Minor histocompatibility antigens are MHC-bound peptides and contribute to the generation of allo-responses after allogeneic transplantation. H60 is a dominant minor H antigen that induces a strong CD8 T-cell response in MHC-matched allogeneic transplantation settings. Here, we report establishment of a TCR transgenic mouse line named J15, wherein T cells express TCRs specific for H60 in complex with H-2K(b), and different fates of the thymocytes expressing J15 TCRs in various thymic antigenic environments. Thymocytes expressing the J15 TCRs were positively selected and differentiated into CD8+ single positive (SP) cells in the thymus of C57BL/6 mice, wherein the cognate antigen H60 is not expressed. However, thymocytes were negatively selected in thymus tissue where H60 was transgenically expressed under the control of the actin promoter, with double-positive stages of cells being deleted. Despite the ability of the H60H peptide (LTFHYRNL) variant to induce cytotoxic activity from H60-specific CTL lines at ~50% of the activity induced by normal H60 peptides (LTFNYRNL), J15-expressing thymocytes were positively selected in the thymus where the variant H60H was transgenically expressed. These results demonstrate that a single amino-acid change in the H60 epitope peptide influences the fate of thymocytes expressing the cognate TCR.
Actins ; Animals ; Histocompatibility Antigens* ; Histocompatibility* ; Mice ; Mice, Transgenic ; Minor Histocompatibility Antigens ; Peptides ; T-Lymphocytes ; Thymocytes* ; Thymus Gland ; Transplantation, Homologous

BACKGROUNDHumoral immunity is an important factor for long-term survival of renal allograft. Here we performed a four-year follow-up to explore the clinical significance of monitoring anti-human leukocyte antigens (HLA) and anti-major histocompatibility complex class I-related chain A (MICA) antibody expression after kidney transplantation.

METHODSWe obtained serial serum samples from 84 kidney transplant patients over a four-year period. All patients were followed up at least 6 months after transplantation and had at least two follow-up points. Anti-HLA and anti-MICA antibody titres and serum creatinine (SCr) levels were evaluated at each follow-up. Patients were divided into 4 groups: HLA(+) MICA(-), HLA(-)MICA(+), HLA(+)MICA(+) and HLA(-)MICA(-). The impact of post-transplant antibody level on kidney allograft function was evaluated.

RESULTSAntibodies were detected in 38.1% (32/84) of the renal allograft recipients. HLA, MICA and HLA+MICA expression was observed in 18.89%, 14.44% and 5.93% of the recipients respectively. The most frequent anti-HLA and anti-MICA specific antibodies identified were A11, A24, A29, A32, A33, A80; B7, B13, B37; DR17, DR12, DR18, DR52, DR53, DR1, DR4, DR9, DR51; DQ7, DQ4, DQ8, DQ2, DQ9, DQ5, DQ6 and MICA02, MICA18, MICA19, MICA07, MICA27. As the time after transplantation elapsed, more recipients developed de novo antibody expression. Total 11.91% (10/84) of the recipients had de novo antibody expression during the follow up. The average level of SCr and the percentage of recipients with abnormal allograft function were significantly higher in recipients with anti-HLA and/or anti-MICA antibody expression than those without. The appearance of anti-HLA and anti-MICA antibody expression always preceded the increase in SCr value.

CONCLUSIONSAnti-HLA and anti-MICA antibody expression has predictive value for early and late allograft dysfunction. The presence of donor specific antibody is detrimental to graft function and graft survival.

Female ; Follow-Up Studies ; Graft Survival ; HLA Antigens ; immunology ; Histocompatibility Antigens Class I ; immunology ; Humans ; Isoantibodies ; analysis ; Kidney Transplantation ; Male ; Minor Histocompatibility Antigens

