Molecular analysis of HLA class II genes in primary Sjögren's syndrome. A study of Israeli Jewish and Greek non-Jewish patients.

In an attempt to define the role of HLA class II genes in predisposition to primary Sjögren's syndrome, patients of two different ethnic groups (Israeli Jews and Greeks of non-Jewish origin) suffering from this disorder were studied. Oligonucleotide genotyping revealed the majority in both groups to carry either DRB1*1101 or DRB1*1104, alleles that are in linkage disequilibrium with DQB1*0301 and DQA1*0501. The high frequency of the two alleles in these SS patients is in contrast with the accepted association of primary SS with HLA-DR3 in Italian and American individuals. Molecular analysis of DQB1 and DQA1 alleles found in American Caucasian and American black SS (or SLE) patients demonstrated high frequencies of DQB1*0201 and DQA1*0501. The fact that the majority of SS patients, across racial and ethnic boundaries, carry a common allele, DQA1*0501, implies its involvement in the predisposition to primary SS. Based on sequence analysis and the computer imaging of the HLA class II molecule structure, a hypothetical model for the role of the DQ molecule in promoting primary SS is proposed.

HLA polymorphism in Moroccan Jewry.

The Moroccan Jewish community living in Israel shows a relatively large genetic distance from other North African Jewish communities. In this work the polymorphism of HLA class I and class II determinants, as defined by serology and oligotyping, is analyzed in 113 healthy unrelated Jews of Moroccan stock. The class I antigens HLA-A1, -B44, and -Cw7 showed the highest frequency, while the most prevalent class II variants were DRB1*0701 and *1104, DQA1*0501, and DQB1*0201 and *0301. HLA A1-B13-DR7, A2-B51-DR10, and A1-B44-DR13 were the most typical three-locus haplotypes. Although the antigen frequency distribution of the Moroccan Jews falls within the Caucasian diversity range, this community has a unique pattern in terms of antigen, gene, and haplotype frequencies. Thus, in the Moroccan Jews DRB1*1305, an allele believed to be the result of a recombination event between DRB1*1301-1302 and DRB1*1101, is represented to a much larger extent than in all the other population groups studied at the 11th IHWS. This allele may therefore be a typical Jewish variant. A particular finding was the high frequencies of HLA-B13, B52, and DR10, alleles common among some Oriental populations. The answer to this enigmatic phenomenon probably must be sought in the tortuous history of this community.

In vitro screening of carcinogenesis inhibitors acting by inhibition of microsomal polycyclic aromatic hydrocarbon activation.

A procedure for in vitro prescreening of carcinogenesis inhibitors acting by the inhibition of the microsomal activation systems is described. It consists of measuring the protection conferred by the investigated chemicals against DNA binding of ultimate carcinogens resulted during G(3H)B[a]P activation. This rapid and reproducible procedure is able to select only carcinogenesis inhibitors which interact with the cytochrome P-450 dependent microsomal enzymes being specific in this respect. The effectiveness of 23 compounds (mainly antioxidants) was tested and the results compared with literary data concerning their activity. The concordance was satisfactory.

Strong linkage disequilibrium of TAP1*0301 and TAP2D alleles with the HLA A1-B35-DRB1*1104-DQA1*0103-DQB1*0603 extended haplotype in Ashkenazi Jews.

On the basis of data collected during the 12th International Histocompatibility Workshop, we postulated a possible linkage disequilibrium between the TAP1C allele and the DRB1*1104-DQA1*0103-DQB1*0603 haplotype characteristic of Ashkenazi Jews. In order to confirm and extend this preliminary observation, a group of 34 subjects carrying this haplotype was analysed for TAP1 and TAP2 polymorphisms and compared with two control groups sharing either the DRB1 or the DQA1 and DQB1 alleles with the test group. The TAP1*0301 and TAP2D alleles were found to be strongly associated with the entire haplotype, but not with the DRB1*1104 or the DQA1*0103-DQB1*0603 alleles when carried separately. These data show a strong linkage disequilibrium of TAP1*0301 and TAP2D alleles with the DRB1*1104-DQA1*0103-DQB1*0603 haplotype of Ashkenazi Jews, extended on the centromeric and telomeric side to the DPB1*0201 and A1-B35 alleles, respectively.

Serologic and molecular analysis of the HLA system in Israeli Jewish patients with oral erosive lichen planus.

