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关键词： histocompatibility antigens   autoimmunity   genetic predisposition   genotype  

摘要： Objectives To comprehensively investigate the association between HLA class II alleles and haplotypes with type 1 diabetes mellitus (T1DM) susceptibility in a Jordanian population. Methods In this case-control study, 205 patients with clinically confirmed T1DM and 99 ethnically matched healthy controls were genotyped for HLA-DRB1, DQA1, and DQB1 loci. Autoantibodies and thyroid function were evaluated. Haplotype frequencies were compared using the BIGDAWG R package, with odds ratios (ORs), 95 % confidence intervals (CIs), and false discovery rate (FDR) correction. Results HLA-DRB1*03:01 (OR=4.94, p<0.001), DRB1*04:02 (OR=3.87, p=0.003), and DRB1*04:05 (case-only;p=0.002) were associated with T1DM. Strong associations were also observed for DQA1*05:01 (OR=6.61, p<0.001) and DQB1*02:01 (OR=5.70, p<0.001). Protective effects were identified for DRB1*07:01, DRB1*15:02, DQA1*05:05, and DQB1*03:01 (all FDR<0.05). Among haplotypes, DR3 similar to DQ2 conferred the greatest risk (OR=5.40, p<0.001), while DRB1*11:04 similar to DQA1*05:05 similar to DQB1*03:01 was protective (OR=0.25, p=0.004). DRB1*03:01 was associated with GAD65 autoantibodies and celiac serology. DQA1*03:01 and DQA1*05:01 were linked to thyroid autoantibodies. No significant differences in age or HbA1c at diagnosis were observed across HLA alleles. Conclusions HLA class II variation was strongly associated with T1DM in Jordan, with DR3 similar to DQ2 and DR4 haplotypes driving susceptibility and DRB1*07, DRB1*15:02, and DQB1*03:01 conferring protection, reflecting global patterns while highlighting region-specific features. These findings support incorporating HLA genotyping into T1DM risk assessment and suggest shared genetic links with other autoimmune diseases.

关键词： HIV-2   IRF3   Mycobacterium tuberculosis   PE_PGRS62   type I IFN  

摘要： Co-infection with Mycobacterium tuberculosis (Mtb) and HIV-2 increased the viral load of HIV-2. Type I interferons (IFNs) are essential for limiting HIV-2 progression. However, it is unclear whether and how Mtb affects HIV-2 co-infection by regulating type I IFNs. Here, Mtb PE_PGRS62 protein was identified as an inhibitor of cGAS-STING-mediated type I IFN expression by performing functional screens. Ectopic expression of PE_PGRS62 impaired type I IFN expression stimulated by cytosolic DNA, while knockout of pe_pgrs62 potentiated Mtb-induced type I IFN and downstream IFN-stimulated gene. PE_PGRS62 interacts directly with IRF3 and inhibits the interaction of IRF3 with TBK1 as well as the binding of IRF3 to the IFNβ promoter. Furthermore, reduced HIV viral load was observed in pe_pgrs62 knockout Mtb-infected macrophages compared with wild type Mtb. These findings reveal an important mechanism by which Mtb infection promotes HIV-2 immune evasion.

关键词： Infectious bursal disease virus   IBDV   major histocompatibility complex   MHC   B locus   genetic resistance  

摘要： Seven lines of major histocompatibility complex (MHC)-B congenic specific pathogen free (SPF) chickens and two lines of non-B congenic SPF chickens with similar B haplotype but differing non-MHC genes were utilized to investigate the effect of the B locus on infectious bursal disease (IBD) development. In initial experiments, chickens were challenged at 28 days of age with the variant infectious bursal disease virus (IBDV) strain AL-2, classical IBDV strain STC, or very virulent (vv) IBDV strain rA. IBD severity was evaluated throughout the 7-day course of infection by assessing survivability and histopathological analysis of bursal lesion scores. Follow-up studies investigated the effects of varying STC challenge doses on IBD development. Results demonstrated that the challenge strain of IBDV has a large impact on B locus-based genetic resistance. The most significant differences in survivability and bursal lesions were noted after challenge with the vvIBDV strain, with MHC-B congenic chicken lines B*13 and B*19 being the most susceptible. Based on survivability, the B*19 chicken line was also characterized as the most susceptible after challenge with high doses (105 EID50) of the STC strain. No differences in survivability were detected among the chicken lines when challenged with the variant strain AL-2. Based on the results with these chicken lines, B locus-based genetic resistance to IBDV is mainly associated with survival during the early stages of infection and has minimal association with bursal damage and bursal lymphocyte depletion. Non-B locus-based genetic differences also have a significant impact on survival during early IBDV *** HIGHLIGHTSThe host B locus and the IBDV pathotype impact development of clinical *** host B locus has significant effects on IBDV-induced early *** host B locus has no significant effect on IBDV-induced bursal damage.