BACKGROUND: Findings on the association of genetic factors and colorectal cancer (CRC) survival are limited and inconsistent, and revealing the mechanism underlying their prognostic roles is of great importance. This study aimed to explore the relationship between functional genetic variations and the prognosis of CRC and further reveal the possible mechanism. METHODS: We first systematically performed expression quantitative trait locus (eQTL) analysis using The Cancer Genome Atlas (TCGA) dataset. Then, the Kaplan-Meier analysis was used to filter out the survival-related eQTL target genes of CRC patients in two public datasets (TCGA and GSE39582 dataset from the Gene Expression Omnibus database). The seven most potentially functional eQTL single nucleotide polymorphisms (SNPs) associated with six survival-related eQTL target genes were genotyped in 907 Chinese CRC patients with clinical prognosis data. The regulatory mechanism of the survival-related SNP was further confirmed by functional experiments. RESULTS: The rs71630754 regulating the expression of endoplasmic reticulum aminopeptidase 1 ( ERAP1 ) was significantly associated with the prognosis of CRC (additive model, hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.08-1.88, P = 0.012). The results of dual-luciferase reporter assay and electrophoretic mobility shift assay showed that the A allele of the rs71630754 could increase the binding of transcription factor 3 (TCF3) and subsequently reduce the expression of ERAP1 . The results of bioinformatic analysis showed that lower expression of ERAP1 could affect the tumor immune microenvironment and was significantly associated with severe survival outcomes. CONCLUSION: The rs71630754 could influence the prognosis of CRC patients by regulating the expression of the immune-related gene ERAP1 . TRIAL REGISTRATION No. NCT00454519 ( https://clinicaltrials.gov/ ).
Humans ; Prognosis ; Genotype ; Polymorphism, Single Nucleotide/genetics* ; Quantitative Trait Loci ; Colorectal Neoplasms ; Tumor Microenvironment ; Aminopeptidases/metabolism* ; Minor Histocompatibility Antigens/genetics*

GVHD (Graft-versus-Host Disease) results from the cytotoxic T lymphocytes from the bone marrow recognizing the recipient's minor histocompatibility antigens. In experimental murine models, either CD4+ or CD8+ T-cell subsets can cause GVHD, depending upon the particular strain combination utilized. Recent studies suggest that the keratinocyte undergo apoptosis in GVHD. However, morphological data supporting this concept are still lacking. The present study was undertaken in order to document apoptosis in experimental acute GVHD via sequential analysis of ultrastructure .Acute GVHD was produced across minor histocompatibility loci using appropriately matched murine strains. Acute GVHD was mediated with the use of highly purified preparations of donor CD4+ and CD8+ T-cell subsets. Whole T cells were used as a positive control and T cell depleted bone marrow as a negative control. Conventional transmission electron microscopy was used to define apoptosis structurally Sequential ultrastructure revealed that the keratinocyte underwent apoptosis in CD4+, CD8+ and whole T cell groups. This study demonstrates the sequential ultrastructure of the keratinocyte undergoing apoptosis from the beginning to the end. Both of the basal and the suprabasal keratinocytes show the morphology of early apoptosis, and the detachment of the tonofibril from the basement membrane and the adjacent cell was the general findings in the apoptotic cell Sequences of the cytoplasmic condensation was demonstrated . Through ultrastructural quantitation the apoptotic indices were depicted in all the experimental groups. Characteristically, numerous lymphocytes underwent apoptosis in CD8+ groups at day 28 and 35.
Apoptosis* ; Basement Membrane ; Bone Marrow Transplantation* ; Bone Marrow* ; Cytoplasm ; Epidermis* ; Humans ; Keratinocytes ; Lymphocytes ; Microscopy, Electron, Transmission ; Minor Histocompatibility Antigens ; Minor Histocompatibility Loci ; T-Lymphocyte Subsets ; T-Lymphocytes ; T-Lymphocytes, Cytotoxic ; Tissue Donors

