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关键词： DRB1*15:03 positive   DRB5 negative   linkage disequilibrium   putative haplotypes  

摘要： The HLA class II region contains nine DRB genes: DRB1, DRB3, DRB4 and DRB5 express functional gene products, whereas DRB2, DRB6, DRB7, DRB8 and DRB9 are pseudogenes. In this study, we assessed the frequency and diversity of two functional genes, DRB1 and DRB5;in particular, HLA-DRB1*15:03 with absence of the associated HLA-DRB5*01:01 allele (DRB1*15:03 positive DRB5*01:01 negative). We aimed to determine the frequency of DRB1*15:03 positive DRB5*01:01 negative in this cohort and to define any putative full or partial haplotypes that may show this genotype pattern. We performed HLA typing by NGS using One Lambda AllType or CareDx AlloSeq Tx17 on 6268 solid organ transplant (SOT) samples using DNA extracted from either buccal swabs or whole blood. The absence of HLA-DRB5 was confirmed by One Lambda LABType rSSOP. Confirmation of DRB1*15 homozygotes was performed by CareDx Copy Number (RUO) tool. In the present cohort, 554 (8.8%) individuals were identified as HLA-DRB1*15:03 positive. Of those, 48 individuals (8.7% of HLA-DRB1*15:03 positive) did not have the associated DRB5*01:01 allele present. We believe that this percentage could be as high as 11.2% when considering DRB1*15:XX homozygotes. Although linkage disequilibrium analysis showed strong LD between DRB1*15:03 and DRB5*01:01 (D ' = 0.89), supporting their co-inheritance on the same haplotype block, a moderate correlation coefficient (r2 = 0.302) implied that DRB5*01:01 is not always present in all DRB1*15:03 carriers. Extended haplotypes associated with this phenomenon were constructed and characterised. Certain HLA-A, B, DRB1 haplotypes were strongly predictive of absent DRB5. To our knowledge, this is the largest cohort ascertaining the diversity and frequency of the HLA-DRB1*15:03 apparent haplotypes. Our results show a considerable proportion of DRB1*15:03 positive individuals lack the DRB5 gene. The results of this study are useful for unrelated donor research, transplantation, anthropological and disease

关键词： TNF-alpha   308 G > A   Migraine risk   Jammu population   Migraine with aura   Migraine without aura   Pro-inflammatory cytokines  

摘要： Migraine is a complex neurological disorder characterized by recurrent unilateral headaches. Its pathophysiology has been associated with inflammatory processes, with TNF-alpha, a pro-inflammatory cytokine, being one such factor implicated in various neurological conditions, including migraine. This study aimed to evaluate the association between the TNF-alpha -308 G > A polymorphism and migraine risk by integrating both a case-control investigation and a meta-analysis to enhance statistical power and reliability. The investigation commenced with a case-control study in the Jammu region of North India, conducted in accordance with STROBE guidelines. To enhance statistical power and reliability, a meta-analysis of independent studies was performed, followed by Trial Sequential Analysis to verify sample size adequacy. First, the case-control study showed that there was no significant association between -308 G > A and overall migraine risk across various genetic models (allele: 0.80 [0.58-1.11], p = 0.193) in the Jammu population. Although the migraine with aura subgroup showed marginal significance in the allelic model (p = 0.02), this association was not supported after adjustment (p = 0.14). Similarly, the meta-analysis revealed no significant association between the polymorphism and overall migraine (allele: 1.21 [0.92-1.58], p = 0.16) or its two clinical subtypes, migraine with aura and without aura. However, when stratified by ethnicity, a significant association was identified in African populations, while no such association was observed in Asian or Caucasian groups. This study underscores the importance of combining case-control data with meta-analysis to strengthen genetic association findings. Future research should focus on larger, multi-ethnic cohorts to validate these findings and improve generalizability.

关键词： MHC-I   antigen presentation   autophagy   cepharanthine   tumor immune escape  

摘要： Major histocompatibility complex class I (MHC-I)-mediated antigen presentation plays a pivotal role in anti-tumor immunity by enabling CD8 T cells to recognize and eliminate malignant cells. In melanoma, modulation of this pathway is critical for improving the efficacy of immunotherapies. Our study demonstrates that the natural compound Cepharanthine (CEP) exhibits notable antitumor activity by enhancing MHC-I-mediated antigen presentation. CEP treatment upregulated MHC-I expression (both membrane-bound and total levels) in melanoma cells in a concentration-dependent manner, thereby improving antigen-presenting capacity. Interestingly, when autophagy was pharmacologically blocked using Bafilomycin A1, co-treatment with CEP did not lead to further elevation of MHC-I expression, suggesting that CEP's effect is mediated through disruption of the autophagic pathway. Mechanistically, CEP induced autophagosome accumulation, as evidenced by an increase in GFP-LC3 puncta. Fluorescence imaging further confirmed that CEP selectively impaired lysosomal acidification without affecting autophagosome-lysosome fusion, thereby inhibiting late-stage autophagic flux. Furthermore, CEP treatment promoted CD8 T cell infiltration into tumor tissues and enhanced the antitumor efficacy of anti-PD-1 therapy, resulting in greater tumor suppression compared to either treatment alone. The study elucidates how CEP's selective lysosomal inhibition creates a tumor microenvironment more susceptible to immune surveillance, primarily through preserved MHC-I surface expression and subsequent T cell recognition. This work highlights CEP as a promising immunomodulatory agent and provides a potential strategy for improving the outcomes of immune checkpoint blockade therapy.

