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Biomedical subjects

C Darke

Publications and source records attributed to C Darke.

At least 73 records · Page 4Linked to original sources
PubMed1996

HLA-A9 antibodies and epitopes.

Fifty pregnancy alloantisera directed towards HLA-A23 and/or A24 antigens were investigated serologically in titration studies against the three sequenced HLA-A9 specificities, A23 (A*2301), A24 (A*2402) and A2403 (A*2403). The reaction patterns of the antisera fell into five categories which allowed the three HLA-A9 specificities to be easily differentiated. Based on the various titre cytotoxicity scores of the antisera five possible antibody specificities were defined: anti-A23; -A24; -A23/24; -A24/2403 and anti-A23/24/2403. One antiserum crossreacted with HLA-A1 and A24. Inspection of the amino acid sequences of 136 HLA-A, B and C molecules allowed the prediction of five unique epitopes corresponding to these antibody specificities, a possible epitope unique to A2403 and confirmation of a likely epitope shared by A1 and A24. These, together with the previously suggested epitopes HLA-A9/ A2/A28 and A1/A23/A24 together with the presence of Bw4 on the three HLA-A9 antigens suggests that the HLA-A9 family of antigens is characterized by a minimum of nine serologically definable epitopes.

Antibodies↗
PubMed1996

Distribution of the HLA-A9 antigen family (A23, A24 and A2403).

Characterization of 50 local anti-HLA-A9 (A23 and/or A24) sera against the HLA-A2403 antigen allowed the retrospective assignment of A2403 and the verification of A23 and A24 specificities in a panel of 9196 volunteer bone marrow donors. The six A2403 positive subjects identified were confirmed by PCR using four sequence-specific primer mixtures. Population analysis showed the distribution and HLA-A/B linkage disequilibrium of HLA-A23 and A24 to be typical of a Northern European Caucasoid population. HLA-A2403 has a phenotype frequency of 0.00065 (gene frequency-0.00033) and is in linkage disequilibrium with HLA-B63 and possibly B35.

Bone Marrow↗
PubMed1996

HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom.

OBJECTIVE: To investigate the HLA class I associations of ankylosing spondylitis (AS) in the white population, with particular reference to HLA-B27 subtypes. METHODS: HLA-B27 and -B60 typing was performed in 284 white patients with AS. Allele frequencies of HLA-B27 and HLA-B60 from 5926 white bone marrow donors were used for comparison. HLA-B27 subtyping was performed by single strand conformation polymorphism (SSCP) in all HLA-B27 positive AS patients, and 154 HLA-B27 positive ethnically matched blood donors. RESULTS: The strong association of HLA-B27 and AS was confirmed (odds ratio (OR) 171, 95% confidence interval (CI) 135 to 218; p < 10(-99)). The association of HLA-B60 with AS was confirmed in HLA-B27 positive cases (OR 3.6, 95% CI 2.1 to 6.3; p < 5 x 10(-5)), and a similar association was demonstrated in HLA-B27 negative AS (OR 3.5, 95% CI 1.1 to 11.4; p < 0.05). No significant difference was observed in the frequencies of HLA-B27 allelic subtypes in patients and controls (HLA-B*2702, three of 172 patients v five of 154 controls; HLA-B*2705, 169 of 172 patients v 147 of 154 controls; HLA-B*2708, none of 172 patients v two of 154 controls), and no novel HLA-B27 alleles were detected. CONCLUSION: HLA-B27 and -B60 are associated with susceptibility to AS, but differences in HLA-B27 subtype do not affect susceptibility to AS in this white population.

Alleles↗
PubMed1996

Major histocompatibility complex class II and complement polymorphisms in postpartum thyroiditis.

