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Clinical results have demonstrated that CD19-targeting chimeric antigen receptor (CAR)-engineered T (CAR-T) cells achieve sustained elimination of autoreactive B cells, leading to promising control of autoimmune diseases with minimal safety concerns. Compared with monoclonal antibody therapy, CAR-T cell therapy achieves deeper targeting of autoreactive B cells and functions as a living drug for patients with autoimmune diseases. Advanced CAR-T cell products, such as CD7-targeting CAR-T cells, have been developed to target autoreactive T cells in autoimmune diseases. Numerous preclinical mouse models have been successfully established to mimic autoimmune diseases, providing valuable systems to study the efficacy and safety of CAR-T cell therapy. Safety and manufacturing are significant concerns for CAR-T cell therapy in treating autoimmune diseases, and various strategies have been developed to address these challenges. Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has demonstrated significant success in treating cancers. The potential of CAR-T cells is now being explored in the context of autoimmune diseases. Recent clinical trials have shown sustained and profound elimination of autoreactive B cells by CAR-T cells, leading to promising autoimmune disease control with minimal safety concerns. These encouraging results have inspired further investigation into CAR-T cell applications for a broader range of autoimmune diseases and the development of advanced cell products with improved efficacy and safety. In this review, we discuss the mechanisms by which CAR-T cells target autoimmune conditions, summarize current preclinical models, and highlight ongoing clinical trials, including CAR-T therapy design, clinical outcomes, and challenges. Additionally, we discuss the limitations and future directions of CAR-T therapy in the treatment of autoimmune diseases. [ABSTRACT FROM AUTHOR]

Celiac disease (CeD) is an immune-mediated disorder affecting the small bowel, associated with genetic factors and increasing global prevalence. This study explores the association between CeD, Systemic Lupus Erythematosus (SLE), primary Sjogren syndrome (pSS), and Systemic Sclerosis (SSc). A systematic review and meta-analysis were conducted following PRISMA guidelines. Searches across multiple databases yielded 2728 articles, with 15 studies selected. Data extraction included study characteristics, prevalence of CeD and CeD antibodies in SLE, pSS, and SSc. Quality assessment utilized the Newcastle-Ottawa Scale. The meta-analysis revealed a pooled prevalence of biopsy-proven CeD in SLE, pSS, and SSc of approximately 3%. Seroprevalence of any CeD antibody in SLE, pSS, and SSc ranged from 3% to 10%. Notably, pSS exhibited the highest prevalence at 5.59%. High heterogeneity was observed in seroprevalence across autoimmune conditions. Quality assessment indicated robust methodological quality in the selected studies. This study highlights a significantly higher prevalence of CeD, especially pSS, compared to the general population. The findings underscore the importance of recognizing elevated CeD antibodies in patients with SLE, pSS and SSc emphasizing the need for early detection and comprehensive care for gastrointestinal symptoms in these conditions. [ABSTRACT FROM AUTHOR]

Innate lymphoid cells (ILCs) are a group of lymphocytes that are devoid of antigen-specific receptors and are mainly found in tissues. The subtypes ILC1, 2, and 3 mirror T-cell functionality in terms of cytokine production and expression of key transcription factors. Although the majority of ILCs are found in tissue (tILCs), they have also been described within the circulation (cILCs). As a result of their better accessibility and putative prognostic value, human cILCs are getting more and more attention in clinical research. However, cILCs are in many aspects functionally distinct from their tILC counterparts. In fact, from the 3 ILC subsets found within the circulation, only for cILC2s could a clear functional correspondence to their tissue counterparts be established. Indeed, cILC2s are emerging as a major driver of allergic reactions with a particular role in asthma. In contrast, recent studies revealed that cILC1s and cILC3s are predominantly in an immature state and constitute progenitors for natural killer cells and ILCs, respectively. We provide an overview about the phenotype and function of the different cILC subtypes compared to tILCs in health and disease, including transcriptomic signatures, frequency dynamics, and potential clinical value. Furthermore, we will highlight the dynamics of the NKp44+ ILC3 subset, which emerges as prognostic marker in peripheral blood for inflammatory bowel disease and leukemia. [ABSTRACT FROM AUTHOR]

Mesenchymal Stem Cells (MSCs) are of interest in the clinic because of their immunomodulation capabilities, capacity to act upstream of inflammation, and ability to sense metabolic environments. In standard physiologic conditions, they play a role in maintaining the homeostasis of tissues and organs; however, there is evidence that they can contribute to some autoimmune diseases. Gaining a deeper understanding of the factors that transition MSCs from their physiological function to a pathological role in their native environment, and elucidating mechanisms that reduce their therapeutic relevance in regenerative medicine, is essential. We conducted a Systematic Review and Meta-Analysis of human MSCs in preclinical studies of autoimmune disease, evaluating 60 studies that included 845 patient samples and 571 control samples. MSCs from any tissue source were included, and the study was limited to four autoimmune diseases: multiple sclerosis, rheumatoid arthritis, systemic sclerosis, and lupus. We developed a novel Risk of Bias tool to determine study quality for in vitro studies. Using the International Society for Cell & Gene Therapy's criteria to define an MSC, most studies reported no difference in morphology, adhesion, cell surface markers, or differentiation into bone, fat, or cartilage when comparing control and autoimmune MSCs. However, there were reported differences in proliferation. Additionally, 308 biomolecules were differentially expressed, and the abilities to migrate, invade, and form capillaries were decreased. The findings from this study could help to explain the pathogenic mechanisms of autoimmune disease and potentially lead to improved MSC-based therapeutic applications. • MSCs from autoimmune patients have increased levels of IL-6. • MSCs from autoimmune patients have a reduced ability to migrate and invade. • MSCs from autoimmune patients have a reduced ability to form capillaries. • MSCs from autoimmune disease are still adherent, spindle-shaped, and capable of differentiation. [ABSTRACT FROM AUTHOR]

MicroRNA-23b-3p has been demonstrated to act as a safeguard against several autoimmune diseases. However, its role in Sjögren's syndrome (SS) remains unclear. In order to investigate its role in SS, we administered agomiR-23b-3p or agomiR-NC to non-obese diabetic (NOD) mice via tail vein weekly for 6 weeks. The study examined the saliva flow rate, histological changes in submandibular glands, and levels of autoantibodies. Additionally, the levels of several cytokines, cell apoptosis, and NF-κB signaling were evaluated. The protective effect of miR-23b-3p was confirmed in a cell model. The results demonstrated that miR-23b-3p overexpression improved salivary flow rates, inhibited lymphocyte infiltration, reduced cytokine levels, and suppressed cell apoptosis in NOD mice. Moreover, NF-κB signaling was inactivated following miR-23b-3p overexpression. In a cellular model of SS, overexpression of miR-23b-3p protected submandibular gland epithelial cells exposed to IFN-γ against apoptosis and inflammation by targeting SOX6. The study concludes that miR-23b-3p alleviates SS by targeting SOX6 and inhibiting the NF-κB signaling pathway. The miR-23b-3p/SOX6 axis represents a promising avenue for the development of novel therapeutic strategies for SS. • MiR-23b-3p was downregulated in a spontaneous animal model for SS. • MiR-23b-3p attenuated SS in mice by modulating Th1/Th17/Treg cells and cell apoptosis. • MiR-23b-3p overexpression inhibited the NF-κB pathway in NOD mice. • MiR-23b-3p exerted its protective effect by targeting SOX6 in vitro. [ABSTRACT FROM AUTHOR]

