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Between 2008 and April 2018, we recruited more than 37 000 potential Arab donors to the Hadassah Bone Marrow Donor Registry, all of whom were typed for high resolution HLA‐A, ‐B, and ‐DRB1. In addition, more than 22% of them were also typed for their HLA‐C and ‐DQB1 alleles. A comparison of the sequences obtained from these donors with the IPD‐IMGT/HLA Database showed 33 novel alleles from five loci (HLA‐A, ‐B, ‐C, ‐DR, ‐DQ). All of these novel HLA alleles were detected in the local Arab communities; 79% of these alleles have not been described in other groups yet and remain unique to the local Arab communities. [ABSTRACT FROM AUTHOR]

Abstract: The occurrence of graft rejection episodes after orthotopic liver transplantation (OLT) despite the use of immunosuppressive drugs designed to suppress T lymphocyte functions, indicates the involvement of other types of cells in this process. The activity of natural killer cells and their killer immunoglobulin-like receptors (KIR) is regulated by human leukocyte antigen (HLA) class I determinants; C and Bw epitopes. Because recipient/donor pairs are usually HLA mismatched, recipient natural killer alloreactivity may be the mediating factor in rejection. In this retrospective study, we have analyzed rejection occurrence and outcome in 66 OLT recipients, 42 with and 24 without C or Bw epitope disparity in the rejection direction. Recipients transplanted from donors with no C epitope disparity had significantly fewer rejection episodes in the first year after transplantation compared with recipients transplanted across C epitope disparity (p = 0.0002). Moreover, this effect was more pronounced when the outcome was analyzed in OLT recipients across negative crossmatching for the anti-HLA class I and II antibodies. In contrast, Bw epitope disparity did not affect the outcome. In conclusion, C epitopes disparity between recipients and donors in the rejection direction appears to influence posttransplant liver outcome. This finding may be helpful in the choice of appropriate liver donor and planning immune suppression. [Copyright &y& Elsevier]

The HLA-Cw*0602 has been associated with psoriasis in different ethnic groups. But, it remains unclear whether HLA-C is the PSORS1 gene (the psoriasis gene in the MHC). Thus, several case–control studies have been performed in order to investigate whether HLA-C itself determines the susceptibility to the disease. We studied 59 Jewish patients with type I psoriasis and 79 matched controls. Polymorphic genes and markers from HLA-B (centromeric to HLA-C) to the corneodesmosin ( CDSN) gene (telomeric to HLA-C) were genotyped in order to determine their contribution to the susceptibility to psoriasis. Neither HLA-Cw*0602 nor the allele CDSN*TTC were significantly associated with psoriasis with the size of the sample studied. The genes and markers telomeric to HLA-C such as the microsatellite C1_4_4 (OR=2.6, 95% CI=1.4–4.7, pc=0.018) the octamer transcription factor ( OTF)-3 gene (OR=2.6, 95% CI=1.6–4.3, pc=0.0001) and the α-helix coiled-coil rod homologue ( HCR) gene (OR=2.5, 95% CI=1.3–4.5, pc=0.004), however, were associated with the disease. These results suggest that a major psoriasis susceptibility gene is likely to be located within a region of 150 kb telomeric to HLA-C and centromeric to the CDSN gene. [ABSTRACT FROM AUTHOR]

The impact of anti-HLA antibodies and crossmatch (CM) on liver transplantation (LT) outcome is still controversial. In this retrospective study we analyzed LT outcome according to pretransplant pre-formed anti-HLA antibodies and CM status. Serum anti-HLA antibodies were screened by ELISA assay, utilizing One Lambda antigen tray-mixed (LAT-M). CMs were performed by the complement dependent cytotoxicity test using Dithiotreitol treated sera. Anti-HLA antibodies were studied in 80 recipients; 56/80 had positive LAT-M tests (PLAT-M), whereas the remaining 24 recipients tested negative for both classes I and II (NLAT-M). Rejection episodes were more frequent in PLAT-M compared with NLAT-M group in post-LT intervals of <1 week (p = 0.05), 1 week–3 months (p = 0.035), and 3–12 months (p = 0.076). Graft and patient survival rates were better, albeit not significantly, in the NLAT-M compared with PLAT-M recipients. CM status was investigated in 62/80 recipients, 18/62 recipients had positive CM (PCM), and 44 had negative CM (NCM). Five of 18 PCM recipients (28%) experienced early graft loss compared with 1/44 (2%) with NCM (p = 0.006). Rejection episodes were more frequent within first 3 months post-LT in PCM recipients compared with NCM (p = 0.015). One-year graft survival rate was better in NCM, compared with PCM recipients (graft loss of 2/44 vs 5/18). NCM PLAT-M had a higher incidence of rejection episodes compared with the NCM NLAT-M group (p = 0.031). The presence of anti-HLA antibodies suggests a deleterious effect on LT outcome, and was associated with an increased incidence of early graft loss and rejection episodes. [Copyright &y& Elsevier]

