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关键词： MHC I   Immune checkpoint inhibitors   Small molecule compounds   Expression regulation  

摘要： Major histocompatibility complex (MHC) class I load antigens and present them on the cell surface, which transduces the tumor-associated antigens to CD8+ T cells, activating the acquired immune system. However, many tumors downregulate MHC I expression to evade immune surveillance. The low expression of MHC I not only reduce recognition by- and cytotoxicity of CD8+ T cells, but also seriously weakens the anti-tumor effect of immunotherapy by restoring CD8+ T cells, such as immune checkpoint inhibitors (ICIs). Accumulated evidence suggested that restoring MHC I expression is an effective strategy for enhancing tumor immunotherapy. This review focuses on mechanisms underlying MHC I downregulation include gene deletion and mutation, transcriptional inhibition, reduced mRNA stability, increased protein degradation, and disruption of endocytic trafficking. We also provide a comprehensive review of small molecules that restore or upregulate MHC I expression, as well as clinical trials involving the combination of ICIs and these small molecule drugs.

关键词： osteoclast   anakinra   periodontal ligament fibroblast   periodontitis   inflammatory bone disease  

摘要： Rheumatoid arthritis and periodontitis are comorbidities that share mutual pathways. IL-1 beta is a pro-inflammatory cytokine that plays a crucial role in both diseases. One of the treatment options for rheumatoid arthritis is the use of an IL-1 receptor antagonist (IL-1RA) such as anakinra. Anakinra tempers the disease by decreasing bone resorption and it could possibly stimulate bone formation. Here, we investigate the effect of anakinra in a periodontal disease setting on osteoclastogenesis by co-culturing periodontal ligament fibroblasts (PDLFs) and peripheral blood mononuclear cells (PBMCs) that contain monocytes, a source of osteoclast precursors, as well as by culturing PBMCs alone. The effect of anakinra on PDLF-mediated osteogenesis was studied under mineralization conditions. To mimic a chronic infection such as that prevalent in periodontitis, 10 ng/mL of IL-1 beta was added either alone or with 10 mu g/mL of anakinra. Osteoclastogenesis experiments were performed using co-cultures of PDLF and PBMCs and PBMCs only. Osteoclastogenesis was determined through the formation of multinucleated cells in co-cultures of PDLF and PBMCs, as well as PBMCs alone, at day 21, and gene expression through qPCR at day 14. Osteogenesis was determined by measuring alkaline phosphatase activity (ALP) per cell at day 14. Anakinra is effective in downregulating IL-1 beta mediated leukocyte clustering and osteoclastogenesis in the co-cultures of both PDLF and PMBCs and PBMCs alone. Gene expression analysis shows that IL-1 beta increases the expression of the osteoclastogenic marker RANKL and its own expression. This higher expression of IL-1 beta at the RNA level is reduced by anakinra. Moreover, IL-1 beta downregulates OPG expression, which is upregulated by anakinra. No effects of anakinra on osteogenesis were seen. Clinically, these findings suggest that anakinra could have a beneficial systemic effect on periodontal breakdown in rheumatoid arthritis patients taking anakinra.

关键词： cardiac involvement   extrapulmonary involvement   genotyping   HLA polymorphism   Sarcoidosis  

摘要： Background:Although numerous candidate genes have been identified in studies investigating the role of genetics in sarcoidosis, the strongest association has been reported with the Major Histocompatibility Complex/Human Leucocyte Antigen (MHC/HLA) region. This study aimed to evaluate HLA polymorphism and assess its association with cardiac and other extrapulmonary involvement in sarcoidosis ***:The study included 67 patients diagnosed with sarcoidosis. A control group of 100 bone marrow donors, who had undergone HLA genotyping previously, was also included. Blood samples were collected from all participants for HLA gene polymorphism analysis. The differences in HLA genotypes were investigated between patients with and without cardiac and other extrapulmonary involvement, and between these groups and the control ***:Cardiac involvement, was present in 17.9% of the patients. The most frequently affected extrapulmonary organ was the skin (23.8%). HLA DQB103 and HLA DQB106 alleles were expressed more frequently in patients with only pulmonary involvement compared to those with extrapulmonary involvement. Conversely, HLA DQA101 was expressed more frequently in patients with extrapulmonary involvement. No statistically significant difference in the expression of HLA DRB1, HLA DQB1, and HLA DQA1 alleles was observed between sarcoidosis patients with and without cardiac ***:Our findings suggest that HLA DQB103 and HLA DQB106 alleles might be protective against extrapulmonary organ involvement, while HLA DQA101 could be a risk factor. These findings may contribute to the prediction of treatment response and prognosis in sarcoidosis patients.

