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Major Histocompatibility Complex Class I (major + histocompatibility_complex_class_i)
Selected AbstractsCholangiocarcinoma in primary sclerosing cholangitis is associated with NKG2D polymorphisms,HEPATOLOGY, Issue 1 2008Espen Melum Primary sclerosing cholangitis (PSC) is often complicated by the development of cholangiocarcinoma (CCA). Genetic variation of natural killer cell receptor G2D (NKG2D) has been associated with cancer susceptibility. An important ligand for NKG2D, major histocompatibility complex class I chain-related molecule A (MICA), serves as a marker of cellular stress. The 5.1 allele of the gene encoding MICA has been associated with PSC. In this study, we aimed to investigate the influence of genetic variations in the NKG2D-MICA receptor-ligand pair on the risk of CCA in patients with PSC. Seven single nucleotide polymorphisms (SNPs) covering the NKG2D gene were genotyped in 365 Scandinavian PSC patients and 368 healthy controls with TaqMan technology. Genotype data on the MICA 5.1 variant were available from previous studies. Forty-nine of the PSC patients (13.6%) had developed CCA at the time of study. Two of the NKG2D SNPs were associated with an increased risk of CCA: rs11053781 [odds ratio (OR) = 2.08, 95% confidence interval (CI) = 1.31-3.29, corrected P (Pc) = 0.011] and rs2617167 (OR = 2.32, 95% CI = 1.47-3.66, Pc = 0.0020). Carriership of the MICA 5.1 allele was associated with resistance against CCA (OR = 0.43, 95% CI = 0.20-0.95, not corrected P = 0.032). Conclusion: Our results show that genetic variants of the NKG2D receptor are associated with development of CCA in PSC patients. This suggests that interaction between NKG2D and MICA is involved in protection against CCA in PSC. Patients who are homozygous for the nonrisk alleles are unlikely to develop CCA; this finding could be helpful in identifying PSC patients with a low CCA risk. (HEPATOLOGY 2007.) [source] Priming of immune responses against transporter associated with antigen processing (TAP)-deficient tumours: tumour direct primingIMMUNOLOGY, Issue 3 2009Xiao-Lin Li Summary We previously showed that introduction of transporter associated with antigen processing (TAP) 1 into TAP-negative CMT.64, a major histocompatibility complex class I (MHC-I) down-regulated mouse lung carcinoma cell line, enhanced T-cell immunity against TAP-deficient tumour cells. Here, we have addressed two questions: (1) whether such immunity can be further augmented by co-expression of TAP1 with B7.1 or H-2Kb genes, and (2) which T-cell priming mechanism (tumour direct priming or dendritic cell cross-priming) plays the major role in inducing an immune response against TAP-deficient tumours. We introduced the B7.1 or H-2Kb gene into TAP1-expressing CMT.64 cells and determined which gene co-expressed with TAP1 was able to provide greater protective immunity against TAP-deficient tumour cells. Our results show that immunization of mice with B7.1 and TAP1 co-expressing but not H-2Kb and TAP1 co-expressing CMT.64 cells dramatically augments T-cell-mediated immunity, as shown by an increase in survival of mice inoculated with live CMT.64 cells. In addition, our results suggest that induction of T-cell-mediated immunity against TAP-deficient tumour cells could be mainly through tumour direct priming rather than dendritic cell cross-priming as they show that T cells generated by tumour cell-lysate-loaded dendritic cells recognized TAP-deficient tumour cells much less than TAP-proficient tumour cells. These data suggest that direct priming by TAP1 and B7.1 co-expressing tumour cells is potentially a major mechanism to facilitate immune responses against TAP-deficient tumour cells. [source] Transcription of major histocompatibility complex class I (Kb) and transporter associated with antigen processing 1 and 2 genes is up-regulated with ageIMMUNOLOGY, Issue 3 2004Alain G. Assounga Summary The transporter associated with antigen processing 1 and 2 (TAP1 and TAP2) genes belong to the ATP-binding cassette family of transporter genes. They provide peptides necessary for the assembly of major histocompatibility complex (MHC) class I molecules by transporting these peptides into the endoplasmic reticulum. As MHC class I protein expression increases with age, we have explored the effect of age on the transcription of MHC class I genes (Kb) and TAP1 and TAP2 genes in C57BL/6 mice. Blood and spleen lymphocytes were isolated from mice aged from 3 months to over 24 months. RNA was extracted and mRNA for Kb, TAP1, TAP2 was quantified using slot-blot hybridization followed by densitometry. There was a parallel age-related increase (1·5-fold) in blood lymphocyte mRNA of these genes from 3 months to 21 months. In mice over 24 months old there was a decrease in Kb and TAP1 mRNA, but an increase in TAP2 mRNA. In spleen lymphocytes an age-related increase in all three mRNA species occurred throughout life. While MHC class I and Tap genes underwent very similar age-related changes, MHC class I mRNA was about 50 times more abundant than either TAP1 or TAP2 mRNA. [source] HLA haplotypes in recurrent aphthous stomatitis: a mode of inheritance?INTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 6 2008E. Albanidou-Farmaki Summary The aim of this study was to investigate the genetic association between recurrent aphthous stomatitis (RAS) and human leucocyte antigen (HLA) class I and II alleles and HLA haplotypes. Families selected had at least one child suffering from recurrent aphthous stomatitis in addition to one or both of the parents. HLA-A, -B and -DR alleles were typed in 29 families, 27 nuclear and two extended (121 subjects). HLA