Biomedical subjects
Publications and source records attributed to C Cullen.
Using sequence-specific oligonucleotide probes, no altered distribution in the frequency of HLA-DPB1 alleles was found in multiple sclerosis patients from Northern Ireland. Although present in the controls, linkage disequilibrium between HLA-DPB1*0101 and HLA-DR17 was not found in multiple sclerosis patients.
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Five new restriction fragment length polymorphisms (RFLPs) using TaqI and a DR beta probe have been found in Caucasian individuals. The families of these individuals have been tissue typed by serological and RFLP methods. The new RFLPs are similar to previously established RFLPs except for the size of one fragment in each instance.
Multiple sclerosis has been shown to be associated with the presence of certain major histocompatibility (MHC) tissue antigens which are coded on chromosome 6. There are racial differences in the antigens associated with MS. The strength of the associations vary in different communities in Western Europe. We have investigated the association between MS and MCH antigens in Northern Ireland in a group of 104 patients. There is a particularly strong association between MS and HLA-DR2, 65.4% compared with 25.5% in 184 controls. A weaker association has been demonstrated with HLA-A3 (44.2% vs 26.5% in controls). There have been conflicting reports concerning an association of HLA-DW2 and HLA-DR2 with a rapidly progressive form of MS. Our data do not support that hypothesis.
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Extensive analysis of restriction fragment length polymorphism using HLA class II and T-cell receptor gene probes has been carried out in an attempt to identify genetic markers more strongly associated with multiple sclerosis than the classically defined antigens DR2, Dw2, and DQw1. The use of DNA pooled from groups of patients and controls from northeast Scotland enabled the screening of 14 restriction endonucleases with five HLA-D region probes (DP alpha, DP beta, DQ alpha, DQ beta, DR beta) and two T-cell antigen receptor probes. Restriction fragment length polymorphisms which discriminated between multiple sclerosis and control pools were identified with four restriction enzymes: Msp1 (DQ alpha), BamH1, Bgl11, and Taq1 (DQ beta). No discriminatory polymorphism was seen with any of the other enzyme/probe combinations. Subsequent Southern blot analysis of individual DNA samples was carried out using these enzymes and probes in two independently conducted studies, in Northern Ireland and northeast Scotland. Following Msp1-digestion and hybridization to DQ alpha, a 3.25-kb fragment was observed in 31% of Scottish patients but in only 4% of controls from the same population. Furthermore, when only DR2-positive individuals were analyzed, there was a significant excess of this fragment in patients from both Scotland (28, or 2.9%) and Northern Ireland (20, or 3.4%). Although the DQ alpha gene characterized by this fragment remains to be determined, this fragment exhibits apparent allelism to DQw1. Therefore, these data raise the possibility that two different DQ alleles, one on each haplotype, may jointly contribute to disease susceptibility.
DNA techniques were applied to typing a population of renal patients in order to assess the number of discrepancies between this technique and the serological technique. Five patients had been given an incorrect type by serology, and in 22 instances allogenotypes were found where previously there had been a serological blank. DNA typing was also able to determine allogenotypic subtypes that correlated with DR antigens difficult to split by serology and to determine allogenotypic subtypes correlating with DR antigens not known to have a split by serology. Whereas DNA typing provided a result first time of testing on all but 3 patients, the average number of serological testings for each patient was 1.9.
The HLA-DR antigens DRw8, DRw11, DRw12, DRw13, DRw14 and DRw17 are strongly associated with the supertypic specificity DRw52. This association has been used to assist in assignment of serological specificity. However, difficulties in the identification of these antigens arise since they are serologically crossreactive. This report describes the application of restriction fragment length polymorphism (RFLP) allogenotyping to assist in the positive identification of DRw8, DRw11, DRw12, DRw13, DRw14, DRw17, DRw52a and DRw52b, and in addition describes further subtypes defined by RFLP which correlate with DQ or Dw associations. We also describe a novel TaqI/DR beta RFLP in a Caucasian family which types serologically as DRw12.
The antigen HLA-DRBr, previously associated with HLA-DQw1, has been found by RFLP to be associated with HLA-DQw3.
A new method of determining class II HLA antigens by genotyping with HLA DNA probes is described. This method compares favourably to the traditional serological methods.
Anger is a poorly understood but very common emotion. When it is misdirected or uncontrolled it becomes dangerous. An analysis of anger and a treatment paradigm is presented, and we outline a research project in which we are using the approach with a group of mentally handicapped adults.
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