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The pathogenesis of alopecia areata, a common autoimmune non-scarring alopecia, remains unclear・ Current studies have shown that the loss of immune privilege of hair follicles due to the up-regulation of MHC molecules and the decrease in immunosuppressive molecules leads to the exposure of self-antigens in the affected area・ This triggers the infiltration of immune cells (such as CD8 + T cells, NK cells, plasmacytoma dendritic cells, and mast cells) around the hair bulb ・ Various immune cells and related cytokines participate in the pathogenesis and development of this disease through diverse signaling pathways・ Due to its complex pathogenesis and diverse clinical manifestations, there are challenges in the diagnosis and treatment in clinic・ This paper aims to provide a comprehensive review on recent advances in understanding the immunological pathogenesis of alopecia areata by focusing on mechanisms underlying immune privilege loss around hair follicles and the interaction between various immune cells in the microenvironment for a deeper understanding of its pathogenesis・ It also seeks to explore new research directions and potential treatment strategies. [ABSTRACT FROM AUTHOR]

Immuno-correlated dermatological pathologies refer to skin disorders that are closely associated with immune system dysfunction or abnormal immune responses. Advancements in the field of artificial intelligence (AI) have shown promise in enhancing the diagnosis, management, and assessment of immuno-correlated dermatological pathologies. This intersection of dermatology and immunology plays a pivotal role in comprehending and addressing complex skin disorders with immune system involvement. The paper explores the knowledge known so far and the evolution and achievements of AI in diagnosis; discusses segmentation and the classification of medical images; and reviews existing challenges, in immunological-related skin diseases. From our review, the role of AI has emerged, especially in the analysis of images for both diagnostic and severity assessment purposes. Furthermore, the possibility of predicting patients' response to therapies is emerging, in order to create tailored therapies. [ABSTRACT FROM AUTHOR]

Background: The high prevalence of chronic inflammatory diseases or autoimmune reactions is a major source of concern and affects the quality of life of patients. Chronic inflammatory or autoimmune diseases are associated with many diseases in humans, including asthma, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and cancer. Splenic tyrosine kinase (SYK) is a non–receptor tyrosine kinase that plays an important role in immune receptor signalling in immune and inflammatory responses. Methods: This is a review article in which we searched for keywords "splenic tyrosine kinase", "inflammation" and "autoimmune diseases" in published literature such as Pubmed and Web of Science to collect relevant information and then conducted a study focusing on the latest findings on the involvement of SYK in chronic inflammatory or autoimmune diseases. Results: This paper reviews the regulation of Fcγ, NF–κB, B cell and T cell–related signalling pathways by SYK, which contributes to disease progression in chronic inflammatory and autoimmune diseases such as airway fibrosis, inflammatory skin disease and inflammatory bowel disease. Conclusion: This paper shows that SYK plays an important role in chronic inflammatory and autoimmune diseases. syk targets hematological, autoimmune and other inflammatory diseases and therefore, inhibition of SYK expression or blocking its related pathways may provide new ideas for clinical prevention and treatment of inflammatory or autoimmune diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: We have identified what is most likely a hereditary inflammatory muscle disease within the Dutch dog breed 'Het Nederlandse Kooikerhondje'. The clinical signs are either locomotory, dysphagia, or a combination of these signs. In most dogs, the muscular enzyme creatine kinase (CK) was elevated. Histopathology revealed an inflammatory myopathy. The Dutch Kooiker dog (het Nederlandse Kooikerhondje) is one of nine Dutch dog breeds. As of 1960, a number of heritable diseases have been noted in this breed. One is an inflammatory myopathy that emerged in 1972, with numbers of affected dogs gradually increasing during the last few decades. The objective of this paper is to describe clinical signs, laboratory results, electromyography and histopathology of the muscle biopsies of the affected dogs. Method: Both retrospectively as well as prospectively affected Kooiker dogs were identified and categorized using a Tiered level of Confidence. Results: In total, 160 Kooiker dogs—40 Tier I, 33 Tier II and 87 Tier III—were included. Clinical signs were (1) locomotory problems, such as inability to walk long distances, difficulty getting up, stiff gait, walking on eggshells; (2) dysphagia signs such as drooling, difficulty eating and/or drinking; or (3) combinations of locomotory and dysphagia signs. CK activities were elevated in all except for one dog. Histopathology revealed a predominant lymphohistiocytic myositis with a usually low and variable number of eosinophils, neutrophils and plasma cells. It is concluded that, within this breed, a most likely heritable inflammatory myopathy occurs. Further studies are needed to classify this inflammatory myopathy, discuss its treatment, and unravel the genetic cause of this disease to eradicate it from this population. [ABSTRACT FROM AUTHOR]

Introduction: The Profile of Fatigue and Discomfort–Sicca Symptoms Inventory–Short Form (PROFAD-SSI-SF) is a 19-item patient-reported outcome (PRO) measure to assess pain, fatigue, and dryness in patients with primary Sjögren's syndrome (pSS). This analysis identified concepts important to measure, and evaluated the content validity and measurement properties of the PROFAD-SSI-SF, in patients with pSS. Methods: Qualitative analyses (GSK Study 208396) used transcripts from an online concept elicitation (CE) discussion forum with patients with pSS and interviews with key opinion leaders (KOLs) to finalize a disease model depicting important concepts for patients with pSS. Cognitive debriefing (CD) interviews with patients with pSS were conducted to further evaluate the content validity of the PROFAD-SSI-SF. Quantitative analyses (GSK Study 213253) used post hoc analyses of blinded data from a phase 2 trial to assess PROFAD-SSI-SF measurement properties. Results: The CE discussion forum (N = 46) revealed dryness (oral 87.0%, ocular 73.9%, cutaneous 37.0%, vaginal 23.9%, nasal 15.2%, otic 6.5%), pain (89.1%), and fatigue (87.0%) as the most reported symptoms. KOLs (N = 5) found the concepts identified in the disease model accurate and understandable, and confirmed that PROs used in pSS studies should focus on dryness, joint pain, and fatigue. In the CD interviews (N = 20), of the 19 participants asked, all found the PROFAD-SSI-SF easy to understand, and 14/19 items were considered relevant by ≥ 18/20 participants. The quantitative analyses found an acceptable fit of the PROFAD-SSI-SF factor structure, with adequate internal consistency, test–retest reliability, convergent validity with other PRO measures, known-groups validity with Patient Global Assessment, and ability to detect change in patients with pSS. Conclusion: The final disease model confirmed that the PROFAD-SSI-SF assesses concepts that are relevant and important to patients with pSS. Our findings support the content validity and measurement properties of the PROFAD-SSI-SF as a fit-for-purpose PRO measure appropriate for use in clinical trials in patients with pSS. Clinical Trial Registration number for the phase 2 trial: Clinicaltrials.gov NCT02631538 Plain Language Summary: Primary Sjögren's syndrome (pSS) is a disease where the immune system attacks the body, causing a number of symptoms, most notably dryness (sicca) of the eyes and mouth. The Profile of Fatigue and Discomfort–Sicca Symptoms Inventory–Short Form (PROFAD-SSI-SF) is a questionnaire for patients with pSS that asks about their symptoms. This paper evaluates how relevant the PROFAD-SSI-SF questions are to patients with pSS, and how consistently and accurately the questionnaire can measure changes in their symptoms. We reviewed information about the symptoms and impacts of pSS from an online discussion forum for patients with pSS. Patients said that dryness, fatigue, and pain were the symptoms that most affected their day-to-day lives and well-being. We combined this information with previous research on pSS to design a diagram explaining the key symptoms and day-to-day impacts of pSS, which was reviewed by five experts in pSS. In doing so, we aimed to confirm whether the most important things to patients about living with pSS are asked in the PROFAD-SSI-SF questionnaire. Next, we asked 20 patients with pSS how easy they found the PROFAD-SSI-SF to complete and if any important concepts were missing; they reported that the PROFAD-SSI-SF was easy to fill in and that the important questions were included. Finally, we looked at data from a clinical trial that used the PROFAD-SSI-SF and found it accurately measures changes in symptoms of patients with pSS. This means that the PROFAD-SSI-SF could be used in clinical trials to help assess new medicines for pSS. [ABSTRACT FROM AUTHOR]

Purpose: This paper is a scoping review of research on multiple sclerosis (MS)‐associated uveitis to determine its epidemiology, pathophysiology, clinical features and treatment. Methods: A comprehensive search of the medical databases MEDLINE (PubMed), EMBASE, Web of Science and Cochrane was carried out on 25 November 2019, to identify papers published between 1980 and 2019 that focus on patients with MS‐associated uveitis. Results: Based on large cohort studies (n ≥ 1000), the prevalence of uveitis in patients with MS is estimated to be 0.53–1.34% (mean = 0.83%), and MS is diagnosed in 0.52–3.20% (mean = 1.30%) of patients with uveitis. The condition is most frequent among middle‐aged women. Patients usually complain of floaters and/or blurred vision, with bilateral intermediate uveitis (with retinal vasculitis) as the most frequent ophthalmological finding. Both MS and intermediate uveitis are associated with HLA‐DRB1*15:01 and IL‐2RA gene polymorphism rs2104286 A > G, suggesting a common genetic background. T cells, and possibly B cells, play an important role in both autoimmune disorders. Multiple sclerosis (MS)‐related uveitis is classically treated as non‐infectious uveitis, with corticosteroids as the first treatment step. Other treatments include immunosuppressants, cryotherapy, laser photocoagulation and vitrectomy. These treatment options have a limited, if any, effect on the course of MS and can be complicated by side‐effects. As treatment strategies for MS have increased in the last decade, it would be interesting to evaluate the efficacy of these new treatments during the course of uveitis. Moreover, the correlation between retinal periphlebitis and MS could be established more accurately with the recently developed techniques of wide‐field fluorescein angiography in a large cohort of MS patients. Conclusion: MS‐associated uveitis is a rare, highly discussed pathology about which much is still unknown. Large epidemiological studies and extrapolation of new MS treatments to this condition are warranted. [ABSTRACT FROM AUTHOR]

Numerous immunotherapeutic agents, such as immune checkpoint inhibitors (ICIs), have been approved for the treatment of genitourinary (GU) malignancies. While ICIs have improved treatment outcomes and expanded treatment options, they can cause immune-related adverse events (irAEs). The scope of irAEs is broad, and this paper aims to review the rheumatologic side effects associated with immunotherapy drugs approved for bladder cancer and renal cell carcinoma. IrAEs are graded by the common terminology criteria for adverse events (CTCAE), which ranges from 1 to 5. The management of irAEs includes corticosteroids or other immunosuppressive therapies, and it may require discontinuation of immunotherapy. Several real world experience studies suggest that most patients with pre-existing autoimmune diseases treated with ICI did not have to discontinue treatment due to immune-mediated side effects. While data suggest autoimmune side effects are manageable, patients with pre-existing autoimmune diseases are often excluded from immunotherapy clinical trials. Better understanding of these irAEs will improve its safety and expand its use in those with underlying autoimmune disease. [ABSTRACT FROM AUTHOR]

Objective: Behçet's disease (BD) is a multisystem inflammatory disease that affects patients along the historic silk road. Thus far, the pathogenesis of the disease has proved elusive due to the complex genetic interactions of the disease. In this paper, we seek to clarify the genetic factors of the disease while also uncovering other diseases of interest that present with a similar genotype as BD. Results: To do this, we employ a convergent functional genomics approach by leveraging the hierarchical similarity tool available in Geneweaver. Through our analysis, we were able to ascertain 7 BD consensus genes and 16 autoimmune diseases with genetic overlap with BD. The results of our study will inform further research into the pathogenesis of Behçet's disease. [ABSTRACT FROM AUTHOR]

Background and objective. Silicone breast implants have been the subject of doubt regarding their long-term safety: banned in 1992 by the FDA for their possible association with connective tissue, autoimmune and rheumatic diseases, they were commercialized again in 2006. In recent times they have been associated again with adverse effects grouped under the term "breast implant illness" (BII), a term popularized by social networks. These are patients wearing silicone breast prostheses, who report nonspecific systemic symptoms or systemic diseases associated with their implants. The present paper tries to update the scientific evidence about BII referring to its characterization, prevalence and treatment. Methods. Narrative review through a secondary search in PubMed, SciELO, DOAJ and Google Scholar using the terms "Breast", "Implant", "Illness" from 2014 to 2020. Secondary references were also analyzed, selecting the most significant. Results. Of the 17 articles included, none considered BII to be a defined disease, but a term popularized by patients and health personnel which included nonspecific symptoms and systemic diseases attributed to silicone prostheses. There is an increase in the incidence in the publications and the prevalence of symptoms has been studied in patients with breast implants, but there are no data on the prevalence of diagnosed BII. There are no laboratory tests to confirm the association of symptoms with breast implants. The search for antibodies to autoimmune diseases is suggested, which can explain the clinical manifestations and rule out other benign or malignant breast pathologies depending on clinical case. Regarding treatment, improvement in symptoms after implant removal has been reported in 6 studies (retrospective cohorts, isolated cases, and studies based on social media accounts). Most of the authors recommend validating the symptoms and, in the event of the patient's desire to remove the implants, carry it out together with a total capsulectomy and pathological study. Reported adverse effects after implant removal are wound infection, breast pain, dissatisfaction with cosmetic results, and the fact that the symptoms of BII do not reverse. Finally, the treatment of autoimmune, rheumatic diseases, and psychiatric disorders is recommended, following current protocols for each pathology. Conclusions. The term BII has been popularized mainly in social networks by patients and health personnel as the set of non-specific symptoms and signs and systemic diseases that the patient associates with her silicone implants. There is no scientific evidence to define it as a recognized disease. In the event of BII manifestations, it is suggested to rule out other diseases and respect the will of the patient for implant removal, under adequate informed consent. More rigorous methodology studies are necessary to demonstrate the association of silicone implants with the manifestations described under the term BII. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis‐associated interstitial lung disease (RA‐ILD) is an irreversible pathologic condition of unknown cause, commonly involving the joint and the lung with variable amounts of fibrotic change. In contrast to rheumatoid arthritis or other chronic interstitial lung diseases such as interstitial pulmonary fibrosis, there is so far no extensively accepted or implemented animal model for this disease. Aims: To provide guidance for those who are investigating the pathogenesis of RA‐ILD with animal models. Materials and Methods: An analysis of papers from PubMed during 1978‐2020. Results: We outline the present status quo for animal models of RA‐ILD about their modeling methods and pathogenesis, compare their pros and cons with respect to their ability to mimic the clinical and histological features of human disease and discuss their applicability for future research. Discussion: There is no doubt that these animal models do provide valuable information relating to the pathogenesis of RA‐ILD and the development of effective therapeutic drugs. Nevertheless, these animal models can not entirely recapitulate clinical pathology and have some limitations in experimental research application. Therefore, it should be emphasized that we should improve and explore animal models in more accordance with the pathogenesis and clinical characteristics of human RA‐ILD. Conclusion: These established animal models of the disease can significantly progress our understanding of the etiology of RA‐ILD, the fundamental mechanisms of its pathogenesis and the identification of new bio‐markers, and can contribute to the development and implementation of novel treatment strategies. [ABSTRACT FROM AUTHOR]

Pemphigus vulgaris is an autoimmune disease that can present initial manifestations in the oral cavity, and can also affect the skin, when it does not have adequate treatment and diagnosis. This paper aims to present a clinical case report in a 43-yearold patient, attended at the Dental Clinic of UNIPAR, Umuarama - Paraná complaining of pain in the gingival and mucous region due to the presence of ulcerations resulting from the rupture of blisters that emerged two months ago. Biopsy was performed and the histopathological result confirmed the diagnosis of pemphigus vulgaris. The patient obtained multidisciplinary treatment with the dental and medical team, obtained an improvement in her clinical condition and abandoned the treatment. After three months without taking any medication, the patient returned with a worsening of her clinical condition, reporting pain during swallowing, recurrence of ulcerations in the oral mucosa, hematemesis, being hospitalized urgently, receiving doses of the corticosteroid medication intravenously. After 12 months of multidisciplinary follow-up, the patient had complete remission of the oral lesions and is controlled for the manifestations of pemphigus vulgaris. This clinical case report shows the importance of early diagnosis and treatment of the manifestations of autoimmune diseases such as pemphigus vulgaris, thus improving the quality of life of patients. [ABSTRACT FROM AUTHOR]

This review paper outlines the definition, pathophysiology, and potential maternal health consequences of cellular fetal microchimerism, the maternal acquisition of intact cells of fetal origin during pregnancy. Increased rates and amounts of cellular fetal microchimerism are associated with several placental syndromes, including preeclampsia and fetal growth restriction. The discovery of cellular fetal microchimerism and methods of detection are briefly outlined, and we present the mechanisms hypothesized to govern pregnancy-related and long-term maternal health effects of cellular fetal microchimerism. Specifically, we discuss the potential implications of cellular fetal microchimerism in wound healing, autoimmunity, cancer, and possibly cardiovascular disease. Cellular fetal microchimerism represents a novel area of research on maternal and transgenerational health and disease, providing exciting opportunities for developing new disease biomarkers and precision medicine with targeted prophylaxis against long-term maternal disease. [ABSTRACT FROM AUTHOR]

This paper surveys some of the important insights that molecular evolution has contributed to evolutionary medicine; they include phage therapy, cancer biology, helminth manipulation of the host immune system, quality control of gametes, and pathogen outbreaks. Molecular evolution has helped to revolutionize our understanding of cancer, of autoimmune disease, and of the origin, spread, and pathogenesis of emerging diseases, where it has suggested new therapies, illuminated mechanisms, and revealed historical processes: all have practical therapeutic implications. While much has been accomplished, much remains to be done. [ABSTRACT FROM AUTHOR]

For many years, a considerable number of patients with autoimmune diseases (ADs) have suffered from a lack of drug response and drug‐related toxicity. Despite the emergence of new therapeutic options such as biological agents, patients continue to struggle with these problems. Unfortunately, new challenges, including the paradoxical effects of biological drugs, have complicated the situation. In recent decades, efforts have been made to predict drug response as well as drug‐related side effects. Thanks to the many advances in genetics, evaluation of markers to predict drug response/toxicity before the initiation of treatment may be an avenue toward personalizing treatments. Implementing pharmacogenetics and pharmacogenomics in the clinic could improve clinical care; however, obstacles remain to effective personalized medicine for ADs. The present study attempted to clarify the concept of pharmacogenetics/pharmacogenomics for ADs. After an overview on the pathogenesis of the most common types of treatments, this paper focuses on pharmacogenetic studies related to the selected ADs. Bridging the gap between pharmacogenetics and personalized medicine is also discussed. Moreover, the advantages, disadvantages and recommendations related to making personalized medicine practical for ADs have been addressed. [ABSTRACT FROM AUTHOR]

