Journal of Clinical Immunology

Background VEXAS syndrome is a late onset autoinflammatory disease caused by somatic UBA1 mutations and characterized by heterogeneous systemic and hematologic manifestations. We aimed to describe all identified Belgian cases through a national multicenter cohort. Methods We conducted a retrospective study across four Belgian tertiary centers. Clinical, biological, genetic, therapeutic, and outcome data were collected using standardized anonymized case report forms. Analyses were descriptive. Results Twenty-one male patients were identified between January 2018 and May 2025. General symptoms such as Fatigue, weight loss and sweating occurred in 95% of cases. The most frequent manifestations were cutaneous (85.7%), hematologic (76.2%), articular (66.7%), thromboembolic (57.1%), chondritis (42.9%), ophthalmologic (38.1%), pulmonary (38.1%). Other manifestations also included vasculitis (61.9%). At diagnosis, 95% had anemia, macrocytic in 57%, and 28.6% had thrombocytopenia. Corticosteroids were the main first line therapy. Second line treatments included anti IL 6 agents (46.7%), JAK inhibitors (20%), and azacitidine (14.3%). Complete remission occurred in 50% of patients receiving anti IL 6 therapy and in 33% treated with either JAK inhibitors or azacitidine. Two patients underwent allogeneic stem cell transplantation, one died from infectious complications. Twenty six infectious episodes were recorded, including opportunistic infections. Six patients (28.6%) died during follow-up, four from infectious complications. Conclusion This first Belgian national cohort confirms the clinical heterogeneity of VEXAS syndrome and highlights substantial infectious morbidity and mortality. Access to targeted second-line therapies, particularly anti IL-6 agents and JAK inhibitors, remains challenging despite apparent clinical benefit.

BackgroundPhospholipase C{gamma}2 (PLC{gamma}2) is an important signaling molecule that receives and transmits signals from various cell surface receptors in most hematopoietic lineages. Variants of PLCG2 cause PLC{gamma}2-associated immune dysregulation (PLAID), a family of conditions that are classified by mutational effect. PLAID with cold urticaria (CU-PLAID) is caused by in-frame deletions of PLCG2 that are dominant negative at physiologic temperatures but become spontaneously active at sub-physiologic temperatures. ObjectiveTo identify genetic lesions that cause PLAID by combining RNA sequencing of full-length PLCG2 with whole genome sequencing. MethodsWe studied nine probands with antibody deficiency and a positive evaporative cooling test, together with two known CU-PLAID patients and three healthy subjects. Illumina sequencing was performed on full-length PLCG2 cDNA synthesized from peripheral blood mononuclear cell RNA and whole genome sequencing was used to identify genetic lesions. Novel alternate transcripts were overexpressed in the Plcg2-deficient DT40 cell overexpression system. ERK phosphorylation was quantified by flow cytometry with and without BCR crosslinking. ResultsTwo probands expressed novel alternative transcripts of PLCG2 with in-frame deletions. The first, expressing PLCG2 without exons 18-19, carried a splice site mutation in intron 19. The second, expressing PLCG2 without exons 19-22, carried a 14kb de novo deletion of PLCG2. DT40 cells overexpressing the exon 18-19 or exon 19-22 deletions failed to phosphorylate ERK in response to BCR crosslinking. ConclusionIn addition to autosomal dominant genomic deletions, de novo deletions and splice site mutations of PLCG2 can also cause CU-PLAID. All of these can be identified by cDNA-based sequencing. Capsule SummaryBy identifying both the first de novo and splice site variants to cause PLCG2-associated immune dysregulation with cold urticaria (CU-PLAID), we demonstrate the diagnostic utility of PLCG2-specific RNA-sequencing.

ImportanceVEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes. This study used a genomic ascertainment approach to overcome these limitations and better define UBA1-related disease. ObjectiveDetermine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach. Design, Setting and ParticipantsThis cohort study evaluated UBA1 variants in exome data from 163,096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record (EHR) data up to January 1st, 2022. Main outcomes and measuresPrevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other symptoms in individuals with somatic UBA1 variation; structured and manual review of EHR; review of bone marrow biopsies; survival in carriers of somatic UBA1 variation. ResultsIn a retrospective study of 163,096 participants (mean age 52.8 years; 94% of European ancestry, 61% female), 11 individuals harbored somatic, known pathogenic UBA1 variants, with 100% having clinical manifestations consistent with VEXAS syndrome. We found a previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) in a symptomatic patient. Disease-causing UBA1 variants were found in [~]1 in 14,000 unrelated individuals, and [~]1 in 4,000 men >50 years old. A disease-causing UBA1 variant confers a [~] 6.6 higher probability of mortality vs. age-, sex-, and BMI-matched non-carriers. The majority (7, 58%) of individuals did not meet criteria for rheumatologic and hematologic diagnoses previously associated with VEXAS syndrome, however all individuals had anemia (mean 7.8 g/dL, median 7.5g/dL), mostly macrocytic (91%) with concomitant thrombocytopenia (91%). Finally, we identified a pathogenic variant in one male prior to onset of VEXAS-related signs or symptoms and two females had disease with heterozygous variants. Conclusions and relevanceThis cohort study showed that the prevalence, penetrance, and expressivity of pathogenic UBA1 variants were higher than expected. More expansive UBA1 testing will lead to molecular diagnoses and improved treatment for patients.

POEMS syndrome is a rare form of plasma cell dyscrasia with multiple clinical features including polyneuropathy and sclerotic bone lesions. As various signs and symptoms can be observed, diagnosis is often delayed and we need an accurate diagnosis tool for these patients. Vascular endothelial growth factor (VEGF) is known to play a major role in the pathology and is frequently increased in sera of the patients but is not specific. This condition is also associated with the presence of a monoclonal immunoglobulin light chain composed of highly restricted variable domains (IGLV1-40, IGLV1-44, IGLV1-36 and IGJV3*02 genes). Using RNA-based high-throughput sequencing (5 RACE RepSeq), we previously showed mutated consensus stretches in the CDR1/FR2 regions of the variable domains of the light chains: (P/A)VNWYQ and (D/G)VNWYQ. We have now added 70 light chain sequences to our cohort and confirmed the variable domain restriction, the consensus stretches and found a new YSVNWYQ pattern on IGLV1-44 light chains. When correlated with our clinical database of POEMS patients, these mutation patterns had an accuracy of 89% and a specificity of 100%. 5RACE RepSeq is an important tool to ensure the diagnosis of patients suspected of having POEMS syndrome, even with a small secretory clone. Samples from an involved organ are mandatory in the case of localized disease.

Germline activating mutations in STAT3 result in immune dysregulation, autoimmunity, and increased malignancy risk, yet the precise molecular mechanisms underlying disease heterogeneity remain unclear. We identified a familial germline STAT3 p.R278H mutation shared between the parent diagnosed with T-cell large granular lymphocytic leukemia and the proband presenting with infantile-onset multisystem autoimmune disease-1. Employing whole-exome sequencing, single-cell RNA sequencing, comprehensive cytokine profiling, and flow cytometry-based immunophenotyping, we characterized their distinct clinical phenotypes and underlying immune dysregulation. Single-cell transcriptomics revealed marked expansion of CD8+ T cells in the proband, accompanied by altered expression of JAK/STAT pathway genes, including elevated STAT3, STAT1, and downstream target genes (BATF, MAF, MYC), but diminished cytokine transcripts (IL1B, TNF). Serum cytokines, however, were markedly elevated, highlighting discordant transcriptional and translational regulation. The parent exhibited additional somatic mutations, notably FLT3-ITD, suggesting a multi-hit model underpinning leukemogenesis rather than direct oncogenic transformation by STAT3 alone. Immunomodulatory therapies, including cyclosporin A and tacrolimus, controlled autoimmune symptoms in the proband, whereas the parent was refractory to conventional treatments, ultimately succumbing after unsuccessful hematopoietic stem cell transplantation. Our findings emphasize that germline STAT3 activating mutations predispose individuals to complex immune dysregulation and require additional somatic mutations to initiate overt malignancy. This study supports comprehensive genetic profiling and precision medicine approaches for patients harboring congenital STAT3 mutations, aiming to optimize clinical management and improve therapeutic outcomes.

