Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes

Autoimmune disorders constitute a diverse group of phenotypes with overlapping features and a tendency toward familial aggregation. It is likely that common underlying genes are involved in these disorders. Until very recently, no specific alleles--aside from a few common human leukocyte antigen class II genes--had been identified that clearly associate with multiple different autoimmune diseases. In this study, we describe a unique collection of 265 multiplex families assembled by the Multiple Autoimmune Disease Genetics Consortium (MADGC). At least two of nine "core" autoimmune diseases are present in each of these families. These core diseases include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), multiple sclerosis (MS), autoimmune thyroid disease (Hashimoto thyroiditis or Graves disease), juvenile RA, inflammatory bowel disease (Crohn disease or ulcerative colitis), psoriasis, and primary Sjogren syndrome. We report that a recently described functional single-nucleotide polymorphism (rs2476601, encoding R620W) in the intracellular tyrosine phosphatase (PTPN22) confers risk of four separate autoimmune phenotypes in these families: T1D, RA, SLE, and Hashimoto thyroiditis. MS did not show association with the PTPN22 risk allele. These findings suggest a common underlying etiologic pathway for some, but not all, autoimmune disorders, and they suggest that MS may have a pathogenesis that is distinct from RA, SLE, and T1D. DNA and clinical data for the MADGC families are available to the scientific community; these data will provide a valuable resource for the dissection of the complex genetic factors that underlie the various autoimmune phenotypes.     

Role of proteomics in biomarker discovery and psychiatric disorders: current status,potentials, limitations and future challenges

Proteomic approaches have advanced clinical research towards more reliable, sensitive and specific biological diagnostic markers for diseases. Mood disorders are most difficult to diagnose and very much prevalent in society; hence, their proper diagnosis becomes essential. Despite tremendous research efforts to dissect the neurobiological basis of psychiatric disorders, the diagnosis and evaluation for such diseases is still poor. Biomarker discovery in psychiatry research has been accelerated by proteomic technologies, accepting the challenges in order to meet disease state-related investigations. Proteomics-based research for disease-specific protein signatures is expected to give a new direction in psychiatry research. Therefore, this may become a more powerful tool to predict the development, course and outcome of the disease towards personalized psychiatric ailments. The review discusses the role of proteomics in elucidating mechanisms of psychiatric disorders, current status, prospects, limitations and new possibilities towards a strong diagnostic tool in the clinical laboratory.     

Selective targeting of the immune response in autoimmune demyelination.

Recent developments in molecular and cellular immunology have led to the formulation of refined models that describe how tolerance to self-antigens is broken and autoimmunity develops. This knowledge can now be used to develop alternative approaches to conventional immunosuppression for the treatment of autoimmune demyelinating disorders. The ideal therapy would reverse established disease or prevent further progression by selectively eliminating the aggressive effector molecules or cells while leaving the immune system virtually intact. Indeed, several groups are engaged in preliminary or advanced clinical studies of promising specific immunotherapies for multiple sclerosis and other autoimmune conditions. Current data suggest that the immune response that results in organ-specific autoimmunity is highly complex and redundant in humans. This suggests that antigen-specific approaches may be less successful than broader immunotherapeutic strategies for treating multiple sclerosis and related diseases.     

Proteomic biomarkers for autoimmune disease

Autoimmune diseases affect 3% of the world population, yet the diagnosis and classification of autoimmune diseases remain based on clinical examination combined with traditional laboratory tests and imaging studies. The development of genomic and proteomic technologies provides an unprecedented ability to identify novel biosignatures to diagnose, classify, and guide therapeutic decision making in patients with autoimmune disease. In this article, we review recent advances in proteomics technologies and their application to autoimmune disease.     

炎症性贫血的病因、诊断与治疗研究进展

感染、自身免疫紊乱、慢性疾病和年龄等很多原因都会导致炎症发生并发展为贫血。炎症性贫血(anemia of inflammation AI)通常为正细胞正色素性贫血,临床表现温和。系统性的铁利用、红细胞生成、红细胞生存期特征的变化导致了炎症性贫血。最佳治疗是纠正病因,然而当病因不清或难以诊断时,治疗炎症性贫血的办法就非常有限了。铁调素(Hepcidin)是近年研究铁利用调节的中心。由于铁调素定量分析技术的发展,人们逐渐认识到其在各种疾病中的作用。最近研究集中在铁调素表达调节通路,并发现了药物治疗的靶点。由于治疗上的巨大进步,分析正常血红蛋白对疾病预后的影响,就可以明确炎性疾病发生和死亡过程中贫血是否具有可逆性。     

