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关键词： endocrine pathology   HLA   diabetes mellitus   obesity   congenital hypothyroidism without goiter   autoimmune disease  

摘要： Endocrine disorders represent a serious public health problem and frequently can be caused by genetic factors or their combination with environmental and lifestyle factors. Assessment of relevant genetic factors is important to estimate the risk of endocrine pathologies in an individual before their manifestation. Identification of genetic variations in proteins of the major histocompatibility complex is important with regard to the autoimmune nature of many endocrine pathologies, including type 1 diabetes. In this study, we investigated the relationship between human leukocyte antigen (HLA) genes and 13 endocrine disorders by using experimental whole-exome sequencing profiles obtained for 895 patients from the National Medical Research Center for Endocrinology, Moscow. In addition, the linkage disequilibrium of the identified alleles in the context of the respective diagnoses was assessed. We identified totally 45 statistically significant associations between HLA alleles and specific diagnoses of endocrine pathologies. Among them, 33 were described for the first time and 12 have been previously reported for type 1 diabetes. Overall, 17 alleles were associated with type 1 diabetes and four alleles - with other forms of diabetes. Furthermore, three alleles were associated with obesity, five - with adrenogenital diseases, three - with hypoglycemia, and three - with precocious puberty. Single alleles were found to be associated with congenital hypothyroidism without goiter, hyperfunction of pituitary gland, adrenomedullary hyperfunction, and short stature due to endocrine disorder. The study shows that early HLA typing can help in detecting genetic risk factors of endocrine disorders. In addition, identification of disease associations with specific HLA alleles can broaden our understanding of the mechanisms involved in the pathogenesis of relevant endocrine disorders.

关键词： Biomarker   Tumor microenvironment   Urothelial cancer   Immunology   Interleukin  

摘要： Interleukin-6 (IL-6) is associated with poor outcomes in bladder cancer (BC) patients, including worse overall survival (OS) and cancer-specific survival (CSS). This study analyzed serum IL-6 levels in 179 BC patients undergoing radical cystectomy and IL-6 concentrations in tumor tissue from 20 additional patients. High serum IL-6 was an independent predictor of OS and CSS, and higher levels were linked to advanced tumor stage, lymph node metastasis, and larger tumor size. Tumor tissue IL-6 was significantly elevated in muscle-invasive BC compared to early-stage tumors. These findings underscore the prognostic potential of IL-6 and its relevance in BC theranostics.
Background: Interleukin-6 (IL-6) is associated with adverse clinical outcome in cancer patients. In bladder cancer (BC) patients, higher IL-6 serum levels have been linked with adverse pathologic features, worse overall survival (OS) and cancer-specific survival (CSS). IL-6 is being investigated as a therapeutic target. However, concentrations in tumor-tissue are not investigated in detail. Objective of this study is to analyze the prognostic value of IL-6 in BC patients and to investigate its concentration in tumor tissue. Methods: In this single center prospective observational study, preoperative serum samples of 179 BC patients undergoing radical cystectomy were collected between September 2019 and September 2022. Tumor-tissue of additional 20 patients was collected during transurethral resection or radical cystectomy for investigation of IL-6 in tumor tissue supernatant. IL-6 concentration was measured by ELISA. Results: Median serum IL-6 concentration was 5.4 pg/mL. High serum IL-6 was an independent predictor of OS (HR 1.95;95% CI, 1.07-3.55;P = .03) and CSS (HR 2.31;95% CI, 1.14-4.68;P = .02) in multivariate Cox regression analyses. Patients with advanced tumor stage, lymph node metastasis, and larger tumor size had significantly higher preoperative serum IL-6 concentration (all P < .01). In

关键词： CAR T-cell therapies   desensitization   kidney transplantation   plasma cell-directed therapies   plasmapheresis  