Studies of genetic factors associated with severe COVID-19 in young adults have been limited in non-Caucasian populations. Here, we use whole exome sequencing to characterize the genetic landscape of severe COVID-19 in a well phenotyped cohort of otherwise healthy, young adults (N=55; mean age 34.1 {+/-} SD 5.0 years) representing 16 countries in Asia, the Middle East, and North Africa. Our findings show enrichment of rare, likely deleterious missense and truncating variants in interferon-mediated and bacterial infection-susceptibility genes, when compared to control, mildly affected, or asymptomatic COVID-19 patients (N = 25), or to general populations representing Asia and the Middle East. Genetic variants tended to associate with mortality, intensive care admission, and ventilation support. Our findings confirm the association of interferon pathway genes with severe COVID-19 and highlight the importance of extending genetic studies to diverse populations given implications for pan-ethnic therapeutic and genetic screening options. Author SummaryBased on the hypothesis that rare monogenic variants contribute to the severity of SARS-CoV-2 infection outcomes, we performed whole exome sequencing in young, previously healthy patients with severe COVID-19 of Asian or Middle Eastern origins. We found an enrichment of rare missense and truncating variants in immune-related genes, mainly associated with interferon pathways and susceptibility to bacterial infections, which can be therapeutic targets. Genetic findings tended to correlate with mortality, intensive care unit (ICU) admission, high dependency unit (HDU) admission, and invasive ventilation.

The genetic risk factors of immune cytopenias are unclear. Immune cytopenias have been reported in various genetic contexts: 1) inherited error of immunity genes, mainly due to rare germline variants, 2) systemic lupus erythematosus, associated with common germline variants, 3) hematological malignancies, and 4) clonal hematopoiesis, the latter two due to somatic variants. However, the respective contribution and interaction of these variants remain to be investigated. Here, we used two large biobanks with whole genome sequencing data to systematically investigate the genetic contribution to immune cytopenia. We found that the four types of genetic variants independently contribute to immune cytopenia risk. We notably found that carriers of variants in some autosomal recessive genes of inherited error of immunity had an increased risk of immune cytopenia. Additionally, common variant-mediated risk of systemic lupus erythematosus also increased the risk of immune cytopenia. Overall, a third to a half of patients with immune cytopenia carried at least one of the four genetic risk variants investigated. Combining the four variants allowed stratifying the risk of immune cytopenia in both general and high-risk population. In general population, the 10-year incidence of immune cytopenia in the lowest and highest risk groups was 0.08% and 1.5%, respectively. In sum, this work identified that different genetic risk factors can lead to immune cytopenia. A large proportion of individuals with immune cytopenia carried an underlying genetic risk factor. Finally, combining these genetic risk factors enabled risk stratification.

Mosaic genetic variation has been implicated in the pathogenesis of both malignant and non-malignant immunological disease. Here, we report a unique case of postnatal acquisition of a gain-of-function (GoF) KRAS variant, with an additional GoF STAT5B variant, in a woman with inflammatory bowel disease, splenomegaly, thrombocytopenia, bronchiectasis, monocytosis, and eosinophilia. Targeted amplicon sequencing revealed widespread distribution of both variants in key immune cell populations, and in historical blood and tissue samples, with the emergence of both variants coinciding with the time of clinical presentation. Short- and long-read single cell RNA sequencing of patient cells highlighted a unique population of monocytes, with a broad distribution of both variants, and dysregulated cytokine signaling pathways. Flow cytometry revealed dysregulated STAT signaling, and the presence of a distinct population of highly granular CD24+ cells. Taken together with the clinical presentation, these findings led to a diagnosis of combined RAS-associated autoimmune leukoproliferative disorder (RALD) and non-clonal STAT5B GoF disease. To our knowledge, this is the first reported combination of two distinct acquired errors of immunity causing a mixed clinical phenotype, and highlights the importance of considering acquired monogenic diseases within a broader genomic context.