Five locus allele-level HLA-A, -B, -C, -DRB1, -DQB1 allele and haplotype frequencies have been calculated for almost 29,000 people from three Arab populations that live in Israel and were recruited as donors to the Hadassah bone marrow donor registry. These groups are of Muslim, Christian and Bedouin Arab descent which represent more than 90% of the Arabs that live in Israel. The goal of the study was to describe the HLA genetic profiles of the Hadassah Arab registry donors and investigate the utility of these donors for the local and international hematopoietic stem-cell transplant community. The results demonstrate that the analyzed Arab populations share at least seven of the top ten most frequent alleles. Comparison with other populations confirmed the proximity of the three Arab populations to each other and to the Be The Match® Middle Eastern population. Despite these similarities, some alleles are private to each of the three groups, possibly because of historical, environmental or societal events. Clinical data showed that Arab donors were HLA matched with Arab and international patients. This analysis indicates the value added by the Hadassah Arab donors to the local and global transplant community. [ABSTRACT FROM AUTHOR]

We report a patient with Castleman's disease (angio-follicular lymph node hyperplasia) associated with a pemphigus vulgaris-like disorder. The patient had the hyaline-vascular mediastinal type of Castleman's disease and developed painful oral erosions and penile lesions. Histologic examination revealed an interface dermatitis including vacuolar changes, necrotic keratinocytes and a lichenoid infiltrate. In addition there was suprabasal vesiculation with acantholysis, reminiscent of pemphigus vulgaris. Direct immunoperoxidase staining for intercellular IgG was positive. HLA typing revealed that the patient did not have an HLA haplotype known to be associated with susceptibility to pemphigus. Until now, Castleman's disease Associated Pemphigus (CDAP) has been regarded as a unique entity presenting as atypical pemphigus vulgaris. However, a review of the literature reveals that the clinical and histologic signs of CDAP are virtually identical to those of paraneoplastic pemphigus and that both entities are associated with a lymphoproliferative disorder. We suggest that CDAP is a form of paraneoplastic pemphigus. [ABSTRACT FROM AUTHOR]

Genetic variation can affect drug pharmacokinetics and pharmacodynamics and contribute to variability between individuals in response to medications. Specifically, differences in allele frequencies among individuals and ethnic groups have been associated with variation in their propensity to develop drug hypersensitivity reactions (HSRs). This article reviews the current knowledge on the genetic background of HSRs and its relevance to Jewish and Arab populations. The focus is on human leukocyte antigen (HLA) alleles and haplotypes as predictive markers of HSRs (“immunopharmacogenetics”), but other genes and alleles are described as well. Also discussed is the translation of the pharmacogenetic information to practice recommendations. [ABSTRACT FROM AUTHOR]

The article offers information on Stevens-Johnson syndrome and toxic epidermal necrolysis caused due to several drugs like phenytoin and allopurinol in which T-cell-mediated skin eruptions occurs. Topics discussed include presence of the human leukocyte antigen; Israeli Ministry of Health requires genotyping before initiation of carbamazepine treatment; need for better dissemination of treatment guidelines related to hypersensitivity reactions.

The human leukocyte antigen ( HLA) alleles B*15:02 and A*31:01 have been identified as predictive markers of adverse cutaneous effects of carbamazepine and phenytoin in Asian and North European populations, respectively. Our aim was to estimate the distribution of these alleles in Jewish and Arab populations in Israel. The HLA-B*15:02 and HLA-A*31:01 carrier rate was estimated based on data from the Hadassah Bone Marrow Registry. Data on Stevens-Johnson syndrome ( SJS)- and toxic epidermal necrolysis ( TEN)-related hospitalizations were obtained from the Israeli Ministry of Health ( MOH) registries and from four Israeli medical centers. Of 83,705 Jewish and Arab-Muslim donors, 81 individuals of known origin carried the HLA-B*15:02. Among them, 66 were Jews of India-Cochin descent. Of the Cochin Jewish donors, 12.7% were B*15:02 carriers. HLA-A*31:01 carrier incidence among Arab and Jewish Israeli populations (3.5% and 2.2%, respectively) was within the range reported in other countries. We did not identify SJS- or TEN-related hospitalizations of Jews of Indian descent. Yet, this population should be considered at greater risk for antiepileptic drug-induced SJS and TEN. Until further data on actual risk are available, such patients should be typed for HLA-B before treatment with carbamazepine or phenytoin. [ABSTRACT FROM AUTHOR]

