搜索结果：Journal of autoimmunity

To study the associations of dietary intake of A and E vitamins, as well as plasma retinols, carotenoids, and tocopherols in relation to development of islet autoimmunity and progression to T1D. The Environmental Determinants of Diabetes in the Young (TEDDY) Study followed 7659 newborns with genetic susceptibility to T1D for 6 years in the USA, Finland, Germany, and Sweden. Dietary vitamin intake was assessed repeatedly with 3-day food-records in full cohort at ages 6 months to 6 years. Plasma retinols, carotenoids, and tocopherols were analysed in a nested case-control setting with 359 children with islet autoimmunity and 1033 matched controls. In the full cohort analyses, dietary intake of retinol, β-carotene, and vitamin E was not associated with the risk of islet autoimmunity or progression to T1D. Further, none of the plasma retinol, carotenoid, and tocopherol biomarkers were associated with islet autoimmunity or T1D in the full nested case-control analyses. We observed effect modification by country, breastfeeding, sex, and follow-up time for both intake and biomarkers of vitamins on the risk of islet autoimmunity or T1D, and some subgroup associations. Finally, a plasma carotenoid metabolite (likely zeinoxanthin) (OR 0.61, 95% CI 0.39, 0.95, p = 0.03) and γ-carotene at 6 months (OR 0.65, 95% CI 0.45, 0.94, p = 0.02) were inversely associated with the odds of developing GADA-first. Retinol, carotenoids and tocopherols were not consistently associated with islet autoimmunity. This study adds to the understanding of factors and their interactions related to T1D development.

The 2023 iteration of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated prevalence, incidence, and health burden for 375 diseases and injuries, including 12 mental disorders. We assess past, current, and emerging trends in the prevalence and burden of mental disorders across sexes and age groups, for 21 regions, 204 countries and territories, and by Socio-demographic Index (SDI) quintile, from 1990 to 2023. Mental disorders included in GBD 2023 were anxiety disorders, major depressive disorder, dysthymia, bipolar disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder, anorexia nervosa, bulimia nervosa, idiopathic developmental intellectual disability, and a residual category of other mental disorders. A literature review identified epidemiological data for each disorder. These were analysed via a Bayesian meta-regression to estimate prevalence by disorder, sex, age, location, and year. Disorder-specific prevalence was multiplied by disability weights representing the severity of health loss associated with each disorder to estimate years lived with disability (YLDs). Deaths due to anorexia nervosa were assessed with a Cause of Death Ensemble modelling strategy to estimate deaths by sex, age, location, and year, and then multiplied by the standard life expectancy at age of death to estimate years of life lost (YLLs). YLDs equalled disability-adjusted life-years (DALYs) for all mental disorders except anorexia nervosa (the only mental disorder considered as an underlying cause of death in GBD), for which DALYs represented the sum of YLDs and YLLs. We presented prevalence, deaths, YLDs, YLLs, and DALYs as counts, age-specific rates per 100 000 population, and age-standardised rates per 100 000 population. We estimated 1·17 billion (95% uncertainty interval 1·06-1·31) prevalent cases of mental disorders globally in 2023, equivalent to an age-standardised prevalence rate of 14 210·7 cases (12 849·5-15 940·1) per 100 000 population. These estimates represented a 95·5% (75·0-121·2) increase in prevalent cases and 24·2% (11·4-41·4) increase in age-standardised prevalence rate between 1990 and 2023. All mental disorders showed increases in prevalent cases between 1990 and 2023, while notable increases were seen in age-standardised prevalence rates for anxiety disorders, major depressive disorder, dysthymia, anorexia nervosa, bulimia nervosa, schizophrenia, and conduct disorder. There were an estimated 171 million (127-228) DALYs due to mental disorders globally across sex and age in 2023, equivalent to an age-standardised DALY rate of 2070·5 DALYs (1519·1-2750·5) per 100 000 population. Mental disorders contributed to 6·1% (4·8-7·6) of all-cause DALYs in 2023, making them the fifth leading cause of global DALYs (up from 12th in 1990). DALYs were almost entirely composed of YLDs. Mental disorders were the leading cause of YLDs in 2023 (up from second in 1990), explaining 17·3% (14·8-20·6) of all-cause global YLDs. Leading causes of mental disorder DALYs were anxiety disorders (ranked 11th among the 304 diseases and injuries at Level 4 of the GBD cause hierarchy), major depressive disorder (15th), and schizophrenia (41st). Globally in 2023, mental disorder age-standardised DALY rates were higher among females (2239·6 [1643·7-3014·1] per 100 000) than among males (1900·2 [1399·8-2510·8] per 100 000), and peaked in the 15-19 years age group (2617·3 [1850·6-3696·8] per 100 000). All locations showed increased mental disorder DALY rates in 2023 compared with 1990, ranging across countries and territories from 1302·4 (952·7-1683·7) per 100 000 in Viet Nam to 3555·8 (2661·9-4715·0) per 100 000 in the Netherlands. Across SDI quintiles, DALY rates ranged from 1853·0 (1352·1-2469·3) per 100 000 for middle SDI to 2184·1 (1606·1-2890·3) per 100 000 for high SDI. A significant health burden was imposed by mental disorders in all countries and territories in 2023, irrespective of the health resources available. In some instances, this burden has increased over time and is unevenly distributed across populations. Stronger surveillance systems, particularly in low-income and middle-income countries, are required. Additionally, we need more coordinated and inclusive policies to reduce the burden through early treatment and prevention, tailored to sex and age differences across locations. Responding to the mental health needs of our global population, especially those most vulnerable, is an obligation, not a choice. Gates Foundation, Queensland Health, and University of Queensland.