摘要： Despite development of kidney paired donation programs and prioritization in kidney allocation schemes, transplantation rates are still low and waiting times remain prolonged for highly sensitized kidney transplant recipients with broad human leukocyte antigen antibody reactivity. Desensitization confers an invaluable option improving access to kidney transplantation for sensitized patients who could not benefit from kidney paired donation programs and kidney allocation schemes. Conventional desensitization strategies use intravenous immunoglobulin combined with either plasmapheresis or monoclonal anti-CD20 antibodies. Imlifidase, IL-6 targeting agents, plasma cell-directed therapies, complement inhibitors, chimeric antigen receptor T-cell therapies, and B cell-activating factor inhibitors are emerging new options in the hope of enhancing and sustaining the efficacy of desensitization to improve allograft longevity. In this review, we discuss the rationale and outcome of desensitization with various strategies alone or in combination. Our aim is also to provide some insight for decision when pursuing desensitization might be successful or futile in sensitized patients.

关键词： IL-39   Inflammation   Autoimmune disease   Dysbiosis   Periodontitis   Autoantibody  

摘要： IL-39, a cytokine from the IL-12 family that appears to be produced primarily by B cells, consists of the IL-23p19 and Ebi3 subunits, which signal through IL-23R/gp130 to activate STAT1/STAT3. Some studies suggest elevated IL-39 levels in certain autoimmune conditions, such as relapsing-remitting multiple sclerosis (RRMS), ankylosing spondylitis (AS), and autoimmune thyroid disease (ATD), possibly indicating a link between IL-39 and autoimmunity mediated by B cells. Preliminary evidence indicates that IL-39 might stimulate NETosis in neutrophils and promote BAFF (B-cell activating factor) secretion, which theoretically, in turn, may activate IL-39 production, T-cell-independent IgA isotype switching and somatic hypermutation. Some reports have revealed correlations between IL-39 and disease-specific autoantibodies, including RF and ACPAs in rheumatoid arthritis (RA), anti-dsDNA in systemic lupus erythematosus (SLE), and anti-AQP4 antibodies in neuromyelitis optica spectrum disorder (NMOSD), although these associations require further confirmation. Theoretically, through NETosis, IL39 could potentially expose intracellular antigens and facilitate their citrullination via peptidyl arginine deiminase (PAD), which might contribute to autoimmunity initiation. Some data suggest that in P. gingivalis-associated dysbiosis, IL-36 gamma may increase IL-39 secretion by epithelial cells. As dysbiosis and inflammatory bowel disease (IBD) increase gut permeability and LPS exposure-a possible stimulus for IL-39 production-the relationships among IL-39, gut dysbiosis, and autoimmunity appear to warrant further investigation. While some studies have reported conflicting results regarding the immunological activity of IL-39 in humans, these theoretical considerations suggest the need for more rigorous, standardized research, as current investigations remain limited by small sample sizes and heavy reliance on animal models or in vitro studies rather than comprehensive human studies ex

关键词： TNF-alpha   OX40L   OX40   hidradenitis suppurativa   Nanobody   xenograft graft-versus-host disease   T cell-dependent antibody response   delayed-type hypersensitivity skin reaction  

摘要： Background: Chronic inflammatory conditions are among the leading causes of disability and mortality. Although therapies have been significantly improved with the introduction of target-specific biologics, many chronic inflammatory conditions can be only moderately controlled by inhibition of individual cytokines. Objective: We sought to compare individual versus simultaneous blockade of TNF-a and OX40L in controlling inflammation. Methods: Analysis was conducted of the murine xenograft graft-versus-host disease model, a novel cynomolgus monkey model of simultaneous T cell-dependent antibody response (TDAR) and delayed-type hypersensitivity (DTH) skin reaction, and samples of patients with hidradenitis suppurativa (HS). Results: Compared with individual inhibition, combined targeting of TNF-a and OX40L using mAbs more potently suppressed TDAR and DTH in cynomolgus monkey. We therefore created SAR442970, a bispecific pentavalent Nanobody containing 2 domains each binding to OX40L and TNF-a and 1 domain binding serum albumin to extend half-life. In xenograft graft-versus-host disease, disease control by SAR442970 was superior compared with treatment with monospecific anti-TNF-a or anti-OX40L Nanobodies. In cynomolgus monkey, SAR442970 potently suppressed TDAR and DTH. The transcriptional signature of inflamed monkey skin showed similarities to that of lesional skin of patients with atopic dermatitis and, even more so, HS and was inhibited by SAR442970 treatment. Increased numbers of cells expressing OX40 were observed in HS lesions, and bioinformatics analyses of single-cell and bulk RNA sequencing data identified cells expressing OX40 as T cells with a highly mobile phenotype. Conclusion: OX40-OX40L interaction is a key pathogenetic feature in HS, and patients with HS might benefit from combined TNF-a/OX40L blockade by SAR442970, which is currently investigated in a clinical phase 2 trial. (J Allergy Clin Immunol Global 2025;4:100483.)

