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SARS-CoV-2 infection is a world-wide public health problem. Several aspects of its pathogenesis and the related clinical consequences still need elucidation. In Italy, Sardinia has had very low numbers of infections. Taking advantage of the low genetic polymorphism in the Sardinian population, we analyzed clinical, genetic and immunogenetic factors, with particular attention to HLA class I and II molecules, to evaluate their influence on susceptibility to SARS-CoV-2 infection and the clinical outcome. We recruited 619 healthy Sardinian controls and 182 SARS-CoV-2 patients. Thirty-nine patients required hospital care and 143 were without symptoms, pauci-symptomatic or with mild disease. For all participants, we collected demographic and clinical data and analyzed the HLA allele and haplotype frequencies. Male sex and older age were more frequent in hospitalized patients, none of whom had been vaccinated during the previous seasonal flu vaccination campaignes. Compared to the group of asymptomatic or pauci-symptomatic patients, hospitalized patients also had a higher frequency of autoimmune diseases and glucose-6-phosphate-dehydrogenase (G6PDH) deficiency. None of these patients carried the beta-thalassemia trait, a relatively common finding in the Sardinian population. The extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 [OR 0.1 (95% CI 0-0.6), Pc = 0.015] was absent in all 182 patients, while the HLA-C*04:01 allele and the three-loci haplotype HLA-A*30:02, B*14:02, C*08:02 [OR 3.8 (95% CI 1.8-8.1), Pc = 0.025] were more frequently represented in patients than controls. In a comparison between in-patients and home care patients, the HLA-DRB1*08:01 allele was exclusively present in the hospitalized patients [OR > 2.5 (95% CI 2.7-220.6), Pc = 0.024]. The data emerging from our study suggest that the extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 has a protective effect against SARS-CoV-2 infection in the Sardinian population. Genetic factors that resulted to have a negative influence on the disease course were presence of the HLA-DRB1*08:01 allele and G6PDH deficiency, but not the beta-thalassemic trait. Absence of influenza vaccination could be a predisposing factor for more severe disease.

Multiple sclerosis (MS) is a chronic inflammatory, likely autoimmune disease of the central nervous system with a combination of genetic and environmental risk factors, among which Epstein-Barr virus (EBV) infection is a strong suspect. We have previously identified increased autoantibody levels toward the chloride-channel protein Anoctamin 2 (ANO2) in MS. Here, IgG antibody reactivity toward ANO2 and EBV nuclear antigen 1 (EBNA1) was measured using bead-based multiplex serology in plasma samples from 8,746 MS cases and 7,228 controls. We detected increased anti-ANO2 antibody levels in MS (P = 3.5 × 10−36) with 14.6% of cases and 7.8% of controls being ANO2 seropositive (odds ratio [OR] = 1.6; 95% confidence intervals [95%CI]: 1.5 to 1.8). The MS risk increase in ANO2-seropositive individuals was dramatic when also exposed to 3 known risk factors for MS: HLA-DRB1*15:01 carriage, absence of HLA-A*02:01, and high anti-EBNA1 antibody levels (OR = 24.9; 95%CI: 17.9 to 34.8). Reciprocal blocking experiments with ANO2 and EBNA1 peptides demonstrated antibody cross-reactivity, mapping to ANO2 [aa 140 to 149] and EBNA1 [aa 431 to 440]. HLA gene region was associated with anti-ANO2 antibody levels and HLA-DRB1*04:01 haplotype was negatively associated with ANO2 seropositivity (OR = 0.6; 95%CI: 0.5 to 0.7). Anti-ANO2 antibody levels were not increased in patients from 3 other inflammatory disease cohorts. The HLA influence and the fact that specific IgG production usually needs T cell help provides indirect evidence for a T cell ANO2 autoreactivity in MS. We propose a hypothesis where immune reactivity toward EBNA1 through molecular mimicry with ANO2 contributes to the etiopathogenesis of MS.

