Distribution of HLA antigens in the armenian population of Nagornyi Karabakh

Characteristics of the distribution of 31 HLA antigens of classes I (A, B, and Cw) and II (DR) in Nagornyi Karabakh Armenians are reported for the first time. It has been found that the antigens most common in this population are A2, A3, A9, B5, B7, B12, Cw4, DR4, DR2, and DR3; the least common antigens are B15, B16, and B40. The results are compared with the data for Armenians living in Armenia and those for major ethnic groups. The frequencies of HLA antigens in Nagornyi Karabakh Armenians match those in Armenians living in Armenia. In the HLA-antigen distribution, Armenians are generally close to Caucasoids.     

Role of HLA antigens in Rh (D) alloimmunized pregnant women from Mumbai, Maharashtra, India

Immunogenetic studies in various diseases provide potential genetic markers. We have studied the incidence of HLA A, B, C, DR and DQ loci antigen in Rh (D) antigen isoimmunized mothers compared to those nonimmunized isoimmunized Rh negative mothers. Seventy six mothers who were immunized to Rh (D) antigen due to pregnancy (responders) and fifty four mothers who did not develop Rh (D) isoimmunization despite positive pregnancies (nonresponders) were selected for the study. Standard methods of serological HLA typing, ABO and Rh (D) groups, and screening for Rh D antibodies were used. 392 unrelated individuals from the population were compared as controls. In addition 45 unrelated individuals from the same population were typed for HLA DRB and DQB gene using PCR-SSP kits. The genotype frequencies of HLA A2, A3, A28, B13, B17, B35, B52, B60, Cw2, Cw6, DR4, and DQ3 were significantly increased, while the frequencies of the HLA A11, A29, A31, B7, B37, B51, Cw1 and DR9 were decreased in the responder women when compared to the non-responder women. HLA A30 (19) split antigen was not identified in immunized women while HLA A23 (9) split antigen was not identified in non immunized women. HLA A3, B17, Cw2 and DR4 showed a significant relative risk among the immunized responder women. When compared with Rh immunized women (responders) reported from USA, England and Hungary the phenotype frequencies of HLA A11, A24, A28, B5, B17, B40, DR2 and DR5 were increased while HLA A23, B8, B18, and DR6 were decreased in the Indian Rh immunized women. Two locus haplotype frequency analysis observed among the responders women revealed that among the significant haplotypes expressed A2–B5, B7–Cw1, DR2–DQ1 were highly significant haplotypes in positive linkage, while A1–B5, and A1–B7 were in significant negative linkage disequilibrium. The haplotype frequencies were ≤one when these common hapoltypes were compared with control population. Thus in the present study it is evident that the inheritance of HLA A3, B17, Cw2 and DR4 increases the relative risk factor by 2.6 times among Indian Rh isoimmunized women. Further, it is evident that there are significant differences in the observed HLA antigen frequencies and two locus haplotypes in Rh isoimmunized women when compared to women from USA, UK and Hungary due to extreme HLA polymorphism in different populations of the world     

Interesting relations in the HLA system

There exists no absolute binding between the antigens HLA-Cw 2, Cw 3 and Cw 4, on the one hand, and HLA-B 27, HLA-B 15 and HLA-Bw 35, on the other hand. Even if 91% of human beings with HLA Cw 4 will simultaneously have the antigen HLA-Bw 35, another antigen as HLA-B 27 or HLA-B 15 can be identified in approximately 55% of individuals with HLA-Cw 2 and Cw 3. In this connection, the joint presence of some pairs of cross-reacting HLA antigens (A 2 and A 28, B 5 and Bw 35, B 7 and B 27, B 8 and B 14, B 12 and Bw 2) could be proved and their frequency be determined. 2 cases of a simultaneous presence of two subtypes of HLA-A 10 antigen, A 25 and A 26, could be found in family examinations. Moreover, two atypical bindings of anti-HLA-Bw 4 and anti-HLA-Bw 6 cytotoxins with HLA antigens could be identified: 7,49% of HLA-Bw 35 positive lymphocytes no positive response with anti-HLA-B 4 and 1,69% of HLA-B 12 with anti-HLA Bw 6. The importance of the findings for determining HLA in practice is discussed.     

