HLA-Dw clusters associated with DR4 in Israeli Jews and the definition of a new DR4 associated Dw subtype: Dw"SHA".

A homozygous typing cell (HTC), that identifies a newly defined HLA-Dw determinant Dw"SHA," is described. The donor of the HTC was a Yeminite Jew and an offspring of first cousin marriage. This cell is not included in the known DR4-associated specificity clusters Dw4,Dw10,Dw13,Dw14,Dw15, or the provisional cluster Dw"KT2." Dw"SHA" was shown to segregate with DR4 positive haplotypes in family analysis, and in a population study was present in three of 43 unrelated DR4 positive individuals. This new Dw determinant was detected in Israeli Jews of Yemenite origin bearing the haplotype HLA-Bw41,DR4,DQw3. This indicates that Bw41,DR4,DQw3,Dw"SHA" may represent a typical allele combination in Yemenite Jews. Among 43 DR4 haplotypes in Israeli Jews, Dw10 had the highest antigen frequency (41.8%), whereas in American Caucasoids and in Japanese, Dw4 and Dw15 were most frequent, 44% and 40.5%, respectively.

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.

Binding of peptides of the human acetylcholine receptor alpha-subunit to HLA class II of patients with myasthenia gravis.

MG is an autoimmune disease in which T cells specific to T-cell epitopes of the human acetylcholine receptor play a role. We have identified two peptides, p195-212 and p259-271, of the human acetylcholine receptor alpha-subunit, to which PBLs of MG patients responded by proliferation. Nevertheless, proliferation assays are relatively complicated to perform and might be affected by medications taken by the patients. Therefore, we tested the possibility of using a different assay to determine recognition of these peptides by MG patients. Thus, we performed a direct binding assay using biotinylated peptides and APCs from peripheral blood of MG patients and healthy controls. With this assay we detected the binding of the two peptides to the surface of intact APCs of both MG patients and control donors. Moreover, the presentation of peptide p259-271 by individuals with MG was significantly higher than that observed in healthy subjects. The peptides were specifically bound to HLA class II determinants on the APCs, as shown by inhibition with antibodies to the HLA class II haplotypes of the individuals investigated. Moreover, the binding of these peptides was in correlation with their ability to induce specific proliferative responses of peripheral blood T cells of these patients. The ability to screen for potentially pathogenic epitopes in each patient is of importance for the future design of specific inhibitory analogues that might be used to treat MG.

Analysis of the antigen specific helper T cell function and HLA-DR of Israeli patients with rheumatoid arthritis (RA).

Forty-three patients with rheumatoid arthritis (RA) were studied for their ability to respond to the synthetic polypeptide antigen (T, G)-A-L as measured by the production of a T cell helper factor by their antigen activated T cells. Sixteen patients (37%) responded to (T, G)-A-L by the production of an antigen specific helper T cell factor, a percentage not significantly different from healthy donors. The production of antigen specific T cell helper factors was affected, although not significantly, by immune modulating drugs and by the presence of rheumatoid factor in sera of patients. The high incidence of HLA-DR 4 reported for RA patients was not observed in this group of RA patients.

Invasive squamous cell carcinoma of the cervix: is HLA-DQ a disease marker in Jewish patients?

HLA class I and class II were investigated in 30 Israeli patients with invasive squamous cell carcinoma of the cervix and compared to healthy controls. None of the studied serological specificities were found to be associated with the disease. Genomic DNA from the patients was amplified by PCR, dot-blotted and hybridized with sequence specific oligonucleotide probes defining the known DQA1 and DQB1 allelic variants. Fifteen out of the 30 patients tested (50%) were found to carry the DQA1*0501 allelic variant, which is common in the local healthy population (67%). DQB1*0302 was found in eight out of 30 patients (27%) while this allele was present in 17% of the healthy population, a difference which is not statistically significant. Our data indicate that there is no apparent association between invasive squamous cell carcinoma of the cervix and the HLA antigens and alleles studied including the alleles of the DQA and DQB loci in the Israeli population. Our findings indicate that MHC genes could not be useful in the diagnosis of squamous cell carcinoma of the cervix.

Epstein-Barr virus-transformed pro-B cells are prone to illegitimate recombination between the switch region of the mu chain gene and other chromosomes.

Six independently maintained sublines of FLEB 14, a fetal-liver-derived Epstein-Barr virus-transformed pro-B cell line that has not yet rearranged its immunoglobulin genes, were examined after in vitro propagation during 19-36 months. Two lines showed no immunoglobulin heavy chain gene rearrangement, whereas one allele was rearranged with breakpoints inside the switch region of the mu chain gene in the remaining four. These rearrangements had been generated by the translocation of different chromosome fragments to the immunoglobulin heavy chain gene cluster-carrying 14q32 band in each of the four lines. Previously, a similar rearrangement was found in a fifth subline concurrently with a reciprocal 6;14 translocation. The transposed pieces have been derived from chromosomes 16 and 18 in two of the more recently rearranged lines. Their origins could not be determined in the remaining two lines, but they were different from each other and the other three 14q+ markers. The 14q+ marker-carrying variant has replaced its diploid progenitor suggesting that the translocation has conveyed some in vitro growth advantage on its carrier. This was also supported by the duplication of the 14q+ marker and the loss of its normal chromosome 14 homologue in one subline during serial culturing. The vulnerability of the switch region of the mu chain gene to illegitimate recombination at the pro-B stage and the possible relevance of this finding for the origin of the Burkitt lymphoma-associated 8;14 (immunoglobulin heavy chain gene cluster/MYC) translocation is discussed.

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.

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.

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.

Local suppression of Epstein-Barr virus (EBV)-specific cytotoxicity in biopsies of EBV-positive Hodgkin's disease.

Epstein-Barr virus (EBV)-positive Hodgkin's and Reed-Sternberg (HRS) cells express the virus-encoded latent membrane proteins LMP1 and LMP2 that could serve as rejection targets in Hodgkin's disease (HD). To examine whether EBV-triggered reactivities can be detected in the tumor, we have compared cytokine mRNA expression, cell phenotype, and cytotoxic activity in biopsies from 8 EBV-carrying and 6 EBV-HD patients. Neither the pattern of lymphokine production nor the cell phenotype of the in vivo-activated interleukin-2-responding populations provided a clear discrimination between EBV+ and EBV- cases. HLA class I-restricted EBV-specific cytotoxicity was shown in interleukin-2-dependent cultures from 3 of 3 EBV- tumors, whereas cultures from 6 of 6 EBV+ tumors were either noncytotoxic or exerted LAK-type cytotoxicity. EBV-specific cytotoxic T lymphocyte precursors were present in the blood of 1 patient carrying an EBV+ tumor. The results suggest that a tumor-associated suppression of EBV-specific T-cell responses may play an important role in the pathogenesis of EBV+ HD.