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The major histocompatibility complex class I-related gene A ( ), is a highly polymorphic gene, serve as a crucial role in immune regulator through its interaction with the NKG2D receptor on natural killer (NK) cells. These polymorphisms may influence immune responses, disease susceptibility, and transplant outcomes. However, the precise mechanisms by which polymorphisms modulate NKG2D receptor activation remain poorly understood. We analyzed 29 representative MICA polymorphic molecules that cover the most prevalent alleles in the population. These variants were systematically examined through Luminex bead assays, monoclonal antibody binding studies, and NKG2D-Ig fusion protein assays. NKG2D receptor activation was assessed using NKG2D reporter cells, while NK cell-mediated cytotoxicity was evaluated through NKL cell killing assays against target cells expressing either Type-I or Type-II MICA molecules. Our analysis identified two major types of polymorphisms based on antigenic epitopes and NKG2D binding characteristics. Type-I MICA characterized by six specific polymorphic site and their associated amino acid variants. exhibited significantly stronger NKG2D receptor binding affinity and more robust receptor activation compared to Type-II polymorphisms. This functional distinction was further corroborated by enhanced NK cells cytotoxicity against target cells expressing Type-I MICA molecules. Importantly, these differences in receptor activation and NK cell killing efficiency were attributable to six critical polymorphic amino acid sites. This study demonstrates the existence of two distinct types of polymorphisms that differentially regulate NKG2D receptor activation and NK cell cytotoxicity. These findings offer new insights into that how genetic variation in MICA may contribute to individual differences in disease susceptibility through immune regulation mechanisms.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by persistent inflammation of the colonic mucosa. This condition can significantly affect the quality of life of those affected. While UC is common, its underlying mechanisms are not yet fully understood, highlighting the need for a comprehensive proteomic analysis of intestinal tissues to identify potential biological changes associated with the disease. This study aimed to investigate the proteomic differences in the intestinal tissues of patients with UC and healthy individuals using high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics methods. The study employed a comprehensive proteomic analysis using LC-MS/MS to identify protein expression differences in intestinal tissues from five patients with UC versus five healthy controls. Subsequent bioinformatics analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, elucidated altered biological processes. We identified 194 upregulated and 323 downregulated proteins in the tissues of patients with UC, indicating a significant difference in protein expression. GO analysis revealed that the upregulated proteins were mainly involved in immune responses and metabolic processes, while the downregulated proteins were associated with organic and cellular metabolism. Additionally, KEGG pathway analysis showed that upregulated proteins were enriched in pathways related to ribosomes and phagosomes, whereas downregulated proteins were primarily linked to oxidative phosphorylation, thermogenesis, and the citric acid cycle, pointing to substantial changes in cellular energy metabolism. Protein-protein interaction (PPI) network analysis identified several key nodes, particularly those connected to ribosomal and phagocytic functions, which may play significant roles in the pathophysiology of UC. This study offers new insights into the biological mechanisms underlying UC and lays the foundation for future therapeutic strategies targeting these proteomic changes. Further experimental validation and clinical investigations are necessary to uncover additional mechanisms of UC and to facilitate the development of effective treatments.

The presence of donor-specific alloantibodies (DSAs) against the MICA antigen results in high risk for antibody-mediated rejection (AMR) of a transplanted kidney, especially in patients receiving a re-transplant. We describe the incidence of acute C4d+ AMR in a patient who had received a first kidney transplant with a zero HLA antigen mismatch. Retrospective analysis of post-transplant T and B cell crossmatches were negative, but a high level of MICA alloantibody was detected in sera collected both before and after transplant. The DSA against the first allograft mismatched MICA*018 was in the recipient. Flow cytometry and cytotoxicity tests with five samples of freshly isolated human umbilical vein endothelial cells demonstrated the alloantibody nature of patient's MICA-DSA. Prior to the second transplant, a MICA virtual crossmatch and T and B cell crossmatches were used to identify a suitable donor. The patient received a second kidney transplant, and allograft was functioning well at one-year follow-up. Our study indicates that MICA virtual crossmatch is important in selection of a kidney donor if the recipient has been sensitized with MICA antigens.

