Dysfunction of immune response regulation as a fundamental cause of autoimmunity onset

Guilt by Association: Inflammation and Shared Genetic Risk Between Stress-Related and Immune Disorders

B lymphocytes have critical roles as positive and negative regulators of immunity. Their inhibitory function has been associated primarily with interleukin 10 (IL-10) because B-cell-derived IL-10 can protect against autoimmune disease and increase susceptibility to pathogens. Here we identify IL-35-producing B cells as key players in the negative regulation of immunity. Mice in which only B cells did not express IL-35 lost their ability to recover from the T-cell-mediated demyelinating autoimmune disease experimental autoimmune encephalomyelitis (EAE). In contrast, these mice displayed a markedly improved resistance to infection with the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium as shown by their superior containment of the bacterial growth and their prolonged survival after primary infection, and upon secondary challenge, compared to control mice. The increased immunity found in mice lacking IL-35 production by B cells was associated with a higher activation of macrophages and inflammatory T cells, as well as an increased function of B cells as antigen-presenting cells (APCs). During Salmonella infection, IL-35- and IL-10-producing B cells corresponded to two largely distinct sets of surface-IgM(+)CD138(hi)TACI(+)CXCR4(+)CD1d(int)Tim1(int) plasma cells expressing the transcription factor Blimp1 (also known as Prdm1). During EAE, CD138(+) plasma cells were also the main source of B-cell-derived IL-35 and IL-10. Collectively, our data show the importance of IL-35-producing B cells in regulation of immunity and highlight IL-35 production by B cells as a potential therapeutic target for autoimmune and infectious diseases. This study reveals the central role of activated B cells, particularly plasma cells, and their production of cytokines in the regulation of immune responses in health and disease.

The challenges in primary sclerosing cholangitis – Aetiopathogenesis, autoimmunity, management and malignancy

Autoimmune diseases are independently associated with COVID-19 severity: Evidence based on adjusted effect estimates

Autoimmune polyglandular syndrome type III (subtype IIIa) has polygenic inheritance and is most common among other polyendocrine autoimmune syndromes. As the main feature polyglandular syndrome-IIIa includes one of the autoimmune thyroid diseases combined with other autoimmune endocrine diseases that are not included in the polyendocrine (polyglandular) autoimmune syndromes types I and II.Because of the rarity of the reported cases of autoimmune polyglandular syndromes, we present the case of patient, diagnosed with type IIIa autoimmune polyglandular syndrome. In the described case the first recorded autoimmune disease was autoimmune diabetes mellitus type I, followed by autoimmune thyroiditis. Based on the occurrence of polyglandular syndrome-IIIa type, it is necessary to emphasize the need for registration and dynamic monitoring of the patients with identified autoimmune diabetes mellitus type I or autoimmune thyroid diseases in order to early diagnosis the combination of these organ-specific autoimmune diseases.

Sarcoma-associated lichen planus–like paraneoplastic autoimmune multiorgan syndrome with colonic perforation

The endocrine system is a frequent target in pathogenic autoimmune responses. Type 1 diabetes and autoimmune thyroid disease are the prevailing examples. When several diseases cluster together in one individual, the phenomenon is called autoimmune polyglandular syndrome. Progress has been made in understanding the genetic factors involved in endocrine autoimmune diseases. Studies on monogenic autoimmune diseases such as autoimmune polyglandular syndrome type 1, immunodysregulation, polyendocrinopathy, enteropathy, X-linked and primary immune deficiencies helped uncover the role of key regulators in the preservation of immune tolerance. Alleles of the major histocompatibility complex have been known to contribute to the susceptibility to most forms of autoimmunity for more than 3 decades. Furthermore, sequencing studies revealed three non-major histocompatibility complex loci and some disease specific loci, which control T lymphocyte activation or signalling. Recent genome-wide association studies (GWAS) have enabled acceleration in the identification of novel (non-HLA) loci and hence other relevant immune response pathways. Interestingly, several loci are shared between autoimmune diseases, and surprisingly some work in opposite direction. This means that the same allele which predisposes to a certain autoimmune disease can be protective in another. Well powered GWAS in type 1 diabetes has led to the uncovering of a significant number of risk variants with modest effect. These studies showed that the innate immune system may also play a role in addition to the adaptive immune system. It is anticipated that next generation sequencing techniques will uncover other (rare) variants. For other autoimmune disease (such as autoimmune thyroid disease) GWAS are clearly needed.

The autoimmune targets in IPEX are dominated by gut epithelial proteins

Autoimmune diseases are chronic conditions initiated by the loss of immunological tolerance to self-antigens. They constitute heterogeneous group of disorders, in which multiple alterations in the immune system result in a spectrum of syndromes that either target specific organs or affect the body systematically. Recent epidemiological studies have shown a possible shift of one autoimmune disease to another or the fact that more than one autoimmune disease may coexist in a single patient or in the same family. Numerous autoimmune diseases have been shown to coexist frequently with thyroid autoimmune diseases. AUTOIMMNUNE THYROID DISEASE AND OTHER ORGAN SPECIFIC NON-ENDOCRINE AUTOIMMUNE DISEASES: This part of the study reviews the prevalence of autoimmune thyroid disease coexisting with: pernicious anaemia, vitiligo, celiac disease, autoimmune liver disease, miastenia gravis, alopecia areata and sclerosis multiplex, and several recommendations for screening have been given. AUTOIMMUNE THYROID DISEASE AND OTHER ORGAN NON-SPECIFIC NON-ENDOCRINE AUTOIMMUNE DISEASES: Special attention is given to the correlation between autoimmune thyroid disease and rheumatoid arthritis, systemic lupus erythematosus, syndrome Sjögren, systemic sclerosis and mixed connective tissue disease. Screening for autoimmune thyroid diseases should be recommended in everyday clinical practice, in patients with primary organ-specific or organ non-specific autoimmune disease. Otherwise, in patients with primary thyroid autoimmune disease, there is no good reason of seeking for all other autoimmune diseases, although these patients have a greater risk of developing other autoimmune disease. Economic aspects of medicine require further analyzing of these data, from cost/benefit point of view to justified either mandatory screening or medical practitioner judgment.

