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It is generally accepted that certain viral infections can trigger the development of autoimmune diseases. However, the exact mechanisms by which these viruses induce autoimmunity are still not understood. In this review, we first describe hypothetical mechanisms by which viruses induce some representative autoimmune diseases. Then, we focus on Epstein–Barr virus (EBV) and discuss its role in the pathogenesis of rheumatoid arthritis (RA). The discussion is mainly based on our own previous findings that (A) EBV DNA and its products EBV-encoded small RNA (EBER) and latent membrane protein 1 (LMP1) are present in the synovial lesions of RA, (B) mRNA expression of the signaling lymphocytic activation molecule-associated protein (SAP)/SH2D1A gene that plays a critical role in cellular immune responses to EBV is reduced in the peripheral T cells of patients with RA, and (C) EBV infection of mice reconstituted with human immune system components (humanized mice) induced erosive arthritis that is pathologically similar to RA. Additionally, environmental factors may contribute to EBV reactivation as follows: Porphyromonas gingivalis peptidylarginine deiminase (PAD), an enzyme required for citrullination, engenders antigens leading to the production of citrullinated peptides both in the gingiva and synovium. Anti-citrullinated peptides autoantibody is an important marker for diagnosis and disease activity of RA. These findings, as well as various results obtained by other researchers, strongly suggest that EBV is directly involved in the pathogenesis of RA, a typical autoimmune disease.

Epstein-Barr virus (EBV) infection can lead to infectious mononucleosis (EBV-IM) and, more rarely, EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), which is characterized by a life-threatening hyperinflammatory cytokine storm with immune dysregulation. Interferon-gamma (IFNγ) has been identified as a critical mediator for primary HLH; however, the detailed role of IFNγ and other cytokines in EBV-HLH is not fully understood. In this study, we used single-cell RNA sequencing to characterize the immune landscape of EBV-HLH and compared it with EBV-IM. Three pediatric patients with EBV-HLH with different backgrounds, one with X-linked lymphoproliferative syndrome type 1 (XLP1), two with chronic active EBV disease (CAEBV), and two patients with EBV-IM were enrolled. The TUBA1B + STMN1 + CD8 + T cell cluster, a responsive proliferating cluster with rich mRNA detection, was explicitly observed in EBV-IM, and the upregulation of SH2D1A—the gene responsible for XLP1—was localized in this cluster. This proliferative cluster was scarcely observed in EBV-HLH cases. In EBV-HLH cases with CAEBV, upregulation of LAG3 was observed in EBV-infected cells, which may be associated with an impaired response by CD8 + T cells. Additionally, genes involved in type I interferon (IFN) signaling were commonly upregulated in each cell fraction of EBV-HLH, and activation of type II IFN signaling was observed in CD4 + T cells, natural killer cells, and monocytes but not in CD8 + T cells in EBV-HLH. In conclusion, impaired responsive proliferation of CD8 + T cells and upregulation of type I IFN signaling were commonly observed in EBV-HLH cases, regardless of the patients’ background, indicating the key features of EBV-HLH.

Background Identifying response markers is highly needed to guide the treatment strategy in patients with metastatic melanoma. Methods A retrospective study was carried out in patients with unresectable/metastatic melanoma (stage IIIb–IV), treated with anti-PD-1 in the first line setting, to better explore the role and the timing of neutrophil/lymphocyte ratio (NLR) as potential biomarker of response. The relationship of NLR with inflammation-immune mediators and the underlying negative effect of raising NLR during immunotherapy, have been investigated with transcriptomic gene analysis. Results The results confirmed previous findings that a high baseline NLR is associated with a poorer prognosis and with higher serum level of lactate dehydrogenase (LDH), regardless of the presence of brain metastases. The transcriptomic analysis showed that high baseline NLR is associated with a characteristic gene signature CCNA1 , LDHA and IL18R1 , which correlates with inflammation and tumorigenesis. Conversely, low baseline NLR is associated with the signature CD3 , SH2D1A , ZAP70 and CD45RA, linked to the immune-activation. The genes positively associated with NLR ( CD39 ( ENTPD1 ), PTEN , MYD88 , MMP9 and LDH ) are involved in processes of immunosuppression, inflammation and tumor-promoting activity. Increased expression of CD39 correlated with TGFβ 2 , a marker of the N2 neutrophils with immunosuppressive activity. Conclusions These results suggest that increasing NLR is associated with an increased neutrophil population, with polarization to the N2 phenotype, and this process may be the basis for the negatively prognostic role of NLR.