Susceptibility to IDDM Is marked by MHC supratypes rather than individual alleles

107 patients with insulin-dependent diabetes mellitus (IDDM) were typed for HLA A, B, C, and DR antigens, and for complement C4A, C4B, and Bf alleles, and the results were compared with those of a combined reference group of 332 appropriately matched healthy subjects. Supratypes (allelic combinations) were identified from the phenotype of each group, and it was shown that the frequency of several supratypes is increased in patients with IDDM, in particular supratypes (A1 Cw7) B8 C4AQ0 C4B1 BfS DR3 (P = 0.0001), (A30 Cw-) B18 C4A3 C4BQ0 BfF1 DR3 (P = 0.0003), (A2 Cw3) B62 C4AR C4B2.9 BfS DR4 (P = 0.0002), and three other supratypes including DR4. It was also shown that increases in the frequency of individual alleles are secondary to increases in supratype frequency. Moreover, supratypes appeared to interact; the presence of two relevant supratypes being particularly important. The absolute risk of IDDM was approximately 0.5 in subjects who were homozygous for B18 C4A3 C4BQ0 BfF1 DR3. We concluded that genetic susceptibility is best recognized by MHC supratypes rather than isolated alleles, and that supratype combinations make the identification of even greater disease risk possible.     

HLA class I polymorphism in the Albanian population

The HLA class I polymorphism was studied in a sample of the Albanian population. Ninety-three unrelated healthy Albanians were typed for HLA-A, -B and -Cw antigens by standard microlyphocytotoxicity test. The antigens with the highest frequencies were: HLA-A2 (34.4%), A3 (14.5%) and A1 (12.4%); B51 (19.3%), B35 (12.4%) and B18 (10.2%); Cw4 (16.2%), Cw7 (16.2%) and Cw6 (10.8%). The HLA haplotypes with high frequency in Albanians included A2-B51 (4.3%), A2-B18 (2.4%), A2-B35 (2.4%), Cw4-B35 (7.6%), and Cw7-B18 (6.5%), which are not significantly different from the other neighboring populations. Low frequency of HLA-A1-B8 haplotype (1.1%) is noted in the Albanian population. The frequency of HLA-B27 antigen (1.1%) is one of the lowest frequencies observed in Caucasians. Such results are important in studies of HLA-A1-B8, HLA-B27 and disease associations. These findings should be also useful in understanding the origin of Albanians, representing a base for future studies about HLA polymorphism in the Albanian population.     

Class I HLA antigens in two long-separated populations: Melanesians and South Amerinds

Class I HLA antigens have been compared in 5,835 Melanesians of Papua New Guinea and 2,028 Amerindians of South America. The sample includes 50 PNGMel ethnolinguistic groups and 22 SAmlnd groups. Both carry 15 serologically defined antigens and an undefined C allele. Except for A2 in Papua New Guinea and Cwl in South America, these antigens are widely distributed in their respective populations. Nine (A2 and A24, B39, B60 and B62, and Cwl, Cw3, Cw4, and Cw7) are common to both. This commonality suggests that these two populations derive from an ancestral population with less polymorphism than modern East Asians. In both populations several theoretically possible haplotypes were absent, and other haplo-types were in positive disequilibrium in both. The parallels in disequilibria suggest that haplotypes are subject to selective forces acting on the level of allelic interaction. Based on three locus haplotype frequencies, the PNGMel groups form five clusters with internally typical linguistic and geographic characteristics and a miscellaneous category, but Samlnd groups show no cluster. © 1995 Wiley-Liss, Inc.     

