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Autoimmune diseases have a prevalence of approximately 7 to 9% and are classified as either organ-specific diseases, including type I diabetes, multiple sclerosis, inflammatory bowel disease and myasthenia gravis, or systemic diseases, including systemic lupus erythematosus, rheumatoid arthritis and Sjögren's syndrome. While many advancements have been made in understanding of the mechanisms of autoimmune disease, including the nature of self-tolerance and its breakdown, there remain unmet needs in terms of effective and highly targeted treatments. T regulatory cells (Tregs) are key mediators of peripheral tolerance and are implicated in many autoimmune diseases, either as a result of reduced numbers or altered function. Tregs may be broadly divided into those generated in the thymus (tTregs) and those generated in the periphery (pTregs). Tregs target many different immune cell subsets and tissues to suppress excessive inflammation and to support tissue repair and homeostasis: there is a fine balance between Treg cell stability and the plasticity that is required to adjust Tregs' regulatory purposes to particular immune responses. The central role of immunoglobulin E (IgE) in allergic disease is well recognized, and it is becoming increasingly apparent that this immunoglobulin also has a wider role encompassing other diseases including autoimmune disease. Anti-IgE treatment restores the capacity of plasmacytoid dendritic cells (pDCs) impaired by IgE- high-affinity IgE receptor (FcεR1) cross-linking to induce Tregs in vitro in atopic patients. The finding that anti-IgE therapy restores Treg cell homeostasis, and that this mechanism is associated with clinical improvement in asthma and chronic spontaneous urticaria suggests that anti-IgE therapy may also have a potential role in the treatment of autoimmune diseases in which Tregs are involved., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Aim: This study aimed to evaluate characteristics of autoimmunity in individuals who have a type 2 diagnosis and are relatives of children with type 1 diabetes. Methods: Pre‐diagnosis samples (median 17 months before onset) from relatives who were later diagnosed with type 2 diabetes were measured for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen‐2 (IA‐2A), zinc transporter 8 (ZnT8A) and insulin (IAA) as well as the type 1 diabetes genetic risk score (GRS2). Associations between islet autoantibodies, insulin treatment and GRS2 were analysed using Fisher's exact and t‐tests. Results: Among 226 relatives (64% men; mean age at sampling 41 years; mean age 54 years at diagnosis), 32 (14%) were islet autoantibody‐positive for at least one autoantibody more than a decade before diagnosis. Approximately half of these (n = 15) were treated with insulin. GADA‐positivity was higher in insulin‐treated relatives than in non‐insulin‐treated relatives (12/18 [67%] vs. 6/18 [33%], p < 0.001). IAA‐positivity was observed in 13/32 (41%) of relatives with autoantibodies. GRS2 scores were increased in autoantibody‐positive relatives (p = 0.032), but there was no clear evidence for a difference according to treatment (p = 0.072). Conclusion: This study highlights the importance of measuring islet autoantibodies, including IAA, in relatives of people with type 1 diabetes to avoid misdiagnosis. [ABSTRACT FROM AUTHOR]

Vitiligo is an autoimmune disease characterized by epidermal melanocyte destruction, with abnormal autoimmune responses and excessive oxidative stress as two cardinal mechanisms. Human umbilical mesenchymal stem cells‐derived exosomes (hUMSCs‐Exos) are regarded as promising therapeutic choice for autoimmune diseases due to potent immunosuppressive and anti‐oxidative properties, which can be potentiated under 3D cell culture condition. Nevertheless, whether exosomes derived from 3D spheroids of hUMSCs (3D‐Exos) exhibit considerable therapeutic effect on vitiligo and the underlying mechanism remain elusive. In this study, systemic administration of 3D‐Exos showed a remarkable effect in treating mice with vitiligo, as revealed by ameliorated skin depigmentation, less CD8+T cells infiltration, and expanded Treg cells in skin, and 3D‐Exos exerted a better effect than 2D‐Exos. Mechanistically, 3D‐Exos can prominently facilitate the expansion of Treg cells in vitiligo lesion and suppress H2O2‐induced melanocytes apoptosis. Forward miRNA profile analysis and molecular experiments have demonstrated that miR‐132‐3p and miR‐125b‐5p enriched in 3D‐Exos greatly contributed to these biological effects by targeting Sirt1 and Bak1 respectively. In aggregate, 3D‐Exos can efficiently ameliorate vitiligo by simultaneously potentiating Treg cells‐mediated immunosuppression and suppressing oxidative stress‐induced melanocyte damage via the delivery of miR‐132‐3p and miR‐125b‐5p. The employment of 3D‐Exos will be a promising treament for vitiligo. [ABSTRACT FROM AUTHOR]

This article examines the connection between the gut microbiome and autoimmune diseases, including type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. The gut microbiome plays a significant role in shaping the immune system and regulating bodily functions. Various factors, such as genetics, age, diet, and geographical location, can impact the risk of developing autoimmune diseases and influence the composition of the gut microbiota. The article also explores the potential of fecal microbiota transplants as a therapeutic option for treating autoimmune diseases. Further research is needed to fully understand these interactions and develop effective treatments. [Extracted from the article]

Summary: Autoimmune (or rheumatic) diseases are increasing in prevalence but selecting the best therapy for each patient proceeds in trial‐and‐error fashion. This strategy can lead to ineffective therapy resulting in irreversible damage and suffering; thus, there is a need to bring the promise of precision medicine to patients with autoimmune disease. While host factors partially determine the therapeutic response to immunosuppressive drugs, these are not routinely used to tailor therapy. Thus, non‐host factors likely contribute. Here, we consider the impact of the human gut microbiome in the treatment of autoimmunity. We propose that the gut microbiome can be manipulated to improve therapy and to derive greater benefit from existing therapies. We focus on the mechanisms by which the human gut microbiome impacts treatment response, provide a framework to interrogate these mechanisms, review a case study of a widely‐used anti‐rheumatic drug, and discuss challenges with studying multiple complex systems: the microbiome, the human immune system, and autoimmune disease. We consider open questions that remain in the field and speculate on the future of drug–microbiome–autoimmune disease interactions. Finally, we present a blue‐sky vision for how the microbiome can be used to bring the promise of precision medicine to patients with rheumatic disease. [ABSTRACT FROM AUTHOR]

Summary: Stem‐like T cells are characterized by their ability to self‐renew, survive long‐term, and give rise to a heterogeneous pool of effector and memory T cells. Recent advances in single‐cell RNA‐sequencing (scRNA‐seq) and lineage tracing technologies revealed an important role for stem‐like T cells in both autoimmunity and cancer. In cancer, stem‐like T cells constitute an important arm of the anti‐tumor immune response by giving rise to effector T cells that mediate tumor control. In contrast, in autoimmunity stem‐like T cells perform an unfavorable role by forming a reservoir of long‐lived autoreactive cells that replenish the pathogenic, effector T‐cell pool and thereby driving disease pathology. This review provides background on the discovery of stem‐like T cells and their function in cancer and autoimmunity. Moreover, the influence of the microbiota and metabolism on the stem‐like T‐cell pool is summarized. Lastly, the implications of our knowledge about stem‐like T cells for clinical treatment strategies for cancer and autoimmunity will be discussed. [ABSTRACT FROM AUTHOR]