The risk of coronary artery disease is exaggerated in patients with autoimmune diseases (AID). A higher risk of complications has been reported during and after percutaneous coronary intervention (PCI) in these patients. We aimed to analyze the in-hospital outcomes and trends of patients with AID, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD) undergoing PCI. We identified all PCI procedures using the National In-patient Sample database from 2016 to 2020. Stratified them into cohorts with RA, SLE and IBD and compared them to cohorts without AID. The Chi-square test and multivariate logistic regression were used for analysis. A p -value <0.005 was considered statistically significant. We identified 2,367,475 patients who underwent PCI. Of these, 1.6 %, 0.5 %, and 0.4 % had RA, IBD and SLE respectively. The odds of mortality were lower among patients with IBD (aOR: 0.56; CI 0.38–0.81, p = 0.002) but patients with RA had higher odds of having composite major complications [(MC) including cerebrovascular accident (CVA), cardiac arrest, acute heart failure (AHF), ventricular arrhythmia (VA), major bleeding, and acute kidney injury (AKI)] (aOR: 0.90; CI 0.83–0.98, p = 0.013). Our SLE cohort had higher rates of CVA (p = 0.017) and AKI (p = 0.002). Our cohort with IBD had lower rates of cardiac arrest but had longer hospital length of stay (4.9 days vs 3.9 days) and they incurred higher hospital charges compared to cohort without IBD. This study depicts the immediate adverse outcomes observed in patients with AID undergoing PCI. In contrast to those without AID, our cohorts with RA exhibited worse outcomes, as indicated by the higher odds of major complications. IBD is associated with lower risks of in-hospital adverse outcomes but with higher resource utilization. [Display omitted] • RA implied higher rates of composite major complications, bleeding complications, and acute heart failure when compared to patients without autoimmune diseases. • Our cohort with SLE undergoing PCI had higher rates of CVA and AKI. • Our patients with IBD had higher rates of blood product transfusion, H-LOS and they incurred higher hospital charges. [ABSTRACT FROM AUTHOR]

Some autoimmune diseases carry elevated risk for atherosclerotic cardiovascular disease (ASCVD), yet the underlying mechanism and the influence of traditional risk factors remain unclear. This study sought to determine whether autoimmune diseases independently correlate with coronary atherosclerosis and ASCVD risk and whether traditional cardiovascular risk factors modulate the risk. The study included 85,512 patients from the Western Denmark Heart Registry undergoing coronary computed tomography angiography. A diagnosis of 1 of 18 autoimmune diseases was assessed. Adjusted OR (aOR) for any plaque, any coronary artery calcification (CAC), CAC of >90th percentile, and obstructive coronary artery disease as well as adjusted HR (aHR) for ASCVD were calculated. During 5.3 years (Q1-Q3: 2.8-8.2 years) of follow-up, 3,832 ASCVD events occurred. A total of 4,064 patients had a diagnosis of autoimmune disease, which was associated with both presence of any plaque (aOR: 1.29; 95% CI: 1.20-1.40), any CAC (aOR: 1.28; 95% CI: 1.19-1.37), and severe CAC of >90th percentile (aOR: 1.53; 95% CI: 1.39-1.68), but not with having obstructive coronary artery disease (aOR: 1.04; 95% CI: 0.91-1.17). Patients with autoimmune diseases had a 46% higher risk (aHR: 1.46; 95% CI: 1.29-1.65) for ASCVD. Traditional cardiovascular risk factors were strongly associated with future ASCVD events, and a favorable cardiovascular risk factor profile in autoimmune patients was associated with ∼54% lower risk compared to patients with presence of risk factors (aHR: 0.46; 95% CI: 0.27-0.81). Autoimmune diseases were independently associated with higher burden of coronary atherosclerosis and higher risk for future ASCVD events, with risk accentuated by traditional cardiovascular risk factors. These findings suggest that autoimmune diseases increase risk through accelerated atherogenesis and that cardiovascular risk factor control is key for improving prognosis in patients with autoimmune diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Patients with autoimmune disease (AD) are at increased risk for complications from COVID-19 infection, so, optimizing vaccine utilization in this population is of particular importance. We compared COVID-19 vaccination perspectives among persons with and without AD. 471 patients in the MetroHealth System and Cleveland Veteran Affairs Medical Center completed a 38-item questionnaire between August 2021 and February 2022. This survey containing questions regarding COVID-19 vaccine perceptions and demographics was administered both to unvaccinated individuals and individuals who delayed vaccination for at least 2 months. Multivariable ordinary least squares regression models were created to assess factors associated with vaccination likelihood. The number of reasons given for (p < 0.001) and against receiving COVID-19 vaccination (p < 0.001) were highly associated with increased and decreased vaccination likelihood respectively. Factors most closely associated with obtaining vaccine were: protecting family (p = 0.045) personal safety (p < 0.001) and preventing serious infection (p < 0.001). Reasons associated with decreased vaccination likelihood were: lack of concern of COVID-19 infection (p < 0.001), vaccine safety (p < 0.001) and beliefs that the vaccine was made too quickly (p = 0.024). AD patients were more likely to cite having a chronic condition (29.1 % vs 17.1 %, p = 0.003) and physician recommendation(s) (18.4 % vs 9.1 %, p = 0.005) as reasons for vaccination and were more concerned about potential medication interaction than non-AD respondents (22.4 % vs 3.3 %, p < 0.001). The number of benefits of vaccination identified strongly related to vaccination likelihood. Affirmative provider recommendations correlated with increased vaccination likelihood in AD patients. Clinical conversations centered on the benefits of COVID-19 vaccination may help increase vaccine acceptance. [ABSTRACT FROM AUTHOR]

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Depuis leur découverte en 2013, les anticorps anti-5'nucléotidase 1A (anti-cN1A) ont fait l'objet de nombreuses publications pour évaluer leur sensibilité et leur spécificité diagnostique. Actuellement utilisés comme une aide au diagnostic de la myosite à inclusions pour laquelle leur spécificité est bonne, ils peuvent être cependant détectés au cours d'autres maladies auto-immunes et en particulier au cours du syndrome de Gougerot-Sjögren (SGS). Leur prévalence, importante au cours de cette maladie, diminue leur performance diagnostique chez des patients présentant à la fois une myosite et un SGS. Les anticorps anti-cN1A pourraient également avoir un rôle pronostique au cours d'un SGS. Since their discovery in 2013, anti-5'nucleotidase 1A (anti-cN1A) antibodies have been the subject of numerous publications to assess their sensitivity and diagnostic specificity. Currently used as an aid in the diagnosis of inclusion body myositis for which their specificity is good, they can be detected in other autoimmune diseases and in particular in Sjögren's Syndrome. Their prevalence, which is significant during this disease, decreases diagnostic performance in patients with both myositis and Sjögren's Syndrome. Anti-cN1A antibodies may also have a prognostic role during SGS. [ABSTRACT FROM AUTHOR]

Recent advances in multi-omics technologies have revealed numerous pathological implications of ARSs in various human diseases, suggesting unexpected activities beyond their canonical roles in protein synthesis. The unique intracellular and extracellular activities of human ARSs beyond translation are opening wide opportunities to develop novel drugs for diseases that are uncurable using current targeted therapy. Since only a portion of total ARSs are involved in epi-translational activities via noncatalytic sites, targeting these activities can exert pharmacological effects without affecting global translation. Even the catalytic sites of human ARSs can be safely targeted if the inhibitors do not severely affect global translation. The extracellular activities mediated by the unique domains in human ARSs can be explored as a source for novel biologics. Aminoacyl-tRNA synthetases (ARSs) are enzymes that catalyze the ligation of amino acids to tRNAs for translation. Beyond their traditional role in translation, ARSs have acquired regulatory functions in various biological processes (epi-translational functions). With their dual-edged activities, aberrant expression, secretion, and mutations of ARSs are associated with human diseases, including cancer, autoimmune diseases, and neurological diseases. The increasing numbers of newly unveiled activities and disease associations of ARSs have spurred interest in novel drug development, targeting disease-related catalytic and noncatalytic activities of ARSs as well as harnessing ARSs as sources for biological therapeutics. This review speculates how the translational and epi-translational activities of ARSs can be related and describes how their activities can be linked to diseases and drug discovery. [ABSTRACT FROM AUTHOR]

• Unusual GI complaints, vasculitis or arthritis may be due to autoimmune processes in people with CF. • Altered immunity, inflammation and dysbiosis in CF create a milieu that can lead to autoimmunity. • Autoimmune markers are increased in CF but are not sufficient to establish an autoimmune diagnosis. • The best-established autoimmune association is in the GI tract; biopsy verifies the diagnosis. Cystic fibrosis (CF) clinicians may see patients who have difficult-to-manage symptoms that do not have a clear CF-related etiology, such as unusual gastrointestinal (GI) complaints, vasculitis, or arthritis. Alterations in immunity, inflammation and intraluminal dysbiosis create a milieu that may lead to autoimmunity, and the CF transmembrane regulator protein may have a direct role as well. While autoantibodies and other autoimmune markers may develop, these may or may not lead to organ involvement, therefore they are helpful but not sufficient to establish an autoimmune diagnosis. Autoimmune involvement of the GI tract is the best-established association. Next steps to understand autoimmunity in CF should include a more in-depth assessment of the community perspective on its impact. In addition, bringing together specialists in various fields including, but not limited to, pulmonology, gastroenterology, immunology, and rheumatology, would lead to cross-dissemination and help define the path forward in basic science and clinical practice. [ABSTRACT FROM AUTHOR]