HLA antigens and clinical subgroups of schizophrenia

Frequencies of HLA A, B, C, and DR antigens were studied in 100 schizophrenic patients and 919 controls from South Sweden. The patients were diagnosed according to the DSM III criteria and divided into four clinical subgroups (hebephrenic, paranoid, residual, and undifferentiated). In the schizophrenic patients as a whole significant increases were found for A2, A3, B17, B27, and Cw2 and decreases for A1, A11, and B8. A previous positive association with A9 from the same population was not confirmed. A significant heterogeneity between the four clinical subgroups was found for A3 and Bw35. Most of the associations between HLA antigens and schizophrenia reported in the literature appear to be fortuitous and dependent on the large number of trials made. However, confirmed increases have been found for A9 and B17, and confirmed decreases have been observed for A1 and B7. Some evidence for a heterogeneity between clinical subgroups was found in the present as well as in previous investigations.     

HLA antigens and other genetic markers in the Mapuche Indians of Argentina

A total of 107 Mapuche Indians living in western Argentina were studied with respect to 16 genetic systems. For HLA, there were a few differences in relation to previous studies; and considering the averages observed in 15 other South American tribes, Mapuche Indians showed low values for A2, A9 and C3, but high ones for A28 and B16. This is the first report of the presence (in low frequencies, 1-6%) of alleles C2, C6 and C7, as well as of DR antigens (most frequent alleles DR4 and DR2) in South American Indians. Some peculiar reactions shown by products of locus B suggest the presence of antigens that are characteristic of the Mapuche. As for the other systems, the frequencies of R1 (Rh) and PGM1(1) were lower but those for r (Rh), GLO1 and Hp1 were higher than the averages obtained considering previous studies of this ethnic group. Other salient findings were the variability observed in the PGM2 and C3 systems, and the low prevalence of Bfs.     

HLA genotypes and HLA-linked genetic markers in Italian patients with classical 21-hydroxylase deficiency

Summary HLA genotype and HLA-linked marker data for 40 unrelated patients from central Italy and 2 unrelated patients from Sardinia with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OH-def) were analyzed. The results confirm that the HLA-linked 21-OH-def gene is associated with several different HLA determinants and complete HLA haplotypes, although the only determinant with significantly increased frequency was the complement C2 allele C2B. The HLA antigens B8 and DR3 were found in significantly decreased frequencies. The haplotype A3, Cw6, Bw47, BfF, DR7, which is exceptionally rare in the general population but which has been found in many other 21-OH-def patients from diverse geographical origins, was also found in one of the Italian patients. This and other HLA haplotype associations found among the Italian patients may represent mutations that have occurred on HLA haplotypes with genetic linkage disequilibrium or, alternatively, may represent mutations that have not yet had time to become randomly associated with different HLA complex determinants. The marked negative associations with B8 and DR3 could, however, result from an interaction between the gene products of the HLA complex and the 21-OH-def phenotype.     

HLA class I antigen and HLA-A, -B, and -C haplotype frequencies in Uruguayans

HLA class I antigens were determined for 959 unrelated Uruguayans. The predominant HLA alleles were A2, Cw4, and B35, and the most frequently observed two-loci haplotypes were A2-B44 and B35-Cw4. The most frequent three-loci HLA haplotype was A2-Cw5-B44. We compared the Uruguayan sample with similar data from other populations.     

Polymorphism of the HLA genetic system in Khanty population

Serological polymorphism of HLA 1 class genes and antigens (A, B, C) was studied in native West-Siberian population of Khants. Genes HLA-A2, A23, A24, B7, B35, B49, Cw4 and Cw7 appeared to be most frequent in this population. HLA-A23/B49 was the most wide-spread haplotype with strong linkage disequilibrium. The main features of the HLA polymorphism indicate profound mongoloid roots of Khants, whereas strong linkage disequilibrium of some HLA alleles confirms the idea of the origin of Khants as a result of ancient mixing of mongoloids and caucasoids.     