The limb-girdle muscular dystrophies—Diagnostic strategies

The limb-girdle muscular dystrophies are a group of disorders where our understanding of their underlying molecular basis has made huge strides over the past years, revealing great heterogeneity at the clinical and molecular level. The availability of direct protein and/ or gene based approaches to diagnosis means that these disorders can now be precisely defined, and such definition of a precise diagnosis is increasingly allowing directed management for these diseases by the ability to predict specific complications such as those of the cardiac or respiratory systems. An algorithm combining clinical, biochemical and molecular testing is described which will aid precision of diagnosis and direct specific testing towards the cases most likely to benefit. This brings advantages for the patients of today in recognising the specific risks of their disorders, and in the future will be the starting point for specific gene and protein based therapies.     

The limb-girdle muscular dystrophies--diagnostic strategies

The limb-girdle muscular dystrophies are a group of disorders where our understanding of their underlying molecular basis has made huge strides over the past years, revealing great heterogeneity at the clinical and molecular level. The availability of direct protein and/ or gene based approaches to diagnosis means that these disorders can now be precisely defined, and such definition of a precise diagnosis is increasingly allowing directed management for these diseases by the ability to predict specific complications such as those of the cardiac or respiratory systems. An algorithm combining clinical, biochemical and molecular testing is described which will aid precision of diagnosis and direct specific testing towards the cases most likely to benefit. This brings advantages for the patients of today in recognising the specific risks of their disorders, and in the future will be the starting point for specific gene and protein based therapies.     

Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo

Generalized vitiligo is an autoimmune disorder in which acquired white patches of skin and overlying hair result from autoimmune loss of melanocytes from involved areas. Although usually sporadic, family clustering of vitiligo may occur, in a non-Mendelian pattern typical of multifactorial, polygenic inheritance. Sporadic vitiligo is associated with autoimmune thyroid disease, pernicious anemia, Addison's disease, and lupus; these same disorders occur at increased frequency in patients' first-degree relatives. Here, we studied 133 'multiplex' generalized vitiligo families, with multiple affected family members. The age of onset of vitiligo is earlier in these 'multiplex' families than in patients with sporadic vitiligo. Affected members of the multiplex vitiligo families have elevated frequencies of autoimmune thyroid disease, rheumatoid arthritis, psoriasis, adult-onset insulin-dependent diabetes mellitus, pernicious anemia, and Addison's disease. Probands' unaffected siblings have elevated frequencies of most of these same autoimmune diseases, particularly if the proband had non-vitiligo autoimmune disease. Familial generalized vitiligo is thus characterized by earlier disease onset and a broader repertoire of associated autoimmune diseases than sporadic vitiligo. This mostly likely reflects a greater inherited genetic component of autoimmune susceptibility in these families. These findings have important implications for autoimmune disease surveillance in families in which multiple members are affected with vitiligo.     

Mass cytometry as a platform for the discovery of cellular biomarkers to guide effective rheumatic disease therapy

The development of biomarkers for autoimmune diseases has been hampered by a lack of understanding of disease etiopathogenesis and of the mechanisms underlying the induction and maintenance of inflammation, which involves complex activation dynamics of diverse cell types. The heterogeneous nature and suboptimal clinical response to treatment observed in many autoimmune syndromes highlight the need to develop improved strategies to predict patient outcome to therapy and personalize patient care. Mass cytometry, using CyTOF®, is an advanced technology that facilitates multiparametric, phenotypic analysis of immune cells at single-cell resolution. In this review, we outline the capabilities of mass cytometry and illustrate the potential of this technology to enhance the discovery of cellular biomarkers for rheumatoid arthritis, a prototypical autoimmune disease.     

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.     

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

Dendritic cells (DCs) are professional antigen-presenting cells that control the generation of adaptive immunity. Consequently, DCs have a central role in the induction of protective immunity to pathogens and also in the pathogenic immune response responsible for the development and progression of autoimmune disorders. Thus the study of the molecular pathways that control DC development and function is likely to result in new strategies for the therapeutic manipulation of the immune response. In this review, we discuss the role and therapeutic value of DCs in autoimmune diseases, with a special focus on multiple sclerosis.     