Inflammation and autoimmune responses contribute to the pathophysiology of Long COVID, and its affective and chronic fatigue syndrome symptoms, labeled "the physio‐affective phenome." To investigate whether Long COVID and its physio‐affective phenome are linked to autoimmunity to the tight junction proteins, zonulin and occludin (ZOOC), and immune reactivity to lipopolysaccharides (LPS), and whether the latter are associated with signs of human herpes virus‐6 (HHV‐6) reactivation, autoimmunity directed against oligodendrocyte and neuronal proteins, including myelin basic protein. IgA/IgM/IgG responses to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), HHV‐6, ZOOC, and neuronal proteins, C‐reactive protein (CRP), and advanced oxidation protein products (AOPPs), were measured in 90 Long COVID patients and 90 healthy controls. The physio‐affective phenome was conceptualized as a factor extracted from physical and affective symptom domains. Neural network identified IgA directed to LPS (IgA‐LPS), IgG‐ZOOC, IgG‐LPS, and IgA‐ZOOC as important variables associated with Long COVID diagnosis with an area under the ROC curve of 0.755. Partial Least Squares analysis showed that 40.9% of the variance in the physio‐affective phenome was explained by CRP, IgA‐myelin basic protein (MBP), and IgG‐MBP. A large part of the variances in both autoimmune responses to MBP (36.3%–39.7%) was explained by autoimmunity (IgA and IgG) directed to ZOOC. The latter was strongly associated with indicants of HHV‐6 reactivation, which in turn was associated with increased IgM‐SARS‐CoV‐2. Autoimmunity against components of the tight junctions and increased bacterial translocation may be involved in the pathophysiology of Long COVID's physio‐affective phenome. [ABSTRACT FROM AUTHOR]

Diversity is the cornerstone of the adaptive immune system, crucial for its effectiveness against constantly evolving pathogens that pose threats to higher vertebrates. Accurately measuring and interpreting this diversity presents challenges for immunologists, as changes in diversity and clonotype composition can tip the balance between protective immunity and autoimmunity. In this review, we present the current methods commonly used to measure diversity from single‐cell T‐cell receptor and B‐cell receptor sequencing. We also discuss two case studies where single‐cell sequencing and diversity estimations have led to breakthroughs in autoimmune disease discovery and therapeutic innovation, and reflect upon the necessity and importance of accurately defining and measuring lymphocyte diversity in these contexts. [ABSTRACT FROM AUTHOR]

While it is known that immunoglobulin replacement therapy (IgRT) used in the treatment of primary immunodeficiency disorders (PIDs) can lead to the passive transfer of autoantibodies, there is no data indicating that these antibodies can cause clinical symptoms in patients. This study aimed to investigate the presence of autoantibodies and their clinical correlation in patients diagnosed with PIDs receiving IgRT. Paediatric patients who were diagnosed with PIDs, and administered IgRT at our immunology clinic between 1 January 2012 and 31 December 2021, were included in the study. The medical records of these patients were retrospectively analysed, and autoantibodies were screened. Autoantibody screening was conducted at least once in 48 cases. Among these cases, 29 cases (60.4%) demonstrated positivity for at least one of the autoantibodies screened in the study. Among these cases, 23 tested positive for anti‐TPO, 9 for anti‐TG and 2 for both anti‐TPO and anti‐TG. Only two of these patients were confirmed to have Hashimoto's thyroiditis. In 30 cases, autoantibodies related to Celiac disease (CD) were screened, with at least one being positive in five different cases; CD was not confirmed. The results of our study suggest that passive transfer of autoantibodies to patients with IgRT does not cause any significant clinical findings. In addition, in cases of PID, autoantibodies detected in the blood passed to patients with IgRT can lead to misdiagnosis. Screening for autoantibodies in patients with PID undergoing IgRT may not yield accurate results in terms of detecting autoimmune diseases. [ABSTRACT FROM AUTHOR]

Aims: This study reports the prevalence and characteristics related to the development of thyroid autoimmunity among children newly diagnosed with type I diabetes (T1D) during the COVID‐19 pandemic in Kuwait. Materials and Methods: This is a prospective observational study of all children under age 14 years newly diagnosed with T1D in Kuwait. We define the duration of the COVID‐19 pandemic from the official declaration of the first identified positive COVID‐19 case on 24 February 2020 until 31 December 2022. For comparison, we use the time period directly before the COVID‐19 pandemic, 1 January 2017 to 23 February 2020. Results: One thousand twenty‐four (1024) children newly diagnosed with T1D in Kuwait during the study period were included. Among newly diagnosed children, 20.3% tested positive for thyroid antibodies during the COVID‐19 pandemic, compared with 14.5% during the pre‐pandemic period (p = 0.015). Children with positive COVID‐19 status were more likely to present with thyroid antibodies (p = 0.035). After adjusting for other characteristics, patients diagnosed with T1D during the COVID‐19 pandemic had double the odds of testing positive for thyroid antibodies (Adjusted odds ratio = 2.173, 95%CI: 1.108, 4.261, p = 0.024). Conclusions: Incident cases of T1D during the COVID‐19 pandemic may be different in aetiology or contextual factors leading to a higher risk of thyroid autoimmunity. Longitudinal studies are needed to understand the role of COVID‐19 in the onset and progression of T1D and on thyroid autoimmunity and disease. [ABSTRACT FROM AUTHOR]

Despite accumulating evidence linking defective lysosome function with autoimmune diseases, how the catabolic machinery is regulated to maintain immune homeostasis remains unknown. Late endosomal/lysosomal adaptor, MAPK and mTOR activator 5 (Lamtor5) is a subunit of the Ragulator mediating mechanistic target of rapamycin complex 1 (mTORC1) activation in response to amino acids, but its action mode and physiological role are still unclear. Here it is demonstrated that Lamtor5 level is markedly decreased in peripheral blood mononuclear cells (PBMCs) of patients with systemic lupus erythematosus (SLE). In parallel, the mice with myeloid Lamtor5 ablation developed SLE‐like manifestation. Impaired lysosomal function and aberrant activation of mTORC1 are evidenced in Lamtor5 deficient macrophages and PBMCs of SLE patients, accompanied by blunted autolysosomal pathway and undesirable inflammatory responses. Mechanistically, it is shown that Lamtor5 is physically associated with ATP6V1A, an essential subunit of vacuolar H+‐ATPase (v‐ATPase), and promoted the V0/V1 holoenzyme assembly to facilitate lysosome acidification. The binding of Lamtor5 to v‐ATPase affected the lysosomal tethering of Rag GTPase and weakened its interaction with mTORC1 for activation. Overall, Lamtor5 is identified as a critical factor for immune homeostasis by intergrading v‐ATPase activity, lysosome function, and mTOR pathway. The findings provide a potential therapeutic target for SLE and/or other autoimmune diseases. [ABSTRACT FROM AUTHOR]