BACKGROUND: In the search for susceptibility genes responsible for leukemia, genetic studies involving HLA association have been in progress extensively since the first report on its effect on the disease. Here we investigated the genetic associations of different leukemias with 4 autosomal mHags, HA-1, -2, -8 and HB-1. In particular, HB-1 is one of the leukemia-associated minor histocompatibility antigens (mHags) that is significantly expressed by Epstein-Barr virus-transformed- and tumor cells of all B lineage acute lymphoblastic leukemia (ALL). METHODS: A simultaneous genotyping method using PCR sequence-specific primers against HA-1, -2, -8 and HB-1 was developed, and their allelic frequencies in 139 healthy controls and 36 leukemia patients were observed. To compare genotype, phenotype, and gene frequencies of mHags with healthy controls, leukemia patients were classified into sub groups of ALL, acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). RESULTS: The genotype frequencies of HA-1, -2 and -8 were not significantly different from healthy controls in every group of leukemia patients. However, the HB-1 H genotype was significantly increased in leukemia patients (P=0.03, OR=1.82, CI=1.08~3.06), particularly in AML (P=0.01, OR=2.4, CI=1.21~4.76) as compared with healthy controls. CONCLUSION: Our results suggested that the genotype of HB-1 H may be associated with leukemia, particularly with AML. In further study, it is necessary to confirm the association of HB-1 with other leukemias in a larger group of patients, and to identify the underlying mechanism of HB-1 responsible for the occurrence of leukemia.
Gene Frequency ; Genotype* ; Humans ; Leukemia* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; Leukemia, Myeloid, Acute ; Minor Histocompatibility Antigens* ; Phenotype ; Polymerase Chain Reaction ; Precursor Cell Lymphoblastic Leukemia-Lymphoma

OBJECTIVE: To explore the expression of IL-35, Epstein-Barr virus-induced gene 3 (EBI3) mRNA and IL-12A mRNA in peripheral blood of patients with allergic rhinitis and its significance. METHOD: Peripheral blood were collected from patients with allergic rhinitis (46 cases) and healthy human controls(30 cases). The level of IL-35 in serum was measured by enzyme-linked immunosorbent assay. The subunit EB13 and IL-12A of IL-35 mRNA expressions in peripheral blood mononuclear cell(PBMC) were detected by SYBR Green real-time quantitative PCR. RESULT: IL-35 level in AR group (251.22 +/- 46.27) ng/L was significantly lower compared with that in the normal control group (382.17 +/- 25.41) ng/L, (P < 0.01). The mRNA expression level of EBI3 in the patients with allergic rhinitis was significantly lower than that in the normal control group (P < 0.01), AR group EB13 mRNA level was about half of that in the normal control group. But the mRNA expression level of IL-12A in the patients with allergic rhinitis has not significant difference with that in the normal control group (P > 0. 05). CONCLUSION The decrease of IL-35 and EBI3 mRNA in AR,indicated that IL-35 and EBl3 mRNA may play an important role in allergic rhinitis.
Adolescent ; Adult ; Case-Control Studies ; Child ; Female ; Humans ; Interleukin-12 Subunit p35 ; blood ; Interleukins ; blood ; Male ; Middle Aged ; Minor Histocompatibility Antigens ; Rhinitis, Allergic ; blood ; Young Adult

BACKGROUND: Rapid platelet engraftment has several economic benefits by reducing the cost of supportive therapy as well as reducing the risk of fatal bleeding due to severe thrombocytopenia. Based on these considerations, we genotyped human platelet alloantigens (HPA) to evaluate the effect of minor transplantation antigen mismatches on the rate and speed of platelet recovery and clinical outcome of transplantation. METHODS: Thirty-five patients with various hematologic diseases transplanted between January 2001 and August 2004 were included. Genomic DNA was isolated from peripheral blood of donor-recipient pairs before transplantation. HPA-1, -2, -3, -4, -5, and -6 genotyping was performed by poly-merase chain reaction (PCR)-sequence specific primers (SSP). The effects of HPA compatibility on platelet recovery, incidences of graft-versus-host disease (GVHD) and relapse, and overall survival was investigated. RESULTS: There were no significant differences in platelet recovery according to HPA matching status. We observed no statistically significant differences in the occurrence of relapse and overall survival according to HPA-1, -2, and -3 matched/mismatched groups of patients, whereas HPA-3 mismatching was found to have a significant effect on GVHD development. There was also no difference in GVHD occurrence according to HPA-1 and -2 matched or mismatched transplants. CONCLUSIONS: Since platelet recovery in the HPA-1, -2, -3, and -5 matched/mismatched groups is not significantly different, the seems that platelet glycoprotein (GP) does not seem to act as a factor influencing the homing of hematopoietic stem cells. The finding that HPA-3 incompatibility may be involved in GVHD can be of importance. If a role for HPA-3 as minor histocompatibility antigens is confirmed by additional studies, we can ameliorate the outcome of allogeneic stem cell transplantation by typing of HPA and selecting the most closely related donors.
Antigens, Human Platelet ; Blood Platelets* ; DNA ; Glycoproteins ; Graft vs Host Disease* ; Hematologic Diseases ; Hematopoietic Stem Cell Transplantation* ; Hematopoietic Stem Cells ; Hemorrhage ; Humans ; Incidence ; Minor Histocompatibility Antigens ; Recurrence ; Stem Cell Transplantation ; Thrombocytopenia ; Tissue Donors