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences ( XIAP, CYBA, SH2D1A, PCSK1 ). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB . The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P  < 4 × 10 −10 ), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P  < 5 × 10 −10 ). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis. Adult forms of inflammatory bowel disease (IBD) are of a polygenic nature, but paediatric and very early onset (VEO) IBD also occur as monogenic forms. Here, using whole exome sequencing, the authors explore both the monogenic and polygenic contribution to VEO-IBD and characterize a rare somatic mosaic VEO-IBD patient.

Background:Sjoegren’s syndrome (SjS) is an understudied systemic autoimmune disease with heterogeneous presentation and many unmet clinical needs. The underlying molecular pathomechanisms that drive SjS are not fully elucidated.Objectives:Our aim was to assess the proteome profiles of the minor salivary gland (MSG) tissues and to identify different subgroups of patients with SjS.Methods:Flash frozen MSG from 18 SjS patients, fulfilling the 2016 ACR/EULAR classification criteria, and 6 sicca controls not fulfilling the classification criteria, were analyzed. Clinical, imaging, functional, laboratory, and histological parameters, including age, gender, salivary gland ultrasound score, Schirmer’s test, unstimulated salivary flow (USF) test, presence of autoantibodies, cryoglobulins, levels of complement components, focus score, numbers of germinal centers, and presence of lymphoepithelial lesions, were collected. Proteome analysis of the MSG tissues was performed by tandem mass spectrometry. Proteins were identified and quantified using Spectronaut software. Differentially expressed proteins were identified using Bayes test. Pearson correlation coefficient r was calculated between log2 protein intensities and the clinical features. Unsupervised hierarchical clustering was performed based on the expression of all detected proteins to identify groups of patients with similar protein expression profiles. Mann-Whitney U test was used to statistically analyze the differences in clinical parameters between the identified clusters.Results:We identified 5577 proteins, 7 of which were differentially expressed between SjS and sicca controls (log2FC >2; p-adj <0,05). All 7 differentially expressed proteins, namely PTPRCAP, IKZF1, CD3E, HDAC3, PIK3CD, SH2D1A, and DOCK10, were upregulated in SjS patients compared to sicca controls (Table 1). PTPRCAP (r=0.585, p-adj=0.013), CD3E (r=0.616, p-adj=0.009), HDAC3 (r=0.448, p-adj=0.0565), PIK3CD (r=0.413, p-adj=0.075), SH2D1A (r=0.671, p-adj=0.004) and DOCK10 (r=0.540, p-adj=0.024) correlated with the focus score in MSG tissues. SH2D1A additionally correlated with cryoglobulins (r=0.590, p-adj=0.067). Unsupervised hierarchical clustering, based on all detected proteins, identified two separate clusters of patients with SjS. Patients from cluster 1 (n=8) had significantly lower focus score compared to patients from cluster 2 (n=10) (median focus score 1.21 vs, 2.0, p=0.002). Additionally, patients from cluster 1 had higher levels of USF compared to patients from cluster 2 (median 0.13 ml/min vs. 0,02 ml/min, p=0,400). Notably, only 29% of patients in cluster 1 tested positive in the USF test, while 70% of patients in cluster 2 showed pathological results.Table 1.List of differentially expressed proteins in SjS compared to sicca controls with their respective Log2FC and p-adjusted values.GeneProteinDifferential expression analysisLog2FCp-adjustedPTPRCAPProtein tyrosine phosphatase receptor type C-associated protein3.580.000IKZF1DNA-binding protein Ikaros3.500.000CD3ET-cell surface glycoprotein CD3 epsilon chain2.550.000HDAC3Histone deacetylase 32.230.000PIK3CDPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta2.920.000SH2D1ASH2 domain-containing protein 1A3.160.000DOCK10Dedicator of cytokinesis protein 102.180.001Conclusion:The total number of proteins identified in our analysis exceeds that of previous studies and allows us to provide the first list of differentially expressed proteins in MSG tissues in SjS and controls that correlate with SjS-relevant measures. Our results indicate that MSG tissues from patients with different levels of lymphocyte infiltration and salivary gland dysfunction differ in the protein expression profiles.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Neža Štucin: None declared, Katja Perdan Pirkmajer: None declared, Alojzija Hočevar: None declared, Britta Maurer Boehringer-Ingelheim, GSK, Novartis, Otsuka, MSD, Novartis, Boehringer Ingelheim, Jannsen-Cilag, GSK, Novartis, Polona Zigon: None declared, Saša Čučnik: None declared, Kerstin Klein: None declared.