Background and purpose: Paraneoplastic neurological autoimmunity is well described with small‐cell lung cancer, but information is limited for other neuroendocrine neoplasms (NENs). Methods: Adult patients with histopathologically confirmed non‐pulmonary NENs, neurological autoimmunity within 5 years of NEN diagnosis, and neural antibody testing performed at the Mayo Clinic Neuroimmunology Laboratory (January 2008 to March 2023) were retrospectively identified. Control sera were available from patients with NENs without neurological autoimmunity (116). Results: Thirty‐four patients were identified (median age 68 years, range 31–87). The most common primary tumor sites were pancreas (nine), skin (Merkel cell, eight), small bowel/duodenum (seven), and unknown (seven). Five patients received immune checkpoint inhibitor (ICI) therapy before symptom onset; symptoms preceded cancer diagnosis in 62.1% of non‐ICI‐treated patients. The most frequent neurological phenotypes (non‐ICI‐treated) were movement disorders (12; cerebellar ataxia in 10), dysautonomia (six), peripheral neuropathy (eight), encephalitis (four), and neuromuscular junction disorders (four). Neural antibodies were detected in 55.9% of patients studied (most common specificities: P/Q‐type voltage‐gated calcium channel [seven], muscle‐type acetylcholine receptor [three], anti‐neuronal nuclear antibody type 1 [three], and neuronal intermediate filaments [two]), but in only 6.9% of controls. Amongst patients receiving cancer or immunosuppressive therapy, 51.6% had partial or complete recovery. Outcomes were unfavorable in 48.3% (non‐ICI‐treated) and neural autoantibody positivity was associated with poor neurological outcome. Discussion: Neurological autoimmunity associated with non‐pulmonary NENs is often multifocal and can be treatment responsive, underscoring the importance of rapid recognition and early treatment. [ABSTRACT FROM AUTHOR]

LRBA is a cytoplasmic protein that is ubiquitously distributed. Almost all LRBA domains have a scaffolding function. In 2012, it was reported that homozygous variants in LRBA are associated with early‐onset hypogammaglobulinemia. Since its discovery, more than 100 pathogenic variants have been reported. This review focuses on the variants reported in LRBA and their possible associations with clinical phenotypes. In this work LRBA deficiency cases reported more than 11 years ago have been revised. A database was constructed to analyze the type of variants, age at onset, clinical diagnosis, infections, autoimmune diseases, and cellular and immunoglobulin levels. The review of cases from 2012 to 2023 showed that LRBA deficiency was commonly diagnosed in patients with a clinical diagnosis of Common Variable Immunodeficiency, followed by enteropathy, neonatal diabetes mellitus, ALPS, and X‐linked‐like syndrome. Most cases show early onset of presentation at <6 years of age. Most cases lack protein expression, whereas hypogammaglobulinemia is observed in half of the cases, and IgG and IgA levels are isotypes reported at low levels. Patients with elevated IgG levels exhibited more than one autoimmune manifestation. Patients carrying pathogenic variants leading to a premature stop codon show a severe phenotype as they have an earlier onset of disease presentation, severe autoimmune manifestations, premature death, and low B cells and regulatory T cell levels. Missense variants were more common in patients with low IgG levels and cytopenia. This work lead to the conclusion that the type of variant in LRBA has association with disease severity, which leads to a premature stop codon being the ones that correlates with severe disease. [ABSTRACT FROM AUTHOR]

Summary: The discovery of toll‐like receptors (TLRs) and the subsequent recognition that endogenous nucleic acids (NAs) could serve as TLR ligands have led to essential insights into mechanisms of healthy immune responses as well as pathogenic mechanisms relevant to systemic autoimmune and inflammatory diseases. In systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis, NA‐containing immune complexes serve as TLR ligands, with distinct implications depending on the additional immune stimuli available. Plasmacytoid dendritic cells (pDCs), the robust producers of type I interferon (IFN‐I), are providing critical insights relevant to TLR‐mediated healthy immune responses and tissue repair, as well as generation of inflammation, autoimmunity and fibrosis, processes central to the pathogenesis of many autoimmune diseases. In this review, we describe recent data characterizing the role of platelets and NA‐binding chemokines in modulation of TLR signaling in pDCs, as well as implications for how the IFN‐I products of pDCs contribute to the generation of inflammation and wound healing responses by monocyte/macrophages. Chemokine modulators of TLR‐mediated B cell tolerance mechanisms and interactions between TLR signaling and metabolic pathways are also considered. The modulators of TLR signaling and their contribution to the pathogenesis of systemic autoimmune diseases suggest new opportunities for identification of novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Summary: Red blood cell autoimmunity and alloimmunity are potentially linked. Quantification of this association can tailor extensively matched red blood cell transfusions in patients with autoimmunity. Using an incident new‐user cohort comprising 47 285 previously non‐transfused, non‐alloimmunised patients, we compared transfusion‐induced red blood cell alloimmunisation incidences in direct antiglobulin test (DAT)‐positive and control patients. Additionally, we performed case–control analyses to handle potential confounding by clinical immunomodulators. Among (IgG and/or C3d) DAT‐positive patients (N = 380), cumulative red blood cell alloimmunisation incidences after 10 units transfused reached 4.5% (95% confidence interval [CI] 2.5–8.2) versus 4.2% (CI 3.9–4.5, p = 0.88) in controls. In case–control analyses, alloimmunisation relative risks among DAT‐positive patients increased to 1.7 (CI 1.1–2.8). Additional adjustments for pre‐DAT transfusion exposure or the extent of Rh/K mismatching did not impact results. In conclusion, while patients with DAT positivity show an intrinsically increased alloimmune red blood cell response, their absolute risk is comparable to control patients due to counteracting co‐existing immunosuppressive conditions. Consequently, isolated DAT positivity in patients lacking overt haemolysis or complicated alloantibody testing does not seem to warrant extended matching strategies. [ABSTRACT FROM AUTHOR]

Scientific outreach activities play an important role in disseminating knowledge, connecting the general public to research and breaking down scientific skepticism barriers. However, the vision‐impaired community is often disadvantaged when the most common audio–visual approach of scientific communication is applied. Here we integrated tactile clues in the scientific communication of immune processes involved in the autoimmune skin disease psoriasis. We fostered the involvement of the vision‐impaired community through interactive experiences, including tactile scientific origami art, a haptic poster and wood‐carved molecular models. Readily accessible science communication that engages a number of senses is a critical step toward making science more inclusive and engaging for individuals with a wide range of sensory abilities. The approach of the 2023 Monash Sensory Science exhibition aligns with the principles of equity, diversity and inclusion and helps to empower a more informed and scientifically literate public. [ABSTRACT FROM AUTHOR]

Objectives: The dysregulated immune response is one of the cardinal features of severe coronavirus disease 2019 (COVID‐19). This study was conducted to clarify the occurrence of autoantibodies (AABs) associated with systemic autoimmune rheumatic diseases (SARDs) in hospitalized patients with a moderate, severe, and critical form of COVID‐19. Methods: The serum samples obtained from 176 hospitalized COVID‐19 patients were investigated in this study, including patients with moderate (N = 90), severe (N = 50), and critical (N = 36) forms of COVID‐19. Also, the serum samples collected from healthy subjects before the COVID‐19 pandemic were used as controls (N = 176). The antinuclear antibodies (ANAs), antidouble‐stranded DNA (anti‐dsDNA), cytoplasmic‐anti neutrophil cytoplasmic antibody (c‐ANCA), perinuclear ANCA (p‐ANCA), antiphospholipid antibodies (aPLs), and anticyclic citrullinated peptide (anti‐CCP) occurrence was evaluated using a solid‐phase enzyme‐linked immunosorbent assay (ELISA). Results: The results showed that the occurrence of ANAs, anti‐dsDNA, anti‐CCP, c‐ANCA, and p‐ANCA was significantly higher in the COVID‐19 patients compared to serum obtained from healthy subjects (p <.0001, p <.0001, p <.0001, p <.05, and p <.001, respectively). The positive number of anti‐CCP tests increased significantly in severe COVID‐19 compared to the moderate group (p <.01). Conclusion: Our study further supports the development of autoantibodies related to systemic autoimmune rheumatologic diseases. To the best of our knowledge, this is the first study with a large sample size that reported the occurrence of anti‐CCP in a severe form of COVID‐19. [ABSTRACT FROM AUTHOR]