关键词： Acute anterior uveitis   ankylosing spondylitis   HLA-B27   spontaneous hyphema  

摘要： PurposeTo report a rare case of spontaneous hyphema associated with human leukocyte antigen (HLA) -B27 positive acute anterior uveitis (AAU) and discuss its possible pathophysiological mechanisms and *** case report of a 27-year-old Chinese man presented as acute anterior uveitis in the right eye (OD).ResultsA 27-year-old male presented with acute onset of pain, photophobia, and blurred vision in OD without a history of trauma. Ophthalmic examination revealed severe anterior uveitis in OD with 2 mm of spontaneous hyphema. Laboratory investigations confirmed HLA-B27 positivity, and radiographic findings established a diagnosis of ankylosing spondylitis (AS). The patient was treated with topical corticosteroids, cycloplegics, systemic corticosteroids, and tranexamic acid. He demonstrated significant clinical improvement with resolution of hyphema and reduction of anterior chamber inflammation by day *** hyphema is an unusual complication of HLA-B27 positive AAU, likely resulting from severe inflammation-induced vasculitis. Early recognition and aggressive management with topical and systemic anti-inflammatory therapy can lead to favorable outcomes. This case highlights the importance of evaluating underlying systemic conditions in patients presenting with atypical anterior segment findings.

摘要： Islet-resident macrophages contribute to hypoxia-induced islet cell death during pancreatic islet transplantation. However, their specific role during this process remains elusive. Here, we report that interleukin-1 alpha (IL-1 alpha) and IL-1 beta are released by islet-resident macrophages, resulting in the suppression of insulin secretion. This may be due to a decreased inflammation-driven expression of pancreatic and duodenal homeobox 1 (PDX-1) and MafA in beta cells. Islet-resident macrophages release significantly less IL-1 alpha when compared to IL-1 beta. However, both cytokines inhibit insulin expression and secretion to a comparable extent. We identified heparan sulfate on the islet surface, which acts as a "molecular glue" potentiating the inhibitory action of IL-1 alpha on insulin expression via specific binding to IL-1 receptor (IL-1R). In vivo analyses revealed that the loss of IL-1 signaling in isolated islets accelerates their revascularization and, thus, enhances their endocrine function. These findings indicate that heparan sulfate fine-tuned IL-1 signaling crucially determines the outcome of islet transplantation.

关键词： COPD   Chaperones   Cytokines   Immunology   Pulmonology  

摘要： IL-33 is a key driver of type 2 inflammation and implicated in pathology of chronic obstructive pulmonary disease (COPD) and asthma. However, the mechanism for IL-33 secretion and regulation in the context of chronic airway disease is poorly understood. We previously reported an airway disease-associated isoform IL-33 Delta 34 that escapes nuclear sequestration and is tonically secreted from epithelial cells. Here, we describe how this IL-33 Delta 34 isoform interacts with HSP70 within cells and is targeted to secretory organelles through coordinated binding to phosphatidylserine (PS) and delivered to compartments for unconventional protein secretion (CUPS). Once secreted, extracellular HSP70 (eHSP70) in complex with IL-33 Delta 34 stabilizes the cytokine by inhibiting oxidation and degradation, which results in enhanced IL-33 Delta 34-receptor binding and activity. We further find evidence that IL-33 along with mediators of the proteostasis network HSP70, HSP90, and the Chaperonin Containing TCP1 (CCT) complex are dysregulated in human chronic airway disease. This phenomenon is reflected in the differential extracellularvesicle (EV) proteome in bronchial wash from COPD and asthma samples, which could mark disease activity and potentiate IL-33 function. This study confirms proteostasis intermediates, chiefly HSP70, as chaperones for noncanonical IL-33 secretion and activity that may be amenable for therapeutic targeting in the chronic airway diseases COPD and asthma.

