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Results for “HLA class II”

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PubMed2003

Helicobacter pylori infection: CagA-specific antibodies are associated with clinical outcome, but not with HLA-class II polymorphisms of the host.

In order to investigate the interrelation between immunogenetic host and bacterial factors the T-cell receptor (TCR) polymorphism TCRBV6S1 A/B, HLA-DRB1 alleles and cagA status was analyzed in 380 unrelated German individuals. H. pylori infection with cagA-positive bacterial strains was significantly associated with peptic ulcer disease in the German cohort. Patients homozygous for the non-functional TCRBV6S1B allele and presenting with peptic ulcer disease showed no CagA-specific antibodies in the majority of cases. There was no association between HLA-DRB1 alleles and the CagA status of infected individuals, although certain alleles show significant association to the infection status in different populations.

Alleles↗
PubMed2003

A humanized model of experimental autoimmune uveitis in HLA class II transgenic mice.

Experimental autoimmune uveitis (EAU) is a disease of the neural retina induced by immunization with retinal antigens, such as interphotoreceptor retinoid-binding protein (IRBP) and arrestin (retinal soluble antigen, S-Ag). EAU serves as a model for human autoimmune uveitic diseases associated with major histocompatibility complex (HLA) genes, in which patients exhibit immunological responses to retinal antigens. Here we report the development of a humanized EAU model in HLA transgenic (TG) mice. HLA-DR3, -DR4, -DQ6, and -DQ8 TG mice were susceptible to IRBP-induced EAU. Importantly, HLA-DR3 TG mice developed severe EAU with S-Ag, to which wild-type mice are highly resistant. Lymphocyte proliferation was blocked by anti-HLA antibodies, confirming that antigen is functionally presented by the human MHC molecules. Disease could be transferred by immune cells with a Th1-like cytokine profile. Antigen-specific T cell repertoire, as manifested by responses to overlapping peptides derived from S-Ag or IRBP, differed from that of wild-type mice. Interestingly, DR3 TG mice, but not wild-type mice, recognized an immunodominant S-Ag epitope between residues 291 and 310 that overlaps with a region of S-Ag recognized by uveitis patients. Thus, EAU in HLA TG mice offers a new model of uveitis that should represent human disease more faithfully than currently existing models.

Amino Acid Sequence↗
PubMed2006

Is HLA class II profile relevant for the study of large-scale differentially expressed genes in type 1 diabetes mellitus patients?

We have previously identified 30 differentially expressed genes when comparing recently diagnosed type 1 diabetes mellitus (DM-1) patients and controls paired for sex, age, and ethnic background. In this article we performed the hierarchical clustering of these genes taking into account the human-leukocyte-antigen (HLA)-DRB1/DQB1 profile. The dendrogram obtained using the Cluster program grouped patients and controls into three clusters, one including individuals with no susceptibility alleles, another including individuals with at least three susceptibility alleles, and a third intermingling susceptibility/protective alleles. In addition to other variables, the results of the present article suggest that the major histocompatibility complex (MHC) class II profile may be of relevance for the study of a large-scale differentially expressed genes.

Algorithms↗
PubMed1996

HLA class II gene frequency in a Czech Population.

In a sample of 212 healthy, unrelated individuals of a Czech (Central Bohemian) population, the phenotype and allele frequencies of HLA-DRB1 and -DQB1 loci were determined. DNA typing technique used was the restriction fragment length polymorphism (RFLP) analysis. The restriction enzymes were TaqI and HindIII and specific DRB1 and DQB1 probes were applied. The most frequent DRB1 and DQB1 alleles found were DRB1*11 and DQB1*06, their respective frequencies being 0.1698 and 0.2594.

Alleles↗
PubMed1998

Hyperacute rejection from antibody against class II HLA antigens.

The clinical significance of anti-B-cell antibodies in kidney and pancreas transplantation remains unresolved. Here, we report an isolated hyperacute rejection of the kidney, but not the pancreas, during a simultaneous kidney-pancreas (SKP) transplant. The hyperacute rejection was due to IgG antibodies directed against class II antigens expressed on B-cells. Antibodies directed against class II antigens are generally not thought to produce hyperacute rejection, since class II antigens allegedly are minimally expressed on vascular endothelium in the kidney. The pancreas was spared and continues to function normally, suggesting that class II antigens were not strongly expressed in this pancreas. The differential susceptibility to B-cell antibodies of the two transplanted organs is noteworthy and should call attention to the danger from IgG antibodies to class II antigens in kidney transplantation.

Acute Disease↗
PubMed2003

Promiscuous binding of proinsulin peptides to Type 1 diabetes-permissive and -protective HLA class II molecules.

