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摘要： In chronic inflammatory disorders of the central nervous system (CNS), tissue-resident self-reactive T cells perpetuate disease. The specific tissue factors governing the persistence and continuous differentiation of these cells remain undefined but could represent attractive therapeutic targets. In a model of chronic CNS autoimmunity, we find that oligodendrocyte-derived IL-33, an alarmin, is key for locally regulating the pathogenicity of self-reactive CD8+ T cells. The selective ablation of IL-33 from neo-self-antigen-expressing oligodendrocytes mitigates CNS disease. In this context, fewer self-reactive CD8+ T cells persist in the inflamed CNS, and the remaining cells are impaired in generating TCF-1low effector cells. Importantly, interventional IL-33 blockade by locally administered somatic gene therapy reduces T cell infiltrates and improves the disease course. Our study identifies oligodendrocyte-derived IL-33 as a druggable tissue factor regulating the differentiation and survival of self-reactive CD8+ T cells in the inflamed CNS. This finding introduces tissue factors as a novel category of immune targets for treating chronic CNS autoimmune diseases.

关键词： Cytokines   Ghrelin   Immune epilepsy   Inflammation  

摘要： Purpose: This study aimed to investigate the relationship between ghrelin levels and severity of inflammation in children with epilepsy by evaluating the differences in total ghrelin, High Mobility Group Box 1 (HMGB1), Interleukin-1 Receptor Type 1 (IL1R1), and Interleukin-1 Beta (IL1-β) levels in patients with drug-resistant and non-drug-resistant epilepsy and comparing these parameters with those of healthy controls. Methods: We measured total ghrelin, HMGB1, IL1R1, and IL1-β levels—known to play roles in epileptogenesis—in patients with severe (n: 28), mild (n:29) epilepsy, and 31 healthy controls. The severe epilepsy group included patients with treatment-resistant epilepsy, while the mild epilepsy group consisted of patients whose seizures could be controlled with monotherapy. Results: Total ghrelin levels, along with HMGB1, IL1R1, and IL1-β, were significantly elevated in children with epilepsy compared to healthy controls. This increase was more pronounced in the drug-resistant epilepsy group, suggesting a potential role for ghrelin in drug-resistant epilepsy. While no direct correlation was found between ghrelin and the inflammatory markers, we observed that ghrelin levels rose significantly when levels of IL1R1, IL1-β, and HMGB1 surpassed their respective cut-off values in epilepsy patients. The biomarkers IL1R1 and IL1-β had the strongest discriminative potential in distinguishing patients with severe epilepsy from healthy controls. Although ghrelin was not as powerful a diagnostic marker as IL1R1 or IL1-β, it still showed moderate diagnostic value. Conclusion: Ghrelin could serve as a biomarker reflecting both inflammation and drug resistance in epilepsy. It may be associated with inflammatory responses in epilepsy and could play a potential role in the pathophysiology of the disease. © 2025 Elsevier B.V.

摘要： Production of recombinant human leukocyte antigen class I (HLA-I) proteins in vitro is fundamental for molecular immunology. However, HLA-I protein refolding has remained inefficient due to challenges in the assembling of the trimolecular complex. Here, we compare various in vitro refolding methods that address the challenges of intrachain disulfide bond formation and assembly of the complex between the light and heavy chains in the presence of the target peptide. We developed methods that uncouple the oxidation of disulfide bond formation of both subunits of HLA-I, followed by renaturation to promote complex formation. CuSO₄-catalyzed air oxidation enhances correct disulfide bond formation when the protein is solubilized with N-lauryl-sarcosine (sarkosyl);however, careful removal of sarkosyl did not prevent heavy chain aggregation. We modified the classical method of HLA-I refolding by pre-oxidizing the β₂m light chain before adding the HLA-I heavy chain and peptide. This method yielded successful complex refolding for HLA-A∗02:01/GILGFVFTL at 24.2 % efficiency, and HLA-C∗12:03/KAYNVTQAF at 14.5 % efficiency. Our results suggest that pre-folded β₂m improves refolding efficiency of HLA-I molecules. This work presents novel approaches to HLA-I refolding that may be applied to other difficult-to-fold protein complexes. © 2025

关键词： Apoptosis   Autophagy   Cancerous colorectal epithelia   Caspases   IL-17a   Mucinosis  

摘要： Background/Aims: IL17-producing Th17 represent a distinct subset of T-cells. The link between IL-17a and the colorectal cancer (CRC) microenvironment has been widely accepted. However, the role of IL-17a in epithelial cell apoptosis, autophagy, mucinosis, ultrastructural changes, and their potential correlations with CRC remains unclear. Materials and Methods: Out of 2890 patients with CRC, 200 were divided into four groups (stage I-IV) and 50 into non-CRC/healthy/control. We investigated the relationship between IL-17a, apoptosis, autophagy, and mucinosis in patients with stage I-IV CRC (in vitro/vivo). In addition to many (para)clinical assessments, IL-17a load in blood and the tumor microenvironment (TME) in patients with CRC were assessed. To examine these associations, the effect of IL-17a on CRC cells was evaluated using qPCR, Western blotting, ELISA, bioluminescence, flow cytometry, and immunohistochemistry (IHC), and ultrastructural changes in the colonic epithelia were assessed by scanning and transmission electron microscopy. Results: IL-17a is overexpressed in stage I–IV in the TME and in stage III–IV in the blood of patients with CRC. IL-17a upregulated apoptosis (caspases, cytochrome c (CYC), higher Bax:Bcl2 ratio), autophagy (SIRT1 and LC3), and the cell cycle (TP53, APC-1) and downregulated B3GALNT2 and mucins and led to morphological and nuclear changes in CRC epithelia. Conclusions: IL-17a is abundantly expressed in the CRC microenvironment, and IL-17a-IL-17aR interactions play a critical role in the control of apoptosis and mucinosis. The observed remarkable association of IL-17a and apoptosis in adenocarcinoma provides valuable insight into the clinical implications of Th17/IL-17 in CRC. © 2025 Instituto Mexicano del Seguro Social (IMSS)

关键词： Disease associations   HLA alleles   Mexican population   MHC   Systematic review  

摘要： Background: The major histocompatibility complex (MHC) plays a crucial role in immune responses and is associated with disease susceptibility. This study systematically reviews MHC class I and class II allele frequencies and their associations with diseases in the Mexican population from 1979 to 2023. Methods: A systematic review following PRISMA guidelines was conducted. Reports were obtained from the Allele Frequency Net Database and PubMed using keywords related to HLA and Mexican populations. A total of 776 reports were screened, and 214 were retained for final analysis. Seventy-six studies comprising allele frequency data from over 20,000 individuals across Mexican states and indigenous communities were analyzed. In addition, over 138 articles were examined to identify alleles associated with various diseases. Results: The analysis identified 117 alleles whose frequencies varied regionally within Mexico. While DPA1*01, DPB1*04:01, and DQA1*03 were predominant, DRB1*04, DQB1*03, and DQA1*05 were also prominent but variable. Certain alleles, such as A*02, B*35, C*04, and C*07, were relatively common in the population. Numerous disease correlations were uncovered, such as B*27′s strong association with spondyloarthropathies. DRB1*15:01 and DRB1*04 conferred an increase in multiple sclerosis, while DRB1*04 may protect against some skin diseases. Conclusion: This review improves the understanding of MHC allele frequencies and disease associations in Mexicans, highlighting genetic diversity. The findings lay the groundwork for future research on genetic predispositions and health outcomes, aiding healthcare strategies in this diverse population. Further studies are needed to address data gaps and refine genetic profiles for targeted medical applications. © 2025 The Author(s)