Analysis of the donor-specific cytotoxic T lymphocyte repertoire in a patient with a long term surviving allograft. Frequency, specificity, and phenotype of donor-reactive T cell receptor (TCR)-alpha beta+ and TCR-gamma delta+ clones

In the present study the transplant specific CTL repertoire of a patient (HLA:A1,3, B8,18, Cw5,7 DR3, DQw2, DPw3) with a long term surviving HLA mismatched kidney graft (HLA: A1,24 B8,27 Cw2,7, DR3, w13 DQw2,6 DPw1,3) has been investigated. This patient was unable to generate specific cytolytic activity against donor-derived PHA-blasts in the MLC in which donor spleen cells or B lymphoblastoid cell line were used as stimulator cells. In addition, the CTL precursor frequencies against donor alloantigens were very low (1/67,000). The patient had otherwise normal immune responses in vivo and in vitro and no signs of transplant rejection. Transplant specific CTL clones were generated in high frequencies (1/195) from T cell bulk cultures activated by PHA in the absence of any sensitization by donor Ag in vitro. The repertoire of 14 donor-reactive CTL clones (12 TCR-alpha beta+ and 2 TCR-gamma delta+) was analyzed. Two TCR-alpha beta+ CD8+ clones were specific for B27. Ten TCR-alpha beta+ CTL clones directed against class II HLA Ag were isolated. Seven of these were CD4+ and recognized DRw13 (3), DQw6 (3), and DPw1 (1), whereas three of these clones were CD4-CD8+ recognizing DRw13 (1) and DQw6 (2). In addition, two donor-specific TCR-gamma delta+ CTL clones were obtained recognizing HLA-A9(23,24) and DQw6. Our data indicate that the precursors of CTL clones specifically directed against donor class I or II HLA Ag are not deleted from the repertoire and that part of this reactivity resides in the TCR-gamma delta+ fraction.     

Association of HLA DR1 with high D-penicillamine binding to monocytes in females

Binding of D-Penicillamine (D-Pen) to human monocytes was examined by flow cytometry with fluorescent D-Pen conjugate. Cells from HLA DR1-positive healthy females bound significantly more D-Pen than cells from DR1-negative healthy females (P = 0.015), and DR1 was associated with the highest binding among HLA DR antigens. In contrast, DR4 was associated with the lowest binding in healthy females. A difference in D-Pen binding between healthy females who were DR1-positive, DR4-negative and those who were DR1-negative, DR4-positive was statistically significant (P = 0.026). Neither healthy females nor healthy males showed significant associations of D-Pen binding with HLA A, B, or C antigens, nor did healthy males show an association between strength of D-Pen binding and any DR antigens.     

Association between Protective and Deleterious HLA Alleles with Multiple Sclerosis in Central East Sardinia

The human leukocyte antigen (HLA) complex on chromosome 6p21 has been unambiguously associated with multiple sclerosis (MS). The complex features of the HLA region, especially its high genic content, extreme polymorphism, and extensive linkage disequilibrium, has prevented to resolve the nature of HLA association in MS. We performed a family based association study on the isolated population of the Nuoro province (Sardinia) to clarify the role of HLA genes in MS. The main stage of our study involved an analysis of the ancestral haplotypes A2Cw7B58DR2DQ1 and A30Cw5B18DR3DQ2. On the basis of a multiplicative model, the effect of the first haplotype is protective with an odds ratio (OR) = 0.27 (95% confidence interval CI 0.13–0.57), while that of the second is deleterious, OR 1.78 (95% CI 1.26–2.50). We found both class I (A, Cw, B) and class II (DR, DQ) loci to have an effect on MS susceptibility, but we saw that they act independently from each other. We also performed an exploratory analysis on a set of 796 SNPs in the same HLA region. Our study supports the claim that Class I and Class II loci act independently on MS susceptibility and this has a biological explanation. Also, the analysis of SNPs suggests that there are other HLA genes involved in MS, but replication is needed. This opens up new perspective on the study of MS.     

