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PubMed2022

Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations.

Tumor necrosis factor receptor-associated factor 3 (TRAF3) is a central regulator of immunity. TRAF3 is often somatically mutated in B cell malignancies, but its role in human immunity is not defined. Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia. Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3 expression. Immunophenotyping showed that patients' B cells were dysregulated, exhibiting increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and heightened inflammatory responses. Patients had mild CD4+ T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells. Guided by this clinical phenotype, targeted analyses demonstrated that common genetic variants, which also reduce TRAF3 expression, are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, higher immunoglobulin levels, and bacterial infections in the wider population. Reduced TRAF3 conveys disease risks by driving B cell hyperactivity via intrinsic activation of multiple intracellular proinflammatory pathways and increased mitochondrial respiration, with a likely contribution from dysregulated T cell help. Thus, we define monogenic TRAF3 haploinsufficiency syndrome and demonstrate how common TRAF3 variants affect a range of human diseases.

Autoimmunity↗

PubMed2026

Phase 1 trial and biomarker analysis of Buparlisib with weekly Cisplatin and Radiotherapy in high risk locally advanced squamous cell cancer of the Head and Neck.

PURPOSE: We evaluated the pan-PI3K inhibitor buparlisib with weekly cisplatin and radiotherapy among patients with locally advanced (LA) squamous cell cancer of the head and neck (SCCHN) and tobacco history. PATIENTS AND METHODS: Patients with stage III/IV LA-SCCHN (AJCC7), ≥10 pack-year tobacco use treated with curative intent were enrolled. Patients received buparlisib during a 2-week run-in phase and during standard 70Gy of radiotherapy plus weekly cisplatin. An exploratory analysis of genomic sequencing was performed on biopsy specimens Results: Twenty-three patients were enrolled (n=17 at the MTD (buparlisib 40 mg daily, CDDP 30mg/m2/week)). Ninety-one percent (21/23) had stage IV disease. HPV was detected in 15 of 18 cases with oral/oropharyngeal disease. 5 patients suffered recurrences of whom 3 had activating mutations along the PI3K pathway. In 5 patients whose disease responded during the 2 week run-in phase with buparlisib alone, 3 of 4 with sequencing data showed loss-of-function mutations in either Tumor Necrosis Factor Receptor Associated Factor 3 (TRAF3), and/or Cylindromatosis Lysine Deubiquinatinase (CYLD). Preclinical studies with mutations in TRAF3 or CYLD via CRISPR/Cas9 knockout in HPV+SCCHN cells demonstrate that loss of TRAF3 or CYLD may sensitize SCCHN cell lines to PI3K through mechanisms other than blocking NFκb pathway. CONCLUSIONS: Buparlisib with CRT was feasible and active, though escalation to the standard weekly cisplatin dose of 40 mg/m2 was not possible. Our data suggests that TRAF3/CYLD mutant SCCHN may be susceptible to PI3K inhibition whereas PI3K pathway activation appeared to be associated with poor outcomes in this limited dataset.

Journal Article↗

PubMed2026

DNA Methylation and Proteomic Profiling of Postmortem Brain Tissue Reveals Epigenetic Dysregulation and Neuroinflammatory in Fragile X-associated Tremor/Ataxia Syndrome (FXTAS).

