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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.

关键词： developmental changes   distribution characteristics   IL-21   Immunohistochemistry   ostrich   thymus  

摘要： Artificially reared ostriches face susceptibility to stress, infections, with mortality rates reaching 40% during the brooding phase. The thymus serves as a vital central and lymphoid immune organ, pivotal in combating external antigenic challenges and aiding in T lymphocyte differentiation. This study aims to investigate the distribution and changes of IL-21 in the thymus of African ostrich chicks, offering a morphological foundation for immune modulation and disease prevention in African ostriches. The current study utilized healthy African ostrich chicks aged 1, 15, 30, 45, 60, 75, and 90 days as experimental cohorts. Paraffin sectioning and immunohistochemical techniques were employed to investigate the morphological characteristics, distribution, and development change patterns of interleukin-21 (IL-21) immunopositive cells in the thymus of ostrich chicks. The results revealed that IL-21 immunopositive (IL-21-ip) cells exhibited a round or oval shape and were predominantly situated in the thymic medulla, with some presence in the cortex and at the corticomedullary junction. The expression intensity of IL-21 in the thymus and the density of positive cells exhibited a gradual increase followed by a decrease as the chicks aged. Both the expression intensity and the quantity of positive cells peaked at 75 days old. These results suggest a potential significant role for IL-21 in regulating thymic development in African ostriches.

关键词： Co-trimoxazole   human leukocyte antigen   severe cutaneous adverse drug reaction   Stevens-Johnson Syndrome and toxic epidermal necrolysis   drug reaction with eosinophilia and systemic symptoms   HLA   human leukocyte antigen   SCAR   severe cutaneous adverse reaction   SJS/TEN   Stevens-Johnson syndrome and toxic epidermal necrolysis   DRESS   drug reaction with eosinophilia and systemic symptoms   HIV   human immunodeficiency virus   PLWH   persons living with HIV   SEA   Southeast Asian   US   United States   SA   South African   SPBS   shared peptide binding specificity   VUMC   Vanderbilt University Medical Centre   MEEI   Massachusetts Eye and Ear Institute   ALDEN   algorithm for drug causality in epidermal necrolysis   HREC   human research ethics committee   DNA   Deoxyribonucleic acid   EDTA   Ethylenediaminetetraacetic acid   ASHI   American society for Histocompatibility and Immunogenetics   NATA   National Association of Testing Authorities   bp   base pairs   PDB   protein data bank   SMX   sulfamethoxazole   SMX-NO   nitroso-sulfamethoxazole   TMP   trimethoprim   OR   odds ratio   Pc   corrected P value   PPV   positive predictive value   NPV   negative predictive value   NNT   number needed to test  

摘要： Background Co-trimoxazole is a leading global cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Co-trimoxazole-induced SCAR are associated with HLA class I alleles including HLA-B*13:01 and HLA-B*38:02 in Southeast Asian (SEA) populations. However, the global generalizability of these associations is unknown but critical for population-appropriate risk stratification and diagnosis. Objective To determine HLA risk factors associated with co-trimoxazole-induced SJS/TEN and DRESS in populations from the United States (US) and South Africa (SA). Methods We performed high-resolution HLA typing on dermatologist-adjudicated co-trimoxazole-induced SCAR patients in the US (n=63) and SA (n=26) compared to population controls. Peptide binding and docking analyses were performed using MHCcluster2.0 and CB-Dock2. Results In a multiple logistic regression model, HLA-B*44:03 (Pc<0.001, OR: 4.08), HLA-B*38:01 (Pc<0.001, OR: 5.66), and HLA-C*04:01 (Pc=0.003, OR: 2.50) were independently associated with co-trimoxazole-induced SJS/TEN in the US. HLA-B* 44:03 was also associated with co-trimoxazole-induced DRESS in SA (Pc=0.019, OR: 10.69). Distinct HLA-B variants with shared peptide binding specificities (SPBS) and HLA-C*04:01 identified 94% and 78% of co-trimoxazole-induced SJS/TEN and DRESS in the US, respectively. The SEA risk allele HLA-B*13:01, with SPBS to HLA-B*44:03, was identified in just 1/63 US SCAR patient. Conclusion HLA alleles with SPBS to SEA-related risk alleles including HLA-B*44:03 (SPBS with HLA-B*13:01) and HLA-B*38:01 (SPBS with HLA-B*38:02) but also HLA-C*04:01 predisposed to co-trimoxazole-induced SCAR in the US and SA. These findings provide biological plausibility and strategies for global risk prediction and diagnosis of co-trimoxazole-induced SCAR.

关键词： CRTH2   B cells   IL-1 beta   Experimental autoimmune encephalomyelitis   p38 MAPK signaling  

摘要： B cells play a critical role in the pathogenesis of autoimmune inflammatory diseases such as multiple sclerosis (MS). As a receptor of prostaglandin D2, chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) is known to be involved in Th2 cell activation, but its function in B lymphocytes is unclear. Here, we show that CRTH2 is critical for an IL-1 beta-producing B cell subset. Mice with B-cell-specific deletion of Crth2 exhibit reduced numbers of IL-1 beta-producing B cells, resulting in amelioration of experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS. Compared to wild-type B cells, adoptive transfer of Crth2-deficient B cells attenuates EAE disease severity in B-cell-deficient recipient mice. The IL-1 beta-producing B cell subpopulation was mainly transitional type 2 B cells identified by flow cytometry and single cell sequencing. Mechanically, CRTH2 promotes IL-1 beta production in B cells through p38 signaling, and pharmacological inhibition of p38 attenuates EAE disease severity in DK-PGD2-treated mice. Taken together, our results reveal a key function of CRTH2 in driving IL-1 beta expression in B cells and in controlling their pathogenic activity in autoimmune diseases.