The objective was to re-evaluate the association between class II HLA-DR and DQ MIIC antigens and postpartum thyroiditis (PPT) and to determine the prevalence of the class III complement allotypes of Properdin factor B (Bf), C4A and C4B in this condition. Two hundred and sixty-five (of 2897) pregnant women screened positive for thyroid autoantibody activity took part. Further blood samples were obtained for HLA class II (185) and complement (193) typing. The severity of the ensuing PPT was assessed by measuring thyroid function during the postpartum year. The HLA-DR and DQ phenotypes were assigned from restriction fragment length polymorphism analysis, and Bf, C4A and C4B allotypes were determined by immunofixation with anti-Bf or anti-C4 antibodies after electrophoresis. A weak association between the HLA class II antigens and PPT, as indicated by a reduced frequency of DR15 and DQ6 together with an increased frequency of-DR5 and DQ7, was confirmed. However, only the change in DR5 frequency remained significant after correction (corrected p < 0.05). Postpartum thyroiditis was also associated with frequency disturbances in BI and C4A allotypes but not C4B allotypes. Whilst this study has not provided evidence of a strong marker gene for PPT, it does not preclude the involvement of the MIIC in this condition. These data show disturbances in complement allotype frequencies, suggesting that the class III region may provide a useful focus for further study of this pathology.

Complement C4a↗
PubMed1996

Serological and molecular identification of an HLA-B8 variant, HLA-B8Jon (B*0802).

The serological and molecular characteristics of the first HLA-B8 variant (B8Jon), located on a haplotype bearing HLA-A1, -B8Jon, -Cw*07, DRB1*0301, DQA1*05, DQB1*0201, BfS, C4AQ0, C4B1 and the microsatellite alleles D6S265-3, 258-11, 105-8, 299-1 and 202-2 are identified and described. This new HLA-B antigen was distinguished from the usual B8 by its lack of reactivity with Bw6 and most Bw4 antisera, together with its failure to react with most antisera cross-reactive with HLA-B8. B8Jon gives a 'weaker' response than HLA-B8 in titration studies with B8 antisera. It cannot be differentiated from the usual B8 by one-dimensional iso-electric focusing. Time course studies, absorption analyses and serological tests on 17 Bw4 antibodies suggest that B8Jon possesses an unusually 'weak' Bw4 epitope. Studies on the Bw4 sequence motif by PCR, using sequence-specific primers, indicate that B8Jon has a Bw4 sequence in common with other HLA-B alleles, including B*4402-B*4405, rather than the Bw6 motif found on the familiar HLA-B8 molecule.

DNA↗
PubMed1995

Expression of an unusual Bw4 epitope by a subtype of HLA-B8 [B*0802].

The primary structure of a variant HLA-B8 antigen has been determined by cDNA cloning and sequencing. The variant, B*0802 differs, from the common B*0801 subtype at positions 77-83 of the alpha 1 helix that determine the Bw4 and Bw6 public epitopes. Whereas B*0801 has the common Bw6 motif, B*0802 has the Bw4 motif found in B*13 and B*44 allotypes. Serological analysis of B cell lines expressing B*0802 and of a B*0802 transfectant made with the HLA-A,B negative cell line 721.221 shows that B*0802 reacts with Bw4-specific antibodies, but at a level much lower than expected for Bw4 positive HLA-B allotypes.

Alleles↗
PubMed1995

Immunogenetic analysis of HLA-DR10 homozygous individuals.

Molecular, cellular and serological analysis of Major Histocompatibility Complex alleles was performed on three individuals who appeared to be HLA-DR10 homozygous by DNA restriction fragment analysis. Each donor was of different ethnic origin: Caucasoid, Asian Indian and African Negroid. The results of our studies show that the Caucasoid and Asian donors are indeed homozygous for the HLA-DR10 allele, while the African donor also possesses the DRB1*0103 allele. Homozygosity for the HLA-A1-B37-Cw6-DR10-DQ5 haplotype in the Caucasoid donor was confirmed by familial segregation analysis. The B-lymphoblastoid cell line produced from this donor should prove useful in studies of HLA immunogenetics.

Alleles↗
PubMed1995

Immunoglobulin allotype frequencies in responders and nonresponders to the Rh(D) antigen.

Immunoglobulin allotype frequencies were determined in well characterised groups of responders (n = 160) and non-responders (n = 32) to Rh(D) antigen immunisation. Allotype frequencies in these groups were compared with frequencies in a normal control population (n = 500). No significant differences in allotype frequencies were observed between the responder and non-responder groups, or when these two groups where compared with a normal control population. These results suggest that the immunoglobulin heavy-chain genes do not influence the anti-Rh(D) immune response.