关键词： acute coronary syndrome   Behçet's disease   coronary aneurysm   immunosuppressive therapy   systemic vasculitis   BD   IL   interleukin  

摘要：

摘要： Gene products from the highly variable major histocompatibility locus, including HLA, are essential for self-recognition and immune surveillance of malignancy. Following allogeneic hematopoietic cell transplantation (alloHCT), genetic and epigenetic alterations in HLA can drive disease recurrence, making precise HLA assessment critical for determining future therapy. However, current methods lack the sensitivity to quantify HLA transcripts at the single-cell level, limiting their clinical utility. We introduce , a novel technique that accurately identifies and quantifies HLA transcripts in single cells using long-read sequencing. When applied to samples from patients with post-transplant relapse, scrHLA-typing successfully detected HLA allele-specific expression, across a range of levels of donor-recipient chimerism, at clinically actionable levels. By characterizing allele expression in residual leukemia cells, our assay identified differences in expression patterns among patients. This capability highlights scrHLA-typing's potential to improve risk stratification and guide the selection of appropriate salvage therapies, enhancing personalized treatment strategies after relapse.

关键词： CCL22   IFN   STING   immunosuppression   macrophage  

摘要： Immunosuppressive elements within the tumor microenvironment include both regulatory T cells (Tregs) and M2 macrophages. A well-described mechanism of Treg recruitment occurs via the chemokine CCL22, and CCL22 has also recently been implicated in the polarization of tumor-associated macrophages to the M2a subtype. Our lab and others have shown that CCL22 is upregulated in cancer cells following activation of the stimulator of interferon genes (STING). STING triggers immune responses against pathogenic nucleic acids as well as self-DNA mislocalized to the cytoplasm, which can accumulate in cancer cells due to chromosomal instability, damaged mitochondria, and increased expression of LINE-1 retrotransposons. STING activation has been associated with both anti-tumor and pro-tumor immune responses, and a potential mechanism of STING-mediated immune evasion is through CCL22 upregulation. CCL22 was first characterized in macrophages, and here we investigate the effects of STING activation on CCL22 expression in macrophages and monocytes. We report that human macrophages and monocytes are resistant to CCL22 upregulation by STING, but that STING-activated macrophages and monocytes release unidentified paracrine factor(s) that dramatically increase CCL22 upregulation in cancer cells in a manner that remains STING-dependent, as evidenced by the inability of STING knockout cells to upregulate CCL22 in response to these factors. We further found that exogenous type I interferons, a major downstream product of STING activation, also upregulate CCL22 in cancer cells via a STING-dependent mechanism and that exogenous IFN-β can directly activate STING.

摘要： Antibody-cytokine fusion proteins are being developed as next-generation cancer immunotherapies, aiming to deliver activation signals to targeted immune populations. Among these, PD1-IL2v-an engineered interleukin-2 variant (IL-2v) lacking CD25 binding, fused to a high-affinity programmed cell death protein 1 (PD-1) blocking antibody-has shown promising results in murine tumor models. Here, using human model systems, we show that PD1-IL2v elicits a multifaceted antitumor T cell response by targeting both CD8+ and conventional CD4+ T (Tconv) cells. Single-cell RNA sequencing (scRNAseq) on a lung cancer patient-derived tumor fragment (PDTF) platform revealed that PD1-IL2v drives the expansion of proliferative, cytotoxic CD8+ T cells exhibiting features of tumor reactivity. This was accompanied by up-regulation of CXCR6, enhancing their migratory capacity. In Tconv cells, PD1-IL2v up-regulated CXCL13 expression and promoted a T follicular helper/T helper 1 (TFH/TH1)-like transcriptional program associated with anti-PD1 responsiveness. Our findings provide mechanistic insights into the effects of IL-2v-targeted delivery to PD-1+ cells within human tumors, supporting the clinical development of next-generation immunocytokines.

摘要： Enhancing regulatory T cell (Treg) function offers a compelling therapeutic strategy for autoimmune disease. Engineered IL-2 muteins selectively expand functional Tregs with minimal impact on other immune cells, but their potential to compromise antiviral immunity remains largely unexplored. Here, we used a murine model of Influenza A virus (Flu) infection to determine how IL-2 mutein shapes T cell responses to respiratory virus infection. IL-2 mutein administration prior to infection suppressed Flu-specific (Flu-sp) CD8 T cell responses and altered their localization and phenotype within the lungs, without affecting bystander CD8 T cells. This suppression correlated with reduced antigen presentation molecule expression on conventional dendritic cells (cDCs) early after infection but did not impact Flu-sp CD8 T cell priming. In contrast, administering IL-2 mutein during infection exacerbated disease and drove CD25-dependent expansion of Flu-sp CD8 T cells. Despite these opposing effects on effector responses, ***24-treated mice generated robust antibody responses and protective T cell memory which were maintained for at least 170 days. These findings reveal that ***24 has temporally distinct effects on antiviral immunity, dampening early effector responses when given before infection, but enhancing effector expansion and disease severity when delivered during infection. Our results provide critical context for the therapeutic application of IL-2 muteins and highlight the importance of treatment timing in balancing immune modulation with protective immunity.