BACKGROUND: Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by FMR1 premutation CGG repeat expansions (55-200 repeats). The epigenetic landscape of the FXTAS brain remains uncharacterized. We performed genome-wide DNA methylation profiling of postmortem prefrontal cortex tissue to identify differentially methylated positions (DMPs) and candidate genes, and sought protein-level support for a neuroinflammatory signal. METHODS: DNA methylation was profiled in postmortem prefrontal cortex (Brodmann area 9) from 27 male FXTAS cases and 29 male controls using the Illumina MethylationEPIC array (EPICv1 and EPICv2 platforms), merging 721,802 common probes. Surrogate variable analysis (SVA) controlled for confounders. DMPs were defined by |Δβ| > 0.10 and FDR < 0.05; exploratory Reactome 2024 pathway analysis was performed on the DMP-associated gene list. Targeted proteomic profiling was performed in the same brain region using the Olink (proximity extension assay) Inflammation panel in 9 FXTAS cases and 12 controls, with SVA-adjusted differential abundance analysis, and concordance assessment against a prior mass spectrometry dataset. RESULTS: We identified 108 significant cg-type DMPs mapping to 80 genes (50 hypermethylated, 58 hypomethylated in FXTAS). The strongest signal was CYP2E1 (7 concordant hypomethylated DMPs, mean Δβ = -0.143), an oxidative stress gene also implicated in Parkinson's disease. FTCD, a one-carbon cycle enzyme, carried 5 hypermethylated DMPs (mean Δβ = +0.210). A cluster of DMP-associated genes with established roles in innate immune and NF-κB signaling, TRAF3 (the single most significant DMP among the inflammation genes, hypermethylated), BATF, RCOR1, and MSI2; they pointed toward neuroinflammatory dysregulation. Additional genes included LINGO1 (myelination inhibitor), SYT3 (synaptic vesicle), and SLC39A4 (zinc transporter). Exploratory Reactome enrichment using the DMP-associated gene set nominated themes including neuroinflammation resolution, axonal growth inhibition, zinc homeostasis, and CYP2E1 metabolism at nominal significance (p<0.05); however, the gene-to-pathway mapping rate was low and no pathway survived correction for multiple testing. Olink proteomic analysis independently identified 60 significantly altered inflammation proteins (59 downregulated), including CXCL8, CXCL10, IL6, IL15, IL18, TLR3, IRAK1/4, and complement C1QA, which were directionally concordant with prior mass spectrometry data. CONCLUSIONS: This integrated study reveals a genome-wide epigenetic signature in the FXTAS prefrontal cortex implicating oxidative stress, myelination failure, zinc dysregulation, one-carbon cycle disruption, and most notably a coordinated set of epigenetically altered genes governing innate immune and NF-κB signaling. Convergence of TRAF3 hypermethylation with independent downregulation of TLR3 and NF-κB-pathway proteins at the protein level supports a coherent, cross-platform model of dysregulated neuroinflammatory signaling in FXTAS, identified here through individual gene- and protein-level convergence rather than formal pathway enrichment. FTCD hypermethylation proposes a self-reinforcing epigenetic loop via SAM depletion. These multi-omic findings establish FXTAS as a disorder of pervasive epigenetic reprogramming and nominate candidate genes for future mechanistic and therapeutic investigation.

CYP2E1↗

PubMed2026

Tonsillar expression quantitative trait loci verify and expand genetic contributors to childhood atopic diseases.

BACKGROUND: The spectrum of causal variants, mechanisms, and immunologic gene networks that influence pediatric atopic traits is not completely understood. Human genetic variation associated with transcript abundance (expression quantitative trait loci [eQTLs]) can help to advance our understanding, yet prior work has focused on profiling immune cell populations collected from peripheral blood primarily in adult populations, leaving tissue-resident lymphocytes collected from children uncharacterized. OBJECTIVE: We sought to characterize gene expression of 4 populations of tonsil-derived immune cell types collected from pediatric patients. METHODS: We collected naive B, germinal center B, naive T, and T follicular helper cells from the discarded tonsils of 103 children across development (age range 1-19). Following genotyping and RNA sequencing of samples, we performed differential expression and eQTL analysis, then statistically linked eQTL signals to relevant atopic traits via colocalization. RESULTS: We found differentially expressed genes across cell types and identified 13,393 expression genes (eGenes) (1,793 eGenes not previously reported in similar datasets) influenced by 27,603 eQTLs (5,199 eQTLs not previously reported). We linked eQTLs to associations identified in pediatric and adult asthma and atopy traits, nominating 78 eGenes including TRAF3, ZBTB10, and JAZF1 in disease-relevant cell types. CONCLUSIONS: Our freely available resource exemplifies the importance of discovery in native tissues and across human development.