The IFIH1 gene, encoding melanoma differentiation-associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation linking it to weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain-of-function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi-Goutieres and Singleton-Merten syndromes, while biallelic loss of this gene causes immunodeficiency. In this study, nine patients suffering from different cases of recurrent infections, inflammatory diseases, severe COVID-19, or multisystem inflammatory syndrome in children (MIS-C) were identified with putative loss-of-function IFIH1 variants by whole exome sequencing. All patients revealed signs of lymphopenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin, and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19, or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss-of-function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS-CoV-2 related disorders.

The varicella-zoster virus (VZV) infects over 95% of the population and establishes latency afterwards. Reactivation of VZV causes herpes zoster (HZ), commonly known as shingles, which presents as a painful rash in mostly the elderly and people with a weakened immune system. However, HZ might occur in otherwise healthy individuals too. In this study, we have studied the immune signature of HZ to better understand HZs pathophysiology. We provide a general overview of the antiviral state and the activation of innate and adaptive immune responses during HZ. Differential gene expression and gene ontology analyses revealed upregulation of several genes and host immune pathways during herpes zoster, especially related to type I IFN response but also related to adaptive immune responses. Intriguingly, no differences in gene expression were noted during convalescence between HZ patients and controls. Furthermore, we conducted the largest HLA association study on HZ to date using the UK Biobank and identified seven protective and four risk HLA alleles associated with the development of herpes zoster. These findings reveal key genes and pathways involved in the host immune response to symptomatic VZV reactivation and provide new molecular insights into the development of HZ.

Multisystem Inflammatory Syndrome in Children associated with COVID-19 (MIS-C) is a late complication of pediatric COVID-19, which follows weeks after original SARS-CoV-2 infection, regardless of its severity. It is characterized by hyperinflammation, neutrophilia, lymphopenia and activation of T cells with elevated IFN-{gamma}. Observing production of autoantibodies and parallels with systemic autoimmune disorders, such as systemic lupus erythematodes (SLE), we explored B cell phenotype and serum levels of type I, II and III interferons, as well as the cytokines BAFF and APRIL in a cohort of MIS-C patients and healthy children after COVID-19. We documented a significant elevation of IFN-{gamma}, but not IFN- and IFN-{lambda} in MIS-C patients. BAFF was elevated in MIS-C patient sera and accompanied by decreased BAFFR expression on all B cell subtypes. The proportion of plasmablasts was significantly lower in patients compared to healthy post-COVID children. We noted the presence of ENA Ro60 autoantibodies in 4/35 tested MIS-C patients. Our work shows the involvement of humoral immunity in MIS-C and hints at parallels with the pathophysiology of SLE, with autoreactive B cells driven towards autoantibody production by elevated BAFF. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=175 SRC="FIGDIR/small/22275245v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@166327dorg.highwire.dtl.DTLVardef@7cde7forg.highwire.dtl.DTLVardef@1f3a3b2org.highwire.dtl.DTLVardef@803175_HPS_FORMAT_FIGEXP M_FIG C_FIG Summary sentenceElevated serum BAFF in children with MIS-C supports the state of polyclonal B cell activation and autoimmune phenomena characterizing this disease.

