The immunogenicity of a viral cytotoxic T cell epitope is controlled by its MHC-bound conformation.
(1/4)
Thousands of potentially antigenic peptides are encoded by an infecting pathogen; however, only a small proportion induce measurable CD8(+) T cell responses. To investigate the factors that control peptide immunogenicity, we have examined the cytotoxic T lymphocyte (CTL) response to a previously undefined epitope ((77)APQPAPENAY(86)) from the BZLF1 protein of Epstein-Barr virus (EBV). This peptide binds well to two human histocompatibility leukocyte antigen (HLA) allotypes, HLA-B*3501 and HLA-B*3508, which differ by a single amino acid at position 156 ((156)Leucine vs. (156)Arginine, respectively). Surprisingly, only individuals expressing HLA-B*3508 show evidence of a CTL response to the (77)APQPAPENAY(86) epitope even though EBV-infected cells expressing HLA-B*3501 process and present similar amounts of peptide for CTL recognition, suggesting that factors other than peptide presentation levels are influencing immunogenicity. Functional and structural analysis revealed marked conformational differences in the peptide, when bound to each HLA-B35 allotype, that are dictated by the polymorphic HLA residue 156 and that directly affected T cell receptor recognition. These data indicate that the immunogenicity of an antigenic peptide is influenced not only by how well the peptide binds to major histocompatibility complex (MHC) molecules but also by its bound conformation. It also illustrates a novel mechanism through which MHC polymorphism can further diversify the immune response to infecting pathogens. (+info)
Relationship between primary nodal generalized osteoarthritis with tissue antigens HLA-A and HLA-B in the western Black Sea region of Turkey.
(2/4)
OBJECTIVE: To investigate the relationship between patients diagnosed with nodal generalized osteoarthritis (NGOA) and tissue antigens HLA-A and HLA-B in the Western Black Sea Region of Turkey. PATIENTS AND METHODS: Forty-six patients with NGOA (64.74+/-8.46) and 60 controls (62.32+/-6.8) were included in the study. Inclusion criteria were: (i) stage 2 and higher OA of the hand and knee based on the Kellgren-Lawrence classification, and (ii) stage 2 and higher lumbar disc degeneration according to Lawrence classification. Family histories were taken from patients. HLA-A and HLA-B were typed by PCR using sequence specific primer. RESULTS: The frequencies of HLA-A(*)02 and HLA-B(*)38 were 58.7% and 15.2%, respectively, in patients with NGOA, and there was a statistically significant relationship between the disease and HLA-A(*)02 and HLA-B(*)38. The relationship between positive family history and HLA-B(*)44 allele was also statistically significant. In the control group, the frequency of HLA-A(*)29 was 11.7% and it was statistically significant. CONCLUSION: To our knowledge this is the first study to demonstrate the epidemiologic association between HLA-A(*)02 and HLA-B(*)38 with NGOA in our population. We conclude that, HLA-B(*)44 positivity may be associated with familial NGOA and HLA-A(*)29 may be a preventive factor against NGOA. (+info)
Presentation of human minor histocompatibility antigens by HLA-B35 and HLA-B38 molecules.
(3/4)
Cytotoxic T lymphocyte (CTL) clones specific for human minor histocompatibility antigens (hmHAs) were produced from a patient who had been grafted with the kidneys from his mother and two HLA-identical sisters. Of eight CTL clones generated, four recognized an hmHA (hmHA-1) expressed on cells from the mother and sister 3 (second donor); two recognized another antigen (hmHA-2) on cells from the father, sister 2 (third donor), and sister 3; and the remaining two clones recognized still another antigen (hmHA-3) on cells from the father and sister 3. Panel studies revealed that CTL recognition of hmHA-1 was restricted by HLA-B35 and that of hmHA-2 and hmHA-3 was restricted by HLA-B38. The HLA-B35 restriction of the hmHA-1-specific CTL clones was substantiated by the fact that they killed HLA-A null/HLA-B null Hmy2CIR targets transfected with HLA-B35 but not HLA-B51, -Bw52, or -Bw53 transfected Hmy2CIR targets. These data demonstrated that the five amino acids substitutions on the alpha 1 domain between HLA-B35 and -Bw53, which are associated with Bw4/Bw6 epitopes, play a critical role in the relationship of hmHA-1 to HLA-B35 molecules. The fact that the hmHA-1-specific CTLs failed to kill Hmy2CIR cells expressing HLA-B35/51 chimeric molecules composed of the alpha 1 domain of HLA-B35 and other domains of HLA-B51 indicated that eight residues on the alpha 2 domain also affect the interaction of hmHA-1 and the HLA-B35 molecules. (+info)
HLA associations in clozapine-induced agranulocytosis.
(4/4)
We previously reported preliminary results of association of clozapine-induced agranulocytosis (CA) with HLA-B38, DR4, DQ3 in five Ashkenazi Jewish patients and with HLA-DR2, DQ1 in four non-Jewish patients. In the present study, 31 additional patients with CA, 10 Ashkenazi Jewish, and 21 of non-Jewish ancestry, were studied. HLA alleles and haplotypes were compared among 52 patients (33 Ashkenazi Jewish, 19 non-Jewish) matched for ethnic background and clinical status. Our results show two associations and define the HLA allele markers for the Ashkenazi Jewish and non-Jewish haplotypes associated with CA. The most important markers for susceptibility for CA in Ashkenazi Jewish patients were DRB1*0402, DQB1*0302, and DQA1*0301, and in non-Jewish patients, HLA-DR*02, DQB1*0502, and DQA1*0102. HLA-DRB1*011 and DQB1*0301 were underrepresented in Ashkenazi Jewish patients when compared with controls. We hypothesize that genes of the major histocompatability complex, other than class I and class II, are responsible for CA; among them are the variants of the heat-shock proteins 70 or the tumor necrosis factor loci. (+info)