Alopecia areata (AA) is a CD8+ T cell–mediated autoimmune disease characterized by nonscarring hair loss. Ivarmacitinib, which is a selective oral Janus kinase 1 inhibitor, may interrupt certain cytokine signaling implicated in the pathogenesis of AA. To evaluate the efficacy and safety of ivarmacitinib in adult patients with AA who have ≥25% scalp hair loss. Eligible patients were randomized 1:1:1:1 to receive ivarmacitinib 2, 4, or 8 mg once daily or placebo for 24 weeks. The primary end point was the percentage change from baseline in the Severity of Alopecia Tool score at week 24. A total of 94 patients were randomized. At week 24, the least squares mean difference in the percentage change from baseline in the Severity of Alopecia Tool score for ivarmacitinib 2, 4, and 8 mg and placebo groups were −30.51% (90% CI, −45.25, −15.76), −56.11% (90% CI, −70.28, −41.95), −51.01% (90% CI, −65.20, −36.82), and −19.87% (90% CI, −33.99, −5.75), respectively. Two serious adverse events—follicular lymphoma and COVID-19 pneumonia—were reported. A small sample size limits the generalizability of the results. Treatment with ivarmacitinib 4 and 8 mg doses in patients with moderate and severe AA for 24 weeks was efficacious and generally tolerated. [ABSTRACT FROM AUTHOR]

Bullous pemphigoid (BP) is an autoimmune blistering disease caused by autoantibodies against hemidesmosomal proteins BP180 and BP230. Recently, several case reports have demonstrated the association of BP with dipeptidyl peptidase-4 inhibitors (DPP-4i), also known as gliptins, which are drugs used to treat type 2 diabetes mellitus. Here, we report a case of BP associated with DPP-4i presenting with skin and oral mucosal lesions. An a-80-year-old woman with type 2 diabetes mellitus was treated with DPP-4i. The clinical diagnosis of DPP-4i-associated BP was confirmed by histological findings of subepidermal blisters, positive direct immunofluorescence testing, and the presence of autoantibodies directing full-length BP180. The symptoms resolved within 5 months after DPP-4i withdrawal. This report suggests that DPP-4i-associated BP may present with oral mucosal lesions. Thus, clinicians should pay close attention to the medical history and medication records of patients with oral blistering diseases. Furthermore, conducting treatment in cooperation with medical departments is necessary. [ABSTRACT FROM AUTHOR]

Diabetes is common in patients with autoimmune stiff-person syndrome (SPS); 60% of cases represent an organ-specific autoimmune disease. The prevalence of circulating anti-glutamic acid decarboxylase (GAD) antibodies among patients with SPS is approximately 60–98%; 60.5% of anti-GAD-positive patients with SPS develop insulin-dependent diabetes mellitus (IDDM). Frequencies of diabetes-associated antibodies in patients with concomitant SPS and IDDM differ strongly from frequencies known from the general population with type 1 diabetes mellitus. Many patients with SPS manifest diabetes only after being treated with high-dose corticosteroids or progress to dependency on insulin therapy following their treatment with high-dose corticosteroids. IDDM in patients with SPS often has multiple causes, combining autoimmune (anti-GAD antibodies) and toxic (steroid-induced) processes. Anti-glutamic acid decarboxylase (GAD) autoantibodies are a hallmark of stiff-person syndrome (SPS) and insulin-dependent diabetes mellitus (IDDM). However, patients with concurrent IDDM and SPS often manifest insulin resistance, and SPS-associated IDDM probably has heterogeneous causes. Some patients manifest IDDM associated only with high titers of anti-GAD65 caused by SPS. By contrast, other patients develop IDDM only after being treated with high-dose corticosteroids or they progress to insulin dependency following their treatment with high-dose corticosteroids. The profile of autoantibodies differs markedly between type 1 diabetes mellitus (T1DM), late-onset diabetes mellitus, and SPS-associated IDDM. Therefore, as with new-onset diabetes after transplantation (NODAT), SPS-associated IDDM should be classified as a specific diabetes entity, the pathophysiology of which requires increased attention. [ABSTRACT FROM AUTHOR]

Data on the association between the development of autoimmune diseases and COVID-19 vaccination are limited. To investigate the incidence and risk of autoimmune connective tissue disorders following mRNA-based COVID-19 vaccination. This nationwide population-based study was conducted in South Korea. Individuals who received vaccination between September 8, 2020-December 31, 2021, were identified. Historical prepandemic controls were matched for age and sex in 1:1 ratio. The incidence rate and risk of disease outcomes were compared. A total of 3,838,120 vaccinated individuals and 3,834,804 controls without evidence of COVID-19 were included. The risk of alopecia areata, alopecia totalis, primary cicatricial alopecia, psoriasis, vitiligo, anti-neutrophil cytoplasmic antibody-associated vasculitis, sarcoidosis, Behcet disease, Crohn disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjogren syndrome, ankylosing spondylitis, dermato/polymyositis, and bullous pemphigoid was not significantly higher in vaccinated individuals than in controls. The risk was comparable according to age, sex, type of mRNA-based vaccine, and cross-vaccination status. Possible selection bias and residual confounders. These findings suggest that most autoimmune connective tissue disorders are not associated with a significant increase in risk. However, caution is necessary when interpreting results for rare outcomes due to limited statistical power. [ABSTRACT FROM AUTHOR]

Oral flora is related to various immune-related diseases. Herein we explored the characteristics of oral flora in patients with pemphigus vulgaris (PV) and analyzed the correlation between oral flora and PV. Twenty-two untreated patients with PV and 12 healthy controls (HC) were included in this case-control study. The characteristics of salivary microbiome were assessed by high-throughput sequencing using the 16S rRNA Illumina MiSeq approach, and differences between the PV and HC groups were determined. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database was applied to screen key metabolic pathways and preliminarily explore potential mechanisms underlying PV occurrence and development. The abundance of oral flora in the PV group was significantly lower than that in the HC group, and there were characteristic changes. The relative abundance of Prevotella and Agrobacterium in the PV group was significantly higher than that in the HC group (P < 0.05) and that of Neisseria , Lautropia , and Fusobacterium was significantly lower (P < 0.05). There was a linear correlation between Prevotella and serum Dsg3 level in PV. KEGG pathway analyses indicated significant differences in nine metabolic pathways between the PV and HC groups (P < 0.05), namely carbohydrate metabolism, digestive system, neurodegenerative disease, glycan biosynthesis and metabolism, drug resistance: antimicrobial, infectious disease: viral, circulatory system, excretory system, and nervous system. The oral flora of patients with PV presented characteristic changes, and several metabolic pathways were affected, including N-glycan biosynthesis and metabolism. Prevotella spp. appear to require the most attention in PV. We believe that oral flora dysbacteriosis contributes to PV occurrence and development. [ABSTRACT FROM AUTHOR]

Assessment of small vessel inflammatory diseases such as rheumatoid vasculitis is challenging. Small arteries such as the dorsalis pedis artery (DPA) are difficult to assess for changes in the arterial wall with medical imaging. Ultrasound imaging is a viable tool for examining the integrity and inflammatory changes in the arterial wall; however, no empirical data on its reliability have been described. We measured the intra- and inter-rater reliability of ultrasound measurements across five parameters evaluating arterial integrity of the proximal DPA in participants with and without small vessel disease. We recruited 10 participants with rheumatoid arthritis and 10 healthy controls. Two sonographers using ultrasound independently measured DPA lumen diameter, artery diameter, lumen-to-arterial diameter ratio, arterial Doppler velocity and inflammatory changes in the proximal wall of the DPA. The intraclass correlation coefficient (ICC) was used to evaluate 95% confidence intervals within and between raters. Bland–Altman analyses were used to assess limits of agreement and were compared with minimal clinically important differences (MCID). Four of five selected parameters were found to have excellent intra- and inter-rater reliability within and between raters (ICC = 0.903–0.996). Acceptable reliability was found for measurement of arterial blood flow velocity within raters (ICC = 0.815–0.909), but not between raters (ICC = 0.634). Standard mean errors in all parameters were within minimal clinically important differences. Ultrasound imaging has been found to be a reliable method of assessment of arterial integrity and inflammation of the proximal DPA in people with small vessel disease. Evaluation of arterial blood flow velocity requires cautious interpretation. [ABSTRACT FROM AUTHOR]

• Circulating CD19+CD24hiCD38hi B cells are expanded in IMN patients. • The frequency of CD19+CD24hiCD38hi B cells are associated with disease severity in IMN patients. • The percentage of CD19+CD24hiCD38hi B cells was positively associated with Th17 cell frequency in IMN patients. • CD19+CD24hiCD38hi B cells in IMN patients displayed a skewed pro-inflammatory cytokine profile. CD19+CD24hiCD38hi regulatory B cells exert immunosuppressive functions by producing IL-10, but their role in idiopathic membranous nephropathy (IMN) remains elusive. Here, we investigated the frequency and functional changes of circulating CD19+CD24hiCD38hi B cells and evaluated the correlation of CD19+CD24hiCD38hi B cells with clinical features and T helper cell subsets in IMN patients. Compared with healthy controls (HCs), IMN patients showed an increased frequency of CD19+CD24hiCD38hi B cells, but a significant reduction in the percentage of CD19+CD24hiCD38hi B cells was observed 4 weeks after cyclophosphamide treatment. The frequency of CD19+CD24hiCD38hi B cells was positively correlated with the levels of 24h urinary protein, but negatively correlated with serum total protein and serum albumin, respectively. CD19+CD24hiCD38hi B cells in IMN patients displayed a skewed pro-inflammatory cytokine profile with a higher level of IL-6 and IL-12, but a lower concentration of IL-10 than their healthy counterparts. Accompanied by upregulation of Th2 and Th17 cells in IMN patients, the percentage of CD19+CD24hiCD38hi B cell subset was positively associated with Th17 cell frequency. In conclusion, CD19+CD24hiCD38hi B cells were expanded but functionally impaired in IMN patients. Their altered pro-inflammatory cytokine profile may contribute to the pathogenesis of IMN. [ABSTRACT FROM AUTHOR]

• EBV and genetic risk together may drive T-bet+ B cells in autoimmune disease • Genetic risk profiles likely determine how EBV shapes T-bet+ B-cell programs • There is a need for more selective therapies targeting pathogenic T-bet+ B cells. B cells expressing the transcription factor T-bet are found to have a protective role in viral infections, but are also considered major players in the onset of different types of autoimmune diseases. Currently, the exact mechanisms driving such 'atypical' memory B cells to contribute to protective immunity or autoimmunity are unclear. In addition to general autoimmune-related factors including sex and age, the ways T-bet+ B cells instigate autoimmune diseases may be determined by the close interplay between genetic risk variants and Epstein–Barr virus (EBV). The impact of EBV on T-bet+ B cells likely relies on the type of risk variants associated with each autoimmune disease, which may affect their differentiation, migratory routes and effector function. In this hypothesis-driven review, we discuss the lines of evidence pointing to such genetic and/or EBV-mediated influence on T-bet+ B cells in a range of autoimmune diseases, including systemic lupus erythematosus (SLE) and multiple sclerosis (MS). We provide examples of how genetic risk variants can be linked to certain signaling pathways and are differentially affected by EBV to shape T-bet+ B-cells. Finally, we propose options to improve current treatment of B cell-related autoimmune diseases by more selective targeting of pathways that are critical for pathogenic T-bet+ B - cell formation. [ABSTRACT FROM AUTHOR]

La sclérodermie systémique (ScS) est une maladie auto-immune rare touchant principalement la femme entre 40 et 60 ans. Elle se caractérise par une fibrose cutanée et viscérale, une altération du réseau microvasculaire et la présence d'auto-anticorps. La ScS peut être associée à une autre connectivite ou à d'autres maladies auto-immunes définissant ainsi le syndrome de chevauchement. L'objectif de notre étude est de décrire ces syndromes de chevauchement. Nous avons analysé les données d'une cohorte rétrospective et bicentrique (unité de médecine interne de l'hôpital Nord de Marseille et unité de médecine interne de l'hôpital d'instruction des Armées Sainte-Anne à Toulon) de patients suivis pour une ScS entre le 1er janvier 2019 et le 1er décembre 2021. Nous avons recueilli leurs caractéristiques cliniques, immunologiques, les maladies auto-immunes et inflammatoires associées ainsi que la morbi-mortalité. La cohorte incluait 151 patients dont 134 étaient des ScS cutanées limitées. Cinquante-deux (34,4 %) patients présentaient au moins une atteinte auto-immune ou inflammatoire associée. L'association de deux connectivites dont la ScS concernait 24 patients (15,9 %) avec un tiers de syndrome de Sjögren et un tiers de myosite auto-immune. La principale maladie auto-immune associée à la ScS était la thyroïdite auto-immune, retrouvée chez 17 patients (11,3 %). La survenue de complications (recours à l'hospitalisation, oxygénothérapie au long cours, décès) n'était pas significativement différente en fonction de l'existence d'un syndrome de chevauchement ou non. La ScS s'accompagne souvent d'autres pathologies auto-immunes. Cette intrication de pathologies associées, modifiant parfois l'évolution de la ScS, impose un suivi personnalisé. Systemic sclerosis (SSc) is a rare auto-immune disease, affecting principally women between 40 and 60 years old. It is caracterised by a cutaneous and visceral fibrosis, an alteration of the microvascular network and the presence of autoantibodies. SSc can be associated with another connectivite tissue disease or to other autoimmune diseases, thus defining the overlap syndrome. The goal of our study is to describe these overlap syndromes. We have analysed the data of a retrospective and bicentrique cohort, from the internal medicine unit of Hôpital Nord in Marseille and from the internal medicine unit of the Hôpital Sainte-Anne in Toulon, of patients followed for a SSc between January 1st, 2019 and December 1st, 2021. We have collected clinical, imunological features, associated auto-immune and inflammatory diseases with its morbidity and mortality. The cohort included 151 patients including 134 limited cutaneous SSc. Fifty-two (34.4%) patients presented at least one associated auto-immune or inflammatory disease. The association of two connectivite tissue diseases including SSc was found in 24 patients (15.9%), a third with Sjögren's syndrome and a third with autoimmune myositis. The principal associated disease to SSc was the autoimmune thyroiditis found in 17 patients (11.3%). The occurrence of complications (hospitalization, long-term oxygene therapy, death) was not significantly different depending on the existence or not of an overlap syndrom. SSc is often associated with other autoimmune diseases. This interrelation between associated pathologies and SSc, modifying sometimes the evolution of SSc, enhances the need of a personalized follow-up. [ABSTRACT FROM AUTHOR]

We aimed to describe the pattern of placental injuries in women with systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome (APS) and non-criteria obstetric APS (NC-OAPS), and to correlate the placental findings with the occurrence of adverse perinatal outcomes. The perinatal outcomes and placental findings of pregnancies of women with SLE, APS, and NC-OAPS and gestational-age matched healthy controls were analyzed and classified according to the 2015 Redline - Classification of placental lesions. 91 women with SLE, APS, and NC-OAPS and 91 controls were included. Mean values of placental weight differed between groups, being significantly lower in NC-OAPS and APS groups compared to controls. Furthermore, 14.3% of placentas in the APS group were under the 3rd percentile, which was significantly higher in comparison with other groups. Regarding histopathological placental findings, maternal-side malperfusion was significantly increased in APS (46.4%) compared to NC-OAPS (14.3%) and SLE (9.5%). Fetal-side maldevelopment was significantly increased in NC-OAPS (19.1%) compared to controls (1.1%) and SLE (2.4%). A significantly increased prevalence of adverse perinatal outcomes (APOs) was observed in all studied groups compared to healthy controls (controls 3.3%, SLE 52.4%, NC-OAPS 57.1%, APS 64.3%). Overall, both maternal (OR 6.8, 95%CI 2.1–22) and fetal-side (OR 4.1, 95%CI 1.3–13.5) lesions were significantly associated with APO. Maternal malperfusion and fetal maldevelopment were the lesions most strongly associated with APOs. Pregnant women with SLE, APS, or NC-OAPS showed a different pattern of histopathological findings. Compared to controls, SLE, APS, and NC-OAPS conferred an increased risk of APOs that was strongly associated with placental maternal-side malperfusion and fetal-side maldevelopment. • Pregnant women with systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS) and non-criteria obstetric antiphospholipid syndrome (NC-OAPS) have an increased risk of adverse perinatal outcomes. • Placental insufficiency is the main cause of of adverse perinatal outcomes (APOs) described in women with SLE, APS and NC-OAPS. • In patients with SLE, APS, or NC-OAPS an inflammatory process is observed in placentas. • The increased risk of stillbirth is related to low placental weight. [ABSTRACT FROM AUTHOR]