In the human genome, miR‐451a, miR‐144‐5p (passenger strand), and miR‐144‐3p (guide strand) reside in clustered microRNA (miRNA) sequences located within the 17q11.2 region. Low expression of these miRNAs is significantly associated with poor prognosis of patients with renal cell carcinoma (RCC) (miR‐451a: P = .00305; miR‐144‐5p: P = .00128; miR‐144‐3p: P = 9.45 × 10−5). We previously reported that miR‐451a acted as an antitumor miRNA in RCC cells. Involvement of the passenger strand of the miR‐144 duplex in the pathogenesis of RCC is not well understood. Functional assays showed that miR‐144‐5p and miR‐144‐3p significantly reduced cancer cell migration and invasive abilities, suggesting these miRNAs acted as antitumor miRNAs in RCC cells. Analyses of miR‐144‐5p targets identified a total of 65 putative oncogenic targets in RCC cells. Among them, high expression levels of 9 genes (FAM64A, F2, TRIP13, ANKRD36, CENPF, NCAPG, CLEC2D, SDC3, and SEMA4B) were significantly associated with poor prognosis (P < .001). Among these targets, expression of SDC3 was directly controlled by miR‐144‐5p, and its expression enhanced cancer cell aggressiveness. We identified genes downstream by SDC3 regulation. Data showed that expression of 10 of the downstream genes (IL18RAP, SDC3, SH2D1A, GZMH, KIF21B, TMC8, GAB3, HLA‐DPB2, PLEK, and C1QB) significantly predicted poor prognosis of the patients (P = .0064). These data indicated that the antitumor miR‐144‐5p/oncogenic SDC3 axis was deeply involved in RCC pathogenesis. Clustered miRNAs (miR‐451a, miR‐144‐5p, and miR‐144‐3p) acted as antitumor miRNAs, and their targets were intimately involved in RCC pathogenesis. Our study showed that expression of miR‐144‐5p and miR‐144‐3p was downregulated, and these microRNAs (miRNAs) acted as antitumor miRNAs in renal cell carcinoma. SDC3 was directly controlled by miR‐144‐5p, and its expression enhanced cancer cell aggressiveness. Clustered miRNAs (miR‐451a, miR‐144‐5p, and miR‐144‐3p) acted as antitumor miRNAs, and their targets were intimately involved in renal cell carcinoma pathogenesis.

Background X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare inborn error of immunity with high mortality rates. Neurological manifestations may be the presenting features and are often fatal; however, their characterization is insufficient, hindering optimal clinical management. The aim of this study is to systematically review the neurological characteristics, outcomes, and survival in XLP1 patients and identify parameters associated with improved prognosis. A PRISMA-guided analysis of PubMed, Web of Science, Scopus, and Embase (up to March 2025) identified studies documenting neurological involvement in genetically verified XLP1 patients. We extracted data on clinical features, neuroimaging findings, therapeutic interventions, and survival. Results We identified 42 genetically verified XLP1 patients with neurological involvement. Central nervous system (CNS) involvement comprised hemophagocytic lymphohistiocytosis (HLH) in 38.1%, vasculitis in 28.6%, and lymphoma in 19% of them. The development of brain vasculitis several months after Burkitt’s lymphoma was a specific presentation. The median age of neurological onset was 5 years. The predominant presenting symptoms were seizures (47.6%), altered consciousness (35.7%), and headaches (21.4%). Neuroimaging frequently revealed abnormalities in the temporal lobe and basal ganglia, often with hemorrhage and edema. Epstein-Barr virus (EBV) was identified in 54.8% of cases, sometimes limited to brain tissue. CSF analysis frequently showed elevated protein and pleocytosis. SH2D1A mutations were diverse, with Arg55 and Trp64 identified as recurrent hot spots. The overall mortality reached 52.4%, with most deaths occurring within five years of neurological onset. Conventional immunosuppressive and cytotoxic treatments were largely ineffective in changing the disease course. In exploratory analysis, hematopoietic stem cell transplantation (HSCT) did not significantly improve survival in the primary dataset, although sensitivity analysis suggested a possible benefit. Conclusions Neurological involvement in XLP1 exhibits clinical heterogeneity and carries a high mortality rate. Early recognition and timely HSCT may improve survival, demonstrating the importance of vigilant neurological monitoring in affected individuals.