AIMS/HYPOTHESIS: Presentation of peptide epitopes derived from beta-cell autoantigens, such as insulin and its precursor molecules, by MHC class II molecules to autoreactive T-cells is believed to play a role in the development of Type 1 diabetes. However, little is known about the interaction between peptides of (prepro)insulin and MHC class II molecules permissive and protective for Type 1 diabetes. In this study therefore, peptides spanning the human preproinsulin sequence were assessed for their binding characteristics to Type 1 diabetes-protective and -permissive HLA molecules. METHODS: HLA-DR2, -DQ6.2 (Type 1 diabetes-protective) and HLA-DR4, -DQ8 (Type 1 diabetes permissive) molecule binding affinity for overlapping synthetic 20mer peptides spanning human preproinsulin was measured in a direct competition binding assay against a biotinylated indicator peptide. RESULTS: All HLA molecules tested showed similarity in their binding characteristics across the preproinsulin molecule, with regions of the insulin A-chain showing the highest affinity and C-peptide regions the lowest affinity for all HLA molecules tested. Furthermore, an insulin peptide implicated as a major CD4+ T-cell target in disease pathogenesis (B9-23) had high affinity binding to both protective and permissive HLA molecules but did not represent the highest affinity region of (prepro)insulin identified in either case. CONCLUSION/INTERPRETATION: The results suggest that peptide binding affinity alone is unlikely to be the major determinant of disease susceptibility in relation to interactions between (prepro)insulin epitopes and HLA molecules. The identification of epitopes derived from beta-cell autoantigens that bind promiscuously to diabetes-permissive HLA molecules could be important in the design of peptide-based immunotherapeutic strategies for the prevention of Type 1 diabetes.

Diabetes Mellitus, Type 1↗
PubMed1996

Investigation of specimen mislabelling in paraffin-embedded tissue using a rapid, allele-specific, PCR-based HLA class II typing method.

Mislabelling of surgical specimens can seriously affect the accuracy of histopathology reports. We describe two cases in which clinically suspected mislabelling was investigated by polymerase chain reaction (PCR)-based HLA DRB and DQB tissue typing of paraffin biopsy-derived DNA, using sequence specific primers (PCR-SSP HLA typing). In the first case, two patients underwent surgery for breast carcinoma. A subcutaneous lymph node containing metastatic carcinoma was received with the breast specimen from one patient, but was clinically considered more likely to originate from the other patient who underwent breast surgery on the same day. In the second case, histological examination of retained products of conception from a young woman revealed adenocarcinoma, but a repeat curettage specimen consisted of secretory phase endometrium. In case 1, PCR-SSP HLA typing confirmed the clinical suspicion that the subcutaneous lymph node received with tissue from one patient originated from the other patient. This result converted the first patient from lymph node positive breast carcinoma to lymph node negative disease. In case 2, there was no evidence from PCR-SSP HLA typing that the endometrial samples had originated from different patients. PCR-SSP HLA typing requires fewer steps than methods based on PCR amplification followed by oligonucleotide probing (PCR-SSOP HLA typing), and relies on the amplification of shorter sequences of DNA. Therefore, this technique can produce more rapid results than PCR-SSOP HLA typing, and is ideally suited to typing partially degraded DNA derived from formalin-fixed and paraffin-embedded tissue.

Adenocarcinoma↗
PubMed2004

Identification and characterization of novel, naturally processed measles virus class II HLA-DRB1 peptides.

Previously, we identified a naturally processed and presented measles virus (MV) 19-amino-acid peptide, ASDVETAEGGEIHELLRLQ (MV-P), derived from the phosphoprotein and eluted from the human leukocyte antigen (HLA) class II molecule by using mass spectrometry. We report here the identification of a 14-amino-acid peptide, SAGKVSSTLASELG, derived from the MV nucleoprotein (MV-N) bound to HLA-DRB1*0301. Peripheral blood mononuclear cells (PBMC) from 281 previously vaccinated measles-mumps-rubella II (MMR-II) subjects (HLA discordant) were studied for peptide recognition by T cells. Significant gamma interferon (IFN-gamma) responses to MV-P and MV-N peptides were observed in 55.9 and 15.3% of subjects, respectively. MV-P- and MV-N-specific interleukin-4 (IL-4) responses were detected in 19.2 and 23.1%, respectively, of PBMC samples. Peptide-specific cytokine responses and HLA-DRB1 allele associations revealed that, for the MV-P peptide, the allele with the strongest association with both IFN-gamma (P = 0.02) and IL-4 (P = 0.03) secretion was DRB1*0301. For MV-N, the allele with the strongest association with IFN-gamma secretion was DRB1*1501 (P = 0.04), and the alleles with the strongest associations with IL-4 secretion were DRB1*1103 and DRB1*1303 (P = 0.01). These results indicate that HLA class II MV proteins can be processed, presented, and identified, and the ability to generate cell-mediated immune responses can be demonstrated. This information is promising for new vaccine design strategies with peptide-based vaccines.

Alleles↗
PubMed2002

Associations of HLA class II alleles with pulmonary tuberculosis in Thais.

Tuberculosis is an important infectious disease in Thailand. Susceptibility to tuberculosis is influenced not only by the environment but also by host genetic factors. In this study, we investigated HLA alleles in 82 patients with tuberculosis from Bangkok and in 160 normal controls. HLA-DRB1, DQA1 and DQB1 genotyping was performed by the PCR-SSO method. The frequency of HLA-DQB1*0502 was increased in tuberculosis patients compared to the normal controls (P = 0.01, OR = 2.06). In contrast, the frequencies of DQA1*0601 and DQB1*0301 were decreased in tuberculosis patients compared to the controls (P = 0.02 and P = 0.01, respectively). Our results suggest that HLA-DQB1*0502 may be involved in the development of pulmonary tuberculosis, whereas HLA-DQA1*0601 and DQB1*0301 may be associated with protection against tuberculosis.