关键词： 缺血性卒中   脑缺血   T淋巴细胞   炎症  

摘要： 缺血性卒中是全球成年人死亡和残疾的主要原因。T淋巴细胞可分为αβT细胞与γδT细胞，其中αβT细胞再分为CD4⁺ T细胞、CD8⁺ T细胞和自然杀伤（natural killer, NK）细胞等亚群。在CD4⁺ T细胞中，辅助性T细胞（T helper cell,Th）1和Th17分泌促炎性因子，可加重缺血性脑损伤；Th2分泌抗炎性因子，能改善神经功能；调节性T细胞（regulatory T cells,Tregs）则通过多种机制发挥神经保护作用。CD8⁺ T细胞通过分泌细胞因子和释放颗粒酶等加重缺血性脑损伤，而NK细胞可通过分泌干扰素-γ导致神经元损伤和血脑屏障破坏。此外，γδT细胞分泌的白细胞介素-17也在卒中病理进程中发挥显著促炎作用。因此，加深理解T淋巴细胞的作用可为缺血性卒中的治疗提供新的思路。

关键词： HLA   Amerindians   Wiwa   Chimila   Way & uacute   u   trans-Pacific contacts   America population   Afro-Americans   Europeans   first free African Americans   Barranquilla   San Basilio Palenque  

摘要： Background/Objectives: The Human Leukocyte Antigen (HLA) system is composed of a set of genes that codify glycoproteins presenting antigenic proteins to clonotypic T cell receptors in order to start the immune response. Class I and Class II classical loci exhibit high allelic diversity;some of them (or their specific combinations that form haplotypes) are quasi-specific or highly frequent in certain populations and thus are useful for population genetic studies. In this study, an HLA genetic comparison of Chimila, Way & uacute;u, Wiwa, and Barranquilla Colombian nonrelated healthy individuals was carried out together with other populations from all over the world to trace their genetic origin, obtain a virtual transplantation list, and inform future epidemiology studies. Methods: HLA-A, -B, -DRB1, and -DQB1 alleles were sequenced using the PCR-SSOP-Luminex method to analyze the HLA genetic profile of each individual. The data obtained were subsequently processed with standard software to obtain HLA alleles, haplotype frequencies, and genetic distances compared with data from global populations to generate relatedness dendrograms and carry out a correspondence analysis. Results: The results obtained place the Chimila, Way & uacute;u, and Wiwa populations phylogenetically close to the other North and South Amerindian populations included in this study. Amerindians are genetically separated from the rest of the world's populations. Chimila, Way & uacute;u, and Wiwa present unique extended HLA haplotypes and specific alleles, such as HLA-B*48 or HLA-A*24:01, shared with Oceanian populations. Conclusions: These genetic results and anthropological data support prehistorical trans-Pacific (bidirectional) contacts that contributed to the settlement of America and also suggest that the effects of ancient European gene flow cannot be discarded.

摘要： Tertiary lymphoid structures (TLSs) are de novo ectopic lymphoid aggregates that regulate immunity in chronically inflamed tissues, including tumours. Although TLSs form due to inflammation-triggered activation of the lymphotoxin (LT)-LT beta receptor (LT beta R) pathway1, the inflammatory signals and cells that induce TLSs remain incompletely identified. Here we show that interleukin-33 (IL-33), the alarmin released by inflamed tissues2, induces TLSs. In mice, Il33 deficiency severely attenuates inflammation- and LT beta R-activation-induced TLSs in models of colitis and pancreatic ductal adenocarcinoma (PDAC). In PDAC, the alarmin domain of IL-33 activates group 2 innate lymphoid cells (ILC2s) expressing LT that engage putative LT beta R+ myeloid organizer cells to initiate tertiary lymphoneogenesis. Notably, lymphoneogenic ILC2s migrate to PDACs from the gut, can be mobilized to PDACs in different tissues and are modulated by gut microbiota. Furthermore, we detect putative lymphoneogenic ILC2s and IL-33-expressing cells within TLSs in human PDAC that correlate with improved prognosis. To harness this lymphoneogenic pathway for immunotherapy, we engineer a recombinant human IL-33 protein that expands intratumoural lymphoneogenic ILC2s and TLSs and demonstrates enhanced anti-tumour activity in PDAC mice. In summary, we identify the molecules and cells of a druggable pathway that induces inflammation-triggered TLSs. More broadly, we reveal a lymphoneogenic function for alarmins and ILC2s.