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland 1 in April 2022 and has now been identified in 35 countries 2 . Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case–control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4 + T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P  = 5.49 × 10 −12 ). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a ‘helper virus’ to support AAV2 replication) and disease susceptibility related to HLA class II status. A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

ObjectivesDrug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors of interleukin 1 (IL-1) or IL-6 in a small group of patients with Still’s disease with atypical lung disease. We sought to characterise features of patients with Still’s disease with DRESS compared with drug-tolerant Still’s controls. We analysed human leucocyte antigen (HLA) alleles for association to inhibitor-related DHR, including in a small Kawasaki disease (KD) cohort.MethodsIn a case/control study, we collected a multicentre series of patients with Still’s disease with features of inhibitor-related DRESS (n=66) and drug-tolerant Still’s controls (n=65). We retrospectively analysed clinical data from all Still’s subjects and typed 94/131 for HLA. European Still’s-DRESS cases were ancestry matched to International Childhood Arthritis Genetics Consortium paediatric Still’s cases (n=550) and compared for HLA allele frequencies. HLA association also was analysed using Still’s-DRESS cases (n=64) compared with drug-tolerant Still’s controls (n=30). KD subjects (n=19) were similarly studied.ResultsStill’s-DRESS features included eosinophilia (89%), AST-ALT elevation (75%) and non-evanescent rash (95%; 88% involving face). Macrophage activation syndrome during treatment was frequent in Still’s-DRESS (64%) versus drug-tolerant Still’s (3%; p=1.2×10−14). We found striking enrichment for HLA-DRB1*15 haplotypes in Still’s-DRESS cases versus INCHARGE Still’s controls (p=7.5×10-13) and versus self-identified, ancestry-matched Still’s controls (p=6.3×10−10). In the KD cohort, DRB1*15:01 was present only in those with suspected anakinra reactions.ConclusionsDRESS-type reactions occur among patients treated with IL-1/IL-6 inhibitors and strongly associate with common HLA-DRB1*15 haplotypes. Consideration of preprescription HLA typing and vigilance for serious reactions to these drugs are warranted.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and subsequent proliferation of synovial tissues, which eventually leads to cartilage and bone destruction without effective treatments. Anti-citrullinated cyclic peptide/protein antibody (ACPA) and rheumatoid factor (RF) are two main characteristic autoantibodies found in RA patients and are associated with unfavorable disease outcomes. Although etiologies and causes of the disease have not been fully clarified yet, it is likely that interactive contributions of genetic and environmental factors play a main role in RA pathology. Previous works have demonstrated several genetic and environmental factors as risks of RA development and/or autoantibody productions. Among these, cigarette smoking and HLA-DRB1 are the well-established environmental and genetic risks, respectively. In this narrative review, we provide a recent update on genetic contributions to RA and the environmental risks of RA with a special focus on cigarette smoking and its impacts on RA pathology. We also describe gene–environmental interaction in RA pathogenesis with an emphasis on cigarette smoking and HLA-DRB1.

ObjectivesIdiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies.MethodsWe collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups.ResultsWe report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10–5. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10–53 and HLA-DRB1*03:01, p=3.25×10–9), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10–26) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10–11). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10–13) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10–6). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10–64) and position 9 of HLA-B (p=7.03×10–11). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies.ConclusionsThese findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.

Pemphigus vulgaris (PV) is a potentially life-threatening autoimmune blistering disease characterized by autoantibodies directed against the desmosomal cadherins desmoglein 3 (DSG3) and desmoglein 1 (DSG1), which are essential for keratinocyte adhesion. While the pathogenic role of these autoantibodies is well established, the upstream events leading to loss of immune tolerance against desmogleins remain incompletely understood. Genetic susceptibility conferred by HLA class II alleles and environmental exposures are thought to interact during disease initiation. In this study, we investigated allele and genotype associations in Turkish PV patients and explored a hypothesis-generating framework linking genetic susceptibility with environmental exposure. Specifically, we examined whether vector-derived cadherin-like proteins could represent potential molecular mimics of desmogleins in genetically predisposed individuals. allele frequencies were analyzed in 86 PV patients and 200 healthy controls using PCR-SSOP and Luminex-based genotyping. analyses included MHC class II peptide-binding prediction (IEDB), structural modeling using AlphaFold, and molecular dynamics simulations performed with GROMACS. These computational approaches were applied to evaluate structural similarity and relative binding compatibility between cadherin-like peptides derived from hematophagous vectors and disease-associated alleles, including *04:02 and *14:01. HLA-DRB1*04:02 and HLA-DRB1*14:01 alleles were significantly enriched in PV patients compared with controls, and the heterozygous HLA-DRB1*04:02/14:01 genotype was overrepresented in the patient cohort. Structural and energetic analyses indicated that selected vector-derived cadherin-like peptides can adopt stable conformations when bound to these HLA variants and display conformational features compatible with DSG3 ectodomain-derived peptides. These findings highlight strong immunogenetic associations in PV and introduce a structurally and immunogenetically informed, hypothesis-generating Vector-derived Cadherin Mimicry (VCM) framework. By integrating genetic association data with computational modeling, this conceptual model suggests that repeated exposure to vector-derived cadherin-like proteins may represent a plausible environmental component contributing to PV susceptibility in genetically predisposed individuals. Experimental validation will be required to further evaluate this framework and its relevance to PV pathogenesis.