Implant-based breast reconstructions contribute considerably to the quality of life of breast cancer patients. A knowledge gap exists concerning the potential role of silicone breast implants in the development of so-called "breast implant illness" (BII) and autoimmune diseases in breast cancer survivors with implant-based reconstructions. BII is a constellation of non-specific symptoms reported by a small group of women with silicone breast implants. The Areola study is a multicenter retrospective cohort study with prospective follow-up aiming to assess the risk of BII and autoimmune diseases in female breast cancer survivors with and without silicone breast implants. In this report, we set out the rationale, study design, and methodology of this cohort study. The cohort consists of breast cancer survivors who received surgical treatment with implant-based reconstruction in six major hospitals across the Netherlands in the period between 2000 and 2015. As a comparison group, a frequency-matched sample of breast cancer survivors without breast implants will be selected. An additional group of women who received breast augmentation surgery in the same years will be selected to compare their characteristics and health outcomes with those of breast cancer patients with implants. All women who are still alive will be invited to complete a web-based questionnaire covering health-related topics. The entire cohort including deceased women will be linked to population-based databases of Statistics Netherlands. These include a registry of hospital diagnostic codes, a medicines prescription registry, and a cause-of-death registry, through which diagnoses of autoimmune diseases will be identified. Outcomes of interest are the prevalence and incidence of BII and autoimmune diseases. In addition, risk factors for the development of BII and autoimmune disorders will be assessed among women with implants. The Areola study will contribute to the availability of reliable information on the risks of BII and autoimmune diseases in Dutch breast cancer survivors with silicone breast implants. This will inform breast cancer survivors and aid future breast cancer patients and their treating physicians to make informed decisions about reconstructive strategies after mastectomy. This study is registered at ClinicalTrials.gov on June 2, 2022 (NCT05400954). [ABSTRACT FROM AUTHOR]

As a ligand-dependent transcription factor, retinoid-associated orphan receptor γt (RORγt) that controls T helper (Th) 17 cell differentiation and interleukin (IL)-17 expression plays a critical role in the progression of several inflammatory and autoimmune conditions. An emerging novel approach to the therapy of these diseases thus involves controlling the transcriptional capacity of RORγt to decrease Th17 cell development and IL-17 production. Several RORγt inhibitors including both antagonists and inverse agonists have been discovered to regulate the transcriptional activity of RORγt by binding to orthosteric- or allosteric-binding sites in the ligand-binding domain. Some of small-molecule inhibitors have entered clinical evaluations. Therefore, in current review, the role of RORγt in Th17 regulation and Th17-related inflammatory and autoimmune diseases was highlighted. Notably, the recently developed RORγt inhibitors were summarized, with an emphasis on their optimization from lead compounds, efficacy, toxicity, mechanisms of action, and clinical trials. The limitations of current development in this area were also discussed to facilitate future research. [Display omitted] • RORγt as a key transcription factor controls Th17 cell development. • Modulation of RORγt activity alleviates inflammatory and autoimmune diseases. • Several small-molecule RORγt inhibitors have been recently developed. • Some of RORγt inhibitors enter clinical evaluations. [ABSTRACT FROM AUTHOR]

Cellular nanovesicles which are referred to as cell-derived, nanosized lipid bilayer structures, have emerged as a promising platform for regulating immune responses. Owing to their outstanding advantages such as high biocompatibility, prominent structural stability, and high loading capacity, cellular nanovesicles are suitable for delivering various immunomodulatory molecules, such as small molecules, nucleic acids, peptides, and proteins. Immunomodulation induced by cellular nanovesicles has been exploited to modulate immune cell behaviors, which is considered as a novel cell-free immunotherapeutic strategy for the prevention and treatment of diverse diseases. Here we review emerging concepts and new advances in leveraging cellular nanovesicles to activate or suppress immune responses, with the aim to explicate their applications for immunomodulation. We overview the general considerations and principles for the design of engineered cellular nanovesicles with tailored immunomodulatory activities. We also discuss new advances in engineering cellular nanovesicles as immunotherapies for treating major diseases. Cellular nanovesicles have emerged as a promising tool to modulate immune responses. This review discusses the biological basis, engineering strategies, and recent advances in leveraging cellular nanovesicles for therapeutic immunomodulation. [Display omitted] [ABSTRACT FROM AUTHOR]

Impaired mobility is amongst the most debilitating symptoms reported by people with multiple sclerosis (MS). Historically, it has been viewed that walking impairments in people with MS are directly caused by the physical damage to the neurons in the central nervous system (CNS) which results from the immunopathology of MS. However, research from over the past 4 decades has revealed that physical function in people with MS is also affected by skeletal muscle dysfunction characterized by a reduced capacity to produce, regulate, and sustain the force-generating muscle contractions that propel human movement. While the immediate CNS damage caused by MS can alter the neural activation of muscle by disrupting neuromotor transmission, chronic reductions in mobility and extreme fatigue can lead to physically inactive lifestyles that negatively affect skeletal muscle through mechanisms of deconditioning. Consequently, people with MS can experience alterations in activation patterns, muscle mass and tissue composition, contractility, metabolism, and perfusion that contribute to reductions in muscle function that ultimately impair key physical functions such as walking. This article provides an overview of the cellular mechanisms that contribute to skeletal muscle dysfunction in people with MS and a discussion of the current evidence suggesting that skeletal muscle may be a key physiological target for interventions aiming to improve mobility in this population. We specifically highlight recent evidence demonstrating the potential for rehabilitation and exercise interventions to induce muscle plasticity in people with MS who have moderate to severe levels of disability. In conclusion, we discuss future directions in basic science and clinical research that may advance our understanding of muscle dysfunction in MS and lead to the development of more precise and effective treatment strategies. [ABSTRACT FROM AUTHOR]

• DN B cells are mostly mature antigen-experienced and isotype-switched cells. • DN B cells with an extrafollicular origin are antibody-secreting cell precursors. • DN B cells can originate from early termination of the germinal center reaction. • DN B cells can derive from switched memory B cells, possibly by immune exhaustion. • DN B cells are pivotal players in aging, autoimmune and infectious diseases. Human B cells can be divided into four main subsets based on differential expression of immunoglobulin (Ig)D and CD27. IgD−CD27− double negative (DN) B cells make up a heterogeneous group of B cells that have first been described in relation to aging and systemic lupus erythematosus but have been mostly disregarded in B cell research. Over the last few years, DN B cells have gained a lot of interest because of their involvement in autoimmune and infectious diseases. DN B cells can be divided into different subsets that originate via different developmental processes and have different functional properties. Further research into the origin and function of different DN subsets is needed to better understand the role of these B cells in normal immune responses and how they could be targeted in specific pathologies. In this review, we give an overview of both phenotypic and functional properties of DN B cells and provide insight into the currently proposed origins of DN B cells. Moreover, their involvement in normal aging and different pathologies is discussed. [ABSTRACT FROM AUTHOR]

In the Division of Pediatric Neurology at the University Medical Center Göttingen we observed that many patients with Bell palsy are overweight or obese. To evaluate whether overweight and obesity are associated with increased risk of Bell palsy in children we conducted this single-centered retrospective study by performing a database search for International Classification of Diseases (ICD)-10 primary and secondary diagnosis of G51.0 (facial nerve palsy) between January 1, 2010, and December 31, 2020. For risk assessment, patients' body mass indices (BMIs) were compared with BMI data of controls from a nationwide child health survey. In total, 202 patients with peripheral facial nerve palsies (pFPs) were included, of which nearly half were classified as Bell palsies; 38% and 24% of the patients with Bell palsy and pFP had a BMI above the 90th percentile, respectively. High BMI was associated with statistically increased odds of Bell palsy in the group of overweight and obese patients (BMI >90th percentile; odds ratio [OR], 2.42; 95% confidence interval [CI], 1.6 to 3.8; P < 0.001) and solely obese patients (BMI >97th percentile; OR, 2.43; 95% CI, 1.4 to 4.3; P = 0.003). We could confirm our observation that overweight and obesity are associated with increased risk of Bell palsy in children. [ABSTRACT FROM AUTHOR]