The major genetic high-risk of developing autoimmune diabetes are HLA-DR3DQ2 and HLA-DR4DQ8 haplotypes. Their importance in Latent Autoimmune Diabetes in Adults (LADA) has only been partly elucidated. Here we aimed to dissect their impact on autoimmunity, diabetic phenotype, and comorbidity. Data from individuals with LADA were collected from two all-population based surveys, the Norwegian HUNT study (n = 231) and the Swedish ESTRID study (n = 519). The presence of DR3DQ2 and/or DR4DQ8 HLA-haplotypes augmented disease-associated parameters in LADA compared with the absence of risk haplotypes; this was seen in HUNT and ESTRID alike. Having both risk haplotypes vs. a single risk haplotype increased propensity for high levels of glutamic acid decarboxylase antibody (GADA) in HUNT, with a similar tendency in ESTRID. In HUNT, those with both risk haplotypes displayed higher propensity for treatment with insulin and higher prevalence of hypothyroidism. In ESTRID, the propensity for insulin treatment was more frequent for DR4DQ8 than for DR3DQ2. Presence of a DR3DQ2 or a DR4DQ8 diabetes risk-haplotype associate with different phenotypes of LADA with implications for the known heterogeneity of the disease. In HUNT, but not in ESTRID, the combination of the high-risk haplotypes DR3DQ2 and DR4DQ8 vs. separate high-risk haplotypes associate with enhanced effects on autoimmunity, signs of progression of disease, as well as on comorbidity. Lastly, exploratory findings are consistent with a stronger negative influence by DR4DQ8 than DR3DQ2 as shown in ESTRID. Measurements that include both DR3DQ2 and DR4DQ8 should be relevant when assessing disease progression in LADA patients.

Type 1 diabetes is a chronic autoimmune disease characterised by progressive pancreatic β-cell destruction and the early appearance of islet autoantibodies (islet-AAb) during the pre-symptomatic phases. Given the growing interest in screening and prevention of type 1 diabetes, this study aimed to assess the prevalence of pancreatic autoimmunity in adults with other organ-specific autoantibodies in order to identify potential target populations for screening programs. Adults previously tested for autoantibodies against specific endocrine glands and/or gastric parietal cells by indirect immunofluorescence were divided into two groups (Autoimmunity group and Control group), according to the presence of at least one organ-specific autoantibody. Stored serum samples from all participants were re-evaluated for islet-AAb and comparisons were performed between groups and, within the Autoimmunity group (Group A), across different patterns of organ-specific autoimmunity. Positivity for at least one islet-AAb was significantly higher in Group A than in Control Group (40.3% vs. 21.0%; p = 0.007). Double and triple islet-AAb positivity were less common overall, but occurred more frequently in Group A. Moreover, in Group A, a significantly higher prevalence of multiple positivity (≥ 2 islet-AAb) was observed in subjects with ovarian autoimmunity and in those with combined pituitary and ovarian autoimmunity than in those with other endocrine autoimmune involvement. Adults with specific autoimmunity disorders, particularly those affecting ovarian and/or pituitary glands, have a higher prevalence of pancreatic autoimmunity. These subjects may benefit from targeted screening to identify the pre-symptomatic stage of T1D and potentially delay progression to clinical disease.