Complotype genetic loci segregate more frequently with HLA-DR than with HLA-B

The loci for BF, C2, C4A, and C4B are very closely linked to each other so that alleles of these plasma protein markers occur in populations in linkage disequilibrium and are inherited as single genetic units called complotypes. These complotypes are coded by a DNA region of the short arm of chromosome 6 embracing approximately 100 kilobases, which serve as a marker of the major histocompatibility complex. We have studied the complotypes of nine families with known HLA-B/DR crossovers. In seven families, the complotypes were inherited with HLA-DR, including in one family with a double recombination. The haplotype HLA-A28, Cw1, B27, FC3, 20, DR4 of JTr resulted from two recombinations between HLA-A2, Cwl, B27, SC42, DR7 and HLA-A28, Cwx or Cw1, B37, FC3, 20, DR4. In the remaining two families (Ro and Lo) the complotypes were inherited with HLA-B. The haplotype A2, Cw5, Bw44, SC30, DR3 of StLo resulted from paternal recombination between the haplotypes A2, Cw5, Bw44, SC30, DR4 and A24, B8, SC01, DR3, and the haplotype A24, Cw4, Bw35, SC31, DR3 of NaRo resulted from maternal recombination between A24, Cw4, Bw35, SC31, DR4 and A26, Bw41, FC31, DR3. Our data suggest that the complotype region maps closer to HLA-D than to HLA-B.     

The polymorphisms of HTC-defined HLA specificities in the Shanghai Chinese population

With reference sera and homozygous typing cells (HTCs) of 3rd Asia-Oceania Histocompatibility Workshop Conference, 56 healthy unrelated subjects in Shanghai were typed for HLA-A, B, C, DR, DQ, and Dw. This paper presents the results of HLA-Dw typing, its relationship to serological class II antigens, and the distribution of Dw in the population. The polymorphism patterns of Chinese Dw specificities were quite different from those in Caucasoids and Japanese. The predominant Dw phenotypes detected in Shanghai Chinese were Dw 2, Dw 3, DKT 2, Dw 7 c, (Dw7 + Dw 17) and Dw 23 (DB 5). And significant correlations were observed between Dw 1 and DR 1, Dw 2 and DR 2, Dw 3 and DR 3, Dw 7 c and DR 7, DB 7 and DRw 8, as well as Dw 23 and DR 9. SMY 129, a novel Dw specificity defined by local HTCs and co-studied by the laboratories joined for Dw typing in 3rd AOHWC showed its correlation with DR 5. Nevertheless, more than fifty percent of Dw specificities could not be assigned in the four correspondent designated serological antigens, DR 2, DR 5, DRw 8 and DR 9, respectively, which, together with other blank Dw specificities, gave a total blank Dw gene frequency as high as 43.2% in the population. It was suggested by further analysis that novel Dw specificities might be identified more effectively if efforts would be concentrated on DR 5 and DR 9, two antigen families which, in some way, might represent the characteristics of HLA system in Chinese. Besides, certain HTC-defined antigens, e.g. Dw 3 and the DR 4-related Dw specificities, have been revealed to be in linkage disequilibrium with other DR antigens in addition with the correspondent designated ones, resulting in some unique haplotype combinations in Shanghai Chinese. It seems to us that the particular patterns of polymorphisms of serum- and cell-defined HLA class II antigens would be helpful to elucidate the mechanisms by which certain diseases are in association with HLA in Chinese in a different manner as compared with that in Caucasoids.     

Population genetics of taiga hunters-deer breeders. Characteristics of the prevalence of HLA system markers among the native population of Central Siberia

The postulated peculiarities of distribution of the HLA antigens in the Evenk population of the Central Siberia indicate this population to be, on the whole, Mongoloid. Prolonged isolated existence of small inbred populations of the Evenks resulted in the number of specific HLA-complex features, such as poor antigen diversity, low level of heterozygosity. Non-homogeneity of gene frequencies was noted, the prevailing genes being A9, B40 with frequencies reaching 50%. Of the remaining alleles found in the Evenks A2, Aw19 in A locus, B5, B15, B17, B27, Bw35 in B locus and Cw2, Cw3, Cw4-in C locus are only widely spread. Similar heterozygosis levels and the HLA-system profiles draw the Evenks and the populations of American Indians and Eskimos closer to one another. On the basis of the fact that significant positive correlation exists between genetic and geographic distances determined for the Evenks and the native populations of America, genetic resemblance of these populations may be considered as evidence for their original relationship. Postulated closeness of native Central-Siberian populations to Americanoids, as regards HLA-system, makes it possible to consider formation of specific complex of HLA-system peculiarities in native American population in the light of their Siberian origin, for the first time.     