The Fc{gamma} receptors (Fc{gamma}Rs) act as modulators of the immune system and have previously been shown to play a role in immune disorders such as systemic lupus erythematosus and immune thrombocytopenic purpura. Thus far, their role in primary immunodeficiencies (PID), including common variable immunodeficiency disorders (CVID), has not been studied. In this paper we explored whether there is an association between the following single nucleotide polymorphisms (SNPs) and CVID: FCGR2A H131R (rs1801274), FCGR2B I232T (rs1050501), and FCGR3A F158V (rs396991). We compared the genotypes of a cohort of 83 patients with PID, including 56 with CVID, against controls. We found a significant difference between our mixed PID cohort and controls at the FCGR2A H131R SNP (X2 =7.884, p=0.019). There was not a significant difference at either of the other SNPs studied. Further, we examined the effect of FCGR SNPs on the incidence of the most common CVID complications within our cohort: anaemias, organ-specific autoimmunity, bronchiectasis, splenomegaly, granulomata, and cytopenias. We found no significant association between SNPs and the development of these complications. In summary, we have shown that there is a link between the FCGR2A H131R SNP and the development of a PID.

Telomere biology disorders (TBDs), exemplified by dyskeratosis congenita (DC), are characterized by genetic defects in telomere maintenance genes, leading to telomere attrition and multi-organ manifestations including bone marrow failure (BMF) and increased malignancy risk. This study aimed to evaluate the prevalence and clinical impact of rare possibly significant variations (PSVs) in telomere-related genes among patients with BMF and clonal hematopoiesis disorders. We analyzed 1320 patients diagnosed with aplastic anemia, myelodysplastic syndrome, acute myeloid leukemia, or acute lymphoblastic leukemia and identified 113 PSVs in 103 patients, significantly exceeding the prevalence in the general population (gnomAD). The most frequently mutated genes were RTEL1 (37%) and CTC1 (30%). While missense variants predominated, novel variants accounted for approximately 27.4%. Patients harboring PSVs exhibited significantly shorter telomeres compared to unaffected relatives, reinforcing telomere length as a critical functional biomarker. Telomere-mediated genetic anticipation was clearly evident: younger patients had notably shorter telomeres compared to their older first-degree relatives, reflecting cumulative generational telomere attrition and progressively severe phenotypes. Despite variability in clinical presentations--with many patients lacking classical mucocutaneous or fibrotic manifestations--telomere shortening provided robust onset information. Our findings emphasize the importance of integrating genetic testing and telomere length measurement into clinical practice for early diagnosis, personalized risk stratification, and tailored management, including reduced-intensity conditioning transplantation and emerging targeted therapies.

BackgroundHaemophagocytic lymphohistiocytosis (HLH) is rare, results in high mortality and is increasingly being diagnosed. Little is known about what is driving the apparent rise in the incidence of this disease. MethodsUsing national linked electronic health data from hospital admissions and death certification cases of HLH that were diagnosed in England between 1/1/2003 and 31/12/2018 were identified using a previously validated approach. We calculated incidence rates of diagnosed HLH per million population using mid-year population estimates by calendar year, age group, sex and associated comorbidity (haematological malignancy, inflammatory rheumatological or bowel diseases (IBD)) associated with the diagnosis of HLH. We modelled trends in incidence and the interactions between calendar year, age and associated comorbidity using Poisson regression. FindingsThere were 1674 people with HLH diagnosed in England between 2003 and 2018. The incidence rate quadrupled (Incidence Rate Ratio (IRR) 2018 compared to 2003: 3.88 95% Confidence Interval (CI) 2.91 to 5.28), increasing 11% annually (adjusted IRR 1.11 95% CI 1.09 to 1.12). There was a rising trend in all age groups except those aged less than 5 years. There was a transition across the age groups with greater increases in those aged 5 to 14 years of HLH associated with rheumatological disease/IBD compared to HLH associated with haematological malignancy, with similar increases in HLH associated with both co-morbidities for those 15-54, and greater increases in associated haematological malignancies for those 55 years and older. InterpretationThe incidence of HLH in England has quadrupled between 2003 and 2018, increasing 11% annually. Substantial variation in the incidence occurred by age group and by HLH associated comorbidities with inflammatory rheumatological diseases or IBD associated HLH increasing more among the young and middle age groups, whereas in older age groups the largest increase was seen with haematological malignancy-associated HLH. Evidence before this studyThere is a paucity of population-based data on the epidemiology of HLH worldwide. The available evidence relies mostly upon a collection of cases series published in The Lancet in 2014 which described 2197 cases of HLH in adults reported in the literature to that point. Almost all of these were from tertiary referral specialist centres and/or described in small case series. The incidence of HLH has only been described in a few reports - and mainly this has focused on children with primary HLH. No previous studies have been large enough to examine trends in incidence by age, sex, underlying risk factors and calendar time. Added value of this studyThis study quantifies the incidence of diagnosed HLH for the first time in a nationwide manner for all age groups. It reports on 1674 patients with HLH from England and shows that there is substantial variation in the incidence by age group, associated disease and calendar time. The results imply reasons for the increase in HLH could be related to the increasing occurrence of haematological cancer, inflammatory rheumatological or bowel diseases and the treatments given for these conditions. This study has been carried out in partnership with the National Congenital Anomalies and Rare Diseases Registration Service and the methodology described can in future be applied to many rare diseases that as yet lack a way of quantifying crucial epidemiological metrics. Implications of all the available evidenceThe incidence of HLH is rising rapidly in people older than 5 years of age. This could be due to an increase in the biologic, immunomodulation or immunosuppressive therapy being used in people with haematological cancer and inflammatory rheumatological and bowel diseases. Further work should focus on how to minimise the risk of HLH occurring, or to improve treatment of this often fatal disease among those who need treatment for an associated comorbidity.