MODY (Maturity-Onset Diabetes of the Young) is characterized by autosomal dominant mode of inheritance, early onset of diabetes in the absence of autoimmunity directed to pancreatic β-cells, impaired insulin secretory capacity, however, maintained over time, and extra-pancreatic manifestations in some patients. Its prevalence has been estimated 0.6% to 6.5% of all diabetes in Europe and the USA. Pathogenic variants in the genes encoding glucokinase or transcription factors HNF1A or HNF4A are responsible for the majority of cases of monogenic forms of diabetes referred to as MODY. The objective of the French National Diagnosis and Care Protocol (PNDS, Protocole National de Diagnostic et de Soins) dedicated to GCK-MODY (formerly MODY2), HNF1A-MODY (MODY3), and HNF4A-MODY (MODY1) is to provide to health professionals a guide for optimal management and care of patients, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), is available on the French Health Authority website (in French). Thorough analysis of personal and family history, clinical examination and biochemical testing are key to raise the diagnosis, which has to be confirmed by molecular analysis. The attending physician, in conjunction with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. Overall, the management of patients with MODY requires the collaboration of several health care providers.

SLE is a heterogeneous systemic autoimmune disease with diverse clinical manifestations. We aimed to identify clinical subgroups of SLE patients using cluster analysis at diagnosis and at the last follow-up and to evaluate their prognostic implications for disease activity, organ damage and mortality. In this single-centre retrospective cohort study, 199 patients with SLE who fulfilled the 1997 American College of Rheumatology (ACR) classification criteria and were regularly followed at the Rheumatology Clinic of Kocaeli University Hospital were included. Patients were divided into clusters based on their clinical involvement at diagnosis and the last visit using the Gower distance and the Partitioning Around Medoids algorithm. Differences between clusters were assessed using one-way analysis of variance, Kruskal-Wallis and &#x3c7;2 analyses. Analyses were performed using SPSS V.29.0 (IBM Corp, Armonk, New York, USA) and R V.4.3.0. At diagnosis, three clusters were identified: Cluster 1 (n=108) with predominant arthritis; Cluster 2 (n=49) with renal and haematological involvement and highest disease activity (SLE Disease Activity Index 2000, p=0.004); Cluster 3 (n=42) with mucocutaneous manifestations, often accompanied by haematological involvement. After a median follow-up of 168 months, four clusters were identified. Cluster 4', a heterogeneous group with mucocutaneous, articular and renal involvement, had significantly higher Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index (SDI) scores (median 4.0 (0-8), p<0.001), indicating poor prognosis. During follow-up, 29.6% of Cluster 1, 22.4% of Cluster 2 and 42.9% of Cluster 3 transitioned to Cluster 4'. Patients with mucocutaneous-predominant disease at diagnosis had a twofold increased risk of transitioning to the poor-prognosis cluster (OR 2.05, 95% CI 1.01 to 4.16, p=0.046). Mortality did not differ significantly between clusters. Cluster analysis based on clinical involvement in SLE can identify homogeneous patient subgroups and predict long-term outcomes. Patients with mucocutaneous-predominant onset, often receiving less intensive treatment, may have a worse prognosis, highlighting the importance of individualised monitoring and management strategies.

Haploinsufficiency of A20 (HA20) is a monogenic disease caused by heterozygous TNFAIP3 variants. Despite the marked clinical variability, no genotype-phenotype correlation or validated laboratory biomarkers have been identified so far. Neurobehavioural abnormalities have been reported in murine models, but their prevalence in humans remains unclear. To describe a cohort of patients with HA20 from two centres, evaluating age-related clinical variability; to assess the prevalence of neuropsychiatric symptoms; to explore the inflammatory profile of the patients, including interferon (IFN)-&#x3b3;-inducible chemokines (CXCL9/10) and type 1 IFN signature (IS), as well as the therapies administered. Clinical and laboratory data of 17 subjects from six families heterozygous for TNFAIP3 variants (American College of Medical Genetics and Genomics class 4-5) were retrospectively collected. Disease activity, treatments, CXCL9/10 and IS levels were collected. Continuous variables were expressed as medians (IQR). Age at onset was compared using the Kruskal-Wallis test, and groups were compared through the Wilcoxon test or Fisher's exact test. Clinical manifestations included oral aphthosis (88%), recurrent fever (53%), gastrointestinal inflammation (53%), autoimmunity (47%), genital ulcers (47%), neuropsychiatric symptoms (41%), arthritis/tenosynovitis (18%) and skin inflammation (12%). Disease onset before 5 years of age was associated with a higher prevalence of neuropsychiatric symptoms during lifetime (p=0.004), whereas arthritis was more common in patients with later onset. The median age at onset differed significantly according to the type of clinical manifestation (p<0.001). Higher IS levels were found in patients with active disease (p<0.01). HA20 shows marked clinical heterogeneity both between and within families. Clinical manifestations appear age-related and early disease onset was associated with increased neuropsychiatric involvement lifetime. Finally, type 1 IS may represent a potential biomarker of disease activity in HA20.

Seroconversion (SV) marks islet autoimmunity (IA) onset and preclinical type 1 diabetes (T1D), yet the contributions beyond T and B lymphocytes remain unclear. We evaluated DNA methylation (DNAm)-derived immune cell ratios between T1D cases and controls around SV. High-resolution immune cell-type deconvolution of peripheral blood DNAm from nested case-control samples in the Diabetes Autoimmunity Study in the Young (DAISY; n=151) and the Environmental Determinants of Diabetes in the Young (TEDDY; n=166) estimated immune cell proportions at pre-SV (the latest visit before SV) and at SV (the first visit with persistent detected autoantibodies) to construct immune cell ratios, such as the neutrophil-to-lymphocyte ratio (NLR). Linear models compared T1D cases to matched T1D controls (IA negative) at pre-SV, SV, and the change across time points. From pre-SV to SV, controls showed expected developmental increases in B-memory/naive, B-CD4T-CD8T memory/naive, and NLR, while cases failed to follow these patterns, with attenuated trajectories of 35%, 38%, and 21%, respectively. Pre-SV, cases had 15% higher NLR and 9% lower CD4T/CD8T. At SV, the combined B-CD4T-CD8T memory/naive ratio was 26% reduced in cases. These patterns may reflect increased neutrophil activation or pancreatic infiltration, altered CD4 and CD8 T cell balance, and delayed or disrupted immune maturation with the persistence or expansion of naive B and T cells or impaired transition to memory B and T subsets following antigen exposure. Our findings highlight early shifts in innate and adaptive immune cell dynamics during T1D pathogenesis and support methylation-derived immune cell ratios as potential biomarkers for risk stratification and mechanistic insight.

Emerging evidence suggests that viral infections, including SARS-CoV-2, may trigger autoimmunity. This study investigated the risk of developing autoimmune diseases following coronavirus disease 2019 (COVID-19) using sequence symmetry analysis. We utilized nationwide population-based data from South Korea by linking the National Health Insurance Service database with the Korea Centers for Disease Control and Prevention Agency COVID-19 registry. This study included 2,678 patients with COVID-19 and 92,725 patients without COVID-19 identified between 01/10/2020 and 30/06/2021, during the early phase of the pandemic. Both groups consisted of individuals who were diagnosed with autoimmune diseases within 180 days before or after the index date. We calculated the adjusted sequence ratio (aSR) to compare the incidence of autoimmune diseases within 180 days before and from 14 to 180 days after the index date (the COVID-19 diagnosis date for the COVID-19 group and the first medical visit for the non-COVID-19 group). The differences in autoimmune disease incidence between the groups were evaluated using the ratio of aSR (RaSR). The incidence of newly diagnosed autoimmune diseases-Behcet's disease (RaSR, 2.03), ankylosing spondylitis (2.04), ulcerative colitis (1.15), Crohn's disease (2.22), psoriasis (1.27), type 1 diabetes mellitus (1.61), and Graves' disease (1.14)-was significantly higher in the COVID-19 group than in the non-COVID-19 group after the index date. Subgroup analysis comparing patients with non-severe COVID-19 with those without COVID-19 yielded consistent findings. Furthermore, the incidence of inflammatory bowel diseases was higher in the non-severe COVID-19 group after the index date (RaSR, 1.29). These findings reinforce growing evidence that COVID-19 could induce autoimmunity and increase the risk of developing autoimmune diseases. Therefore, clinicians should remain vigilant for potential autoimmune complications in patients with a history of COVID-19 when clinically indicated.

Paraneoplastic syndromes are complexes of symptoms that can arise as a result of an immune response to an underlying malignancy. Various types of paraneoplastic syndromes exist: endocrine, metabolic, dermatological, rheumatological, hematological, and neurological. These syndromes occur more frequently than we might think, but their incidence varies greatly depending on the syndrome and the type of cancer. They can be difficult to recognize due to the wide variety of symptom complexes, and are frequently the first manifestation of a malignancy. Paraneoplastic syndromes can arise from humoral factors or autoimmunity, with immune-mediated paraneoplastic syndromes often not responding adequately to treatment of the underlying malignancy. Early recognition of a paraneoplastic syndrome is crucial both for diagnosing a malignancy at an earlier stage and for preserving the patient's quality of life.

Information on childhood cancer burden is crucial for effective cancer policy planning. Unfortunately, observed paediatric cancer data are not available in every country, and previous global burden estimates have not discretely reported several common cancers of childhood. We aimed to inform efforts to address childhood cancer burden globally by analysing results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, which now include nine additional cancer causes compared with previous GBD analyses. GBD 2023 data sources for cancer estimation included population-based cancer registries, vital registration systems, and verbal autopsies. For childhood cancers (defined as those occurring at ages 0-19 years), mortality was estimated using cancer-specific ensemble models and incidence was estimated using mortality estimates and modelled mortality-to-incidence ratios (MIRs). Years of life lost (YLLs) were estimated by multiplying age-specific cancer deaths by the standard life expectancy at the age of death. Prevalence was estimated using survival estimates modelled from MIRs and multiplied by sequelae-specific disability weights to estimate years lived with disability (YLDs). Disability-adjusted life-years (DALYs) were estimated as the sum of YLLs and YLDs. Estimates are presented globally and by geographical and resource groupings, and all estimates are presented with 95% uncertainty intervals (UIs). Globally, in 2023, there were an estimated 377&#x2008;000 incident childhood cancer cases (95% UI 288&#x2008;000-489&#x2008;000), 144&#x2008;000 deaths (131&#x2008;000-162&#x2008;000), and 11&#xb7;7 million (10&#xb7;7-13&#xb7;2) DALYs due to childhood cancer. Deaths due to childhood cancer decreased by 27&#xb7;0% (15&#xb7;5-36&#xb7;1) globally, from 197&#x2008;000 (173&#x2008;000-218&#x2008;000) in 1990, but increased in the WHO African region by 55&#xb7;6% (25&#xb7;5-92&#xb7;4), from 31&#x2008;500 (24&#x2008;900-38&#x2008;500) to 49&#x2008;000 (42&#x2008;600-58&#x2008;200) between 1990 and 2023. In 2023, age-standardised YLLs due to childhood cancer were inversely correlated with country-level Socio-demographic Index. Childhood cancer was the eighth-leading cause of childhood deaths and the ninth-leading cause of DALYs among all cancers in 2023. The percentage of DALYs due to uncategorised childhood cancers was reduced from 26&#xb7;5% (26&#xb7;5-26&#xb7;5) in GBD 2017 to 10&#xb7;5% (8&#xb7;1-13&#xb7;1) with the addition of the nine new cancer causes. Target cancers for the WHO Global Initiative for Childhood Cancer (GICC) comprised 47&#xb7;3% (42&#xb7;2-52&#xb7;0) of global childhood cancer deaths in 2023. Global childhood cancer burden remains a substantial contributor to global childhood disease and cancer burden and is disproportionately weighted towards resource-limited settings. The estimation of additional cancer types relevant in childhood provides a step towards alignment with WHO GICC targets. Efforts to decrease global childhood cancer burden should focus on addressing the inequities in burden worldwide and support comprehensive improvements along the childhood cancer diagnosis and care continuum. St Jude Children's Research Hospital, Gates Foundation, and St Baldrick's Foundation.

Immune complexes (ICs) play a central role in autoimmune diseases, where they accumulate in tissues, activate Fc gamma receptor-expressing cells, and promote chronic inflammation. However, the role of ICs as directional migratory cues for human leukocytes remains poorly defined. Here, we identify pro-inflammatory Slan&#xa0;+&#xa0;non-classical monocytes (SlanMo), a CD14dim CD16++ monocyte subset, as the only blood leukocyte population that migrates directionally toward ICs. Using in vitro transmigration assays, we demonstrate that SlanMo respond to ICs in a concentration-dependent, gradient-dependent, and CD16-mediated manner. Strikingly, SlanMo follow IC gradients with high specificity, enabling their active and directed migration towards high concentrations of ICs. This migration is independent of G protein-coupled receptor signaling, and is, therefore, not dependent on chemokines. Guided by our phosphoproteomic analysis of migrating SlanMo, we identified ROCK, Lyn, crk, FAK, and moesin as relevant signaling proteins. Our transcriptomic profiling of SlanMo after migration on immobilized ICs versus uncoated surfaces revealed enrichment of pathways linked to SLE as well as an upregulation of genes associated with antigen processing, endocytosis, and protein digestion. These findings suggest that ICs can act as directional cues for selective leukocyte recruitment of pro-inflammatory SlanMo which may be of relevance in IC-rich environments such as in SLE.

The causal relationship between high-sensitivity troponins (hs-cTn) and cardiovascular risk in asymptomatic adults remains incompletely established. [cite: 11] The objective of this systematic review is to evaluate the prognostic value of hs-cTn (hs-cTnI and hs-cTnT) in the general population free of clinical cardiovascular disease, and their potential to enhance the prediction of future cardiovascular risk when incorporated into conventional cardiovascular risk stratification models. [cite: 12] Methods: The literature search was conducted in the following electronic databases: PubMed, Google Scholar, ScienceDirect, and SpringerLink, to identify prospective cohort studies published between January 1, 2016, and February 28, 2024, examining the relationship between hs-cTn and cardiovascular risk in asymptomatic adult populations. [cite: 13] The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS). [cite: 14] Results: The 19 studies included in this review involved a total of 250,513 participants. [cite: 15] The results confirm a significant association between hs-cTn levels and cardiovascular events. [cite: 16] The addition of these biomarkers to traditional risk prediction models often enhances their predictive performance, as evidenced by increases in the C-index (Concordance index), Net Reclassification Improvement (NRI), and Integrated Discrimination Improvement (IDI). [cite: 17] hs-cTnI and hs-cTnT were moderately or weakly correlated but complementary, as they were associated with different types of cardiovascular events. [cite: 18] Conclusion: The inclusion of hs-cTn in predictive scores slightly improves their predictive accuracy. [cite: 19] Nevertheless, it remains necessary to demonstrate their clinical benefit through randomized trials before incorporating them into routine practice. [cite: 20].

Childhood-onset systemic lupus erythematosus (cSLE) is associated with significant morbidity and mortality. While numerous variants have been associated with adult-onset SLE, limited data exist on genetic variation within cSLE. We aimed to investigate genetic factors of early-onset cSLE, defined as onset of cSLE prior to age 10. Employing a case-only design, we performed whole genome sequencing analysis on 37 subjects with early onset cSLE. We hypothesised that rare, functional variants with large effects in genes associated with SLE contribute to the risk of early-onset cSLE and that the polygenic risk score (PRS) would be inversely associated with age of onset and presence of nephritis. A total of 153 linkage disequilibrium-independent variants were analysed and compared with previously reported SLE single-nucleotide polymorphisms. Rare (minor allele frequency (MAF) &#x2264;1%), damaging protein-altering (Combined Annotation Dependent Depletion; CADD&#x2265;20) variants, including variants isolated to previously reported monogenic SLE genes (n=49), were prioritised for secondary analysis. 37.8% of our cSLE cohort carried at least one rare, pathogenic variant in monogenic SLE genes. We identified 31, 012 rare, damaging, pathogenic variants in our cSLE cohort, including two genes implicated in mitochondrial protein degradation (AFG3L2, SPG7) and several genes in the interferon pathway (IFIH1, IFNGR1). We found that higher PRS scores were associated with increased nephritis odds (p=0.0092) but not age of onset (p>0.05). Burden testing using the optimal sequence kernel association test (SKAT-O) revealed nominal enrichment of rare variants (MAF&#x2264; 5%) in immune-related genes, including ISG15, PSMB9 and RNASEH2A, several of which are involved in type I interferon and antigen presentation pathways. These results have the potential to enhance our understanding of cSLE. Further studies must be conducted to expand our findings.

Cardiovascular (CV) diseases are the leading cause of mortality in patients with systemic lupus erythematosus (SLE). While traditional risk factors inadequately assess CV risk, SLE-specific determinants remain elusive. We have conducted a study of CV outcomes in a cohort of SLE patients, aiming to facilitate individualized risk assessment. The LESLY cohort comprised patients diagnosed with SLE at the University Hospital of Lyon between January 2002 and August 2020. CV events (CVE) were defined as myocardial ischemia or stroke. Complete-case multivariable analyses identified predictors of CV risk, among baseline SLE characteristics and traditional CV factors. The identified predictors were subsequently employed to develop machine learning models estimating CV risk in patients with SLE. The dataset was partitioned into training (80%, n&#x202f;=&#x202f;699) and validation (20%, n&#x202f;=&#x202f;175) sets. CVE occurred in 55 LESLY patients (6.3%), including 27 acute coronary syndromes and 25 ischemic strokes, over a mean follow-up of 8.8&#x202f;&#xb1;&#x202f;5.2 years. Antiphospholipid antibodies (HR&#x202f;=&#x202f;3.51 [1.91-6.43], p&#x202f;<&#x202f;0.001) and inaugural skin involvement (HR&#x202f;=&#x202f;2.69 [1.25-5.77], p&#x202f;=&#x202f;0.011) were the most potent predictors of CVE occurrence. Finally, an Elastic Net Penalized Cox model accurately predicted individualized CV risks in an internal validation cohort (C-index 0.791 [95% CI: 0.674-0.906]; Brier score 6.4% [95% CI: 3.7-9.8%]). This study corroborates the primacy of CVD in SLE, underscoring the predictive roles of inaugural skin involvement and antiphospholipid antibodies. These findings enabled the development of an exploratory risk stratification model that may inform clinical decision-making for cardiovascular risk management in SLE, pending external validation.