MicroRNAs in systemic rheumatic diseases

MicroRNAs (miRNAs) are endogenous, non-coding, single-stranded RNAs about 21 nucleotides in length. miRNAs have been shown to regulate gene expression and thus influence a wide range of physiological and pathological processes. Moreover, they are detected in a variety of sources, including tissues, serum, and other body fluids, such as saliva. The role of miRNAs is evident in various malignant and nonmalignant diseases, and there is accumulating evidence also for an important role of miRNAs in systemic rheumatic diseases. Abnormal expression of miRNAs has been reported in autoimmune diseases, mainly in systemic lupus erythematosus and rheumatoid arthritis. miRNAs can be aberrantly expressed even in the different stages of disease progression, allowing miRNAs to be important biomarkers, to help understand the pathogenesis of the disease, and to monitor disease activity and effects of treatment. Different groups have demonstrated a link between miRNA expression and disease activity, as in the case of renal flares in lupus patients. Moreover, miRNAs are emerging as potential targets for new therapeutic strategies of autoimmune disorders. Taken together, recent data demonstrate that miRNAs can influence mechanisms involved in the pathogenesis, relapse, and specific organ involvement of autoimmune diseases. The ultimate goal is the identification of a miRNA target or targets that could be manipulated through specific therapies, aiming at activation or inhibition of specific miRNAs responsible for the development of disease.     

Recent thymic emigrants as the bridge between thymoma and autoimmune diseases

Recent thymic emigrants (RTEs) are naïve T cells that egress the thymus following intrathymic development. This continuous process, including self-renewal, is crucial to establish and maintain human immune function. Several biomarkers can identify RTEs, but none of them is specific. Additional methods to detect and study RTEs phenotypically and functionally revealed alterations in RTEs in various adverse health conditions, including autoimmune diseases, systemic disorders and thymic abnormalities such as thymoma. Often associated with autoimmune disease, thymoma is the only tumor that can generate RTEs. However, a causal relationship between RTEs and autoimmune disease remains uncertain. Here, we review current knowledge about the connections between thymoma, RTEs and autoimmune diseases to provide new perspectives for therapeutic strategies.     

Amplification of autoimmune disease by infection

Reports of infection with certain chronic persistent microbes (herpesviruses or Chlamydiae) in human autoimmune diseases are consistent with the hypothesis that these microbes are reactivated in the setting of immunodeficiency and often target the site of autoimmune inflammation. New experimental animal models demonstrate the principle. A herpesvirus or Chlamydia species can be used to infect mice with induced transient autoimmune diseases. This results in increased disease severity and even relapse. The evidence suggests that the organisms are specifically imported to the inflammatory sites and cause further tissue destruction, especially when the host is immunosuppressed. We review the evidence for the amplification of autoimmune inflammatory disease by microbial infection, which may be a general mechanism applicable to many human diseases. We suggest that patients with autoimmune disorders receiving immunosuppressing drugs should benefit from preventive antiviral therapy.     

Apoptosis in human disease: a new skin for the old ceremony?

Naturally occurring cell death or apoptosis is essential for the maintenance of tissue homeostasis and serves to remove extraneous or dangerous cells in a swift and unobtrusive manner. Recent studies have indicated a role for apoptosis in a plethora of human diseases. Hence, dysregulation of apoptosis has been implicated in autoimmune disease, acquired immune deficiency syndrome, and other viral (and bacterial) infections, as well as in neurodegenerative disorders and cancer. Furthermore, dysregulated apoptosis signaling may impinge on other age-related disorders such as osteoporosis and atherosclerosis and perhaps on the process of aging itself. The present review provides an overview of human diseases, which are associated with defective or inadvertent apoptosis, with examples of pathological conditions in which putative apoptosis defects have been elucidated at the molecular level. Novel apoptosis-modulating therapeutic strategies are also discussed.     

Celiac Disease and the Endocrinologist: a Diagnostic Opportunity

ObjectiveTo review the association of celiac disease and various endocrine disorders and present the related clinical experience of a 3-physician adult endocrinology practice.MethodsWe provide an overview of the pertinent literature, discuss the clinical manifestations, genetics, and pathogenesis of celiac disease, and describe our clinical experience during a 5-year period.ResultsCeliac disease has been associated with numerous disorders, including several conditions treated by endocrinologists—type 1 diabetes mellitus, autoimmune thyroid disease, Addison disease, osteomalacia, secondary hyperparathyroidism, vitamin D or iron deficiency, fertility problems, hypogonadism in men, and autoimmune hypopituitarism. After our clinical awareness was raised about these potential comorbidities, 18 patients were newly diagnosed with celiac disease in our clinical practice during a 5-year interval. All patients had been referred for endocrine evaluation or were undergoing follow- up for ongoing management of endocrine disorders. When a “celiac-associated” endocrine disorder coexists with other factors associated with celiac disease, we recommend performance of IgA class antibody testing, and either antiendomysial or anti-tissue transglutaminase antibodies provide high specificity and sensitivity for the diagnosis of celiac disease.ConclusionEndocrinologists have an opportunity to diagnose celiac disease, a relatively common disorder with profound clinical implications that can often be associated with various endocrinopathies. (Endocr Pract. 2008;14: 381-388)     