A number of epidemiological studies have shown a strong association between exposure to ambient airborne particulate matter (PM 2.5, PM < 1.0) and lung or cardiovascular diseases characterised by high mortality and morbidity. However, much less is known about the role of air pollution in the pathogenesis of autoimmune diseases, which constitutes a significant problem in modern society. This paper summarises the state of current research regarding the influence of PM on the development and/or progression of autoimmune diseases. A brief review of the great body of research concerning pathogenesis of autoimmune disorders is presented. Then, the scope of our review is narrowed to the research related to the impact of particulate matter on oxidative and nitrosative stress, as well as exacerbation of chronic inflammation, because they can contribute to the development of autoimmune diseases. Moreover, we discuss the impact of various components of PM (metal, organic compounds) on PM toxicity and the ability to generate oxidants. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWASs) for autoimmune diseases (ADs) have identified many risk loci and have provided insights into the etiology of each disease. Some of these loci, such as PTPN22, IL23R and STAT4, are shared among different ADs, and the combination of risk loci may determine an individual's susceptibility for a disease. The majority of GWAS loci are expression quantitative trait loci (eQTLs), where disease-causing variants regulate expression of neighboring (or sometimes distant) genes. Because the eQTL effects are often cell type-specific, the incorporation of epigenetic data from disease-related cell types and tissues is expected to refine the identification of causal variants. The cumulative eQTL effects in multiple genes may influence the activity or fate of immune cells, which in turn may affect the function of the immune system in individuals. In this paper, I review the etiology of ADs by focusing on important immune cells (Th1 cells, Th17 cells and regulatory T cells), important pathways (antigen-receptor signaling and type I interferon signaling) and relevant genes identified in GWASs. [ABSTRACT FROM AUTHOR]

Context: T helper (Th) cells as an important part of the immune is responsible for elimination of invading pathogens. But, if Th cell responses are not regulated effectively, the autoimmune diseases might develop. The Th17 subset usually produces interleukin-17A which in experimental models of organ-specific autoimmune inflammation is very important. Evidence Acquisitions: Directory of open access journals (DOAJ), Google Scholar, Embase, Scopus, PubMed and Web of Science have been searched. Results: Fifty-six articles were found and searched. In the present review article, we tried to summarize the recently published data about characteristics and role of Th1 and Th17 cells and discuss in detail, the potential role of these T helpers immune responses in renal inflammation and renal injury, focusing on glomerulonephritis. Published papers in animal and human studies indicated that autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, classically believed to be Th1-mediated, are mainly derived from a Th17 immune response. Identification of the Th17 subgroup has explained seemingly paradoxical observations and improved our understanding of immune-mediated inflammatory responses. Conclusions: Secretion of IL-17A, as well as IL-17F, IL-21, IL-22, suggests that Th17 subset may play a crucial role as a pleiotropic pro-inflammatory Th subset. There is experimental evidence to support the notion that Th1 and Th17 cells contribute to kidney injury in renal inflammatory diseases like glomerulonephritis. [ABSTRACT FROM AUTHOR]

Cytokines are polipeptides functioning as intercellular messengers, with essential roles in the regulation of immune functions. The main lymphocytic subtypes release specific cytokines, by which they are fulfilling a part of their functions. T-17 helper lymphocytes (LTH17) are of utter importance in the control of extracellular pathogens. Recent studies have shown the role of this lymphocytic subset in the onset and maintaining of chronic inflammation. In rheumatoid arthritis (RA), disease initiation is characterised by the selection of a certain lymphocytic phenotype synthetising interleukin 17 A (IL-17A), exerting local proinflammatory effects, demonstrated by the strong association between local IL-17 levels and articular destruction. Furthermore, the interaction between IL-17 and the tumor necrosis factor (TNF) contributes significantly to the damage and persistent inflammation of RA. Similar mechanisms have been demonstrated in anlylosing spondylitis and psoriatic arthritis. The discovery of the pathogenic implications of IL-17 in autoimmune diseases led to new treatment targets, currently several biologic agents aimed at IL-17 being in trial. The present paper is reviewing the most recent data showing the role of IL-17, of LTH17, and also of T helper 1 and T regulatory lymphocytes in the pathogenesis of autoimmune arthritides. [ABSTRACT FROM AUTHOR]

During the past few years technological advance have been allowed the developing of techniques that help to the diagnosis of multiple diseases. In the case of the autoimmune diseases, immunological techniques are helpful since they allow the detection of multiple autoantibodies at the same time with small volumes of sample. Together with the development of the new techniques, sensitivity and specificity in the detection of the antibodies specificities' also have been increased, in such a way that the clinicians can count with tests that allow them to make early diagnoses with greater certainty and also to follow the course of the disease based on the variation of the antibodies presents in the patient's samples. It is important to emphasize that the new techniques of laboratory that are used for the support of the diagnosis of autoimmune diseases, no longer are exclusive for research laboratories but by their facility of standardization, quality control and reproducibility they can be used in clinical laboratory of medium and small sizes. In the present paper we describe those techniques with greater application in the clinical laboratory of autoimmune diseases. [ABSTRACT FROM AUTHOR]