Expression quantitative trait locus↗

PubMed2026

A genome-wide cross-trait analysis characterizes the shared genetic architecture between rheumatoid arthritis and psychiatric disorders.

OBJECTIVES: Patients with RA have a 2- to 3-fold elevated risk of psychiatric disorders, suggesting an underlying genetic link between these phenotypes. However, the shared genetic architectures and pathological mechanisms driving RA-psychiatric disorder comorbidity remain to be fully elucidated. Herein, we performed cross-trait analysis to investigate the shared genetic architecture between RA and psychiatric disorders. METHODS: Leveraging European-ancestry genome-wide association studies (GWASs) datasets of RA (n = 1 026 690) and 10 major psychiatric disorders (n = 14 307-1 222 882), we performed cross-trait pleiotropic analysis to identify the shared pleiotropic loci and genes between RA and psychiatric disorders, followed by functional annotation and Mendelian randomization analysis to explore the pathological mechanisms underlying RA-psychiatric disorder comorbidity. RESULTS: Our analysis revealed significant positive genetic correlations between RA and seven psychiatric disorders, such as major depressive disorder. From these correlations, we identified 61 pleiotropic loci jointly influencing RA and psychiatric disorder risk, along with 208 pleiotropic genes predominantly involved in immune and inflammatory response biological processes. Druggable target exploration identified 21 drug-gene interactions involving pleiotropic genes, with two genes (RHOA and TRAF3) classified in the clinically actionable category, representing potential therapeutic targets for both RA and psychiatric disorders. Mendelian randomization further demonstrated a bidirectional causal relationship between RA and schizophrenia, while supporting the causal roles of attention-deficit/hyperactivity disorder, major depressive disorder and post-traumatic stress disorder in increasing RA risk. CONCLUSION: Our findings elucidate the shared genetic architecture between RA and psychiatric disorders, providing novel insights into the pathological mechanisms underlying their comorbidity and laying the groundwork for improved comorbidity management.

Arthritis, Rheumatoid↗

PubMed2026

Immune Cell-Stratified Regulatory Contexts Associated With BMI-Related Multi-System Disease Risk: A Cell-Stratified Mendelian Randomization Study Using Single-Cell eQTL Data.

AIMS: Body mass index (BMI) is associated with multisystem disease risk, but the immune cell-specific regulatory contexts underlying BMI-related genetic associations with disease outcomes remain unclear. METHODS: We applied a cell-stratified Mendelian randomization framework integrating European-ancestry BMI GWAS data, GWAS datasets for 33 disease outcomes across five disease systems, single-cell cis-eQTL data from 28 peripheral blood immune cell types, and dynamic CD4+ T cell eQTL data. SuSiE-based colocalization was used to identify BMI-associated loci sharing causal variants with immune-cell gene expression. These variants were used as cell-stratified instruments for Mendelian randomization. RESULTS: Across 28 immune cell types, 1326 colocalized variants regulating 1426 genes were identified. In primary MR analyses, genetically predicted BMI showed Bonferroni-significant associations with 26 disease outcomes. Cell-stratified analyses identified 87 Bonferroni-significant associations across 17 disease outcomes. Cardiovascular diseases showed the broadest cell-stratified associations, followed by respiratory and metabolic diseases. CD4+ T cell regulatory contexts contributed one of the largest shares of prioritized associations, and BMI-related effects varied across CD4+ T cell activation states. Cross-disease prioritization highlighted recurrent immune feature genes, including TRAF3 and FGFR1. CONCLUSION: These findings prioritize CD4+ T cell regulatory contexts as potential immunogenetic links between BMI and multi-system disease risk, while requiring further validation in diverse populations and mechanistic models.

Humans↗