Recent technical advances have enabled unbiased transcriptomic and epigenetic analysis of each cell, known as "single-cell analysis". Single-cell analysis has a variety of technical approaches to investigate the state of each cell, including mRNA levels (transcriptome), the immune repertoire (immune repertoire analysis), cell surface proteins (surface proteome analysis), chromatin accessibility (epigenome), and accordance with genome variants (eQTLs; expression quantitative trait loci). As an effective tool for investigating robust immune responses in coronavirus disease 2019 (COVID-19), many researchers performed singlecell analysis to capture the diverse, unbiased immune cell activation and differentiation. Despite challenges elucidating the complicated immune microenvironments of chronic inflammatory diseases using existing experimental methods, it is now possible to capture the simultaneous immune features of different cell types across inflamed tissues using various single-cell tools. In this review, we introduce patient-based and experimental mouse model research utilizing single-cell analyses in the field of chronic inflammatory diseases, as well as multi-organ atlas targeting immune cells. [ABSTRACT FROM AUTHOR]

• IL-41 was elevated in the serum of RA patients. • Serum IL-41 was positively correlated with DAS28-CRP, CRP, ESR, MPV, and CAR and negatively correlated with PLT. • IL-41 may be a potential new diagnostic biomarker for RA. Interleukin (IL)-41 is upregulated in the synovial tissue of rheumatoid arthritis (RA) patients, but its serum level has not been reported. The present study aimed to determine IL-41 expression in serum from RA patients and to clarify the relationships between IL-41 and disease-related parameters in RA patients. The study included 46 RA patients and 32 healthy controls (HC). Baseline data were obtained by routine physical examinations and immune-related parameters were measured by an automated chemiluminescent immunoassay analyzer. The correlations between IL-41 and disease activity score in 28 joints (DAS28) and serum clinical data were analyzed using the Pearson correlation test. Serum IL-41 concentrations were higher in RA patients than in HC. Serum IL-41 was positively correlated with DAS28 based on C-reactive protein (DAS28-CRP), CRP, erythrocyte sedimentation rate (ESR), mean platelet volume (MPV), and CRP-to-albumin ratio (CAR) and negatively correlated with platelet count, while rheumatoid factor was significantly correlated with ESR, CRP, and CAR. Receiver operating characteristic curve analysis showed that IL-41 had diagnostic value for RA, especially when combined with MPV. The present findings suggest that IL-41 is increased in the serum of RA patients and may be a potential new diagnostic biomarker for RA. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are vital for maintaining immune self-tolerance, and their impaired function leads to autoimmune disease. Mutations in FoxP3, the master transcriptional regulator of Tregs, leads to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in humans and the early lethal "scurfy" phenotype with multi-organ autoimmune disease in mice. We recently identified serine/arginine-rich splicing factor 1 (SRSF1) as an indispensable regulator of Treg homeostasis and function. Intriguingly, Treg-conditional SRSF1-deficient mice exhibit early lethal systemic autoimmunity with multi-organ inflammation reminiscent of the scurfy mice. Importantly, SRSF1 is decreased in T cells from patients with the autoimmune disease systemic lupus erythematosus (SLE), and low SRSF1 levels inversely correlate with disease severity. Given that the Treg-specific deficiency of SRSF1 causes similarly profound autoimmune disease outcomes in mice as the deficiency/mutation in FoxP3, we aimed to evaluate the genes and molecular pathways controlled by these two indispensable regulatory proteins. We performed comparative bioinformatic analyses of transcriptomic profiles of Tregs from Srsf1- knockout mice and two Foxp3 mutant mice––the FoxP3-deficient Δ Foxp3 and the Foxp3 M370I mutant mice. We identified 132 differentially expressed genes (DEGs) unique to Srsf1-ko Tregs, 503 DEGs unique to Foxp3 M370I Tregs, and 1367 DEGs unique to Δ Foxp3 Tregs. Gene set enrichment and pathway analysis of DEGs unique to Srsf1-ko Tregs indicate that SRSF1 controls cytokine and immune response pathways. Conversely, FoxP3 controls pathways involved in DNA replication and cell cycle. Besides the distinct gene signatures, we identified only 30 shared genes between all three Treg mutants, mostly contributing to cytokine and immune defense pathways. Prominent genes included the chemokines CXCR6 and CCL1 and the checkpoint inhibitors FASLG and PDCD1. Thus, we demonstrate that SRSF1 and FoxP3 control common and distinct molecular pathways implicated in autoimmunity. Our analyses suggest that SRSF1 controls crucial immune functions in Tregs contributing to immune tolerance, and perturbations in its levels lead to systemic autoimmunity via mechanisms that are largely distinct from FoxP3. • SRSF1- and FoxP3-deficient mice share similar autoimmune disease phenotypes. • SRSF1 controls gene programs in regulatory T cells discrete from FoxP3. • SRSF1 regulates cytokine signaling and leukocyte differentiation pathways in regulatory T cells. • SRSF1 and FoxP3 control shared and distinct molecular pathways to autoimmunity. [ABSTRACT FROM AUTHOR]

Background: Whether immunocompromising conditions affect the immunogenicity of COVID-19 booster vaccination remains a concern, which impedes the vaccination campaign in people most vulnerable to COVID-19-associated morbidity and mortality. We aimed to evaluate the effect of immune dysfunction on immunogenicity of homologous and heterologous prime-boost COVID-19 vaccination.Methods: Between July and August, 2021, 399 participants were randomized to receive ChAdOx1/ChAdOx1 8 weeks apart, ChAdOx1/mRNA-1273 8 weeks apart, ChAdOx1/mRNA-1273 4 weeks apart, and mRNA-1273/mRNA-1273 4 weeks apart. The anti-SARS-CoV-2 spike IgG antibody titers on the day before booster vaccination and 4 weeks after booster vaccination were compared between participants with and without immunocompromising conditions.Results: Among ChAdOx1-primed participants, a trend of lower anti-SARS-CoV-2 spike IgG titers before booster vaccination were found in participants with autoimmune diseases (geometric means, 34.76 vs. 84.25 binding antibody units [BAU]/mL, P = 0.173), compared to those without. Participants receiving immunosuppressants and/or immunomodulators had significant lower anti-SARS-CoV-2 spike IgG titers before booster vaccination than those without (geometric means, 36.39 vs. 83.84 BAU/mL; P = 0.001). Among mRNA-1273-boosted participants, anti-SARS-CoV-2 spike IgG titers 4 weeks after booster vaccination were similar across all the strata. Participants with autoimmune diseases and receiving immunosuppressants and/or immunomodulators, had numerically lower anti-SARS-CoV-2 spike IgG titers 4 weeks after booster vaccination compared to those without (geometric means, 1474.34 vs. 1923.23 and 1590.61 vs. 1918.38 BAU/mL; P > 0.05).Conclusion: The immunogenicity of prime vaccination with ChAdOx1 decreased by immune dysfunction, but enhanced after receiving boost vaccination with mRNA-1273. Our study results support the efficacy of mRNA-1273 booster dose among immunocompromised hosts. [ABSTRACT FROM AUTHOR]

This study assessed whether suicide attempts before 20 years of age were associated with medical morbidity later in life. We carried out a cohort study of 169,806 girls under age 20 years between 1989 and 2019 in Quebec, Canada. The cohort included 8086 girls admitted for suicide attempts, matched on age and year with 161,720 girls with no attempt. Outcomes included hospitalization for medical conditions, such as infection, allergic disorders, autoimmune disease, cardiovascular disease, cancer, and death from nonpsychiatric causes during 31 years of follow-up. We computed hazard ratios (HR) and 95% confidence intervals (CI) for the association of adolescent suicide attempt with these health outcomes using Cox regression models adjusted for preexisting mental illness, substance use disorders, and socioeconomic deprivation. Compared with matched controls, adolescent girls with suicide attempts had a greater risk of hospitalization for infection (HR 1.55, 95% CI 1.44–1.68), allergic disorders (HR 1.72, 95% CI 1.45–2.05), cardiovascular disease (HR 1.31, 95% CI 1.12–1.52), and mortality (HR 3.11, 95% CI 1.69–5.70). Associations were present regardless of the age at the time of the suicide attempt, but were stronger for girls with repeated attempts. Associations were also more pronounced within the first 5 years of the attempt, although suicide attempts remained strongly associated with mortality throughout the 31-year follow-up period. The findings suggest that adolescent girls with suicide attempts have an elevated risk of medical morbidity and mortality and may benefit from closer clinical management to prevent adverse health outcomes. • Adolescent girls with suicide attempts have a greater risk of morbidity later on. • Associations are present with infectious, allergic, and cardiovascular conditions. • Associations with these conditions are stronger in the first 5 years of follow-up. • Suicide attempt is associated with premature death over 31 years of follow-up. • There is no clear association with autoimmune disease and cancer. [ABSTRACT FROM AUTHOR]