OTHER ARTICLES PUBLISHED IN THIS MINI-REVIEW SERIES ON Th17 CELLS Function and regulation of human T helper 17 cells in health and disease. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04037.x Are T helper 17 cells really pathogenic in autoimmunity? Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04039.x CD4+ T helper cells: functional plasticity and differential sensitivity to regulatory T cell-mediated regulation. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04040.x Development of mouse and human T helper 17 cells. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04041.x Uncommitted (naive) CD4+ T helper cells (Thp) can be induced to differentiate to specific lineages according to the local cytokine milieu, towards T helper type 1 (Th1), Th2, Th17 and regulatory T cell (Treg) phenotypes in a mutually exclusive manner. Each phenotype is characterized by unique signalling pathways and expression of specific transcription factors, notably T-bet for Th1, GATA-3 for Th2, forkhead box P3 (FoxP3) for Tregs and receptor-related orphan receptor (ROR)α and RORγt for Th17 cells. Tregs and Th17 cells have been demonstrated to arise from common precursors in a reciprocal manner based on exposure to transforming growth factor (TGF)-β or TGF-β plus interleukin (IL)-6 and carry out diametrically opposing functions, namely suppression or propagation of inflammation, respectively. However, while epigenetic modifications in Th1 and Th2 differentiated cells prevents their conversion to other phenotypes, Th17 cells generated in vitro using TGF-β and IL-6 are unstable and can convert to other phenotypes, especially Th1, both in vitro and in vivo. Tregs are generated from naive precursors both in the thymus (natural, nTregs) and in the periphery (induced, iTregs). The highly suppressive function of Tregs enables them to control many inflammatory diseases in animals and makes them particularly attractive candidates for immunotherapy in humans. The stability of the Treg phenotype is therefore of paramount importance in this context. Recent descriptions of Treg biology have suggested that components of pathogens or inflammatory mediators may subvert the suppressive function of Tregs in order to allow propagation of adequate immune responses. Unexpectedly, however, a number of groups have now described conversion of Tregs to the Th17 phenotype induced by appropriate inflammatory stimuli. These observations are particularly relevant in the context of cell therapy but may also explain some of the dysregulation seen in autoimmune diseases. In this paper, we review Treg to Th17 conversion and propose some potential mechanisms for this phenomenon. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is often considered the prototype organ-specific autoimmune disease in clinical immunology circles. The key disease features − precise destruction of a single endocrine cell type occurring on a distinct genetic and autoimmune background − have been unravelled in recent years to such an extent that there is a growing expectation that the disease should be curable. T1D is something of an orphan disease, currently managed by endocrinologists yet dependent upon the wit of immunologists, both basic and clinical, to find the best approaches to prevention and cure. Type 1 diabetes thus represents one of the most active arenas for translational research, as novel immune-based interventions find their way to the clinic. The first serious attempt at immune-based treatment for T1D was in 1984, the first at prevention in 1993; current and planned trials will take us into the next decade before reporting their results. This paper represents the first attempt at a comprehensive review of this quarter century of endeavour, documenting all the strategies that have emerged into clinical studies. Importantly, the intense clinical activity has established robust infrastructures for future T1D trials and frameworks for their design. The evident success of the monoclonal anti-CD3 antibody trials in established T1D demonstrate that modulation of islet autoimmunity in humans after the onset of overt disease can be achieved, and give some reason to be cautiously optimistic for the ability of these and other agents, alone and in combination, to provide an effective immunotherapy for the disease. [ABSTRACT FROM AUTHOR]

Uncommitted (naive) murine CD4+ T helper cells (Thp) can be induced to differentiate towards T helper 1 (Th1), Th2, Th17 and regulatory (Treg) phenotypes according to the local cytokine milieu. This can be demonstrated most readily both in vitro and in vivo in murine CD4+ T cells. The presence of interleukin (IL)-12 [signalling through signal transduction and activator of transcription (STAT)-4] skews towards Th1, IL-4 (signalling through STAT-6) towards Th2, transforming growth factor (TGF)-β towards Treg and IL-6 and TGF-β towards Th17. The committed cells are characterized by expression of specific transcription factors, T-bet for Th1, GATA-3 for Th2, forkhead box P3 (FoxP3) for Tregs and RORγt for Th17 cells. Recently, it has been demonstrated that the skewing of murine Thp towards Th17 and Treg is mutually exclusive. Although human Thp can also be skewed towards Th1 and Th2 phenotypes there is as yet no direct evidence for the existence of discrete Th17 cells in humans nor of mutually antagonistic development of Th17 cells and Tregs. There is considerable evidence, however, both in humans and in mice for the importance of interferon (IFN)-γ and IL-17 in the development and progression of inflammatory and autoimmune diseases (AD). Unexpectedly, some models of autoimmunity thought traditionally to be solely Th1-dependent have been demonstrated subsequently to have a non-redundant requirement for Th17 cells, notably experimental allergic encephalomyelitis and collagen-induced arthritis. In contrast, Tregs have anti-inflammatory properties and can cause quiescence of autoimmune diseases and prolongation of transplant function. As a result, it can be proposed that skewing of responses towards Th17 or Th1 and away from Treg may be responsible for the development and/or progression of AD or acute transplant rejection in humans. Blocking critical cytokines in vivo, notably IL-6, may result in a shift from a Th17 towards a regulatory phenotype and induce quiescence of AD or prevent transplant rejection. In this paper we review Th17/IL-17 and Treg biology and expand on this hypothesis. [ABSTRACT FROM AUTHOR]