Aims: To find clinical and immunological signatures of the SARS‐CoV‐2 and the COVID‐19 pandemic on children newly diagnosed with type 1 diabetes (T1D). Methods: A single‐centre, retrospective, observational study comparing the clinical and immunological characteristics of children diagnosed with T1D the year before and during the first 2 years of the COVID‐19 pandemic. Data extracted from the medical records included clinical and demographic parameters, COVID‐19 PCR results and the presence of anti‐islet, thyroid and celiac‐related antibodies. Also obtained from the medical records was a family history of T1D, celiac disease and autoimmune thyroid disease in a first‐degree family member. Results: A total of 376 children were diagnosed with T1D during the study period. A total of 132 in the pre‐COVID era and 246 in the first 2 years of the pandemic. At diagnosis, the pH in children with DKA was lower, and HbA1c tended to be higher in the COVID‐19 group compared to the pre‐COVID‐19 group (7.30 [7.18, 7.35] vs 7.33 [7.19, 7.36], p = 0.046) and (110.9 [86.9, 129.5] vs 100 [80.3, 129.5], p = 0.067]) respectively. Multiple islet antibodies (IA) were significantly more common among patients in the pre‐COVID‐19 group compared to the COVID‐19 group (72% vs 61%, p = 0.032). Tissue transglutaminase antibodies were more common among children diagnosed in the COVID‐19 compared to the pre‐COVID group (16.6% vs 7.9%, p = 0.022). Conclusions: Our findings suggest that SARS‐CoV‐2 and the environmental alterations caused by the pandemic affected the clinical characteristics and the immunological profile of children diagnosed with T1D. It is, therefore, plausible that the virus plays a role in the autoimmune process causing T1D. [ABSTRACT FROM AUTHOR]

Background: Intravenous immunoglobulins (IVIgs) derived from the pooled plasma of thousands of donors contain numerous types of IgG molecules, including autoantibodies commonly used to diagnose autoimmunity. While these autoantibodies can cause misinterpretation of serological tests for IVIg recipients, their profiles in IVIg preparations are not fully understood. Study Design and Methods: Using binding‐capability based immune assays, we measured 18 varieties of clinically relevant autoantibodies in domestic blood donor‐derived IVIg products. In addition, we analyzed an IVIg product from a US brand to evaluate the influence of regional and racial differences. Based on the determined autoantibody titers, pharmacokinetics of passively acquired autoantibodies and their possible detection period in serum were estimated. Results: Anti‐thyroglobulin (Tg), anti‐thyroidperoxidase (TPO), and anti‐Sjögren's‐syndrome‐related antigen A (SS‐A) antibodies were present in considerable amounts in IVIg products. Notably, these three autoantibodies can be detected in IVIg recipients' sera for up to 3 months after infusion. Discussion: To the best of our knowledge, this is the first study that analyzed multiple autoantibody profiles in both pooled plasma and IVIg products and that further evaluated their potential influences on diagnosis of autoimmunity. Clinicians should keep in mind that IVIgs contain several autoantibodies and that their infusion can produce false‐positive serology results. To establish an accurate diagnosis, serological tests must be carefully interpreted and clinical symptoms should be more purposefully considered if patients are receiving IVIg therapy. [ABSTRACT FROM AUTHOR]

Summary: Since their description by Metchnikoff in 1905, phagocytes have been increasingly recognized to be the entities that traffic to sites of infection and inflammation, engulf and kill infecting organisms, and clear out apoptotic debris all the while making antigens available and accessible to the lymphoid organs for future use. Therefore, phagocytes provide the gateway and the first check in host protection and immune response. Disorders in killing and chemotaxis lead not only to infection susceptibility, but also to autoimmunity. We aim to describe chronic granulomatous disease and the leukocyte adhesion deficiencies as well as myeloperoxidase deficiency and G6PD deficiency as paradigms of critical pathways. [ABSTRACT FROM AUTHOR]

Summary: Over 200,000 individuals in the United States alone live with Down Syndrome (DS), the most common genetic disorder associated with intellectual disability. DS has a constellation of features across the body, including dysregulation of the immune system. Individuals with DS have both a higher frequency of autoimmunity and more severe infections than the general population, highlighting the importance of understanding the immune system in this population. Individuals with DS present with dysregulation of both the innate and adaptive immune systems. Elevated cytokine levels, increased type I and type II IFN signaling, a shift toward memory phenotypes in T cells, and a decrease in the size of the B‐cell compartment are observed in individuals with DS, which contribute to both autoinflammation and severe infections. Herein, we discuss the current knowledge of the immune system in individuals with Down Syndrome as well as ideas of necessary further investigations to decipher the mechanisms by which trisomy 21 leads to immune dysregulation, with the ultimate goal of identifying clinical targets to improve treatment. [ABSTRACT FROM AUTHOR]

Background: Molecular mimicry is hypothesized to be a mechanism by which autoimmune diseases are triggered. It refers to sequence or structural homology between foreign antigens and self-antigens, which can activate cross-reactive lymphocytes that attack host tissues. Elucidating the role of molecular mimicry in human autoimmunity could have important clinical implications. Objective: To review evidence for the role of molecular mimicry in major autoimmune diseases and discuss potential clinical implications. Methods: Comprehensive literature review of clinical trials, observational studies, animal models, and immunology studies on molecular mimicry in multiple sclerosis, type 1 diabetes, rheumatoid arthritis, lupus, Guillain-Barre syndrome, autoimmune myocarditis, and primary biliary cirrhosis published from 2000-2023. Results: Substantial indirect evidence supports molecular mimicry as a contributor to loss of self-tolerance in several autoimmune conditions. Proposed microbial triggers include Epstein-Barr virus, coxsackievirus, Campylobacter jejuni, and bacterial commensals. Key mechanisms involve cross-reactive T cells and autoantibodies induced by epitope homology between microbial and self-antigens. Perpetuation of autoimmunity involves epitope spreading, inflammatory mediators, and genetic factors. Conclusions: Molecular mimicry plausibly explains initial stages of autoimmune pathogenesis induced by infection or microbiota disturbances. Understanding mimicry antigens and pathways could enable improved prediction, monitoring, and antigen-specific immunotherapy for autoimmune disorders. However, definitive proof of causation in humans remains limited. Further research should focus on establishing clinical evidence and utility. [ABSTRACT FROM AUTHOR]

Cluster of differentiation 47 (CD47) occupies the outer membrane of human cells, where it binds to soluble and cell surface receptors on the same and other cells, sculpting their topography and resulting in a pleiotropic receptor‐multiligand interaction network. It is a focus of drug development to temper and accentuate CD47‐driven immune cell liaisons, although consideration of on‐target CD47 effects remain neglected. And yet, a late clinical trial of a CD47‐blocking antibody was discontinued, existent trials were restrained, and development of CD47‐targeting agents halted by some pharmaceutical companies. At this point, if CD47 can be exploited for clinical advantage remains to be determined. Herein an airing is made of the seemingly conflicting actions of CD47 that reflect its position as a junction connecting receptors and signalling pathways that impact numerous human cell types. Prospects of CD47 boosting and blocking are considered along with potential therapeutic implications for autoimmune diseases and cancer. [ABSTRACT FROM AUTHOR]