Interferon-induced thyroiditis during treatment of chronic hepatitis C

Thyroid function disorders affect between 5% and 15% of patients treated with IFNα and RBV for chronic hepatitis C. Women and patients with thyroid peroxidase antibodies (TPOAb) found before the treatment are at risk of developing the disorders (46.1% vs. 5.4%). The spectrum of IFNα-induced thyroiditis (IIT) includes two groups. Disorders with an autoimmune background are: presence of thyroid autoantibodies without clinical disease, Hashimoto's disease and Graves' disease. The second group comprises diseases caused by the direct toxic effect of IFNα on the thyroid gland, i.e. destructive thyroiditis and non-autoimmune hypothyroidism. Thyroid diseases are not an absolute contraindication for IFNα and RBV therapy. In patients diagnosed with thyroid dysfunction, before the antiviral therapy it is necessary to achieve euthyreosis. Thyroid function disorders may occur at any moment of the therapy. The earliest have been observed in the 4th week of treatment, and the latest 12 months after its termination. During the therapy, in order to diagnose IIT early, it is recommended to determine TSH level every 2-3 months depending on the presence of TPOAb before the treatment. The diagnosis and treatment of thyroid function disorders should be conducted in co-operation with an endocrinologist.     

Principal Component Analysis Characterizes Shared Pathogenetics from Genome-Wide Association Studies

Genome-wide association studies (GWASs) have recently revealed many genetic associations that are shared between different diseases. We propose a method, disPCA, for genome-wide characterization of shared and distinct risk factors between and within disease classes. It flips the conventional GWAS paradigm by analyzing the diseases themselves, across GWAS datasets, to explore their “shared pathogenetics”. The method applies principal component analysis (PCA) to gene-level significance scores across all genes and across GWASs, thereby revealing shared pathogenetics between diseases in an unsupervised fashion. Importantly, it adjusts for potential sources of heterogeneity present between GWAS which can confound investigation of shared disease etiology. We applied disPCA to 31 GWASs, including autoimmune diseases, cancers, psychiatric disorders, and neurological disorders. The leading principal components separate these disease classes, as well as inflammatory bowel diseases from other autoimmune diseases. Generally, distinct diseases from the same class tend to be less separated, which is in line with their increased shared etiology. Enrichment analysis of genes contributing to leading principal components revealed pathways that are implicated in the immune system, while also pointing to pathways that have yet to be explored before in this context. Our results point to the potential of disPCA in going beyond epidemiological findings of the co-occurrence of distinct diseases, to highlighting novel genes and pathways that unsupervised learning suggest to be key players in the variability across diseases.     

The use of post‐translationally modified peptides for detection of biomarkers of immune‐mediated diseases

Biomarkers are decision‐making tools at the basis of clinical diagnostics and essential for guiding therapeutic treatments. In this context, autoimmune diseases represent a class of disorders that need early diagnosis and steady monitoring. These diseases are usually associated with humoral or cell‐mediated immune reactions against one or more of the body's own constituents. Autoantibodies fluctuating in biological fluids can be used as disease biomarkers and they can be, thus, detected by diagnostic immunoassays using native autoantigens. However, it is now accepted that post‐translational modifications may affect the immunogenicity of self‐protein antigens, triggering an autoimmune response and creating neo‐antigens. In this case, post‐translationally modified peptides represent a more valuable tool with respect to isolated or recombinant proteins. In fact, synthetic peptides can be specifically modified to mimic neo‐antigens and to selectively detect autoantibodies as disease biomarkers. A ‘chemical reverse approach’ to select synthetic peptides, bearing specific post‐translational modifications, able to fishing out autoantibodies from patients' biological fluids, can be successfully applied for the development of specific in vitro diagnostic/prognostic assays of autoimmune diseases. Herein, we report the successful application of this approach to the identification of biomarkers in different autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd.