation and autoimmunity suggesting genetic regulation. This has been confirmed by the requirement for individual genes as well as genome wide association studies. Importantly, many of the genes required for mercury-induced inflammation and autoimmunity are also required for idiopathic systemic autoimmunity. A notable difference is that mercury-induced autoimmunity does not require type I IFN. This observation suggests that mercury-induced autoimmunity may arise by both common and specific pathways, thereby raising the possibility of devising criteria for environmentally associated autoimmunity.General significanceMercury exposure likely contributes to the pathogenesis of autoimmunity.     

Is the origin of type 1 diabetes in the gut?

In type 1 diabetes, insulin-producing beta-cells in the pancreas are destroyed by immune-mediated mechanisms. The manifestation of the disease is preceded by the so-called pre-diabetic period that may last several years and is characterized by the appearance of circulating autoantibodies against beta-cell antigens. The role of the gut as a regulator of type 1 diabetes was suggested in animal studies, in which changes affecting the gut immune system modulated the incidence of diabetes. Dietary interventions, alterations in the intestinal microbiota and exposure to enteric pathogens, regulate the development of autoimmune diabetes in animal models. It has been demonstrated that these modulations affect the gut barrier mechanisms and intestinal immunity. Because the pancreas and the gut belong to the same intestinal immune system, the link between autoimmune diabetes and the gut is not unexpected. The gut hypothesis in the development of type 1 diabetes is also supported by the observations made in human type 1 diabetes. Early diet could modulate the development of beta-cell autoimmunity; weaning to hydrolysed casein formula decreased the risk of beta-cell autoimmunity by age 10 in the infants at genetic risk. Increased gut permeability, intestinal inflammation with impaired regulatory mechanisms and dysregulated oral tolerance have been observed in children with type 1 diabetes. The factors that contribute to these intestinal alterations are not known, but interest is focused on the microbial stimuli and function of innate immunity. It is likely that our microbial environment does not support the healthy maturation of the gut and tolerance in the gut, and this leads to the increasing type 1 diabetes as well as other immune-mediated diseases regulated by intestinal immune system. Thus, the interventions, aiming to prevent or treat type 1 diabetes in humans, should be targeting the gut immune system.     

HLA class II haplotype DRB1*04–DQB1*0301 contributes to risk of familial generalized vitiligo and early disease onset

Generalized vitiligo is a common autoimmune disorder characterized by white patches of skin and overlying hair caused by loss of pigment‐forming melanocytes from involved areas. Familial clustering of vitiligo is not uncommon, and patients and their relatives are at increased risk for a specific complex of other autoimmune diseases. Compared with sporadic vitiligo, familial vitiligo is characterized by earlier disease onset and greater risk and broader repertoire of autoimmunity, suggesting a stronger genetic component, and perhaps stronger associations with specific alleles. To determine whether the major histocompatibility complex (MHC) contributes to the familial clustering of vitiligo and vitiligo‐associated autoimmune/autoinflammatory diseases, we performed case–control and family‐based association analyses of HLA class II‐DRB1 and ‐DQB1 alleles and haplotypes in affected probands and their parents from 76 European‐American Caucasian families with familial vitiligo. Affected probands showed a significantly increased frequency of DRB1*04–DQB1*0301 and a significantly decreased frequency of DRB1*15–DQB1*0602 compared with a large sample of reference chromosomes. Family‐based association analyses confirmed these results. Probands with DRB1*04–DQB1*0301 developed vitiligo an average of 13.32 yr earlier than probands with DRB1*15–DQB1*0602. Overall, our results indicate that specific MHC‐linked genetic variation contributes to risk of familial vitiligo, although HLA does not completely explain familial clustering of vitiligo‐associated autoimmune/autoinflammatory diseases.     

HLA class II haplotype DRB1*04-DQB1*0301 contributes to risk of familial generalized vitiligo and early disease onset