关键词： melanoma   tetrandrine   MHC-I   autophagy   proteasome   TPC2 channel  

摘要： MHC-I-mediated antigen presentation is pivotal in antitumor immunity, enabling the recognition and destruction of tumor cells by CD8+ T cells. Both the proteasome and autophagy serve as essential cellular degradation mechanisms that regulate the stability and functionality of MHC-I molecules. In melanoma, modulating the pathways that affect MHC-I antigen presentation is pivotal and can profoundly influence the therapeutic outcomes of immunotherapy. Our initial effort of this study was a screening process to identify natural compounds capable of amplifying MHC-I surface expression on B16 melanoma cells. Utilizing flow cytometry with fluorescently tagged antibodies, we identified tetrandrine (Tet), a bisbenzylisoquinoline alkaloid derived from the root of Stephania tetrandra, as a potent enhancer of MHC-I-mediated antigen presentation in B16 melanoma cells. We demonstrate that tetrandrine (2.5, 5, 7.5 mu M) dose-dependently upregulates both surface and total MHC-I protein levels in B16 or A375 melanoma cells by simultaneously inhibiting autophagy and proteasomal activity, two key pathways involved in MHC-I degradation. This dual inhibition stabilizes MHC-I molecules, leading to enhanced tumor antigen presentation and improved recognition by CD8+ T cells. In co-culture systems, tetrandrine treatment increased CD8+ T cell activation and cytotoxicity against melanoma cells, evidenced by elevated IFN-gamma secretion and increased tumor cell apoptosis. Administration of tetrandrine (50 mgkg-1d-1, i.g., for 15 days) significantly suppressed melanoma growth in mouse models accompanied by increased CD8+ T cell infiltration and activation within the tumor microenvironment. Notably, tetrandrine synergized with anti-PD-1 immune checkpoint therapy, leading to enhanced tumor growth inhibition compared to either treatment alone. We revealed that tetrandrine (7.5 mu M) blocked the lysosomal calcium efflux channel TPC2, disrupting lysosomal calcium homeostasis

关键词： Yersinia pseudotuberculosis   apoptosis   caspase inhibitors   caspase substrates   caspases   in vitro kinetics   inflammasomes   pyroptosis  

摘要： Caspases are a family of cysteine proteases that act as molecular scissors to cleave substrates and regulate biological processes such as programmed cell death and inflammation. Extensive efforts have been made to identify caspase substrates and to determine factors that dictate substrate specificity. We recently discovered that that the human inflammatory caspases (caspases-1, -4, and -5) cleave the cytokines IL-1β and IL-18 in a sequence-dependent manner. Here, we report the development of a new peptide-based probe and inhibitor based on the tetrapeptide sequence of IL-18 (LESD). We found that this inhibitor was most selective and potent at inhibiting caspase-8 activity (IC = 50 nM). We also discovered that our LESD-based inhibitor is more potent than the currently used z-IETD-FMK inhibitor that is thought to be the most selective and potent inhibitor of caspase-8. Accordingly, we demonstrate that the LESD based inhibitor prevents caspase-8 activation during infection in primary bone-marrow derived macrophages. Furthermore, we characterize the selectivity and potency of currently known substrates and inhibitors for the apoptotic and inflammatory caspases using the same activity units of each caspase. Our findings reveal that VX-765, a known caspase-1 inhibitor, also inhibits caspase-8 (IC = 1 μM) and even when specificities are shared, the caspases have different efficiencies and potencies for shared substrates and inhibitors. Altogether, we report the development of new tools that will facilitate the study of caspases and their roles in biology.

关键词： Anti-interferon-gamma autoantibodies   Non-tuberculous mycobacteria   Clinical characteristics  

摘要： Background Patients with positive anti-IFN-gamma autoantibodies (AIGAs) are characterized by susceptibility to disseminated infection by multiple pathogens. The clinical characteristics of non-tuberculous mycobacterial (NTM) infection with AIGAs positivity remain unclear. Methods A prospective cohort study was conducted at the First Affiliated Hospital of Guangxi Medical University from January 2021 to January 2024. A total of 93 patients diagnosed with NTM infection were divided into two groups: AIGAs-positive with NTM infection and AIGAs-negative with NTM infection. The clinical manifestations, laboratory data, imaging examination, and pathogens were analyzed to characterize the disease. Results A total of 44 AIGAs-positive and 49 AIGAs-negative patients with NTM infection were enrolled. Disseminated infections were significantly more common among AIGAs-positive patients (P < 0.001), with frequent co-infections involving Talaromyces marneffei (TM) and viruses. Additionally, AIGAs-positive patients exhibited elevated inflammatory markers and immunoglobulins. In the AIGAs-positive group, lymph nodes, bones, skin, and blood were the most frequently affected sites. Chest CT scans exhibited a range of findings. Over a mean follow-up period of 36 months, 56.82% of patients with AIGAs positivity experienced exacerbations despite undergoing regular anti-NTM therapy. Conclusions AIGAs-positive patients with NTM infection exhibit elevated inflammatory markers, abnormal immune indicators, and coagulation function. Disseminated infections involving multiple organs are common, with frequent co-infection with TM and viruses. These patients may have unique symptoms, signs, and imaging findings compared to AIGAs-negative patients. Recurrence is common among these patients, highlighting the need for timely identification and intervention.