Vasculopathy is a core pathological feature of systemic sclerosis (SSc), but its immune regulatory mechanisms remain incompletely understood. In particular, the expression patterns, clinical relevance, and functional roles of CD8+CD28- and CD8+CD28+ angiogenic T cell (Tang) subpopulations in SSc have not been fully defined. This study aimed to systematically investigate the distribution, clinical significance, and molecular characteristics of these Tang subsets in SSc. We identified CD8+ Tang subpopulations in the lung tissue of patients with SSc-associated interstitial lung disease (SSc-ILD), with a gradual decrease in CD28-related signals along the inferred differentiation trajectory. In the peripheral blood of patients with SSc, CD8+CD28- Tang were increased, whereas CD8+CD28+ Tang were decreased. These alterations were associated with vascular complications, including ILD, digital ulcers, and advanced microvascular lesions, as well as with disease activity, and may serve as biomarkers of treatment response. Functional experiments showed that CD8+CD28- Tang impaired endothelial cell proliferation, migration, tube formation, and survival through a GZMB-dependent mechanism associated with reduced Akt activation, whereas CD8+CD28+ Tang exerted protective effects through VEGF/AREG-related activation of EGFR/Erk signaling. In summary, our data support an association between CD8+CD28-/CD8+CD28+ Tang imbalance and clinical parameters of vasculopathy in SSc, while in vitro findings indicate distinct endothelial-injurious and endothelial-protective functions of these two subsets, suggesting that they may contribute to vascular dysfunction in SSc.

Psoriasis is a chronic inflammatory skin disease characterised by keratinocyte hyperproliferation and immune cell infiltration driven by cytokines such as IL-17A. The dual-specificity phosphatase 6 (DUSP6) is a negative regulator of MAPK signalling and was previously reported to be a key mediator of arthritis severity. Here, we examine the role of DUSP6 in a mouse model of psoriasis. Psoriasis was studied in the imiquimod-induced model (IMQ). The skin of DUSP6+/+ and DUSP6-/- mice was treated with IMQ cream. Disease severity was assessed using well-established clinical and histologic systems. Skin inflammatory genes were quantified by qPCR.DUSP6-/- mice exhibited significantly reduced skin inflammation with lower PASI clinical scores (mean DUSP6-/- 1.8 and DUSP6+/+ 8.4; p&#x2009;<&#x2009;0.0001). Histologic scores for epidermal thickening, parakeratosis and immune cell infiltration were decreased in the DUSP6-/- mice (p&#x2009;<&#x2009;0.0005), and mRNA levels of IL1&#x3b2;, IL17A and STAT3 were lower in DUSP6-/- skin (p&#x2009;&#x2264;&#x2009;0.05) compared with DUSP6+/+. In conclusion, DUSP6 is required for the development of psoriasis-like skin inflammation in mice. In the absence of DUSP6, mice were protected and had significantly lower levels of pathogenic genes, suggesting a new and central role for DUSP6 in skin inflammation and a potential therapeutic target in psoriasis.