关键词： acute lung injury   CXCL1   granulopoiesis   IFN-gamma   T cell  

摘要： Legionella pneumophila causes severe pneumonia, resulting in acute lung injury. L. pneumophila pneumonia induces neutrophil recruitment to the lung through CXC chemokines. Previously, blocking CXCR2, the common receptor for CXC chemokines, but not CXCL1 or CXCL2, resulted in attenuated neutrophil accumulation and reduced survival following pulmonary L. pneumophila infection. However, gene-deficient mice were unavailable at that time and therefore, mechanisms of host protection and neutrophil homeostasis, including granulopoiesis and neutrophil release from the bone marrow, have not been investigated. Here, we delineated the role of CXCL1 and CXCL2 in host defense and neutrophil homeostasis using gene-deficient mice. Deficiency of CXCL1, but not CXCL2, impairs bacterial clearance and neutrophil accumulation in the lung. Furthermore, the increase of IL-18 and IFN-gamma proteins in the lung caused by L. pneumophila infection is decreased in Cxcl1-/- mice. Moreover, this reduction in IFN-gamma production in Cxcl1-/- mice is associated with a decrease in the gamma delta TCR-expressing IFN-gamma+ subset. In vivo treatment with IL-18 or IFN-gamma was found to restore neutrophil-dependent bacterial clearance in Cxcl1-/- mice. Production of CXCL1 not only by hematopoietic cells, but also by nonhematopoietic cells, is critical to augment host defense. In Cxcl1-/- mice, there is an impairment in emergency granulopoiesis in bone marrow and in neutrophil release to the blood. Also, Il-18-/- mice displayed impairment of neutrophil recruitment to the lung and bacterial clearance, neutrophil release, and emergency granulopoiesis. Collectively, CXCL1 derived from both hematopoietic and nonhematopoietic cells is essential to control L. pneumophila infection through the IL-18-IFN-gamma axis and neutrophil homeostasis.

关键词： Eleusine indica   Inflammatory bowel disease   Transmural inflammation   TNBS   p38 MAPK   TNF-alpha  

摘要： Inflammatory bowel disease (IBD) is a relapsing-remitting gastrointestinal disorder characterized by chronic mucosal inflammation and dysregulated immune responses to gut microorganisms. Despite the many advancements in its management, current treatments are often limited by their adverse effects, high cost, and incomplete remission. Eleusine indica, a medicinal plant used in folkloric medicine, is known for its anti-inflammatory properties. However, its efficacy in IBD remains not known. This study evaluated the potential effect of the hydroethanolic extract of Eleusine indica (EI) in a rat model of trinitrobenzene sulphonic acid (TNBS)-induced colitis. Colitis was induced in Sprague Dawley rats via rectal administration of TNBS. Rats were subsequently treated orally with EI (200, 400, or 600 mg/kg) or sulfasalazine (500 mg/kg) for 7 days. Disease activity index (DAI), colon weight-to-length ratio, macroscopic and histopathological changes, haematological parameters, and serum levels of markers of inflammation: TNF-alpha, p38 MAPK, and of oxidative stress: glutathione (GSH) were assessed. EI significantly improved the DAI (p < 0.05) and reduced colon weight-to-length ratio (p < 0.05) and macroscopic colonic damage in TNBS-induced rats. Histopathological analysis revealed preserved mucosal architecture and reduced inflammatory infiltration in EI-treated groups. EI also significantly downregulated TNF-alpha (p < 0.0001) and p38 MAPK (p < 0.0001) while preserving GSH levels (p < 0.05), indicating suppression of inflammation and oxidative stress. Haematological parameters showed reversal of TNBS-induced leucocytosis (p < 0.05). EI demonstrated potent anti-colitic activity comparable to sulfasalazine. The findings from this study support its potential as a herbal therapeutic option for IBD.

关键词： HIV-1   posttreatment control   HIV remission   immunogenetics   NK cells   HLA   KIR   HLA-B∗35   primary infection   ART interruption   Translation to patients  

摘要： Background There is currently no curative treatment for HIV-1 infection. However, some individuals (defined as posttreatment controllers) durably control viremia after the discontinuation of antiretroviral therapy (ART). Although the ability to achieve this HIV-1 remission status is enhanced by early treatment initiation, the mechanisms leading to posttreatment HIV-1 control remain unclear. Methods We retrospectively explored the immunogenetic characteristics of long-term posttreatment controllers from the ANRS VISCONTI study and persons monitored since primary HIV-1 infection in the ANRS PRIMO cohort and evaluated their influence on clinical parameters and outcome after ART discontinuation. Findings We identified a major histocompatibility complex (MHC)-related fingerprint favoring sustained HIV-1 remission. HLA-B∗35 alleles, which are associated with rapid progression to AIDS during natural HIV-1 infection, were paradoxically overrepresented among posttreatment controllers and had a positive impact on outcome after treatment discontinuation in people who began therapy during primary infection. Specifically, the influence of HLA-B∗35 alleles was observed when they were carried in combination with other HLA class I alleles expressing Bw4 and C2 ligands of killer immunoglobulin-like receptors (KIRs) in a genetic context that favors KIR education of natural killer (NK) cells (Bw4TTC2 genotype). Accordingly, posttreatment controllers with HLA-B∗35 alleles carry distinct KIR genotypes and NK cells. Conclusions The combination of HLA-B∗35 with Bw4TTC2 genotype, associated with KIR education of NK cells, was abundant among posttreatment HIV-1 controllers and promoted viral control after interruption of early-initiated antiretroviral treatment. These results support a role of NK cells in sustained HIV-1 remission. Funding The VISCONTI study and the PRIMO cohort are funded by the ANRS-MIE.