The human leucocyte antigen (HLA) system shows extensive variation in the number and function of loci and the number of alleles present at any one locus. Allele distribution has been analysed in many populations through the course of several decades, and the implementation of molecular typing has significantly increased the level of diversity revealing that many serotypes have multiple functional variants. While the degree of diversity in many populations is equivalent and may result from functional polymorphism(s) in peptide presentation, homogeneous and heterogeneous populations present contrasting numbers of alleles and lineages at the loci with high-density expression products. In spite of these differences, the homozygosity levels are comparable in almost all of them. The balanced distribution of HLA alleles is consistent with overdominant selection. The genetic distances between outbred populations correlate with their geographical locations; the formal genetic distance measurements are larger than expected between inbred populations in the same region. The latter present many unique alleles grouped in a few lineages consistent with limited founder polymorphism in which any novel allele may have been positively selected to enlarge the communal peptide-binding repertoire of a given population. On the other hand, it has been observed that some alleles are found in multiple populations with distinctive haplotypic associations suggesting that convergent evolution events may have taken place as well. It appears that the HLA system has been under strong selection, probably owing to its fundamental role in varying immune responses. Therefore, allelic diversity in HLA should be analysed in conjunction with other genetic markers to accurately track the migrations of modern humans. [ABSTRACT FROM AUTHOR]

Objectives: Narcolepsy is a sleep disorder with a genetic association with the haplotype DRB1*1501, DQA1*0102, DQB1*0602. This haplotype has been described in different ethnic groups suffering from narcolepsy (Japanese, Caucasian, African Americans, Jews). In a recent study we have found the haplotype DRB1*1502, DQB1*0601, DQA1*0103 in three patients with hypersomnolence. The similarity of this haplotype to the narcoleptic haplotype DRB1*1501, DQB1*0602 and DQA1*0102 has raised the question of whether this haplotype is a marker for sleepiness, or rather indicates a variant of non-cataplectic narcolepsy. This study was conducted to further investigate this question.Methods: HLA-DNA analysis was carried out in 20 healthy Jewish patients (age 23.9±6.3 years; 13 Ashkenazi, seven non-Ashkenazi) who had objective measures of hypersomnolence. All underwent whole-night polysomnography, multiple sleep latency test and tissue typing.Results: HLA-DNA analysis revealed HLA-DR2 in eight patients of whom five (25%) carried the haplotype DRB1*1502, DQB1*0601, DQA1*0103 (vs. 1.4% in the Israeli population, P<0.0001). Six patients were diagnosed as non-cataplectic narcoleptics. Five of them carried the haplotype DRB1*1502, DQB1*0601, DQA1*0103. Forty percent of the patients carried the haplotype DRB1*04, DQB1*0302, which was not statistically different from its prevalence in the healthy Israeli population (25%).Conclusions: This is the first report describing the haplotype DRB1*1502, DQB1*0601, DQA1*0103 in narcoleptic patients (non-cataplectic). This haplotype is close but different from the already known narcoleptic haplotype DRB1*1501, DQA1*0102, DQB1*0602. We assume that this haplotype represents a variant of non-cataplectic narcolepsy rather than association with hypersomnolence. However, in order to conclude whether this haplotype is a marker for the lack of cataplexy, or represents a variant of non-cataplectic narcolepsy, a larger group of patients should be investigated. [Copyright &y& Elsevier]

Objective: The Israeli Yemenite Jewish community has displayed an exceptionally rapid increase in the frequency of type 1 diabetes, having the highest rate of all Israeli ethnic groups. We studied the role of the environment, in relation to the nature and frequency of HLA class II genes, to evaluate its possible involvement in the development of diabetes.Research Design and Methods: We interviewed 196 elderly Yemenite women, who had immigrated to Israel as adults, in programmed encounters about signs and symptoms of type 1 diabetes, infant feeding customs, and infectious diseases in Yemen. We also performed HLA oligotyping of DRB1, DQA1, and DQB1 genes in 120 unrelated Yemenite Jews, including 44 type 1 diabetic patients and 76 healthy control subjects, and used these data in correspondence analysis comparing Yemenites with different Israeli ethnic groups.Results: Interviews indicated that early exposure to cow's milk was very common in Yemen. However, none of the women could recall classical presentations of diabetes. HLA oligotyping showed that gene frequencies of non-Asp-57 (of the HLA-DQB chain) in the patients (0.94) and control subjects (0.6) were similar to those of other populations with a known high incidence of type 1 diabetes. Correspondence analysis revealed that Yemenite Jews are genetically distinct from other ethnic groups in Israel.Conclusions: The genetic distinctiveness of Yemenite Jews may explain their unusually high incidence of type 1 diabetes in Israel. Despite the presence of highly susceptible diabetogenic HL4 class II genes in this community, early exposure to cow's milk did not cause phenotypic expression of diabetes in Yemen. This finding suggests that in this population, either cow's milk does not play a crucial role in triggering diabetes, or environmentally conferred protection, such as frequent infectious disease in Yemen, was dominant. [ABSTRACT FROM AUTHOR]