Both systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) diseases are related to the genetic and environmental factors, causing damage to the skin. The mutations of keratin 1 gene (KRT1) were reported to associate with skin diseases. The single-nucleotide polymorphism (SNP, rs14024) and the indel polymorphism (cds-indel, rs267607656), consisting mostly of the common haplotypes and could be used for genotyping of KRT1. We used the PCR with sequence specific primers (PCR-SSP) to determine the genotype of KRT1 in 164 SLE, 99 SSc patients, and 418 healthy controls. The results showed that the mutant with G at SNP rs14024 was associated with the high risk to SLE (p = 6.48×10-5) and SSc (p = 8.75×10-5), while the deletion allele at rs267607656 was associated with the low risk to SSc (p = 4.89×10-4) comparing to the normal controls. Haplogenotype, Del-/MU+ was associated with high susceptibility to SLE (OR = 1.87, p = 0.001) and SSc (OR = 2.29, p = 2.34×10-4). In contrast, the Haplogenotype Del+/MU- was associated with resistance to SLE (OR = 0.35, p = 6.24×10-5) and SSc (OR = 0.34, p = 0.001). This study demonstrates that the variations in KRT1 and the specific polymorphism of KRT1 in this Chinese Han population are associated with autoimmune diseases SLE and SSc. Typing KRT1 might be helpful to identify SLE and SSc patients.

Anti-endothelial cell antibodies (AECAs) are usually directed against the surface antigens on the vascular endothelial cells. Clinical studies suggest a pathogenic role for nonhuman leukocyte antigen in antibody-mediated rejection; however, the antigens on the donor vascular endothelium that serve as the first-line targets for an immune response during allograft rejection have not been fully identified. Here, we used immunoprecipitation and mass spectrometry to identify antigens from the sera of kidney transplant recipients who were experiencing antibody-mediated rejection. Keratin 1 (KRT1) was identified as a novel antigenic target expressed on endothelial cells. To validate our finding, we produced recombinant proteins representing the three most common alleles of KRT1. The serum used for immunoprecipitation showed a strong reaction to KRT1 recombinants in western blot and ELISA. In the kidney transplant cohort, more AECA-positive recipients than AECA-negative recipients had KRT1 antibodies (32.2% versus 11.9%, p=0.002). Sera from 255 renal recipients were tested by ELISA. Of the 77 recipients with deteriorating graft function (serum creatinine > 120 μmol/L), 23 had anti-KRT1 antibodies. KRT1-IgG positivity was, therefore, associated with a higher risk of kidney transplant rejection (29.9% (23/77) versus 16.9% (30/178), p=0.0187). A better understanding of this antigenic target will improve long-term allograft survival.

Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia 1 . This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML. The receptor LILRB4 on monocytic leukaemia cells suppresses T cell activity and support the infiltration of tumour cells into tissues.

Background Ureaplasma spp . can be classified into different serovars. It is unknown whether distinct serovars are associated with clinical signs and symptoms. Methods We conducted a multicentre cross-sectional study. U. parvum serovars were identified on the basis of their multiple-banded antigen (MBA) genes. After adjusting for demographic variables and other reproductive tract infections, the odds ratio (OR) and 95% confidence interval (CI) were calculated to determine the impact of U. parvum serovars on clinical symptoms. Results Among 5,277 individuals, U. parvum serovars 3 and 6 were the most prevalent serovars (17.9% and 16.0%, respectively). Potential confounders, such as age, body mass index (BMI), ethnicity, education level, contraceptive methods, number of sexual partners, gravidity, parity, and other sexually transmitted infections (STIs) that are associated with clinical symptoms ( P  < 0.1) were adjusted for in the univariate analysis . U. parvum serovar 14 was strongly positively associated with certain clinical symptoms, including redness and swelling of the vaginal wall (crude OR: 3.53, 95% CI: 1.92–6.49; adjusted OR: 5.21, 95% CI: 2.56–10.58), cervical bleeding and swelling (crude OR: 3.89, 95% CI: 2.38–6.36; adjusted OR: 7.37, 95% CI: 3.82–14.23), and cervical ectropion (crude OR: 2.08, 95% CI: 1.25–3.45; adjusted OR: 3.04, 95% CI: 1.60–5.74). In contrast, U. parvum serovar 3 was negatively associated with a variety of clinical symptoms, whereas no correlations were detected between U. parvum serovars 1and 6 with clinical symptoms. Conclusions Different U. parvum serovars exhibit distinct correlations with clinical symptoms, suggesting that U. parvum serovars are pathogenically heterogeneous and that further differentiation of serovars may be necessary. Trial registration The study was registered with ClinicalTrials.gov ( https://www.clinicaltrials.gov ; ID: NCT04694495; Registration Date: 2021–01-05).