Generalized vitiligo is a common autoimmune disorder characterized by white patches of skin and overlying hair caused by loss of pigment-forming melanocytes from involved areas. Familial clustering of vitiligo is not uncommon, and patients and their relatives are at increased risk for a specific complex of other autoimmune diseases. Compared with sporadic vitiligo, familial vitiligo is characterized by earlier disease onset and greater risk and broader repertoire of autoimmunity, suggesting a stronger genetic component, and perhaps stronger associations with specific alleles. To determine whether the major histocompatibility complex (MHC) contributes to the familial clustering of vitiligo and vitiligo-associated autoimmune/autoinflammatory diseases, we performed case-control and family-based association analyses of HLA class II-DRB1 and -DQB1 alleles and haplotypes in affected probands and their parents from 76 European-American Caucasian families with familial vitiligo. Affected probands showed a significantly increased frequency of DRB1*04-DQB1*0301 and a significantly decreased frequency of DRB1*15-DQB1*0602 compared with a large sample of reference chromosomes. Family-based association analyses confirmed these results. Probands with DRB1*04-DQB1*0301 developed vitiligo an average of 13.32 yr earlier than probands with DRB1*15-DQB1*0602. Overall, our results indicate that specific MHC-linked genetic variation contributes to risk of familial vitiligo, although HLA does not completely explain familial clustering of vitiligo-associated autoimmune/autoinflammatory diseases.     

Infections and autoimmunity--good or bad?

The relationship between infections and autoimmunity is complex. Current evidence indicates that microbes can initiate, enhance, or, conversely, abrogate autoimmunity. In this paper, we will review experimental examples illustrating mechanisms involved in these three scenarios. Microbial infections can act as environmental triggers inducing or promoting autoimmunity resulting in clinical manifestations of autoimmune disease in genetically predisposed individuals. However, increasing evidence suggests the opposite outcome, which is the prevention or amelioration of autoimmune processes following microbial encounters. These latter observations support conceptually the "hygiene hypothesis," suggesting that cleaner living conditions will lead to enhanced incidence of autoimmune disorders, asthma, and allergies. Because proof of concept in humans is difficult to obtain, we will discuss relevant animal model data in context with likely or proven human associations. Knowledge of mechanisms that underlie either positive or negative effects of infections on autoimmunity will facilitate exploration of molecular details for prospective clinical studies in the future.     

Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families

Generalized vitiligo is an autoimmune disorder characterized by acquired white patches of skin and overlying hair, the result of loss of melanocytes from involved areas. The most common disorder of pigmentation, vitiligo occurs with a frequency of 0.1-2.0% in various populations. Family clustering of cases is not uncommon, in a non-Mendelian pattern suggestive of multifactorial, polygenic inheritance. We surveyed 2624 vitiligo probands from North America and the UK regarding clinical characteristics, familial involvement, and association with other autoimmune disorders, the largest such survey ever performed. More than 83% of probands were Caucasians, and the frequency of vitiligo appeared approximately equal in males and females. The frequency of vitiligo in probands' siblings was 6.1%, about 18 times the population frequency, suggesting a major genetic component in disease pathogenesis. Nevertheless, the concordance of vitiligo in monozygotic twins was only 23%, indicating that a non-genetic component also plays an important role. Probands with earlier disease onset tended to have more relatives affected with vitiligo, suggesting a greater genetic component in early onset families. The frequencies of six autoimmune disorders were significantly elevated in vitiligo probands and their first-degree relatives: vitiligo itself, autoimmune thyroid disease (particularly hypothyroidism), pernicious anaemia, Addison's disease, systemic lupus erythematosus, and probably inflammatory bowel disease. These associations indicate that vitiligo shares common genetic aetiologic links with these other autoimmune disorders. These results suggest that genomic analysis of families with generalized vitiligo and this specific constellation of associated autoimmune disorders will be important to identify the mechanisms of genetic susceptibility to autoimmunity.     

CD4 T cell-dependent autoimmunity against a melanocyte neoantigen induces spontaneous vitiligo and depends upon Fas-Fas ligand interactions

Better understanding of tolerance and autoimmunity toward melanocyte-specific Ags is needed to develop effective treatment for vitiligo and malignant melanoma; yet, a systematic assessment of these mechanisms has been hampered by the difficulty in tracking autoreactive T cells. To address this issue, we have generated transgenic mice that express hen egg lysozyme as a melanocyte-specific neoantigen. By crossing these animals to a hen egg lysozyme-specific CD4 TCR transgenic line we have been able to track autoreactive CD4+ T cells from their development in the thymus to their involvement in spontaneous autoimmune disease with striking similarity to human vitiligo vulgaris and Vogt-Koyanagi-Harada syndrome. Our findings show that CD4-dependent destruction of melanocytes is partially inhibited by blocking Fas-Fas ligand interactions and also highlights the importance of local control of autoimmunity, as vitiligo remains patchy and never proceeds to confluence even when Ag and autoreactive CD4+ T cells are abundant. Immune therapy to enhance or suppress melanocyte-specific T cells can be directed at a series of semiredundant pathways involving tolerance and cell death.     

Polymorphisms in the CD28/CTLA4/ICOS genes: role in malignant melanoma susceptibility and prognosis?