OBJECTIVETo investigate the genetic association pattern between single-nucleotide polymorphisms (SNP) of key genes in T regulatory cells signaling pathways and the efficacy of allergic rhinitis (AR) specific immune therapy(SIT).

METHODSA population of 102 AR patients(Beijing Tongren hospital, from January to Decemeber 2012) caused by simple dust mite received standardized specific immune therapy, who lived in Beijing region was recruited. In immunotherapy before and after 1 years of treatment, the study objects were scored by nasal symptoms score, nasal signs score and total score of daily life distress three indicators to assess the efficacy. A total of 43 reprehensive marker SNP which were in FOXP3, IL-2, TGF-βand EBI3 gene regions and the upstream and downstream 1 000 kb were selected according to the Beijing people database from Hapmap website. The individual genotyping was performed by MassARRAY platform.Plink software was used for statistic analysis.

RESULTSSubgroup analysis for the efficacy evaluation of three indicators displayed that IL-2_rs77468365, FOXP3(rs2280883, rs2232365 and rs3761548) were associated with the improvement of sneezing in nasal symptoms. IL-2_rs77468365, FOXP3(rs2280883, rs2232365 and rs3761548) were associated with the improvement of runny nose in nasal symptoms. TGF-β(rs747857, rs6508975, rs2241715, rs12462166, rs12983775, rs1800470 and rs2317130)and FOXP3(rs2280883, rs2232365 and rs3761548)were associated with the improvement of nasal obstruction in nasal symptoms. FOXP3(rs2280883, rs2232365 and rs3761548)were associated with the improvement of nasal itching in nasal symptoms. IL-2_rs77468365 and FOXP3(rs2280883, rs2232365 and rs3761548) were associated with the overall improvement in nasal symptoms. EBI3_rs670188 and FOXP3(rs2280883, rs2232365, rs3761549, rs3761548 and rs3761547) were associated with the improvement of inferior turbinate mucosa swelling in nasal signs. IL-2_rs77468365, EBI3_rs393581, TGF-β(rs11466359 and rs11466345), FOXP3(rs2280883, rs17847095, rs2232365 and rs3761548)were associated with the improvement of inferior turbinate mucosa color in nasal signs. EBI3(rs393581, rs4740 and rs353702), FOXP3(rs2280883, rs2232365 and rs3761548)were associated with the improvement of water discharge in nasal signs. IL-2_rs77468365, EBI3(rs393581, rs4740 and rs353702), FOXP3( rs2280883, rs2232365 and rs3761548)were associated with the overall improvement in nasal signs. TGF-β(rs12461895, rs2241717 and rs7258445), FOXP3(rs2280883, rs2232365, rs3761549, rs3761548 and rs3761547)were associated with the improvement of life puzzle.

CONCLUSIONThe genetic polymorphism (SNPs) of four important functional candidate genes( FOXP3, IL-2, TGF-βand EBI3) in T regulatory cells signaling pathways were detected in significant correlation with the efficacy of allergic rhinitis specific immune therapy.