Alleles↗
PubMed2004

Umbilical cord blood-naive T cells but not adult blood-naive T cells require HLA class II on antigen-presenting cells for allo-immune activation.

Because a relatively low incidence and severity of graft-versus-host disease after umbilical cord blood (UCB) transplantation is observed, we investigated whether T cells from UCB or adult blood (AB) were differentially activated by antigen-presenting cells with or without human leukocyte antigen (HLA)-DR expression. T cells from UCB or AB, or CD45RA(+) naive T cells and CD45RO(+) memory T cells separated from AB, were stimulated with the HLA-DR(+) or HLA-DR(-) cell line AML193. On days 1-3 after stimulation, numbers of interleukin (IL)-2, IL-4, IL-10 or interferon gamma (IFN-gamma)-secreting cells were determined by enzyme-linked immunospot analysis. No IL-4 or IL-10 was produced. AML193-DR(+) cells induced IL-2 and IFN-gamma secretion with slower kinetics and lower levels in UCB T cells than in AB T cells. AML193-DR(+) cells induced comparable IL-2 but higher IFN-gamma secretion in CD45RA(+) T cells from AB than in UCB T cells. AML193-DR(-) cells did not induce IL-2- or IFN-gamma secretion in UCB T cells, but stimulated both CD45RA(+) and CD45RO(+) T cells from AB to secrete IL-2 and IFN-gamma. Thus, not only the absence of memory T cells but also the inability to respond to HLA-DR-negative antigen-presenting cells and the slower kinetics and level of activation found for naive T cells from UCB as compared with AB may partly explain the reduced antirecipient reactivity after UCB transplantation.

Antigen-Presenting Cells↗
PubMed1995

Clip binds to HLA class II using methionine-based, allele-dependent motifs as well as allele-independent supermotifs.

The invariant chain (Ii) region that interacts with class II and inhibits premature peptide binding has been mapped to amino acids 82-107, known as CLIP. It is unclear whether CLIP binds directly to the class II peptide binding groove and thus competitively blocks binding of other peptides, or whether it binds to conserved class II sites and indirectly inhibits peptide binding by inducing conformational changes in class II. Here we show evidence that strongly suggests that CLIP binds within the peptide binding groove, as CLIP binds to various HLA-DR alleles using allele-dependent as well as allele-independent, methionine-based binding motifs. First, a core sequence of 12 amino acids was identified within CLIP which is required for optimal binding to DR1, DR2, DR3(17) and DR7. This sequence is composed of CLIP p88-99 (SKMRMATPLLMQ). By substitution analysis, all three methionine residues appeared to control CLIP binding to HLA-DR. However, whereas M90 controlled binding to all four alleles, M92 and M98 were of different importance for the various alleles: M92 is involved in CLIP binding to DR1 and DR3(17) but not to DR2 or DR7, and M98 controls CLIP binding to DR2, DR3(17) and DR7 but not DR1. Also, CLIP competes with known immunogenic peptides for class II binding in a manner indistinguishable from regular, class II binding competitor peptides. Finally, the dissociation rates of CLIP-class II complexed are similar to those of antigenic peptide-class II complexes. Thus, CLIP most likely binds to the class II peptide binding groove, since most allelic class II differences are clustered here. CLIP uses unconventional methionine anchor residues representing an allele-independent supermotif (M90) as well as allele-dependent motifs (M92 and M98).

Alleles↗
PubMed1995

An analysis of HLA class II gene polymorphism in British and Greek idiopathic membranous nephropathy patients.

Fifty-two British and 29 Greek idiopathic membranous nephropathy (IMN) patients were analysed for DRB, DQA1, DQB1 and DPB1 gene polymorphism using second exon amplification and sequence-specific oligonucleotides (SSO). In addition 100 British and 92 Greek controls were analysed. A highly significant increased frequency of the DRB1*0301 allele was found in IMN patients from Britain (80%), when compared to controls (27%, OR 10.6, P = 0.000004). A lower frequency of DRB1*0301 was observed in Greek IMN patients (33%), but this was just significant before correction, when compared to Greek controls (15%, OR 3, P = 0.02). The DRB3 allele most often associated with DRB1*0301 was DRB3*0101 (OR 4.2, P = 0.00025) in British patients and DRB3*0201/2 (OR 11, P = 0.006) in Greek patients. In Greek IMN patients a decrease in DR16 was found (OR 0.08, P = 0.004), and the overall incidence of DR2 was significantly lowered when both sets of IMN patients were combined (OR 0.21, chi 2 17.6, P = 0.00013). The incidence of DQA1*0501 was raised in both Greek (96% vs. 66%, OR 9.7, chi 2 6.9, P = 0.009) and British IMN (85% vs. 45%, OR 7.4, chi 2 20, P = 0.00007) patients. This gives some support to a proposal for a major role for this allele in IMN.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