The immune system is a complex interconnected network consisting of many parts including organs, tissues, cells, molecules and proteins that work together to protect the body from illness when germs enter the body. An autoimmune disease is a disease in which the body's immune system attacks healthy cells. It is known that when the immune system is working properly, it can clearly recognize and kill the abnormal cells and virus-infected cells. But when it doesn't work properly, the human body will not be able to recognize the virus-infected cells and, therefore, it can attack the body's healthy cells when there is no invader or does not stop an attack after the invader has been killed, resulting in autoimmune disease.; This paper presents a mathematical modeling of the virus-infected development in the body's immune system considering the multiple time-delay interactions between the immune cells and virus-infected cells with autoimmune disease. The proposed model aims to determine the dynamic progression of virus-infected cell growth in the immune system. The patterns of how the virus-infected cells spread and the development of the body's immune cells with respect to time delays will be derived in the form of a system of delay partial differential equations. The model can be used to determine whether the virus-infected free state can be reached or not as time progresses. It also can be used to predict the number of the body's immune cells at any given time. Several numerical examples are discussed to illustrate the proposed model. The model can provide a real understanding of the transmission dynamics and other significant factors of the virus-infected disease and the body's immune system subject to the time delay, including approaches to reduce the growth rate of virus-infected cell and the autoimmune disease as well as to enhance the immune effector cells. [ABSTRACT FROM AUTHOR]

Background: Stickler syndrome is a connective tissue disorder with predominantly autosomal dominant inheritance, with ocular, auditory and joint involvement. Thyroid dysfunction was not described as part of alterations in Stickler syndrome and in particular, the association between Stickler's syndrome and Graves' disease has never been previously reported in literature. Moreover, the presence of Graves' disease is uncommon in the pediatric age (especially in children younger than 6 years old). Case presentation: We report the case of a 5-years old child affected by Stickler syndrome who received the diagnosis of Graves's disease, in absence of suggestive symptoms, during health supervision. Conclusions: This is the first evidence of thyroid dysfunction and autoimmune pattern for Sticker syndrome. Further clinical reports are expected before suggesting the implementation of new clinical skills for Stickler syndrome, but this paper may contribute to improve personalized management of this rare disorder. [ABSTRACT FROM AUTHOR]

The human organism is a very complex system. To be in good health, its components must function properly. One of the most important systems of an organism is the immune system. It protects the body from the harmful effects of various external and internal agents. Sometimes, however, the immune system starts attacking its own healthy cells, tissues and organs. Then autoimmune diseases arise. They are widespread in recent decades. There is evidence that often autoimmune responses occur due to viral infections. In this paper, a new mathematical model of a general autoimmune disease is proposed. It describes the interactions between viral particles and host cells. The model is formulated by using integro-differential equations of Boltzmann type. This approach is typical for the nonequilibrium statistical mechanics. A preliminary qualitative and quantitative analysis of the model is presented. [ABSTRACT FROM AUTHOR]

Autoimmune disorders are a spectrum of diseases caused by impaired self-tolerance of the immune system. Previous studies underscored the association between autoimmune disorders and lymphomas. However, only a few papers studied the exact mechanisms of this association. The effect of IL-2, IL-5, IL-6, IL-10 and TNF-α, contribution of NOTCH, FAS and MHC receptor families, the interplay of various immune cells, and the relation of immunosuppressive agents and development of autoimmune disorders are the proposed mechanisms for this association. Each individual autoimmune disorder associates with particular types of lymphomas and their common pathways are not necessarily similar to other pairs of autoimmune disorder-lymphomas. Thus, the lymphomas susceptibility in various autoimmune disorders could not be investigated through a single pathway. In this review, we demonstrate the association between each pair of autoimmune disorder-lymphoma and the underlying pathways. By clarifying these associations, follow-up plans could be made leading to early diagnosis of lymphomas. [ABSTRACT FROM AUTHOR]

Several allergic and immunologic diseases including asthma, food allergy (FA), chronic spontaneous urticaria (CSU), atopic dermatitis (AD), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), and Behçet's disease (BD) are characterized by the involvement of Th2 immunity. Several mediators lead to immunoglobulin (Ig)E production, thus including key cytokines such as interleukin (IL)-4, IL-5, and IL-13. Among them, IL-31 and IL-33 have been recently studied as novel biomarkers and future therapeutic targets for allergic and immunological disorders. IL-31 is a proinflammatory cytokine—it regulates cell proliferation and is involved in tissue remodeling. IL-33, acting through its receptor suppression of tumorigenity (ST2L), is an alarmin cytokine from the IL-1 family, whose expression is mediated by tissue damage. The latter has a pleiotropic effect, as it may modulate specific and innate immune cells functions. To date, several researchers have investigated the involvement of IL-31 and IL-33 in several allergic and immune-mediated diseases. Further studies are needed to understand the future applications of these molecules as novel therapeutic agents. This paper aims to give the readers a complete and updated review of IL-31 and IL-33 involvement among the most common autoimmune and allergic disorders. [ABSTRACT FROM AUTHOR]