BackgroundPatients with Common Variable Immunodeficiency (CVID) exhibit diverse clinical manifestations, indicating heterogeneity in pathogenic mechanisms. Systematic application of standardised phenotyping in large cohorts is essential to dissect this heterogeneity. The Human Phenotype Ontology (HPO) provides a structured framework for capturing and comparing disease phenotypes. ObjectiveTo evaluate the implementation and outcomes of HPO-based phenotyping in CVID patients enrolled for whole-genome sequencing in a large national adult primary immunodeficiency cohort. MethodsWe developed a web-based Phenotype Capture Tool and delivered structured clinician training to standardise HPO annotation. Numerical laboratory parameters were mapped to corresponding HPO terms to enrich patient records. ResultsWe coded the phenotypes of 526 CVID patients across 11 UK centres. Clinician training increased phenotype granularity and improved phenotyping consistency between clinicians. We assigned 883 unique HPO terms across the cohort and applied logical rules to the terms to classify patients into an infection-only group and a complex phenotype group (42% vs 58%, respectively). Patients in the complex phenotype group were significantly more likely to have reduced switched memory and expanded CD21low B cells, as well as pathogenic variants in IUIS-listed genes overall and pathogenic NFKB1 variants specifically. Having a pathogenic variant in an IUIS-listed gene was associated with Autoimmune hemolytic anemia and having a pathogenic NFKB1 variant specifically was associated with Autoimmune neutropenia. ConclusionThis is the first study to systematically collect granular HPO-coded phenotypes in a large real-world CVID cohort, refining the CVID landscape and providing a comprehensive CVID HPO term set relevant for international research. Clinical ImplicationHPO allows systematic capture of CVID phenotypes with low inter-clinician variability and improves comparison of cohorts, enhancing identification of disease heterogeneity essential to support genotype-phenotype studies and targeted therapeutic strategies. Capsule summaryHPO-based phenotyping of 526 CVID patients improved annotation quality, identifying immunological and genetic associations with clinical manifestations, distinguishing infection-only from complex disease and refining clinical characterisation to support international collaboration.