The appearance of vitiligo and spontaneous regression of the primary lesion in melanoma patients illustrate a relationship between tumor immunity and autoimmunity. T lymphocytes play a major role both in tumor immunity and autoimmunity. CD28, Cytotoxic T lymphocyte antigen 4 (CTLA4) and inducible costimulator (ICOS) molecules are important secondary signal molecules in the T lymphocyte activation. Single nucleotide polymorphisms (SNPs) in the CD28/CTLA4/ICOS gene region were reported to be associated with several autoimmune diseases including, type-1 diabetes, SLE, autoimmune thyroid diseases and celiac disease. In this study, we investigated the association of SNPs in the CD28, CTLA4 and ICOS genes with the risk of melanoma. We also assessed the prognostic effect of the different polymorphisms in melanoma patients. Twenty-four tagging SNPs across the three genes and four additional SNPs were genotyped in a cohort of 763 German melanoma patients and 734 healthy German controls. Influence on prognosis was determined in 587 melanoma cases belonging to stage I or II of the disease. In general, no differences in genotype or allele frequencies were detected between melanoma patients and controls. However, the variant alleles for two polymorphisms in the CD28 gene were differentially distributed in cases and controls. Similarly no association of any polymorphism with prognosis, except for the rs3181098 polymorphism in the CD28 gene, was observed. In addition, individuals with AA genotype for rs11571323 polymorphism in the ICOS gene showed reduced overall survival. However, keeping in view the correction for multiple hypothesis testing our results suggest that the polymorphisms in the CD28, CTLA4 and ICOS genes at least do not modulate risk of melanoma and nor do those influence the disease prognosis in the investigated population.     

Vitamin D and autoimmunity: is vitamin D status an environmental factor affecting autoimmune disease prevalence?

The environment in which the encounter of antigen with the immune system occurs determines whether tolerance, infectious immunity, or autoimmunity results. Geographical areas with low supplies of vitamin D (for example Scandinavia) correlate with regions with high incidences of multiple sclerosis, arthritis, and diabetes. The active form of vitamin D has been shown to suppress the development of autoimmunity in experimental animal models. Furthermore, vitamin D deficiency increases the severity of at least experimental autoimmune encephalomyelitis (mouse multiple sclerosis). Targets for vitamin D in the immune system have been identified, and the mechanisms of vitamin D-mediated immunoregulation are beginning to be understood. This review discusses the possibility that vitamin D status is an environmental factor, which by shaping the immune system affects the prevalence rate for autoimmune diseases such as multiple sclerosis, arthritis, and juvenile diabetes.     

Autoimmunity and inflammation: murine models and translational studies

Autoimmune and inflammatory diseases, including type 1 diabetes, multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis, constitute an important and growing public health burden. However, in many cases our understanding of disease biology is limited and available therapies vary greatly in their efficacy and safety. Animal models of autoimmune and inflammatory diseases have provided valuable tools to researchers investigating their aetiology, pathology, and novel therapeutic strategies. Although such models vary in the degree to which they reflect human autoimmune and inflammatory diseases and caution is required in the extrapolation of animal data to the clinical setting, therapeutic approaches first evaluated in established animal models, including collagen-induced arthritis, experimental autoimmune encephalomyelitis, and the nonobese diabetic mouse, have successfully progressed to clinical investigation and practice. Similarly, these models have proven useful in providing support for basic hypotheses regarding the underlying causes and pathology of autoimmune and inflammatory diseases. Here we review selected murine models of autoimmunity and inflammation and efforts to translate findings from these models into both basic insights into disease biology and novel therapeutic strategies.     

Toward defining the autoimmune microbiome for type 1 diabetes

Several studies have shown that gut bacteria have a role in diabetes in murine models. Specific bacteria have been correlated with the onset of diabetes in a rat model. However, it is unknown whether human intestinal microbes have a role in the development of autoimmunity that often leads to type 1 diabetes (T1D), an autoimmune disorder in which insulin-secreting pancreatic islet cells are destroyed. High-throughput, culture-independent approaches identified bacteria that correlate with the development of T1D-associated autoimmunity in young children who are at high genetic risk for this disorder. The level of bacterial diversity diminishes overtime in these autoimmune subjects relative to that of age-matched, genotype-matched, nonautoimmune individuals. A single species, Bacteroides ovatus, comprised nearly 24% of the total increase in the phylum Bacteroidetes in cases compared with controls. Conversely, another species in controls, represented by the human firmicute strain CO19, represented nearly 20% of the increase in Firmicutes compared with cases overtime. Three lines of evidence are presented that support the notion that, as healthy infants approach the toddler stage, their microbiomes become healthier and more stable, whereas, children who are destined for autoimmunity develop a microbiome that is less diverse and stable. Hence, the autoimmune microbiome for T1D may be distinctly different from that found in healthy children. These data also suggest bacterial markers for the early diagnosis of T1D. In addition, bacteria that negatively correlated with the autoimmune state may prove to be useful in the prevention of autoimmunity development in high-risk children.     