haplotypes of all family members with RAS were compared with those who were RAS negative. Although major histocompatibility complex class I and II gene analysis failed to demonstrate any significant association between RAS and HLA antigens, the study of HLA haplotypes revealed a significant association between HLA haplotypes and susceptibility to RAS. The results indicate that susceptibility to RAS segregates in families in association with HLA haplotypes. [source] Reduction of major histocompatibility complex class I expression on bladder carcinoma following tumor antigen-pulsed dendritic cell vaccine: Implications for immunoresistance in therapyINTERNATIONAL JOURNAL OF UROLOGY, Issue 7 2010Mengqiang Li Objectives: To clarify the relationship between a decreased major histocompatibility complex class I (MHC-I) expression on bladder tumors and decreased immunological efficacy of tumor antigen-pulsed dendritic cell vaccine in a rat bladder carcinoma model induced by N-methyl-N-nitrosourea irrigation. Methods: Enzyme-linked immunosorbent assay was used to evaluate interferon-gamma concentration in the serum and colorimetric lactate dehydrogenase release assay in vitro was used to test the cytotoxicity capability of T lymphocytes. MHC-I expression on tumor cells was detected by flow cytometry and analyzed with CellQuest software. Results: The tumor antigen sensitized dendritic cell vaccine group showed decreased hyperplastic formations, lower pathological stages in rat bladders and more potent cytotoxicity activity (P < 0.001) than the dendritic cell vaccine group. Additionally, immunization with pulsed dendritic cell vaccine induced higher specific cytokine production of interferon-gamma. Nevertheless, a decreased MHC-I expression on bladder tumors was tested after immunotherapy by pulsed dendritic cell vaccine on week 15. As expected, the cytotoxic activity of T lymphocytes from rats on tumor cells with low MHC-I expression was also decreased to 19.70 ± 4.82% as compared with tumor cells with high MHC-I (52.10 ± 8.66%, P = 0.005). Conclusions: Tumor antigen sensitized dendritic cell vaccine has beneficial activity on N-methyl-N-nitrosourea-induced bladder cancer in situ in rats, but therapeutic responses are accompanied by decreased MHC-I expression on tumors, possibly suggesting poor long-term therapeutic outcomes. [source] Innate and adaptive immune activation in the brain of MPS IIIB mouse modelJOURNAL OF NEUROSCIENCE RESEARCH, Issue 4 2009Julianne DiRosario Abstract Mucopolysaccharidosis (MPS) IIIB is a lysosomal storage disease with severe neurological manifestations due to ,- N -acetylglucosaminidase (NaGlu) deficiency. The mechanism of neuropathology in MPS IIIB is unclear. This study investigates the role of immune responses in neurological disease of MPS IIIB in mice. By means of gene expression microarrays and real-time quantitative reverse transcriptase,polymerase chain reaction, we demonstrated significant up-regulation of numerous immune-related genes in MPS IIIB mouse brain involving a broad range of immune cells and molecules, including T cells, B cells, microglia/macrophages, complement, major histocompatibility complex class I, immunoglobulin, Toll-like receptors, and molecules essential for antigen presentation. The significantly enlarged spleen and lymph nodes in MPS IIIB mice were due to an increase in splenocytes/lymphocytes, and functional assays indicated that the T cells were activated. An autoimmune component to the disease was further suggested by the presence of putative autoantigen or autoantigens in brain extracts that reacted specifically with serum IgG from MPS IIIB mice. We also demonstrated for the first time that immunosuppression with prednisolone alone can significantly slow the central nervous system disease progression. Our data indicate that immune responses contribute greatly to the neuropathology of MPS IIIB and should be considered as an adjunct treatment in future therapeutic developments for optimal therapeutic effect. © 2008 Wiley-Liss, Inc. [source] Heightened Expression of the Cytotoxicity Receptor NKG2D Correlates with Acute and Chronic Nephropathy After Kidney TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2007M. Seiler The activating cytotoxicity receptor NKG2D binds to stress-regulated molecules encoded by the major histocompatibility complex class I chain-related (MIC) and UL-16-binding protein (ULBP)/retinoic acid early transcript (RAET) gene family. To assess whether acute allograft rejection leads to an induction of these inducible ligands and their receptor NKG2D, we examined the mRNA profiles in kidney transplant biopsies. Expression levels were correlated with the incidence of acute rejection (aRx) episodes and chronic allograft nephropathy (CAN) proven by histology. Whereas MICA, ULBP1/3 and RAET1-E did not display heightened gene expression, elevated levels of NKG2D mRNA could be associated with aRx (p < 0.001). Immunohistology of kidney biopsies diagnosed with aRx revealed NKG2D+ cells in tubulointerstitial areas positive for CD8+ cells. Most importantly, elevated levels of NKG2D mRNA were associated with restricted long-term graft function assessed by the glomerular filtration rate at 6, 12 and 18 months posttransplantation. Induced NKG2D mRNA expression was still observable in biopsies diagnosed with CAN (p < 0.001), demonstrating a higher sensitivity and specificity compared to CD3, granzyme B and granulysin mRNA measurement. Significant elevated levels of NKG2D mRNA could be further detected in urine sediment prior to aRx, suggesting this receptor as a new candidate marker for the diagnosis of acute and chronic allograft rejection. [source] | ||||||||||