Oral erosive lichen planus is a distinct subtype of the common dermatosis lichen planus. Although the etiology of lichen planus is still obscure, it is known that cell-mediated immune mechanisms and genetic factors underlie its pathogenesis. Previous studies have found an association between lichen planus and HLA-DR3 or DR9 in different population groups. The present work was designed to elucidate, at the serologic and molecular levels, whether and which HLA genes are associated with oral erosive lichen planus in Israeli Jewish patients. A significant association with HLA-DR2 (RR = 4.7; pc < 0.0013) and a decrease in DR4 (RR = 0.3; p < 0.03) among the patients were noted. Oligotyping of DR2 alleles showed the presence of all three common variants (DRB1*1501, DRB1*1502 and DRB1*1601) in the patients, although none of the variants was overrepresented significantly. Three possible explanations for the role of HLA genes in the predisposition to oral erosive lichen planus are discussed. The most attractive theory for the pathogenesis of the disease seems to include the involvement of non-classical HLA genes.

Comparative analysis of HLA polymorphism at the serologic and molecular level in Moroccan and Ashkenazi Jews.

The Jewish people comprise two major groups, one encompassing the Jews of Ashkenazi (Central and Eastern European) origin and the other including those of Sephardic (Middle Eastern and North African) descent. To the latter belong the Jews of Moroccan stock, who form the largest Jewish subgroup among the non-Ashkenazi population living in Israel. As the members of each of these groups differ in physiognomy and life style, it was of interest to investigate whether these differences are also reflected in their respective HLA compositions. To this end, 132 subjects of Ashkenazi and 113 individuals of Moroccan origin residing in Israel were tested and the results compared with data for other populations made available by the 11th International Histocompatibility Workshop. Comparison between their HLA profiles and those of non-Jews revealed that the Jewish groups in some aspects resembled one another but in others showed disparities. The dissimilarities between the various groups are expressed in terms of gene and haplotype frequencies, as well as in HLA-disease associations (as for example rheumatoid arthritis, erosive lichen planus, primary Sjögren's syndrome, pemphigus vulgaris). However, both Jewish groups shared some unique features with respect to HLA class II allelic frequencies, pointing to a common ancestry.

Evidence for the genetic role of human leukocyte antigens in low frequency DRB1*1501 multiple sclerosis patients in Israel.

A strong association exists between multiple sclerosis (MS) and the DRB1*1501 haplotype, in most populations. Linkage of Multiple Sclerosis (MS) with the MHC or HLA region on chromosome 6p21 has previously been observed in DRB1*1501 positive MS families. A group of 13 Israeli multiplex MS families with a very low frequency of DRB1*1501 haplotype were examined in this study. Association and a linkage test were performed in order to identify a non-DRB1*1501 effect of HLA on susceptibility for MS. MS multiplex families and healthy controls were molecularly typed for six highly polymorphic markers located within the MHC region: DRB1, DQA1 and DQB1, BAT-2, MIB and D6S248. Data analyses included: (a) an association study comparing the patient group with both healthy relative, and healthy control groups (b) a transmission test for linkage disequilibrium (TDT) of the MS-associated alleles in the multiplex families, and (c) multipoint non-parametric linkage (NPL) and parametric LOD score analyses using the GENEHUNTER program. The DRB1*1303 allele was significantly more frequent among the MS patients. There was a trend towards transmission disequilibrium of DRB1*1303, but was not statistically significant. Allele sharing and LOD score analyses revealed no evidence for linkage. The high frequency of DRB1*1303 observed in our family patients provides evidence to support the association with this allele that previously described in sporadic non-Ashkenazi MS patients. Thus, DRB1*1303 may serve as genetic risk factor for MS. Our study exemplifies the genetic heterogeneity in MS as there is a genetic effect of HLA on MS susceptibility in our low frequency DRB1*1501 patients.

Do specific pockets of HLA-C molecules predispose Jewish patients to psoriasis vulgaris?

BACKGROUND: Psoriasis vulgaris was reported to be associated with a specific alanine residue at position 73 of HLA-C alleles in Japanese patients. OBJECTIVE: Our purpose was to determine the role of HLA genes in susceptibility to psoriasis vulgaris in the Israeli Jewish population. METHODS: Twenty-eight Israeli patients were analyzed for their HLA class I and II specificities by means of serologic and molecular methods. RESULTS: All patients possessed in their HLA-C antigens an alanine residue at position 73 (p < 0.002). A significantly increased frequency of HLA-Cw6 and of Cw7 was also observed among the patients (p < 0.02). CONCLUSION: Our study clearly shows that alanine in position 73 is significantly associated with psoriasis vulgaris in Jewish patients. Cw6 and Cw7 have a unique antigen-binding pocket containing both alanine at position 73 and a negatively charged aspartic acid at position 9. These residues are most probably important in determining the conformation of the C pocket and in turn the nature of the peptide bound to it. We suggest that this combination confers the highest risk of the development of psoriasis vulgaris.