Cell death: a trigger of autoimmunity?

Systemic autoimmune diseases are characterized by the production of antibodies against a broad range of self-antigens. Recent evidence indicates that the majority of these autoantigens are modified in various ways during cell death. This has led to the hypothesis that the primary immune response in the development of autoimmunity is directed to components of the dying cell. In this article, we summarize data on the modification of autoantigens during cell death and the possible consequences of this for autoimmunity.     

Water Buffalo (Bubalus bubalis) as a spontaneous animal model of Vitiligo

Vitiligo is a multifactorial acquired depigmenting disorder. Recent insights into the molecular mechanisms driving the gradual destruction of melanocytes in vitiligo will likely lead to the discovery of novel therapies, which need to be evaluated in animal models that closely recapitulate the pathogenesis of human vitiligo. In humans, vitiligo is characterized by a spontaneous loss of functional melanocytes from the epidermis, but most animal models of vitiligo are either inducible or genetically programmed. Here, we report that acquired depigmentation in water buffalo recapitulates molecular, histological, immunohistochemical, and ultrastructural changes observed in human vitiligo and hence could be used as a model to study vitiligo pathogenesis and facilitate the discovery and evaluation of therapeutic interventions for vitiligo.     

Mouse models for multiple sclerosis: Historical facts and future implications

Multiple sclerosis (MS) is an inflammatory and demyelinating condition of the CNS, characterized by perivascular infiltrates composed largely of T lymphocytes and macrophages. Although the precise cause remains unknown, numerous avenues of research support the hypothesis that autoimmune mechanisms play a major role in the development of the disease. Pathologically similar lesions to those seen in MS can be induced in laboratory rodents by immunization with CNS-derived antigens. This form of disease induction, broadly termed experimental autoimmune encephalomyelitis, is frequently the starting point in MS research with respect to studying pathogenesis and creating novel treatments. Many different EAE models are available, each mimicking a particular facet of MS. These models all have common ancestry, and have developed from a single concept of immunization with self-antigen. We will discuss the major changes in immunology research, which have shaped the EAE models we use today, and discuss how current animal models of MS have resulted in successful treatments and more open questions for researchers to address.     

Mucosal modulation of immune responses to heat shock proteins in autoimmune arthritis

Induction of oral tolerance to antigens that are targets of self-reactive immune responses is an attractive approach to antigen-specific immune therapy of autoimmune diseases. Oral tolerization has indeed proven to be safe and effective in amelioration of autoimmune diseases in animal models. In humans, results have been somewhat controversial. The emphasis given to clinical outcome rather than to immunomodulation, and the difficulty in identifying appropriate candidate antigens contribute to the controversy. Heat shock proteins are promising targets for immune intervention. Immune reactivity to heat shock proteins has indeed been correlated with autoimmune arthritis in animal models, and abnormal immune responses to heat shock proteins have been described in human arthritis as well. Despite significant recent progress, little is known at a molecular level regarding the mechanisms which are responsible for a switch from autoimmunity to tolerance in humans. This is particularly true with respect to sequential analysis of several molecular and immunologic markers during both the course and treatment of disease. Novel approaches are currently under way to fill the gaps. We will briefly detail here the experience gained to date, and identify some of the avenues which future research will explore.     

Epitope spreading in animal models: array of hope in rheumatoid arthritis and multiple sclerosis

The paradigm for pathogenic autoimmunity is the generation of high-titre, affinity-matured autoantibodies to a restricted family of autoantigens, in the appropriate genetic context. Genetic determinants of autoimmunity are largely found within the major histocompatibility complex (MHC) and the 'genotype to serotype to phenotype' concept is supported in a number of autoimmune diseases, where both genotype and serotype are well established. The serotype is autoantigen-driven, with evidence of epitope spreading as the disease evolves from asymptomatic to pathogenic autoimmunity. In rheumatoid arthritis and multiple sclerosis, where the autoantigens are poorly characterised, the use of an array in animal models may produce a hint of what happens in human disease. A more complete picture will be obtained from animals transgenic for human MHC, immunised with known human autoantigens.