Biomedical subjects
Publications and source records attributed to W R Mayr.
The genetic structure of the HLA gene complex, which represents the major histocompatibility complex of man, is described. The polymorphisms at the various HLA loci as well as the biologic function of the HLA system with respect to the immune response are discussed.
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The influence of treatment of platelets with citrate buffer (pH 7.2), chloroquine, or citric acid at pH 3 on the expression of HLA class I antigens and 'thrombocyte-specific' glycoproteins was investigated by means of flow cytometry. After treatment with citric acid at pH 3 and chloroquine, the expression of HLA class I was significantly reduced, while the density of the molecules GPIa/IIa, GPIIb, and GPIIb/IIIa (GP = glycoprotein) carrying 'thrombocyte-specific' antigens was not or only weakly decreased on the surface of the platelets. The use of two monoclonal antibodies (HC-10 and HC-A2) against the native heavy chain of the HLA class I molecule revealed that 'antigen stripping' with chloroquine or citric acid does not affect the entire molecule: only the beta 2-microglobulin is cleaved, or only some epitopes on the heavy chain are altered by this procedure. The treatment with citric acid yielded better results with respect to the removal of HLA class I activity and the preservation of 'thrombocyte-specific' glycoproteins. The presence of the heavy chain of HLA class I molecules on the surface of platelets after treatment with citric acid and chloroquine confirms the hypothesis that platelets--like nucleated cells--bear HLA class I antigens inserted in the cell by a cytoplasmic and a transmembrane domain.
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Forty-five patients with myeloproliferative or myelodysplastic syndromes, treated with recombinant interferon-alpha (rIFN-alpha) for a minimum of 1 up to 4 years, were examined for the occurrence of thyroid autoimmunity. During treatment, the rate of thyroid autoimmunity rose to more than 20%. The decrease in severity and frequency of thyroid autoimmunity after withdrawal of IFN shows that this is a potentially reversible side effect. The key determinant for the manifestation of this IFN-related autoimmune phenomenon seems to be a predisposition for autoimmunity, since patients with initially detectable thyroid antibodies are prone to exacerbations of thyroid autoimmunity. Concurrent with thyroid autoimmunity, hypothyroidism occurred but did not correlate with the levels of thyroid antibodies, although severe hypothyroidism in two patients was accompanied by increased levels of thyroid antibodies. This investigation shows that thyroid autoimmunity and consecutively hypothyroidism must be expected in certain patients treated with rIFN-alpha during long periods. Furthermore, it may be assumed that IFN-alpha does not induce the development of autoimmunity, but rather enhances the levels of pre-existent thyroid antibodies.
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A total of 52 nonrelated Caucasian patients (21 male, 31 female, age at onset of the disease: 7-74 years, average: 31.6 years) suffering from intermediate uveitis were tissue typed for 56 different HLA-A, -B, -C and -DR-antigens. No significant association between any specific HLA-antigen and the disease, both when comparing the total patient group with a large, healthy control population, or any of the different subgroups (male vs. female, early vs. late onset, mild vs. severe course) could be demonstrated.
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The etiology of autoimmune diseases is multifactorial with genetic factors being an important prerequisite. There are two clinical manifestations of autoimmune thyroiditis: the goitrous form (Hashimoto's thyroiditis) and the atrophic variant, which is characterized by hypothyroidism (primary myxoedema). Different genetic markers were assumed to be predisposing factors for the distinct clinical presentation. In the present study, we determined HLA A,B,C,DR,DQ alloantigens serologically and HLA-DQ by gene analysis in patients with nongoitrous autoimmune thyroiditis and randomly chosen controls. To verify the exact classifications, thyroid volume (median 5.85 ml) was measured by ultrasonography. HLA-DR5 was found in 16 of 36 (44%) patients with nongoitrous autoimmune thyroiditis and in only 26 of 175 controls (15%) (Pc = 0.0018). There was a tendency towards a lower frequency of HLA-DR7 with 6% positivity in patients vs. 29% in controls (Pc = 0.052). Regarding HLA-DQ, DQ7 was found in 17 of 35 patients (48%) vs. 21 of 98 controls (21%) (Pc = 0.028) (relative risk 3.5). No other association was found with HLA-A,B,C and HLA-DR and -DQ. Our data indicate that the genetic susceptibility to autoimmune nongoitrous thyroiditis is closely associated to HLA-DR5 and DQ7 and not distinct from goitrous disease. We conclude that factors other than genetic ones explain the different immunological and clinical manifestation of chronic lymphocytic thyroiditis.
Corneas used for transplantation are typically obtained from donors up to 48 hr post mortem. By this time, standard HLA typing usually is impossible because of the lack of viable lymphocytes in spleen and peripheral blood. To increase the number of HLA-typed corneas, we developed a method in which the retinal pigment epithelial (RPE) cells of the donor eye are isolated, cultured in the presence of 1000 IU/ml interferon-gamma (IFN-gamma), and, after 4 d, are typed for HLA Class I and Class II antigens in the standard NIH cytotoxicity assay. Sixty five donors were typed simultaneously using peripheral blood lymphocytes and RPE. One hundred and sixteen out of 120 HLA-A antigens, 125/127 HLA-B, 106/108 HLA-C, and 92/100 HLA-DR antigens were identical using the same technique. Donor age, sex, cause of death, time of enucleation post mortem, and time of RPE preparation post mortem, as well as duration of culture period prior to stimulation with IFN-gamma did not correlate with the results of HLA typing. These data show that RPE cells can substitute for lymphocytes in post mortem HLA typing. Consequently, every donor with corneas suitable for transplantation can be prepared for matched transplantation.
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The basis and efficiency of paternity testing using conventional markers (alloantigens or electrophoretically defined polymorphisms in blood) for individuals involved in cases of affiliation are shown. A possible use of DNA polymorphisms in paternity cases is discussed. Due to the fact that the formal genetics of DNA polymorphisms have not been fully validated by the analysis of large numbers of informative meioses, it is not yet possible to include these systems in routine paternity testing. As the vast majority of cases can be resolved by conventional markers, the inclusion of DNA polymorphisms is not usually necessary; in some cases, however, they can provide additional information.
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It has been known for a long time that there is an increased incidence of Graves' disease and immune thyroiditis in certain families. Genetic research of this disease has shown that it is most probably transmitted in a multifactorial way, i.e. that environmental as well as genetic factors play a role in the genesis of the diseases. This hypothesis is supported by the fact that the rate of concordance is maximally 50% in identical twins. The following model of threshold values is conceivable for the formal genetics of Graves' disease and immune thyroiditis: the diseases break out whenever the sum of environmental (viruses, bacteria, iodine excess, hormones, stress) and genetic (MHC and non MHC-restricted) factors is higher than a given threshold. One of the major genes influencing the genesis of the diseases seems to be HLA-DR3 (or a closely linked gene in strong linkage disequilibrium). If this gene is present, fewer environmental factors are possibly needed.