• The article highlights the potential of CAR Tregs to target autoimmune responses in T1D specifically. • It emphasizes using CRISPR/Cas9 and machine learning to enhance Treg-based therapies. • Key challenges include maintaining Treg stability and translating preclinical successes into clinical treatments. Autoimmune diseases (ADs) are among the most significant health complications, with their incidence rising in recent years. Type 1 diabetes (T1D), an AD, targets the insulin-producing β cells in the pancreas, leading to chronic insulin deficiency in genetically susceptible individuals. Regulatory immune cells, particularly T-cells (Tregs), have been shown to play a crucial role in the pathogenesis of diabetes by modulating immune responses. In diabetic patients, Tregs often exhibit diminished effectiveness due to various factors, such as instability in forkhead box P3 (Foxp3) expression or abnormal production of the proinflammatory cytokine interferon-gamma (IFN-γ) by autoreactive T-cells. Consequently, Tregs represent a potential therapeutic target for diabetes treatment. Building on the successful clinical outcomes of chimeric antigen receptor (CAR) T-cell therapy in cancer treatment, particularly in leukemias, the concept of designing and utilizing CAR Tregs for ADs has emerged. This review summarizes the findings on Treg targeting in T1D and discusses the benefits and limitations of this treatment approach for patients suffering from T1D. [ABSTRACT FROM AUTHOR]

• Sensory processing sensitivity is related with fatigue, especially cognitive and psychosocial ones. • High sensitive person scale might unveil subject with a higher risk of fatigue. • Sensory processing sensitivity could provide hints for possible personalized cognitive-behavioral rehabilitation interventions. Fatigue is a common symptom in Multiple Sclerosis (MS), but its determinants are not clarified yet. Sensory processing sensitivity (SPS) is a personality trait characterized by enhanced sensitivity towards endogenous and exogenous stimuli, and higher attention toward minimal stimuli, resulting in overarousal and fatigue. to evaluate the association between SPS and fatigue in MS patients. 192 consecutive MS patients (age of 43.3 ± 12.1 years; females 67.2 %; median EDSS of 2.5 (0 – 7)) underwent clinical (EDSS, age, gender), cognitive (BICAMS, Trial Making Test [TMT]), psychosocial (Beck Anxiety Inventory [BAI], Beck Depression Inventory [BDI], Modified Fatigue Impact Scale [MFIS]) and sensitivity evaluation (Highly Sensitive Person [HSP]Scale). Patients were classified as HSP if the score was greater than 14. A stepwise regression model was applied to explore association between SPS and MFIS total scores and sub-scores, by accounting for age, gender, education, EDSS, Cerebral FS scores, TMT-Part A and part B scores, BAI, BDI, and Pittsburgh Sleep Quality Index (PSQI). Total HSP was 17.2 ± 6.8 and 129 patients (67 %) were classified as highly sensitive persons (HSP). HSP patients were more female patients (p = 0.02) with a longer disease duration (p = 0.03). HSP people showed higher total MFIS score (27.6 ± 20.6 vs 13.2 ± 14.1, p < 0.001), higher physical MFIS score (p < 0.001), higher cognitive MFIS score (p < 0.001), higher psychosocial MFIS score (p < 0.001) vs non-HSP patients. Higher total MFIS was associated with SPS trait (coeff. 6.9, p = 0.006). Specifically, SPS trait was associated with higher cognitive MFIS (coeff. 5.3, p < 0.001) and higher psychosocial MFIS (coeff. 0.7, p = 0.02). SPS was associated with fatigue. Since SPS could be easily and quickly assessed in clinical settings, SPS could unveil a higher propensity of a patient toward fatigue occurrence over the disease course and could provide hints for possible preventive cognitive behavior therapy. [ABSTRACT FROM AUTHOR]

Immunosuppressants, biologic agents, antifibrotic drugs, and other drugs can be used to treat autoimmune disease-associated interstitial lung disease (ILD), but the preferred treatment is uncertain. We aimed to evaluate the efficacy and safety of multiple drugs in the treatment of autoimmune disease-associated ILD. PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched for relevant randomized controlled trials (RCTs) from inception to July 2023. Primary outcomes were percentage of predicted forced vital capacity (FVC% predicted) and discontinuations for adverse events (AEs). We estimated summary mean differences (MDs) and odds ratios (ORs) using network meta-analysis with fixed effects. The analysis is based on 15 RCTs involving 1832 patients. In terms of FVC% predicted, mycophenolate mofetil (MMF) (MD 1.27, 95 % credible interval [CrI] 0.08 to 2.43), cyclophosphamide (1.89, 0.10 to 3.68), rituximab (9.29, 2.79 to 15.80), tocilizumab (6.30, 3.27 to 9.34), nintedanib (1.71, 0.54 to 2.88), pirfenidone (2.03, 0.65 to 3.40) and nintedanib+MMF (2.43, 0.95 to 3.89) were more effective than placebo. Analysis based on a small sample size showed that riociguat also had good therapeutic potential when compared with placebo. By contrast, bosentan and pomalidomide showed no significant difference compared with placebo. Regarding discontinuations for AEs, nintedanib (OR 2.09, 95 %CrI 1.20 to 3.73) and pirfenidone (3.46, 1.31 to 10.56) were associated with higher dropout rates than placebo, and the combination therapy of nintedanib+MMF did not increase the risk of AEs compared with nintedanib monotherapy. MMF, cyclophosphamide, rituximab, tocilizumab, nintedanib and pirfenidone are effective in the treatment of autoimmune disease-associated ILD. The efficacy of riociguat and the superiority of combination therapy need to be demonstrated in more RCTs. The tolerance of nintedanib and pirfenidone is a concern, but most of their AEs are mild and controllable. [Display omitted] [ABSTRACT FROM AUTHOR]

Accelerated, inflammatory atherosclerosis and cardiovascular disease have been associated with several autoimmune diseases including RA, AS, SLE, APS and SSc. Non-invasive, ultrasound- based techniques are suitable for the assessment of preclinical vascular pathophysiology. Multiple vascular and other biomarkers including vitamin D, ferritin, prolactin, suPAR, BNP fragments, oxLDL/β2GPI complexes, anti-Hsp60 and others have been associated with cardiometabolic comorbidities. The control of the underlying inflammatory disease is crucial for minimising cardiovascular risk in autoimmune diseases. • Cardiovascular disease have been associated with autoimmune diseases. • Non-invasive techniques are suitable to assess of preclinical vascular pathophysiology. • Multiple vascular and other biomarkers have been associated with cardiometabolic comorbidities. • The control of the underlying inflammatory disease is crucial for minimising cardiovascular risk. [ABSTRACT FROM AUTHOR]