This study aimed to investigate the occurrence of thyroid autoantibodies at the onset of type 1 diabetes mellitus (T1DM) in children and adolescents, and to assess whether the presence of islet autoantibodies is associated with thyroid autoantibody presence. This retrospective cross-sectional study included 122 children and adolescents newly diagnosed with T1DM who visited Qingdao University Affiliated Women's and Children's Hospital between January 2022 and December 2024. We collected their blood glucose, glycated hemoglobin (HbA1c), C-peptide levels, and autoantibodies to islet cell antigen (ICA), glutamate decarboxylase (GADA), islet antigen-2 (IA-2A), insulin (IAA) and zinc transporter 8 (ZnT8A), thyroid peroxidase antibodies (TPOAb), and antithyroglobulin antibodies (TGAb). 84.4% of patients had at least one islet autoantibody, with IA-2A showing the highest positivity rate (64.8%) and ZnT8A the lowest (3.3%). No patient tested positive for all five antibodies. In comparison of 42 thyroid autoantibody (TA)-positive patients (34.4%) with 80 TA-negative patients, the TA-positive group was older (7.8 &#xb1; 3.0 years vs. 6.6 &#xb1; 3.1 years, P&#xa0;=&#xa0;0.045). The GADA positivity rate (60.9% vs. 41.4%, P&#xa0;=&#xa0;0.004) and IAA positivity rate (33.3% vs. 11.3%, P&#xa0;=&#xa0;0.003) were significantly higher in the TA-positive group than in the TA-negative group, with a higher median GADA titer (29.3 U/ml vs. 5.2 U/ml, P&#xa0;=&#xa0;0.029). Logistic regression analysis revealed that GADA positivity (OR&#xa0;=&#xa0;3.18, 95% CI: 1.44-7.01, P&#xa0;=&#xa0;0.004) and IAA positivity (OR&#xa0;=&#xa0;3.94, 95% CI: 1.53-10.15, P&#xa0;=&#xa0;0.004) were significantly associated with TA positivity. After adjusting for age, sex, BMI, and family history of diabetes, both remained independently associated with TA (aOR=2.68 and 4.06, respectively). Additionally, GADA titer showed a weak positive correlation with TPOAb titer (r = 0.204, P&#xa0;=&#xa0;0.024). Positive GADA and IAA antibodies were independently associated with thyroid autoimmunity in children with newly diagnosed type 1 diabetes, and GADA titer correlated with TPOAb titer. These findings support the consideration of early screening and long-term monitoring of thyroid function in children with newly diagnosed type 1 diabetes, particularly those positive for GADA and/or IAA antibodies.

To evaluate long-term clinico-serological response to direct-acting antivirals (DAAs) in patients with HCV-related cryoglobulinemic vasculitis (HCV-CV), and to compare the incidence of severe disease complications before/after antiviral therapy (AVT). The study also aimed to explore patterns of disease evolution following AVT. This retrospective multicenter study included 161 HCV-CV patients (mean age 63.9&#xa0;&#xb1;&#xa0;11.1 years; 64.6% females) treated with DAAs and achieving sustained virological response. The mean observation period was 8.2&#xa0;&#xb1;&#xa0;5.2 years, including pre-AVT (2.2&#xa0;&#xb1;&#xa0;5.5) and post-AVT (5.6&#xa0;&#xb1;&#xa0;2.7) phases. Complete response (CR) was defined as full resolution of baseline CV symptoms, partial response (PR) as &#x2265;50% improvement, all others were non-responders (NR). Post-AVT, significant reductions were observed in purpura (64% to 14%), fatigue (72% to 35%), arthralgias (55% to 26%), sicca syndrome (32% to 16%), skin ulcers (13% to 4%), and liver involvement (74% to 25%) (all p&#xa0;<&#xa0;0.01), along with decreased cryocrit % (3.5&#xa0;&#xb1;&#xa0;4.6 to 0.5&#xa0;&#xb1;&#xa0;1.5, p&#xa0;<&#xa0;0.0001) and increased C4 levels (9.6&#xa0;&#xb1;&#xa0;8.5 to 20.2&#xa0;&#xb1;&#xa0;11&#xa0;mg/dl; p&#xa0;<&#xa0;0.0001). CR was achieved in 74%, PR in 14%, NR in 12% of patients. Severe CV complications occurred more frequently pre-AVT than post-AVT (71% vs. 29%; p&#xa0;<&#xa0;0.0001), particularly in NR patients (47% vs PR 26% and CR 12%; p&#xa0;=&#xa0;0.0006), and those with persistent cryoglobulins (53% vs 12% without; p&#xa0;<&#xa0;0.0001). Of note, NR patients showed mean higher cryocrit (p&#xa0;=&#xa0;0.0046) and lower C4 (p&#xa0;=&#xa0;0.025) levels evaluated within the last 12 months before DAAs. DAAs significantly improved the clinical course of HCV-CV. Three post-treatment subsets can be identified: CR patients with minor residual symptoms, PR requiring careful monitoring, and NR group at high-risk for severe CV complications. Persistent serum cryoglobulins are predictors of long-term worse clinical course.