摘要： Background and aims: Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality worldwide, yet the underlying molecular mechanisms remain less understood. Chronic low-grade inflammation is a complex immune response contributing to the pathophysiology of cardiovascular disease. This response is signaled in part by interleukin-6 (IL-6), a pleiotropic, pro-inflammatory cytokine. Phenotypic variance in circulating IL-6 level may be explained in part by DNA methylation which is increasingly being associated with cardiovascular effects. Methods: In this study we evaluated methylated DNA (CpG sites) associated with blood IL-6 levels across similar to 4,400 ancestrally diverse individuals (81 % self-reported White;9 % Black or African American, 8 % Hispanic or Latino/a, and 2 % Chinese American). Results: We identified 178 CpG sites associated with IL-6 (p<0.05/similar to 395,000). Among the sites, cg04437762 is located within the transcription unit of IL6R, a current therapeutic target for inflammatory disease, and cg26692003 and cg00464927 were significant for IL6 and IL6ST trans-CpG-gene transcripts. Functional gene expression downstream of methylation identified cellular response to IL-6 and B-cell regulation and activation pathways. Four genes were linked with both a genetic component of cardiovascular disease and an IL-6 associated CpG site. Three CpG sites identified through Mendelian randomization analyses supported inference of a causal effect on IL-6 levels, including the LYN gene that regulates immune cell signaling and has been previously associated with atherosclerosis. Conclusions: Overall, we identified several novel IL-6-CpG sites and downstream pathways affected by methylation. Follow-up functional studies including the regulation of IL-6 would complement current knowledge of CVD pathophysiology and potential therapeutic targets.

关键词： anti-inflammatory   diabetes   electrostatic complexation   Il-1Ra   interleukin-1   nanoparticles   protein delivery  

摘要： Diabetes is a prevalent and potentially serious endocrine disorder characterized by elevated blood glucose levels and beta-cell destruction. Interleukin-1 receptor antagonist (IL-1Ra), a competitive inhibitor of the IL-1 receptor, downregulates inflammatory pathways contributing to beta-cell destruction. However, its short half-life (4-6 h) and rapid clearance hinder its clinical effectiveness. In this study, a dual-polymeric system comprising cationic and lipid-based polymers is developed for IL-1Ra delivery. IL-1Ra nanocomplexes (IL-1Ra NCs) are formed through electrostatic interactions, confirmed by SDS-PAGE, TEM, and particle size analysis (167.57 +/- 1.08 nm for IL-1Ra NCs vs 153.21 +/- 1.85 nm for blank NCs) with zeta potentials of +8.66 +/- 0.46 mV versus +24.03 +/- 1.1 mV. In vitro, IL-1Ra NCs demonstrate anti-inflammatory activity against IL-1 beta-induced inflammation in cells. In vivo pharmacokinetic studies show significant improvements in Cmax, AUC, half-life (t1/2), and mean residence time (MRT) for IL-1Ra NCs compared to free IL-1Ra, suggesting reduced dosing frequency and enhanced patient compliance. Mice treated with IL-1Ra NCs exhibit a significant reduction in fasting blood glucose levels (232.25 +/- 23.64 mg dL-1 vs 367.88 +/- 21.83 mg dL-1 in the diabetic control). Furthermore, IL-1Ra NCs preserve beta-cell integrity and exhibit an improved anti-inflammatory response as assessed by H&E and IHC analysis.