[Display omitted] • Hypersensitivity mechanisms underlie autoimmune disease development. • Treatments for autoimmunity focus on managing downstream effects & symptoms. • Targeting upstream mechanisms (e.g., self-tolerance) can prevent/eliminate disease. • Hydrogel-based drug delivery can improve outcomes and may minimize off-target effects. • Advances may be made through combinatorial therapies and smart material selection. A robust adaptive immune response is essential for combatting pathogens. In the wrong context such as due to genetic and environmental factors, however, the same mechanisms crucial for self-preservation can lead to a loss of self-tolerance. Resulting autoimmunity manifests in the development of a host of organ-specific or systemic autoimmune diseases, hallmarked by aberrant immune responses and tissue damage. The prevalence of autoimmune diseases is on the rise, medical management of which focuses primarily on pharmacological immunosuppression that places patients at a risk of side effects, including opportunistic infections and tumorigenesis. Biomaterial-based drug delivery systems confer many opportunities to address challenges associated with conventional disease management. Hydrogels, in particular, can protect encapsulated cargo (drug or cell therapeutics) from the host environment, afford their presentation in a controlled manner, and can be tailored to respond to disease conditions or support treatment via multiplexed functionality. Moreover, localized delivery to affected sites by these approaches has the potential to concentrate drug action at the site, reduce off-target exposure, and enhance patient compliance by reducing the need for frequent administration. Despite their many benefits for the management of autoimmune disease, such biomaterial-based approaches focus largely on the downstream effects of hypersensitivity mechanisms and have a limited capacity to eradicate the disease. In contrast, direct targeting of mechanisms of hypersensitivity reactions uniquely enables prophylaxis or the arrest of disease progression by mitigating the basis of autoimmunity. One promising approach is to induce self-antigen-specific tolerance, which specifically subdues damaging autoreactivity while otherwise retaining the normal immune responses. In this review, we will discuss hydrogel-based systems for the treatment of autoimmune disease, with a focus on those that target hypersensitivity mechanisms head-on. As the field continues to advance, it will expand the range of therapeutic choices for people coping with autoimmune diseases, providing fresh prospects for better clinical outcomes and improved quality of life. [ABSTRACT FROM AUTHOR]

Sleep problems are a common comorbidity in autistic children and adolescents. Little is known about the role of sleep problems in parental well-being in the context of autism. The current study utilised actigraphy and questionnaire-based measures in mothers of autistic children and adolescents (n = 11), and mothers of typically developing (TD) children and adolescents (n = 11). Actigraphy is an objective, non-intrusive method for examining sleep. It involves wearing a wristwatch-like microcomputer that records motion. Measures included the Pittsburgh Sleep Quality Index, Autoimmune Disease in Family Members Questionnaire, Parenting Stress Index-Short Form, World Health Organization Quality of Life Abbreviated Version (WHOQOL-BREF), Hospital Anxiety and Depression Scale, and the Multidimensional Scale of Perceived Social Support. Mothers of autistic children had significantly greater difficulties with subjective sleep quality, sleep duration, sleep efficiency, and daytime dysfunction, than mothers of TD children. In mothers of autistic children, parental use of sleep medication on the PSQI was positively associated with objective sleep onset latency using actigraphy, with a large effect size. Families with an autistic child had significantly more family members with osteoarthritis and rheumatoid arthritis than did families of TD children. Families of autistic children had significantly more autistic family members than did families of TD children. Mothers of autistic children had significantly higher levels of stress, anxiety, depression, and lower levels of quality of life and perceived social support, than parents of TD children. Sleep problems identified via actigraphy were associated with parental stress, anxiety and depression, and quality of life. • This study measures sleep quality in mothers of children and adolescents with autism (n=11) and without autism (n=11). • Mothers of autistic children reported significantly poorer sleep quality, duration, efficiency, and more daytime dysfunction. • Mothers of autistic children reported higher levels of anxiety, depression and lower quality of life and social support. • Relationships were identified between actigraphy variables and parental stress, anxiety and depression, and quality of life. [ABSTRACT FROM AUTHOR]

Despite impaired humoral response in patients treated with immunosuppressants (ISPs), recent studies found similar severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection compared to controls. One potential explanation is the rapid generation of humoral response on infection, but evidence is lacking. We investigated the longitudinal dynamics of the SARS-CoV-2 antibody repertoire after SARS-CoV-2 delta and omicron breakthrough infection in patients with immune-mediated inflammatory diseases (IMIDs) receiving ISP therapy and controls. As a prospective substudy of the national Target-to-B! (T2B!) consortium, we included IMID patients receiving ISPs therapy and controls who reported SARS-CoV-2 breakthrough infection between July 1, 2021, and April 1, 2022. To get an impression of the dynamics of the antibody repertoire, 3 antibody titers of wild-type RBD, wild-type S, and omicron RBD were measured at 4 time points after SARS-CoV-2 breakthrough infection. We included 302 IMID patients receiving ISPs and 178 controls. Antibody titers increased up to 28 days after breakthrough infection in both groups. However, in IMID patients receiving therapy with anti-CD20 and sphingosine-1 phosphate receptor modulators, antibody titers were considerably lower compared to controls. In the anti-TNF group, we observed slightly lower antibody titers in the early stages and a faster decline of antibodies after infection compared to controls. Breakthrough infections were mostly mild, and hospitalization was required in less than 1% of cases. Most ISPs do not influence the dynamics of the SARS-CoV-2 antibody repertoire and exhibit a rapid recall response with cross-reactive antibody clones toward new virus variants. However, in patients treated with anti-CD20 therapy or sphingosine-1 phosphate receptor modulators, the dynamics were greatly impaired, and to a lesser extent in those who received anti-TNF. Nevertheless, only a few severe breakthrough cases were reported. [ABSTRACT FROM AUTHOR]

• Multiple sclerosis-related mortality increased by 0.65 % annually in the US. • Women showed higher mortality than men. • Non-Hispanic Whites exhibited the highest mortality. • States with lower daily sunlight had higher death rates. • Mortality rates were similar in urban and rural areas. Multiple sclerosis (MS) is a neuroinflammatory condition with a prevalence of about 309.2 per 100,000 people in the United States. We aim to identify MS-related mortality trends in the USA from 1999 to 2020, stratified by age, sex, race, and geography, and its correlation with sunlight. Death certificates from the CDC-WONDER database were examined for adults aged ≥25 years. Crude rates (CR) and age-adjusted mortality rates (AAMRs) per 1,000,000 persons and annual percent change (APC) were calculated. We also retrieved data for daily sunlight from 1999 to 2011. From 1999 to 2020, a total of 121,694 deaths occurred due to MS. The AAMR rose from 23.6 in 1999 to 29.7 in 2020 (APC 0.65), with a stable trend till 2018 (APC -0.22) followed by an abrupt increase towards 2020 (APC 9.27). Women had higher AAMR than men. Non-Hispanic (NH) Whites exhibited the highest AAMR (28.5), followed by NH Blacks (25.9), NH American Indians/Alaska Natives (9.6), Hispanics or Latino (6.8), and NH Asian or Pacific Islanders (1.9). AAMRs also varied substantially by region (Midwest: 32.4; Northeast: 26.9; West: 26.2; South: 19.4). States with the highest AAMRs were Montana, Wyoming, Colorado, and Oregon. The states with lower daily sunlight had higher AAMRs (r = -0.559, p = 0.000). AAMRs were comparable in urban (25) and rural (26.3) areas. Most deaths occurred in medical facilities (33.92 %) and nursing homes / long-term care (30.80 %), followed by home (27.79 %), and hospice (4.06 %). Adults ≥ 65 years depicted the highest mortality rates (CR 64.4) while adults aged 25 to 44 years showed the lowest rates (CR 4.6). We found an overall stable trend in MS-related mortality rates in the US till 2018 with a sharp increase thereafter. We observed highest mortality among women and NH White adults, among residents of Midwest and Northeast regions, and among adults ≥ 65 years. Higher disease burden in recent years calls for devising timely policies focused on these high-risk populations. [ABSTRACT FROM AUTHOR]

Phosphoinositide 3-kinase (PI3K) pathway, controlling diverse functions in cells, is one of the most frequently dysregulated pathways in cancer. Several negative regulators have been reported to intricately constrain the overactivation of PI3K pathway. Phosphatidylinoinosidine-3-kinase interacting protein 1 (PIK3IP1), as a unique transmembrane protein, is a newly discovered negative regulator of PI3K pathway. PIK3IP1 negatively regulates PI3K activity by directly binding to the p110 catalytic subunit of PI3K. It has been reported that PIK3IP1 is frequently low expressed in tumors and autoimmune diseases. In tumor cells and impaired cardiomyocyte, PIK3IP1 inhibits cell proliferation and survival. Consistently, the expression of PIK3IP1 is related with the condition of cancer. In addition, PIK3IP1 inhibits the inflammatory response and immune function via maintaining the quiescent state of immune cells. Thus, low expression of PIK3IP1 represents the severe condition of autoimmune diseases. PIK3IP1 is regulated by transcription factors, epigenetic factors or micro-RNAs to facilitate its normal function in different cellular contexts. This review integrates the total findings on PIK3IP1 in different disease, and summaries the structure, biological functions and regulatory mechanisms of PIK3IP1. [ABSTRACT FROM AUTHOR]