ELF4 is an ETS family transcription factor involved in immune regulation, and germline loss-of-function mutations in ELF4 have been known as "deficiency in ELF4, X-linked"(DEX). To date, ELF4-related disease has been exclusively associated with germline mutations. Here, we report a pediatric patient with recurrent mucocutaneous inflammation and periodic fever caused by a somatic truncating mutation in ELF4. By directly comparing ELF4-mutant and wild-type immune cells within the same individual using full-length single-cell RNA sequencing, we identified mutation-associated transcriptional alterations across multiple immune cell types. Pathway analyses revealed cell type-specific immune alterations, characterized by reduced antiviral and interferon-related signaling in NK cells and enhanced inflammatory pathways related to Th17 differentiation and inflammatory bowel disease in CD16+ monocytes. This study expands the disease spectrum of ELF4 deficiency by identifying somatic truncation of ELF4 as a genetic mechanism underlying autoinflammatory diseases and biased immune programs.

BackgroundHTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is an incapacitating neuroinflammatory disorder for which no disease-modifying therapy is available, but corticosteroids provide some clinical benefit. ObjectiveTo investigate systemic cytokines and GlycA as possible biomarkers of immunopathogenesis and therapeutic response to corticosteroid pulse therapy in HAM/TSP. MethodsWe prospectively followed 110 People living with HTLV-1 (PLwHTLV-1, 67 asymptomatic individuals and 43 HAM/TSP patients), for a total of 906 person-years. Plasma cytokine levels (IL-2/4/6/10/17A, IFN-{gamma}, TNF) and GlycA were quantified by Cytometric Bead Array and 1NMR, respectively. Cytokine signaling and prednisolone response were validated in an independent cohort by nCounter digital transcriptomics. We applied logistic regression and machine learning algorithms to predict disease progression and glucocorticoid response. ResultsIL-6 was positively correlated with age and GlycA in asymptomatics but not HAM/TSP patients. Systemic IFN-{gamma} and IL-17A levels were increased in HAM/TSP patients, as compared to asymptomatics. All patients significantly decreased IL-17A levels post-treatment but only prednisolone-responders decreased IFN-{gamma} levels post-treatment. Higher pre-treatment GlycA and TNF levels significantly predicted a negative therapeutic outcome, which was associated with higher post-treatment IFN-{gamma} levels. Low IL-4 and IL-10 levels in incident HAM/TSP can be reverted to increased IL-10 and IL-4/IL-13 signaling by prednisolone in vitro. Conclusions1) An age-related increase in systemic IL-6/GlycA levels reveals inflammaging in PLwHTLV-1. 2) IFN-{gamma} and IL-17A are biomarkers of untreated, active HAM/TSP disease, while pre-treatment GlycA and TNF predict therapeutic response to prednisolone pulse therapy. 3) Low IL-4/IL-10 and high IFN-{gamma} signaling in incident HAM/TSP can be normalized by prednisolone.

Homozygous OTU deubiquitinase with linear linkage specificity (OTULIN) variants cause OTULIN-Related Autoinflammatory Syndrome (ORAS). This disease is characterized by early-onset autoinflammation, fever, panniculitis, diarrhea, and arthritis. In contrast, heterozygous and compound-heterozygous OTULIN variants have been associated with a phenotype defined by abscess development in different organs. Whether homozygous OTULIN variants can cause abscessing in affected patients is currently unknown. Here, we report a juvenile female patient harboring a novel homozygous OTULIN variant (Chr5:14687605G>T, p.V185F; referred to as OTULINV185F), presenting with autoinflammation and sterile abscesses in lung and skin. Through in silico analysis and functional assays, we show that OTULINV185F impairs OTULIN function, leading to compromised degradation of linear ubiquitin linkages. Notably, the patient clinically improved on anti-TNF therapy. Our findings underscore the diverse clinical manifestations of OTULIN dysfunction and call for a new classification of the disease that includes abscess formation as potential ORAS symptom.