X-linked lymphoproliferative disease type 1 (XLP1) is an inborn error of immunity (IEI) caused by pathogenic variants in the gene, leading to severe immune dysregulation, often triggered by Epstein-Barr virus (EBV) infection. Hemophagocytic lymphohistiocytosis (HLH) is one of the most severe manifestations of XLP1 with high mortality. Present a clinical case of fatal HLH associated with a novel variant, highlighting the variability of clinical presentation and the potential role of co-infections. We analyzed clinical and laboratory data of three brothers who died from HLH in early age. Genetic evaluation was performed using a 576-gene panel for IEI (Veritas, Spain, supported by the Jeffrey Modell Foundation). Alive siblings and parents were tested in Scientific Medical Genetic Center LeoGENE, Ukraine. A 1-year-old boy was admitted with a persistent 4-day fever and clinical signs of hepatosplenomegaly, anemia, neutropenia, hypertransaminasemia, and hypoproteinemia. Immunophenotyping revealed decreased CD4, increased CD8 T cells, reduced NK cell counts, and elevated immunoglobulin levels. This patient demonstrated high EBV viremia and positive serological markers for SARS-CoV-2. Despite intensive treatment, HLH progressed rapidly, leading to fatality within 35 days. Genetic testing identified a novel, likely pathogenic hemizygous variant, c.175delC (p.Thr59Glnfs*22), not previously reported in affected individuals or the gnomAD database. Family history shows that two older male siblings died at 11 months and 1 year 9 months from a rapidly developed disease presented by fever, hepatosplenomegaly, dermatitis, enterocolitis, anemia, thrombocytopenia, and hypertransaminasemia. The second affected sibling tested positive for EBV serology. The family also included a healthy sister and brother, both with positive EBV serology (IgG) but no detectable viremia. Carrier testing confirmed that the mother and sister are heterozygous carriers, while two male siblings (one of them was born 1 month ago) are unaffected. We identified a novel variant associated with fatal HLH in XLP1. Our findings highlight the importance of early genetic diagnosis before EBV exposure to improve patient outcomes. The potential role of co-infections, including SARS-CoV-2, in triggering HLH in XLP1 remains an area for further investigation.

A small percentage of people living with HIV (PLHIV) spontaneously regulate viral replication without suppressive antiretroviral treatment (ART) and are categorized into ‘elite controllers’ (EC, HIV-RNA < 50 c/mL) and ‘viremic controllers’ (VC, HIV-RNA between 50-10,000 c/ml). Some EC and VC may lose controller status in time. Here we provide extensive plasma proteomics to identify biomarkers and pathways related to spontaneous viral control and its long-term preservation among 36 EC and 147 VC (discovery) and 14 EC and 5 VC (validation). VC exhibited higher concentrations of CRTAM, LY9, and CD6 and lower concentrations of VAT1 compared to EC in both the discovery and validation cohort. Longitudinal analysis of pre- and post-ART samples (median follow-up: 5.3 years) revealed downregulation of various immune-related proteins in both EC and VC. Over a 17-year follow-up period, loss of viral control occurred in 31% of VC and 3% of EC. T-cell associated proteins (CRTAM, LY9, CD6), along with ICAM3, SH2D1A, C1QL2, and CNGB3, predicted loss of viral control years before its occurrence. Markers of chronic immune activation (sPD-L1, sCD25, IL-10, TGF-β, IFN-γ, and TNF-α) and systemic inflammation (TNF, IL-1β, IL-6, and sCD14) were not predictive. Our findings underscore the dynamic interplay between T cell function and viral replication in maintaining HIV control and identify key biomarkers that predict viral load surges. Elite and viremic controllers of HIV can spontaneously regulate viral replication, but some lose this ability over time. In this longitudinal cohort study, 31% of viremic and 3% of elite HIV controllers lost viral control over 17 years. Specific T-cell– related proteins distinguish controller types and predict loss years in advance.

X-linked lymphoproliferative disease (XLP) was first described in the 1970s as a fatal lymphoproliferative syndrome associated with infection with Epstein-Barr virus (EBV). Features include hemophagocytic lymphohistiocytosis (HLH), lymphomas, and dysgammaglobulinemias. Molecular cloning of the causative gene, , has provided insight into the nature of disease, as well as helped characterize multiple features of normal immune cell function. Although XLP type 1 (XLP1) provides an example of a primary immunodeficiency in which patients have problems clearing primarily one infectious agent, it is clear that XLP1 is also a disease of severe immune dysregulation, even independent of EBV infection. Here, we describe clinical features of XLP1, how molecular and biological studies of the gene product, SAP, and the associated signaling lymphocyte activation molecule family receptors have provided insight into disease pathogenesis including specific immune cell defects, and current therapeutic approaches including the potential use of gene therapy. Together, these studies have helped change the outcome of this once almost uniformly fatal disease.