COVID‐19 is a severe infectious disease caused by a SARS‐CoV‐2 infection. It has caused a global pandemic and can lead to acute respiratory distress syndrome (ARDS). Beyond the respiratory system, the disease manifests in multiple organs, producing a spectrum of clinical symptoms. A pivotal factor in the disease's progression is autoimmunity, which intensifies its severity and contributes to multi‐organ injuries. The intricate interaction between the virus' spike protein and human proteins may engender the generation of autoreactive antibodies through molecular mimicry. This can further convolute the immune response, with the potential to escalate into overt autoimmunity. There is also emerging evidence to suggest that COVID‐19 vaccinations might elicit analogous autoimmune responses. Advanced technologies have pinpointed self‐reactive antibodies that target diverse organs or immune‐modulatory proteins. The interplay between autoantibody levels and multi‐organ manifestations underscores the importance of regular monitoring of serum antibodies and proinflammatory markers. A combination of immunosuppressive treatments and antiviral therapy is crucial for managing COVID‐19‐associated autoimmune diseases. The review will focus on the generation of autoantibodies in the context of COVID‐19 and their impact on organ health. [ABSTRACT FROM AUTHOR]

Although one of the most common systemic autoimmune disorders, Sjögren disease (SjD) may be overlooked in patients presenting with non‐specific symptoms or no complaints of sicca symptoms. SjD is not a condition to be missed as patients could present with serious extra‐glandular manifestations, including lymphomas. In this article, we discuss the diagnostic pitfalls of this disorder and encourage physicians to consider carefully the 'non‐textbook' presentations. [ABSTRACT FROM AUTHOR]

Summary: Cyclic thrombocytopenia (CTP) is characterized by periodic platelet oscillation with substantial amplitude. Most CTP cases have a thrombocytopenic background and are often misdiagnosed as immune thrombocytopenia with erratically effective treatment choices. CTP also occurs during hydroxyurea treatment in patients with myeloproliferative diseases. While the aetiology of CTP remains uncertain, here we evaluate historical, theoretical and clinical findings to provide a framework for understanding CTP pathophysiology. CTP retains the intrinsic oscillatory factors defined by the homeostatic regulation of platelet count, presenting as reciprocal platelet/thrombopoietin oscillations and stable oscillation periodicity. Moreover, CTP patients possess pathogenic factors destabilizing the platelet homeostatic system thereby creating opportunities for external perturbations to initiate and sustain the exaggerated platelet oscillations. Beyond humoral and cell‐mediated autoimmunity, we propose recently uncovered germline and somatic genetic variants, such as those of MPL, STAT3 or DNMT3A, as pathogenic factors in thrombocytopenia‐related CTP. Likewise, the JAK2 V617F or BCR::ABL1 translocation that drives underlying myeloproliferative diseases may also play a pathogenic role in hydroxyurea‐induced CTP, where hydroxyurea treatment can serve as both a trigger and a pathogenic factor of platelet oscillation. Elucidating the pathogenic landscape of CTP provides an opportunity for targeted therapeutic approaches in the future. [ABSTRACT FROM AUTHOR]

An increasing number of cases have reported that coronavirus disease 2019 (COVID‐19) can lead to immune system dysregulation and induce autoimmune diseases, but the mechanism is unclear. We treated a patient who presented with an unknown fever after infection with the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in 2023. After excluding the possibility of infection, malignancy, and other connective tissue diseases, we considered the diagnosis of IgG4‐related disease in consideration of the patient's pathology and clinical findings. In this article, we summarize our diagnostic experience and summarize the case reports of IgG4‐related diseases associated with SARS‐CoV‐2 infections since the COVID‐19 pandemic. [ABSTRACT FROM AUTHOR]

The aetiology of type 1 diabetes (T1D) is considered multifactorial with the contribution of the MHC on chromosome 6 being most important. Multiple factors also contribute to the aetiology of colorectal neoplasia, but the final event causing the change from normal mucosa to polyp and from polyp to cancer is due to a single somatic mutation event. Repeated formation of colorectal neoplasia within an at‐risk population results in a predictable, tapering, exponential neoplasia distribution. Critical mutations driving colorectal neoplasia formation occur in mutation‐prone DNA. These observations led to three hypotheses related to T1D. First, a single somatic mutation within the MHC of antigen presenting cells results in a change in phenotype from normal to T1D. Second, the distribution of additional autoimmune diseases (AAIDs) among persons with T1D adheres to a predictable, tapering, exponential distribution. And third, critical mutations driving development of T1D occur in mutation‐prone DNA. To address the hypotheses in an orderly fashion, a new analytical method called genome‐wide aetiology analysis (GWEA) consisting of nine steps is presented. All data required for GWEA of T1D are obtained from peer‐reviewed publications or publicly available genome and proteome databases. Critical GWEA steps include AAID distribution among persons with T1D, analysis of at‐risk HLA loci for mutation‐prone DNA, determination of the role of non‐MHC genes on GWAS, and verification of human data by cell culture or animal experiments. GWEA results show that distribution of AAID among persons with T1D adheres to a predictable, tapering, exponential distribution. A single, critical, somatic mutation within the epitope‐binding groove of at‐risk HLA loci alters HLA‐insulin‐peptide‐T‐cell‐receptor (TCR) complex binding affinity and creates a new pathway that leads to loss of self‐tolerance. The at‐risk HLA loci, in particular binding pockets P1, P4 and P9, are encoded by mutation‐prone DNA: GC‐rich DNA sequence and somatic hypermutation hotspots. All other genes on GWAS can but do not have to amplify the new autoimmune pathway by facilitating DNA mutations, changing peptide binding affinity, reducing signal inhibition or augmenting signal intensity. Animal experiments agree with human studies. In conclusion, T1D is caused by a somatic mutation within the epitope‐binding groove of an at‐risk HLA gene that affects HLA‐insulin‐peptide‐TCR complex binding affinity and initiates an autoimmune pathway. The nature of the peptide that binds to a mutated epitope‐binding groove of an at‐risk HLA gene determines the type of autoimmune disease that develops, that is, one at‐risk HLA locus, multiple autoimmune diseases. Thus, T1D and AAIDs, and therefore common autoimmune diseases, share a similar somatic mutation‐based aetiology. [ABSTRACT FROM AUTHOR]

This article, published in the European Journal of Immunology, explores the role of MHCII expression in autoreactive germinal center B cells. The study used an autoimmune bone marrow chimera model and found that B cells depend on MHCII expression for participation in the germinal center. However, B cells with a 50% reduction in surface MHCII were still able to compete effectively with wild-type B cells. The findings provide insights into the requirements for germinal center participation and shed light on the behavior of autoreactive B cells in autoimmune diseases. [Extracted from the article]

In COVID‐19, hyperinflammatory and dysregulated immune responses contribute to severity. Patients with pre‐existing autoimmune conditions can therefore be at increased risk of severe COVID‐19 and/or associated sequelae, yet SARS‐CoV‐2 infection in this group has been little studied. Here, we performed single‐cell analysis of peripheral blood mononuclear cells from patients with three major autoimmune diseases (rheumatoid arthritis, psoriasis, or multiple sclerosis) during SARS‐CoV‐2 infection. We observed compositional differences between the autoimmune disease groups coupled with altered patterns of gene expression, transcription factor activity, and cell–cell communication that substantially shape the immune response under SARS‐CoV‐2 infection. While enrichment of HLA‐DRlow CD14+ monocytes was observed in all three autoimmune disease groups, type‐I interferon signaling as well as inflammatory T cell and monocyte responses varied widely between the three groups of patients. Our results reveal disturbed immune responses to SARS‐CoV‐2 in patients with pre‐existing autoimmunity, highlighting important considerations for disease treatment and follow‐up. [ABSTRACT FROM AUTHOR]