The complexity and variety of autoimmune diseases and phenotypes is a source of continuing fascination and frustration for both physicians and scientists. Even in the setting of exciting advances in understanding the molecular basis of immune recognition and regulation, the fundamental causes of the autoimmune diseases are unknown, and it is still unclear to what extent these diseases are pathogenically related. The mere presence of autoimmune phenomena is not a compelling unifying feature, since these phenomena can occur in a variety of circumstances, including in normal subjects. Studies in animal models and the discovery of a few rare highly penetrant genes involved in human polyendocrine syndromes [1], have provided some direct evidence that abnormalities in thymic selection [2] can cause autoimmunity in humans. However, it is still not clear to what extent altered thymic selection operates in the more common autoimmune diseases [3], and other peripheral regulatory mechanisms are also likely to be important [4, 5]. Comprehensive genetic analysis in humans is one of the most promising avenues of gaining insight into this question. In the last few years, this approach has begun to bear fruit. The intracellular tyrosine phosphatase, PTPN22, has recently been associated with a variety of autoimmune diseases, including type 1 diabetes [6], rheumatoid arthritis [7], systemic lupus [8] and autoimmune thyroid disease [9–11]. These discoveries have provided some of the first direct evidence that these diseases are genetically related, and also raise a host of new questions to be addressed. As discussed in this review, the example of PTPN22 illustrates how human genetics is likely to provide new insights into pathogenesis and unravel new relationships among the autoimmune diseases.

Novel Vitiligo Susceptibility Loci on Chromosomes 7 ( AIS2) and 8 ( AIS3), Confirmation of SLEV1 on Chromosome 17, and Their Roles in an Autoimmune Diathesis

SP0228 Polyautoimmunity. Diagnosis and Significance

Autoimmune diseases, such as multiple sclerosis and type-1 diabetes, are the outcomes of a failure of immune tolerance. Immune tolerance is sustained through interplays between two inter-dependent clusters of immune activities: immune stimulation and immune regulation. The mechanisms of immune regulation are exploited as therapeutic targets for the treatment of autoimmune diseases. One of these mechanisms is immune checkpoints (ICPs). The roles of ICPs in maintaining immune tolerance and hence suppressing autoimmunity were revealed in animal models and validated by the clinical successes of ICP-targeted therapeutics for autoimmune diseases. Recently, these roles were highlighted by the clinical discovery that the blockade of ICPs causes autoimmune disorders. Given the crucial roles of ICPs in immune tolerance, it is plausible to leverage ICPs as a group of therapeutic targets to restore immune tolerance and treat autoimmune diseases. In this review, we first summarize working mechanisms of ICPs, particularly those that have been utilized for therapeutic development. Then, we recount the agents and approaches that were developed to target ICPs and treat autoimmune disorders. These agents take forms of fusion proteins, antibodies, nucleic acids, and cells. We also review and discuss safety information for these therapeutics. We wrap up this review by providing prospects for the development of ICP-targeting therapeutics. In summary, the ever-increasing studies and results of ICP-targeting of therapeutics underscore their tremendous potential to become a powerful class of medicine for autoimmune diseases.

IMPENDING PERICARDIAL TAMPONADE AS THE INITIAL PRESENTATION OF AUTOIMMUNE POLYGLANDULAR SYNDROME 3B

To evaluate the Vitamin D status of patients with a single autoimmune disease and of patients with several autoimmune diseases. We enrolled 35 patients with isolated type 1 diabetes mellitus (T1DM), 60 with autoimmune polyendocrine syndromes (APS) including T1DM and 72 control subjects. Among patients with APS, 10 were classified as type 2 (Addison's disease + T1DM), whereas the other 50 as type 3 (autoimmune thyroid disease + T1DM + other autoimmune diseases). Vitamin D (25-OHD) levels were assessed by a chemiluminescent immunoassay in all patients and controls on samples drawn in the morning of the same months. Both groups of APS and T1DM patients showed 25-OHD levels significantly lower than healthy controls (p < 0.001 for both vs controls), without any significant difference between the two groups (p = 0.80). The highest prevalence of vitamin D deficiency (values <20 ng/ml) was observed in APS type 3 subgroup (8 out of 50 patients, 16%). Patients with APS present reduced vitamin D circulating levels, but the vitamin D status is not different between patients with single or multiple autoimmune diseases. The kind of autoimmune disease, rather than the association of several autoimmune diseases, may influence negatively the levels of vitamin D. Further prospective studies are needed to clarify if impaired vitamin D level is a causal factor in the pathogenesis of autoimmune diseases or a consequence of them.