Ingileif Jonsdottir, Kari Stefansson and colleagues show that variants in the HLA class II region contribute to tuberculosis risk in populations of European ancestry. They propose that the associated variants influence disease risk by altering expression of HLA class II molecules presenting protective M. tuberculosis antigens to T cells. Mycobacterium tuberculosis infections cause 9 million new tuberculosis cases and 1.5 million deaths annually 1 . To identify variants conferring risk of tuberculosis, we tested 28.3 million variants identified through whole-genome sequencing of 2,636 Icelanders for association with tuberculosis (8,162 cases and 277,643 controls), pulmonary tuberculosis (PTB) and M. tuberculosis infection. We found association of three variants in the region harboring genes encoding the class II human leukocyte antigens (HLAs): rs557011[T] (minor allele frequency (MAF) = 40.2%), associated with M. tuberculosis infection (odds ratio (OR) = 1.14, P = 3.1 × 10 −13 ) and PTB (OR = 1.25, P = 5.8 × 10 −12 ), and rs9271378[G] (MAF = 32.5%), associated with PTB (OR = 0.78, P = 2.5 × 10 −12 )—both located between HLA - DQA1 and HLA - DRB1 —and a missense variant encoding p.Ala210Thr in HLA - DQA1 (MAF = 19.1%, rs9272785), associated with M . tuberculosis infection ( P = 9.3 × 10 −9 , OR = 1.14). We replicated association of these variants with PTB in samples of European ancestry from Russia and Croatia ( P < 5.9 × 10 −4 ). These findings show that the HLA class II region contributes to genetic risk of tuberculosis, possibly through reduced presentation of protective M . tuberculosis antigens to T cells.

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6–7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P  = 2.4 × 10 −12 ). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P  = 4.8 × 10 −12 ), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P  = 3.4 × 10 −7 ). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (β = 0.32; P  = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production. Autoimmune pulmonary alveolar proteinosis (aPAP) is a complex lung disease caused by abnormal surfactant homeostasis. Here, the authors carry out a genome-wide association study of aPAP in a Japanese cohort, finding variants in the MHC and suggesting predisposition to abnormal antibody production.

ObjectivesLung exposures including cigarette smoking and silica exposure are associated with the risk of rheumatoid arthritis (RA). We investigated the association between textile dust exposure and the risk of RA in the Malaysian population, with a focus on women who rarely smoke.MethodsData from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis population-based case–control study involving 910 female early RA cases and 910 female age-matched controls were analysed. Self-reported information on ever/never occupationally exposed to textile dust was used to estimate the risk of developing anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA. Interaction between textile dust and the human leucocyte antigen DR β-1 (HLA-DRB1) shared epitope (SE) was evaluated by calculating the attributable proportion due to interaction (AP), with 95% CI.ResultsOccupational exposure to textile dust was significantly associated with an increased risk of developing RA in the Malaysian female population (OR 2.8, 95% CI 1.6 to 5.2). The association between occupational exposure to textile dust and risk of RA was uniformly observed for the ACPA-positive RA (OR 2.5, 95% CI 1.3 to 4.8) and ACPA-negative RA (OR 3.5, 95% CI 1.7 to 7.0) subsets, respectively. We observed a significant interaction between exposure to occupational textile dust and HLA-DRB1 SE alleles regarding the risk of ACPA-positive RA (OR for double exposed: 39.1, 95% CI 5.1 to 297.5; AP: 0.8, 95% CI 0.5 to 1.2).ConclusionsThis is the first study demonstrating that textile dust exposure is associated with an increased risk for RA. In addition, a gene–environment interaction between HLA-DRB1 SE and textile dust exposure provides a high risk for ACPA-positive RA.