Beijing ; Forkhead Transcription Factors ; genetics ; Genotype ; Humans ; Immunotherapy ; Interleukin-2 ; genetics ; Interleukins ; genetics ; Minor Histocompatibility Antigens ; Polymorphism, Single Nucleotide ; Rhinitis, Allergic ; genetics ; therapy ; Signal Transduction ; T-Lymphocytes, Regulatory ; cytology ; Transforming Growth Factor beta1 ; genetics ; Turbinates ; pathology

OBJECTIVETo analyze the association of micoRNA-related genes DROSHA single nucleotide polymorphisms (SNP) rs10719 and rs6877842, DICER1 rs3742330and GEMIN4 rs3744741 with prognosis of T-cell lymphoma.

METHODSPolymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to determine the genotypes of the above 4SNPs and their associations with complete remission (CR) rate and overall survival (OS) in 163 patients with TCL.

RESULTSPatients carrying the rs6877842 CG genotype had a significantly higher CR rate compared with those carrying the CC genotype (OR=0.07, 95% CI 0.01-0.72, P=0.026); the same for patients carrying the DICER1 rs3742330 GG genotype compared with those carrying the GA genotype (OR=0.15, 95% CI 0.02-0.97, P=0.047) or the AA genotype (OR=0.11, 95% CI 0.02-0.71, P=0.020). In addition, patients with the DICER1 rs3742330 GG genotype had a significantly improved OS compared with those carrying the GA (HR=9.02, 95% CI 1.22-66.92, P=0.031) or AA genotype (HR=8.77, 95% CI 1.19-64.67, P=0.033). The other two SNPs of rs10719 and rs3744741 had no significant association with CR or OS.

CONCLUSIONDROSHA rs6877842 and DICER1 rs3742330 were independent factors for TCL CR, and DICER1 rs3742330 was also an independent prognostic factor for TCL OS.

DEAD-box RNA Helicases ; genetics ; Genetic Predisposition to Disease ; Genotype ; Humans ; Lymphoma, T-Cell ; diagnosis ; genetics ; MicroRNAs ; genetics ; Minor Histocompatibility Antigens ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; Prognosis ; Ribonuclease III ; genetics ; Ribonucleoproteins, Small Nuclear ; genetics

PURPOSE: Numerous studies have assessed the association of SP110 gene variants with tuberculosis (TB), but the results were inconsistent. Through a comprehensive review and meta-analysis, our study aimed to clarify the nature of genetic risks contributed by 11 polymorphisms for the development of TB. MATERIALS AND METHODS: Through searching PubMed, web of science, China National Knowledge Infrastructure (CNKI) databases, a total of 11 articles including 13 independent studies were selected. The pooled odd ratios (ORs) along with their corresponding 95% confidence interval (CI) were estimated for allelic comparisons, additive model (homozygote comparisons; heterozygote comparisons), dominant model and recessive model. We also assessed the heterogeneity across the studies and publication bias. RESULTS: The results of combined analysis revealed a significantly increased risk of TB for single nucleotide polymorphism (SNP) rs9061 in all five comparisons (allelic comparisons: OR=1.28, 95% CI=1.14–1.44, p<0.0001; homozygote comparisons: OR=2.84, 95% CI=1.84–4.38, p<0.00001; heterozygote comparisons: OR=1.23, 95% CI=1.05–1.43, p=0.009; dominant model: OR=1.32, 95% CI=1.14–1.53, p=0.0003; recessive model: OR=2.26, 95% CI=1.18–4.34, p=0.01). In subgroup analysis, the risk of TB associated with SNP rs9061 appeared to be increased. Moreover, increased risk of TB was also found in Asian subgroup of SNP rs11556887, while decreased risk of TB appeared in large sample size subgroup of SNP rs1135791. No significant association was observed between other SNPs and the risk of TB. CONCLUSION: Our meta-analysis suggested that the variant of SNP rs9061 might be a risk factor for TB.
Alleles ; Asian Continental Ancestry Group/genetics ; China ; Confidence Intervals ; Genetic Predisposition to Disease ; Heterozygote ; Homozygote ; Humans ; Minor Histocompatibility Antigens/*genetics ; Nuclear Proteins/*genetics ; Odds Ratio ; *Polymorphism, Single Nucleotide ; Risk Factors ; Tuberculosis, Pulmonary/*genetics