Gigantomastia is a rare entity characterized by diffuse and excessive breast enlargement. It mainly occurs during puberty and pregnancy as a consequence of hormonal fluctuations. We report an unusual case of gigantomastia in a 29‐year‐old woman with a history of personal and familiar autoimmune phenomena. She had autoimmune thyroiditis and several positive autoantibodies, and developed 3 crises of the disease, 1 related to pregnancy (possibly hormone‐mediated), and 2 unrelated to pregnancy in which an autoimmune role is raised based in clinical, histological and laboratory findings. Immunological aspects that may be involved in this presentation of the disease are discussed. [ABSTRACT FROM AUTHOR]

Myeloid‐derived suppressor cells (MDSCs) are well recognized as critical factors in the pathology of tumors. However, their roles in autoimmune diseases are still unclear, which hampers the development of efficient immunotherapies. The role of different MDSCs subsets in multiple sclerosis, inflammatory bowel diseases, rheumatoid arthritis, type 1 diabetes, and systemic lupus erythematosus displayed different mechanisms of immune suppression, and several studies pointed to MDSCs' capacity to induce T‐helper (Th)17 cells and tissue damage. These results also suggested that MDSCs could be present in different functional states and utilize different mechanisms for controlling the activity of T and B cells. Therefore, various therapeutic strategies should be employed to restore homeostasis in autoimmune diseases. The therapies harnessing MDSCs could be designed either as cell therapy or rely on the expansion and activation of MDSCs in vivo, or their depletion. Cumulatively, MDSCs are inevitable players in autoimmunity, and rational approaches in developing therapies are required to avoid the adverse effects of MDSCs and harness their suppressive mechanisms to improve the overall efficacy of autoimmunity therapy. [ABSTRACT FROM AUTHOR]

Background and purpose: The gut microbiome is involved in autoimmunity. Data on its composition in chronic inflammatory demyelinating polyneuropathy (CIDP), the most common chronic autoimmune disorder of peripheral nerves, are currently lacking. Methods: In this monocentric exploratory pilot study, stool samples were prospectively collected from 16 CIDP patients (mean age 58 ± 10 years, 25% female) before and 1 week after administration of intravenous immunoglobulin (IVIg). Gut microbiota were analyzed via bacterial 16S rRNA gene sequencing and compared to 15 age‐matched healthy subjects (mean age 59 ± 15 years, 66% female). Results: The gut microbiota of CIDP patients showed an increased alpha‐diversity (p = 0.005) and enrichment of Firmicutes, such as Blautia (p = 0.0004), Eubacterium hallii (p = 0.0004), or Ruminococcus torques (p = 0.03), and of Actinobacteriota (p = 0.03) compared to healthy subjects. IVIg administration did not alter the gut microbiome composition in CIDP in this short‐term observation (p = 0.95). Conclusions: The gut microbiome in IVIg‐treated CIDP shows distinct features, with increased bacterial diversity and enrichment of short‐chain fatty acid producing Firmicutes. IVIg had no short‐term impact on the gut microbiome in CIDP patients. As the main limitation of this exploratory pilot study was small cohort size, future studies also including therapy‐naïve patients are warranted to verify our findings and to explore the impact of long‐term IVIg treatment on the gut microbiome in CIDP. [ABSTRACT FROM AUTHOR]

It is now 60 years since Ian Mackay and Macfarlane Burnet published their seminal text "The Autoimmune Diseases" in which they examined the full scope of human inflammatory pathology as a manifestation of the underlying structure and function of the immune system. Here I revisit this approach to ask to what extent has the promise of Mackay and Burnet's work been exploited in clinical medicine as currently practiced. In other words, is immunology doing well? Despite spectacular headline contributions of immunology in clinical medicine, I present evidence suggesting a performance ceiling in our capacity to answer the relatively straightforward questions that patients frequently ask about their own diseases and find that this ceiling exists across almost all of the 100 immune‐mediated inflammatory diseases examined. I propose that these questions are difficult, not so much because the immune system is overwhelmingly complex but rather that we have more to learn about the relatively simple agents and rules that may underpin self‐organizing complex interacting systems as revealed in studies from other disciplines. The way that the immune system has evolved to exploit the ancient machinery determining three independent cell fate timers as described in this Journal would be a great place to start to decode the self‐organizing principles that underpin the emergent pathology that we observe in the clinic. [ABSTRACT FROM AUTHOR]

Introduction: In acute conditions, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) causes multi‐organ damage due to the induction of inappropriate immune responses, particularly lung tissue fibrosis. To evaluate the consequence of the deterioration of the immune system, autoimmune markers were assessed. Method s : In a case–control study, 108 patients with coronavirus disease 2019 (COVID‐19) were admitted to the intensive care unit (ICU), and 158 outpatients with mild clinical symptoms, with SARS‐CoV‐2 reverse transcription quantitative polymerase chain reaction (RT‐qPCR) positive tests, were included for comparison. The demographic and hematologic variables and presence of the main autoantibodies in sera of 40 eligible ICU‐hospitalized COVID‐19 patients and 40 COVID‐19 outpatients were assessed. Out of 108 COVID‐19 ICU‐hospitalized patients, 40 were selected as the control group (40/158) who had no underlying diseases before hospitalization, according to their self‐declaration and clinical records at the time of admission. Results: The results demonstrated that the main complete blood count indices, such as red blood cells and platelets, decreased dramatically in ICU‐hospitalized patients. Furthermore, the autoantibody profiles were positive in 45% and 15% of ICU‐admitted patients for antinuclear antibodies and antineutrophilic cytoplasmic autoantibodies, respectively. In ICU patients, anti‐PM/Scl 100 or AMA‐M2 was 33%. Anti SS‐A, anti‐SS‐B, anti‐Ro‐52, and anti‐Jo‐1 in 11.5% for each one were reactive. Other autoantibodies of the ICU group were as follows: CENP (5.6%), Rib‐protein (5.6%), and nucleosome (5.6%). However, only two individuals in the control group had positive results for SS‐A and SS‐B (5%). Conclusion: Induction of such particular autoantibodies by the virus can justify the multi‐organ involvement and severity of the disease in ICU patients, which may also cause other organ involvement in the long term. [ABSTRACT FROM AUTHOR]

An infection with severe acute respiratory syndrome coronavirus (SARS‐CoV‐2) may have a significant impact on the human immune system. Interactions between the virus and defence mechanisms may promote the development of autoimmune processes which manifest as antinuclear antibody (ANA) synthesis. Since many different viruses are suspected to take part in the pathogenesis of different systemic autoimmune rheumatic diseases (SARDs), we examined whether coronavirus disease 2019 convalescents who suffer from mild to moderate disease have a higher risk of developing ANA and anti‐β2‐glicoprotein I IgG antibodies (β2 GPI). In a retrospective study, we examined 294 adults among volunteer blood donors divided into convalescents (N = 215) and healthy controls (N = 79). For ANA detection, we used line‐blotting, a type of indirect immunofluorescence assay (IF), to determine antigenic specificity and ELISA for β2 GPI. We found a lower incidence of ANA in convalescents than in healthy controls, with the majority of these antibodies directed to antigens with no known clinical significance. Additionally, no participants were positive for β2 GPI in either group. Our results show that COVID‐19 with mild to moderate symptoms in the generally healthy population does not induce the development of ANA or anti‐β2 GPI antibodies for at least 6 months following the disease. [ABSTRACT FROM AUTHOR]