Introduction: Idiosyncratic drug-induced neutropenia and agranulocytosis is seldom discussed in the literature, especially for new drugs such as biotherapies outside the context of oncology. In the present paper, we report and discuss the clinical data and management of this relatively rare disorder, with a focus on biotherapies used in autoimmune and auto-inflammatory diseases. Materials and methods: A review of the literature was carried out using the PubMed database of the US National Library of Medicine. We searched for articles published between January 2010 and May 2019 using the following key words or associations: "drug-induced neutropenia", "drug-induced agranulocytosis", and "idiosyncratic agranulocytosis". We included specific searches on several biotherapies used outside the context of oncology, including: tumor necrosis factor (TNF)-alpha inhibitors, anti-CD20 agents, anti-C52 agents, interleukin (IL) 6 inhibitors, IL 1 inhibitors, and B-cell activating factor inhibitor. Results: Idiosyncratic neutropenia remains a potentially serious adverse event due to the frequency of severe sepsis with severe deep tissue infections (e.g., pneumonia), septicemia, and septic shock in approximately two-thirds of all hospitalized patients with grade 3 or 4 neutropenia (neutrophil count (NC) ≤ 0.5 × 109/L and ≤ 0.1 × 109/L, respectively). Over the last 20 years, several drugs have been strongly associated with the occurrence of idiosyncratic neutropenia, including antithyroid drugs, ticlopidine, clozapine, sulfasalazine, antibiotics such as trimethoprim-sulfamethoxazole, and deferiprone. Transient grade 1–2 neutropenia (absolute blood NC between 1.5 and 0.5 × 109/L) related to biotherapy is relatively common with these drugs. An approximate 10% prevalence of such neutropenia has been reported with several of these biotherapies (e.g., TNF-alpha inhibitors, IL6 inhibitors, and anti-CD52 agents). Grade 3–4 neutropenia or agranulocytosis and clinical manifestations related to sepsis are less common, with only a few case reports to date for most biotherapies. Special mention should be made of late onset and potentially severe neutropenia, especially following anti-CD52 agent therapy. During drug therapy, several prognostic factors have been identified that may be helpful when identifying 'susceptible' patients. Older age (>65 years), septicemia or shock, renal failure, and a neutrophil count ≤0.1 × 109/L have been identified as poor prognostic factors. Idiosyncratic neutropenia should be managed depending on clinical severity, with permanent/transient discontinuation or a lower dose of the drug, switching from one drug to another of the same or another class, broad-spectrum antibiotics in cases of sepsis, and hematopoietic growth factors (particularly G-CSF). Conclusion: Significant progress has been made in recent years in the field of idiosyncratic drug-induced neutropenia, leading to an improvement in their prognosis (currently, mortality rate between 5 and 10%). Clinicians must continue their efforts to improve their knowledge of these adverse events with new drugs as biotherapies. [ABSTRACT FROM AUTHOR]

Background: In the liver, several types of cells are involved in antigen presentation. In addition to myeloid antigen presenters such as Kupffer cells or dendritic cells, liver sinusoidal endothelial cells (LSECs) can express MHC and costimulatory molecules and are capable of presenting antigens. Objective: Targeting LSECs could be of therapeutical use in treatment of autoimmune disorders. Being in permanent contact with blood from systemic and portal circulations, LSEC is an important player in taking up and eliminating blood-borne soluble antigens and in determining the nature of the immune response such antigens stimulate. Generally, LSECs promote tolerance in both MHC I and II systems. Naïve CD4+ T-cells primed by LSECs using the MHC class II pathway can differentiate into two types of regulatory T-cells (Tregs): one expressing Forkhead-Box-Protein P3 (FoxP3) and the other lacking this transcription factor. These peripherally induced Tregs are important in maintaining tolerance to antigens that are not presented in thymus. This tolerogenic effect of LSECs has been rather controversial because they constitutively carry low levels of MHC II, but the exposure of MHC class II molecules may rise under the influence of inflammatory cytokines. Material and methods: Data analysis of scientific papers regarding the fascinating roles of liver sinusoidal endothelial cells in the immunologic microenvironment of the liver and the prospects of using these mechanisms therapeutically. Results: There are encouraging studies which used this technique and succeeded in curing experimental autoimmune encephalomyelitis in mice so we consider that this topic should be furthermore researched. Conclusions: LSECs possess the most potent endocytic capacity in the body; therefore, developing special nanoparticles which can deliver autoantigen peptides only to LSECs could be an efficient way to induce tolerance for the autoantigen. [ABSTRACT FROM AUTHOR]

Relapsing Polychondritis (RP) is a rare, recurrent and autoimmune multisystem disorder affecting cartilaginous structures, such as auricles, joints, nasal septum, larynx and tracheobronchial tree. Ocular manifestations may be observed in 42,3-65% of cases. Episcleritis and scleritis are the most common findings. However, RP is frequently misdiagnosed, leading to potentially severe, debilitating and, sometimes, fatal disease. There is no established standardized therapeutic protocol for RP. Current medical therapy is largely empiric and based on case reports. The aim of this paper is to document one case of ocular involvement in RP disease, emphasizing clinical and imaging findings that can help to establish an early diagnosis. [ABSTRACT FROM AUTHOR]