Serologic polymorphism of the HLA Class 2 antigens in the Russian population]

Two hundred and thirty Russian Moscovities (108 healthy individuals and 122 cadaver kidney donors) were typed for antigens HLA-DR1-DRw10, HLA-DRw52-DRw53, and HLA-DQw1 and DQw3. HLA-DR1, 2, 3, 4, 5 and 7 were investigated in all individuals, the other having been only studied in portions of the material. The HLA class 2 antigens' polymorphism in Russian population has been shown to have features common to all Caucasians. Most widely distributed antigen is DR2 (phenotype frequency is 36%). Antigens DRw8, DR9 and DRw10 are rare. DR allele distribution demonstrated perfect fits to Hardy--Weinberg expectations. Antigens DR5 and DR4 are considered most difficult to define at early stage of the study.     

Association between HLA class II antigens and hepatitis C virus infection

The aim was to confirm the influence of HLA Class II antigens on the progression of HCV infection and to assess the relationship between these antigens and histological damage, HCV viral load and HCV genotype. 143 patients were enrolled and divided into three groups. Group A included 34 anti-HCV positive, HCV-RNA negative patients with ALT persistently normal; group B included 39 patients with HCV-RNA positive and abnormal ALT level; group C included 70 normal subjects. Serological HCL typing was performed with lymphocytotoxicity test by Terasaky and McClelland, using lymphobeads HLC class II. The frequency of HLA DR11 (5) was significantly higher in the control group (52.9%) and in group A (64.7%), than in group B (28.2%). Allele HLA DR6 was demonstrated in a similar proportion (26%) among control group and group B, while HLA DR14 (6) was less frequent among controls (18% vs 1.4%). In group A the frequency of HLA DR14 (6) was 3% compared to group B, HLA DR17 (3) was prevalent (15.4%) in group B. Liver damage was associated with the detection of HLA DR14 (6) and HLD DR17 (3) antigens. Significantly lower levels of HCV-RNA were measured in subjects with HLA DR11 (5) than in these with either DR6 or DR17 (3). HLA class II antigens appear crucial for resolution or progression of HCV hepatitis. The punctual identification of these genetic factors may, therefore, prove to be useful in predicting disease evolution, in guiding the appropriate therapy for patients with poor prognosis, and in encouraging the development of now therapeutic strategies.     

Expression of class II antigens by subsets of activated T cells

Gene products coded for within the HLA complex play an important role in the control of immune responses. Class I antigens, coded for by the HLA-A, B, and C loci, are expressed by virtually all mononuclear blood cells. Class II antigens, coded for by the DR, DQ, and DP loci, have a more limited tissue distribution. They are expressed by B cells, monocytes, and by activated, but not by resting, T cells. The class II molecules of B cells and antigen-presenting cells have long been of interest to immunologists, since they are involved in the presentation of antigen, in communication between T cells and B cells and between T cells and adherent cells, and in susceptibility to certain diseases. The class II antigens expressed by activated T cells, however, remain largely uncharacterized in terms of their specificity, functional significance, and molecular nature. We have studied the expression of DR and DQ antigens by activated T cells and then examined the expression of DR versus DQ antigens by Leu 2a and Leu 3a subsets of mitogen-activated populations. Our results demonstrated that, as for class II-positive macrophages, the intensity of staining with monoclonal antibodies directed against DR antigens was much greater than that obtained with those directed against DQ antigens. Interestingly, the percentages of Leu 2a- and Leu 3a-positive cells which expressed DR antigens were quite similar, as were the percentages of Leu 2a and Leu 3a cells which expressed DQ. Thus, there does not seem to be preferential expression of DR versus DQ antigens by mitogen-activated T-cell subsets. Finally, though both DR-positive-DQ-positive and DR-positive-DQ-negative populations were detected, few or no DR-negative-DQ-positive cells were observed in these populations.