The article discusses the ongoing debate surrounding the relationship between autoimmune conditions and natural SARS-CoV-2 infection or COVID-19 vaccination. The authors highlight a recent study that found a small percentage of individuals who received mRNA vaccines developed neutralizing anti-type-I interferon antibodies, which can contribute to autoimmune disorders. They also discuss evidence suggesting that both natural infection and vaccination are associated with the onset or exacerbation of autoimmune conditions. The article emphasizes the need for more comprehensive studies to determine the exact risk factors for autoimmunity and the appropriate monitoring of autoantibodies. It also acknowledges the complexities introduced by SARS-CoV-2 variants and the sequence of infection and vaccination. Overall, the article provides insights into the potential link between COVID-19 and autoimmunity, but further research is needed to fully understand this relationship. [Extracted from the article]

Sjogren's syndrome (SS) is an autoimmune disease that affects primarily the salivary glands, making perturbations in the oral ecosystem and potential factors of salivary flow that influence the onset and development of the disease. The oral cavity contains diverse microorganisms that inhabit various niches such as the oral microbial "biomap." It does not seem specific enough to establish a characteristic microbiome, given the diversity of clinical manifestations, variable rates of salivary secretion, and influential risk factors in patients with SS. This review discusses the biogeography of the oral microbiome in patients with SS such as saliva, tongue, tooth, mucosa, and gum. The microorganisms that were more abundant in the different oral niches were Gram‐positive species, suggesting a higher survival of cell wall bacteria in this arid oral environment. Reduced salivary flow appears not to be linked to the cause of dysbiosis alone but influences host‐associated risk factors. However, much work remains to be done to establish the role of the microbiome in the etiopathogenesis of autoimmune diseases such as SS. Future studies of the microbiome in autoimmunity will shed light on the role of specific microorganisms that have never been linked before with SS. [ABSTRACT FROM AUTHOR]

PD‐1 and CTLA‐4 can play an important role in addressing the issue of autoimmune diseases. PD‐1 is a transmembrane glycoprotein expressed on T, B, and Dentric cells. This molecule functions as a checkpoint in T cell proliferation. Ligation of PD‐1 with its ligands inhibits the production of IL‐2, IL‐7, IL‐10, and IL‐12 as well as other cytokines by macrophages, natural killer (NK) cells, and T cells, which can suppress cell proliferation and inflammation. Today, scientists attempt to protect against autoimmune diseases by PD‐1 inhibitory signals. In this review, we discuss the structure, expression, and signaling pathway of PD‐1. In addition, we discuss the importance of PD‐1 in regulating several autoimmune diseases, reflecting how manipulating this molecule can be an effective method in the immunotherapy of some autoimmune diseases. Significance statement: 1.The structure, expression, and signaling pathway of PD‐1 were discussed in this article.2.The importance of PD‐1 in regulating several autoimmune diseases reflects how manipulating this molecule can effectively treat some autoimmune diseases. [ABSTRACT FROM AUTHOR]

Summary: Blockade of immune checkpoints has transformed the therapy of several cancers. However, immune‐related adverse events (irAEs) have emerged as a major challenge limiting the clinical application of this approach. B cells are recognized as major players in the pathogenesis of human autoimmunity and have been successfully targeted to treat these disorders. While T cells have been extensively studied as therapeutic targets of immune checkpoint blockade (ICB), these checkpoints also impact B cell tolerance. Blockade of immune checkpoints in the clinic is associated with distinct changes in the B cell compartment that correlate with the development of irAEs. In this review, we focus on the possible role of humoral immunity, specifically human B cell subsets and autoantibodies in the pathogenesis of ICB‐induced irAEs. There remains an unmet need to better understand the T:B cell cross talk underlying the activation of pathogenic B cells and the development of ICB‐induced irAEs. Such studies may identify new targets or approaches to prevent or treat irAEs and improve the application of ICB therapy in cancer. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are essential for immune homeostasis and suppression of pathological autoimmunity but can also play a detrimental role in cancer progression via inhibition of anti‐tumor immunity. Thus, there is broad applicability for therapeutic Treg targeting, either to enhance function, for example, through adoptive cell therapy (ACT), or to inhibit function with small molecules or antibody‐mediated blockade. For both of these strategies, the metabolic state of Tregs is an important consideration since cellular metabolism is intricately linked to function. Mounting evidence has shown that targeting metabolic pathways can selectively promote or inhibit Treg function. This review aims to synthesize the current understanding of Treg metabolism and discuss emerging metabolic targeting strategies in the contexts of transplantation, autoimmunity, and cancer. We discuss approaches to gene editing and cell culture to manipulate Treg metabolism during ex vivo expansion for ACT, as well as in vivo nutritional and pharmacological interventions to modulate Treg metabolism in disease states. Overall, the intricate connection between metabolism and phenotype presents a powerful opportunity to therapeutically tune Treg function. [ABSTRACT FROM AUTHOR]

The etiology of type 1 diabetes (T1D) foreshadows the pancreatic islet beta‐cell autoimmune pathogenesis that heralds the clinical onset of T1D. Standardized and harmonized tests of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen‐2 (IA‐2A), and ZnT8 transporter (ZnT8A) allowed children to be followed from birth until the appearance of a first islet autoantibody. In the Environmental Determinants of Diabetes in the Young (TEDDY) study, a multicenter (Finland, Germany, Sweden, and the United States) observational study, children were identified at birth for the T1D high‐risk HLA haploid genotypes DQ2/DQ8, DQ2/DQ2, DQ8/DQ8, and DQ4/DQ8. The TEDDY study was preceded by smaller studies in Finland, Germany, Colorado, Washington, and Sweden. The aims were to follow children at increased genetic risk to identify environmental factors that trigger the first‐appearing autoantibody (etiology) and progress to T1D (pathogenesis). The larger TEDDY study found that the incidence rate of the first‐appearing autoantibody was split into two patterns. IAA first peaked already during the first year of life and tapered off by 3–4 years of age. GADA first appeared by 2–3 years of age to reach a plateau by about 4 years. Prior to the first‐appearing autoantibody, genetic variants were either common or unique to either pattern. A split was also observed in whole blood transcriptomics, metabolomics, dietary factors, and exposures such as gestational life events and early infections associated with prolonged shedding of virus. An innate immune reaction prior to the adaptive response cannot be excluded. Clarifying the mechanisms by which autoimmunity is triggered to either insulin or GAD65 is key to uncovering the etiology of autoimmune T1D. [ABSTRACT FROM AUTHOR]