BackgroundCo-trimoxazole is a leading global cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Co-trimoxazole-induced SCAR are associated with HLA class I alleles including HLA-B*13:01 and HLA-B*38:02 in Southeast Asian (SEA) populations. However, the global generalizability of these associations is unknown but critical for population-appropriate risk stratification and diagnosis. ObjectiveTo determine HLA risk factors associated with co-trimoxazole-induced SJS/TEN and DRESS in populations from the United States (US) and South Africa (SA). MethodsWe performed high-resolution HLA typing on dermatologist-adjudicated co-trimoxazole-induced SCAR patients in the US (n=63) and SA (n=26) compared to population controls. Peptide binding and docking analyses were performed using MHCcluster2.0 and CB-Dock2. ResultsIn a multiple logistic regression model, HLA-B*44:03 (Pc<0.001, OR: 4.08), HLA-B*38:01 (Pc<0.001, OR: 5.66), and HLA-C*04:01 (Pc=0.003, OR: 2.50) were independently associated with co-trimoxazole-induced SJS/TEN in the US. HLA-B*44:03 was also associated with co-trimoxazole-induced DRESS in SA (Pc=0.019, OR: 10.69). Distinct HLA-B variants with shared peptide binding specificities (SPBS) and HLA-C*04:01 identified 94% and 78% of co-trimoxazole-induced SJS/TEN and DRESS in the US, respectively. The SEA risk allele HLA-B*13:01, with SPBS to HLA-B*44:03, was identified in just 1/63 US SCAR patients. ConclusionHLA alleles with SPBS to SEA-related risk alleles including HLA-B*44:03 (SPBS with HLA-B*13:01) and HLA-B*38:01 (SPBS with HLA-B*38:02) but also HLA-C*04:01 predisposed to co-trimoxazole-induced SCAR in the US and SA. These findings provide biological plausibility and strategies for global risk prediction and diagnosis of co-trimoxazole-induced SCAR. HIGHLIGHTS BOXO_ST_ABSWhat is already known about this topic?C_ST_ABSHLA alleles including HLA-B*13:01 and HLA-B*38:02 are risk factors for co-trimoxazole-induced SCAR in Asian populations. However, the generalizability of these associations to other global populations is unknown but critical for population-appropriate risk stratification and diagnosis. What does this article add to our knowledge?HLA alleles with shared peptide binding specificities (SPBS) to Asian-related risk alleles including HLA-B*44:03 (SPBS with HLA-B*13:01) and HLA-B*38:01 (SPBS with HLA-B*38:02) but also HLA-C*04:01 predisposed to co-trimoxazole-induced SCAR in the US and South Africa. How does this study impact current management guidelines?HLA alleles previously associated with co-trimoxazole-induced SCAR do not identify risk across populations. However, HLA alleles with SPBS provide biological plausibility and strategies for global and population-appropriate clinical risk stratification and diagnosis of cotrimoxazole-induced SCAR.

IntroductionPatients with Coronavirus Disease 2019 (COVID-19) frequently experience a hyperinflammatory syndrome, that leads to unfavorable outcomes. This condition resembles Secondary Hemophagocytic Lymphohistiocytosis (sHLH) described in neoplastic, rheumatic and other infectious diseases. However, it has not been prospectively studied on these patients. A scoring system (HScore) has been validated for sHLH, and recently proposed to evaluate hyperinflammation in COVID-19. Methods143 patients aged [&ge;]18 years admitted because of COVID-19 were enrolled in a prospective, single-center, cohort study. HScore was calculated within the 72 hours since admission. The incidence of sHLH during hospitalization was evaluated. Additionally, the relationship between HScore [&ge;]130 points and either the requirement of mechanical ventilation or 60-days mortality was explored. ResultsThe median age of enrolled patients was 57 (21-100), and 63.6% were male. The median HScore was 96 (33-169). One patient was diagnosed with sHLH (incidence 0,7%), due to a HScore of 169. After adjusting for age, sex, comorbidities and obesity, HScore [&ge;]130 was independently associated with the composite clinical outcome (HR 2.13, p=0.022). ConclusionsHLH is not frequent among COVID-19 patients. HScore can efficiently predict the risk for poor outcomes.