Female↗
PubMed1995

Nature of HLA-associated predisposition to childhood acute lymphoblastic leukemia.

A molecular analysis was carried out in 63 sequentially diagnosed childhood acute lymphoblastic leukemia (ALL) patients and 1011 controls to investigate the homozygosity rate for HLA-DR53. HLA-DR53 is associated with acute myeloblastic leukemia at the protein level, and our previous study has shown its association with early-onset chronic myeloid leukemia only in homozygous form at the DNA level. In the present study, the homozygosity rates for DR53 were 17.5 and 13.6% in patients and controls, respectively. Ten of the 11 homozygous patients were boys. In the common ALL group (n = 40), all seven DR53 homozygous patients were boys, and among 19 girls this genotype was not observed (P = 0.006). For males, homozygosity for DR53 revealed a relative risk (RR) of 3.29 (P = 0.008) for common ALL. Five of the 11 relapsed patients were homozygous for DR53. Heterozygous frequencies for HLA-DR53 were not different between patients and controls. Homozygosity for DR53 was associated with a very high relapse rate (45.5 vs 7.7%, P = 0.002, RR = 9.1). These results extended our findings in chronic myeloid leukemia and showed the recessive nature and the male predominance of the interactive HLA influence on the development of childhood leukemia. Molecular mimicry of an HLA-DR53 epitope by oncogenic (retro)viruses or putative susceptibility genes in linkage disequilibrium with HLA-DR53 may be responsible for this association.

Adolescent↗
PubMed1994

TAP1 and TAP2 polymorphism in multiple sclerosis patients.

The frequency of TAP1 and TAP2 gene polymorphisms in MS patients was compared with that of a normal population. A significant increase in TAP2-379-VAL homozygosity and TAP2-565-ALA homozygosity was found in HLA-DRB1*1501-DQB1*0602-negative patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Alleles at D6S265 and D6S105 define a haemochromatosis-specific genotype.

Hereditary haemochromatosis is an HLA-linked, recessive disorder with HLA-A3 a strong marker for the gene. We have identified molecular markers for two serologically indistinguishable subtypes of HLA-A3 and examined these in 42 patients with haemochromatosis. The common HLA-A3 subtype HLA-A*0301 (highly correlated with allele 1 of D6S265) was a slightly better marker for haemochromatosis (RR = 10.1, Chi2 = 30) than the serologically recognized A3 antigen (RR = 9.1; Chi2 = 27.3). Allele 8 of the more telomeric locus D6S105 was also strongly associated with haemochromatosis (RR = 13.0; Chi2 = 21.1) but alleles at this locus were not in strong linkage disequilibrium with HLA-A alleles in the control subjects. The co-occurrence of D6S265-1 and D6S105-8 alleles yielded a higher risk (RR = 16.9; Chi2 = 44). Homozygosity for the haplotype including these markers was specific for haemochromatosis, i.e. did not occur in 376 healthy subjects but was observed in 21.4% of patients. These results refine the HLA-A3 association with haemochromatosis, suggest that the haemochromatosis gene is located on the telomeric side of HLA-A and define a possible haplotype in which the first mutation may have occurred.

Adolescent↗
PubMed1994

Molecular characterization of the HLA-DR2LUM haplotype.

Molecular studies of HLA-DRB, -DRA and -DQB1 genes in the variant DR2 haplotype, DR2LUM, were performed using the homozygous lymphoblastoid cell line, CTS. The results of HLA Class II gene RFLP and PCR analyses suggest that DR2LUM was created by a homologous recombination event between HLA-DR1 and HLA-DR15 haplotypes. Evidence for the presence of a recombinational "hotspot" in haplotypes possessing a DRB6 pseudogene is presented. The results of this study have important implications for detection of HLA-DR2 alleles in DRB gene oligotyping strategies, and suggest that the CTS cell line will be a useful addition to cell panels for characterizing HLA antisera.

Alleles↗