Background and purpose: Outcome and rechallenge data on central nervous system (CNS) autoimmunity triggered by immune checkpoint inhibitors (ICIs) are limited. We aim to describe a large series of patients with ICI‐triggered CNS autoimmunity, and to compare these patients with spontaneous paraneoplastic syndromes (PNS). Methods: We retrospectively reviewed Mayo Clinic patients with ICI‐triggered CNS autoimmunity (February 2015–June 2021). Clinical characteristics were compared to spontaneous PNS patients (with antineuronal nuclear antibody [ANNA]‐1 or anti‐Hu neurological autoimmunity, and/or neuroendocrine tumors [NET]) evaluated within the same period. Results: Thirty‐one patients were included (55% female, median age = 63 years, range = 39–76). Median time from ICI initiation was 3.65 months (range = 0.8–44.5). The most common associated malignancies were melanoma and small cell lung cancer. CNS manifestations included encephalitis (n = 16), meningoencephalitis (n = 8), cerebellar ataxia (n = 4), demyelinating syndrome (n = 2), and myelopathy (n = 1). Magnetic resonance imaging was abnormal in 62%. Cerebrospinal fluid was inflammatory in 70%. Neural autoantibodies were identified in 47%, more frequently in patients with NET (p = 0.046). ICI was discontinued in 97%; 90% received immunosuppressive treatment. After median 6.8 months follow‐up (range = 0.7–46), 39% had unfavorable outcomes (grade ≥ 3). This was associated with higher severity degree at onset, shorter period from ICI to neurological symptom onset, and encephalitis. Four patients were rechallenged with ICI, and one relapsed. Patients with NET and with ANNA‐1 ICI‐triggered CNS autoimmunity had associated peripheral nervous system manifestations more frequently than their spontaneous counterparts (p = 0.007 and p = 0.028, respectively). Conclusions: One third of ICI‐related CNS autoimmunity patients have unfavorable outcomes. Relapses may occur after ICI rechallenge. Neural autoantibodies are often present, more commonly in patients with NET. [ABSTRACT FROM AUTHOR]

Chemokine (C–C) ligand 17 (CCL17) was first identified as thymus‐ and activation‐regulated chemokine when it was found to be constitutively expressed in the thymus and identified as a T‐cell chemokine. This chemoattractant molecule has subsequently been found at elevated levels in a range of autoimmune and inflammatory diseases, as well as in cancer. CCL17 is a C–C chemokine receptor type 4 (CCR4) ligand, with chemokine (C–C) ligand 22 being the other major ligand and, as CCR4 is highly expressed on helper T cells, CCL17 can play a role in T‐cell–driven diseases, usually considered to be via its chemotactic activity on T helper 2 cells; however, given that CCR4 is also expressed by other cell types and there is elevated expression of CCL17 in many diseases, a broader CCL17 biology is suggested. In this review, we summarize the biology of CCL17, its regulation and its potential contribution to the pathogenesis of various preclinical models. Reference is made, for example, to recent literature indicating a role for CCL17 in the control of pain as part of a granulocyte macrophage–colony‐stimulating factor/CCL17 pathway in lymphocyte‐independent models and thus not as a T‐cell chemokine. The review also discusses the potential for CCL17 to be a biomarker and a therapeutic target in human disorders. [ABSTRACT FROM AUTHOR]

In the last 20 years, discoveries about the autoimmune regulator (AIRE) protein and its critical role in immune tolerance have provided fundamental insights into understanding the molecular basis of autoimmunity. This review provides a comprehensive overview of the effect of AIRE on immunological tolerance and the characteristics of autoimmune diseases in Autoimmune Polyendocrinopathy‐Candidiasis‐Ectodermal Dystrophy (APECED), which is caused by biallelic AIRE mutations. A better understanding of the immunological mechanisms of AIRE deficiency may enlighten immune tolerance mechanisms and new diagnostic and treatment strategies for autoimmune diseases. Considering that not all clinical features of APECED are present in a given follow‐up period, the diagnosis is not easy in a patient at the first visit. Longer follow‐up and a multidisciplinary approach are essential for diagnosis. It is challenging to prevent endocrine and other organ damage compared with other diseases associated with multiple autoimmunities, such as FOXP3, LRBA, and CTLA4 deficiencies. Unfortunately, no curative therapy like haematopoietic stem cell transplantation or specific immunomodulation is present that is successful in the treatment. [ABSTRACT FROM AUTHOR]

Type I IFNs are critical for host responses to viral infection and are also implicated in the pathogenesis of multiple autoimmune diseases. Multiple subtypes exist within the type I IFN family, in particular 13 distinct IFN‐α genes, which signal through the same heterodimer receptor that is ubiquitously expressed by mammalian cells. Both evolutionary genetic studies and functional antiviral assays strongly suggest differential functions and activity between the 13 IFN‐α subtypes, yet we still lack a clear understanding of these different roles. This review summarizes the evidence from studies describing differential functions of IFN‐α subtypes and highlights potential reasons for discrepancies between the reports. We examine both acute and chronic viral infection, as well as autoimmunity, and integrate a more recent awareness of the importance of anti‐IFN‐α autoantibodies in shaping the type I IFN responses in these different conditions. [ABSTRACT FROM AUTHOR]

Proteasome‐associated autoinflammatory syndrome‐2 (PRAAS2) is characterized by early onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We report the case of a premature baby (GA 35+5 weeks) born with disseminated and confluent red papules, diagnosed with PRAAS2. A novel de novo frameshift proteasome maturation protein (POMP) mutation (c.333delT (p.t111fs)) was detected, confirming the diagnosis. [ABSTRACT FROM AUTHOR]

Aims: Knowledge on the spectrum of thyroid disorders amongst Turner syndrome (TS) patients in Southeast Asia is limited. This study aimed to evaluate the prevalence of thyroid autoimmunity, the spectrum of autoimmune thyroid disease and association with age and karyotype amongst Malaysian TS girls. Methods: A cross‐sectional study was conducted at 11 paediatric endocrine units in Malaysia. Blood samples for antithyroglobulin antibodies, antithyroid peroxidase antibodies and thyroid function test were obtained. In patients with pre‐existing thyroid disease, information on clinical and biochemical thyroid status was obtained from medical records. Results: Ninety‐seven TS patients with a mean age of 13.4 ± 4.8 years were recruited. Thyroid autoimmunity was found in 43.8% of TS patients. Nineteen per cent of those with thyroid autoimmunity had autoimmune thyroid disease (Hashimoto thyroiditis in 7.3% and hyperthyroidism in 1% of total population). Patients with isochromosome X and patients with 45,X mosaicism or other X chromosomal abnormalities were more prone to have thyroid autoimmunity compared to those with 45,X karyotype (OR 5.09, 95% CI 1.54–16.88, P = 0.008 and OR 3.41, 95% CI 1.32–8.82, P = 0.01 respectively). The prevalence of thyroid autoimmunity increased with age (33.3% for age 0–9.9 years; 46.8% for age 10–19.9 years and 57.1% age for 20–29.9 years) with autoimmune thyroid disease detected in 14.3% during adulthood. Conclusion: Thyroid autoimmunity was significantly associated with the non 45,X karyotype group, particularly isochromosome X. Annual screening of thyroid function should be carried out upon diagnosis of TS until adulthood with more frequent monitoring recommended in the presence of thyroid autoimmunity. [ABSTRACT FROM AUTHOR]

The nodes of Ranvier (NoR) are essential domains for nerve conduction and their disruption plays a key role in the pathophysiology of immune‐mediated neuropathies. Our understanding of the specialized nodal regions and the immune mechanisms that affect them is growing and has led to the update of peripheral neuropathy classification to include the autoimmune nodopathies, defined by the site of the autoimmune attack. Autoantibodies directed against molecules of the nodal region (as neurofascin‐140/186, neurofascin‐155, contactin‐1, contactin‐associated protein 1, contactin‐associated protein 2, gangliosides, LGI4, or myelin‐associated glycoprotein), macrophage‐induced paranodal demyelination, and phenotypic changes of the nodal domains of Schwann cells have been identified as key mechanisms in the pathogenesis of the autoimmune neuropathies. This review explores the current knowledge of the autoimmune vulnerability of the NoR, including the underlying mechanisms leading to dysfunction in the diverse autoimmune disorders. [ABSTRACT FROM AUTHOR]