DR Locus Antigens Research Articles

HLA Antigens in Nadars a Native Dravidian Caste Group of Tamil Nadu, South India

One hundred and thirty seven unrelated Nadar individuals residing in Tamil Nadu, (South India) were studied for HLA A, B, C and DR locus antigen profiles. The allele frequencies of HLA A9, B5, Cw4, Cw7, DR2 and DR6 were increased while frequencies of HLA A10, B8, B16, B46, B78, Cw5, Cw9 and DR9 were decreased in the Nadars. The gene frequencies of HLA A1, A3, A28, B5, B17, B37, Cw4, Cw5, DR1, DR6 and DR10 were increased while that of A2, A19, B16, B46, Cw3, DR5 and DR9 were decreased when compared with gene frequencies of other Asian populations reported. Two Locus haplotype analyses revealed that A11-B5, A1-B17, A3-B44, A24-B51, B5- Cw9, B44-Cw1, DR4-DQ2 and DR6-DQ1 were significant haplotypes among the positive linkage disequilibrium haplotypes. Where as A1-B5, B5-Cw1 and DR1-DQ2 were significant haplotypes among the negative linkage disequilibrium haplotypes. The haplotypes A3-B44, A24-B51, B44-Cw1 and DR6-DQ1 observed in Nadars were unique when compared to other Indian populations reported in literature. The observed antigen frequencies and linkage disequilibrium in Nadars suggest the influence of genetic drift caused by selection, geography and culture with a lesser degree of admixture. Further the study reveals that the Nadar population of India cannot be considered as a single panmictic population with reference to genetic characteristics, which may have a clinical relevance in unrelated donor selection for allogenic Bone marrow transplantation in India.

HLA Antigen Distribution in Selected Gujarati Subcaste from Mumbai, Maharastra, India

Indian population is well known for its genetic diversity. Among the numerous endogamous communities, which are restricted very much by cus- tom, marriage and occupation we have collected 178 unrelated Gujarati speaking individuals, belonging to Lohanas, Banyas and Gujarati Brahmins caste groups. We present here the HLA- A, B, C and DR locus antigen distribution of these endogamous caste groups compared with each other. The HLA antigens were identified by using the standard complement mediated NIH microlymphocytotoxicity assay. The phenotypic fre- quencies of HLA- A2, A9, B5, B35, B40, DR2, DR3 in Banyas, A10, A19, B8, B17, Cw3, DR7 in Lohanas and A1, B7, B22, Cw5, DR1 in Gujarati Brahmins were found to be significantly increased. The phenotype frequen- cies of A10, B13, DR6 in Banyas, B15, B22, DR4 in Lohanas and A2, A10, B8, B13, B37, Cw7, DR6 in Gujarati Brahmins were found to be significantly de- creased among the HLA antigens tested. Haplotype analy- sis revealed that A33-B44-DR7 haplotype were present in all the three caste groups while, A1-B17 in Brahmins, A11-B35, A2-B5, A3-B18 in Lohanas and A11-B62, A3-B40 in Banyas were unique among the caste groups. Haplotype A24-B5 was identified among Lohanas and Banyas. The observed antigen frequencies and linkage disequilibrium among the three Gujarati caste groups sug- gest the influence of genetic drift caused by selection, geography and culture. The study also reveals that the caste groups in India cannot be considered as a single panmictic population with reference to genetic charac- teristics, which may have a clinical relevance in unre- lated donor selection for allogenic bone marrow trans- plantation in India.

HLA Antigen Distribution in Maratha Community from Mumbai, Maharastra, India

Two hundred and eighty nine unrelated Marathas residing in Mumbai, Maharastra, (Western In- dia) were studied for HLA A, B, C and DR locus antigen profiles. The HLA antigen maximum likelihood gene fre- quencies of HLA A1, A2, A9 (24), A11, A19 (33), B5, B7, B35, B40 (61), Cw3, Cw6, DR2, DR5, DR7, DQ1 and DQ2 were increased while that of HLA A3, A10 (26), A36, B8, B13, B16 (38), B18, B21, B22 (55), B53, B73, Cw5, Cw7, DR3, DR4, DR9, and DQ3 were decreased in the Marathas. HLA antigens A25 (10), B14, B39 (16), B54 (22), B56 (22), B58 (17) and Cw8 were not identi- fied in the present investigation. Two Locus haplotype analyses revealed the presence of A10-B8, A1-B17, A24- B52, B5-Cw9, B13-Cw3, B15-Cw2, B35-Cw4, DR2-DQ1, DR5-DQ3 and DR1-DQ9 haplotypes with positive link- age disequilibrium among the marathas. Haplotype A2- B12 was the only haplotype identified in negative link- age disequilibrium. The observed maximum likelihood gene frequencies, haplotype frequencies and linkage dis- equilibrium in Marathas suggest the influence of genetic drift caused by selection, geography and culture. Further the study reveals that the Hindu population of India can- not be considered as a single panmictic population due to vast allelic diversity and immense heterozygosity in haplotypes.

HLA Antigen Distribution in Maratha Community from Mumbai, Maharastra, India

Two hundred and eighty nine unrelated Marathas residing in Mumbai, Maharastra, (Western In- dia) were studied for HLA A, B, C and DR locus antigen profiles. The HLA antigen maximum likelihood gene fre- quencies of HLA A1, A2, A9 (24), A11, A19 (33), B5, B7, B35, B40 (61), Cw3, Cw6, DR2, DR5, DR7, DQ1 and DQ2 were increased while that of HLA A3, A10 (26), A36, B8, B13, B16 (38), B18, B21, B22 (55), B53, B73, Cw5, Cw7, DR3, DR4, DR9, and DQ3 were decreased in the Marathas. HLA antigens A25 (10), B14, B39 (16), B54 (22), B56 (22), B58 (17) and Cw8 were not identi- fied in the present investigation. Two Locus haplotype analyses revealed the presence of A10-B8, A1-B17, A24- B52, B5-Cw9, B13-Cw3, B15-Cw2, B35-Cw4, DR2-DQ1, DR5-DQ3 and DR1-DQ9 haplotypes with positive link- age disequilibrium among the marathas. Haplotype A2- B12 was the only haplotype identified in negative link- age disequilibrium. The observed maximum likelihood gene frequencies, haplotype frequencies and linkage dis- equilibrium in Marathas suggest the influence of genetic drift caused by selection, geography and culture. Further the study reveals that the Hindu population of India can- not be considered as a single panmictic population due to vast allelic diversity and immense heterozygosity in haplotypes.

Analysis of factors that affect outcome of primary cadaveric renal transplantation in the UK

In the UK, kidneys are exchanged between centres on the basis of matching for HLA. We analysed various factors that might affect graft outcome to establish whether exchange of kidneys on this basis remains valid. 6363 primary cadaveric renal transplants carried out in 23 centres in the UK between 1986 and 1993 were used in the analysis. 6338 (99.6%) patients who underwent transplantation were followed up at 1 year. 5-year follow-up data were available for 2907 (97.8%) of the 2972 patients who survived to 5 years. We made random checks to validate the data. A multifactorial analysis with Cox's proportional hazards models was used to analyse factors that had a possible effect on graft outcome. To ensure that the analysis of matching was constant during the 8-year study, our analysis was based on the HLA antigens used for organ exchange (11 A locus antigens, 27 B locus antigens, and 12 DR locus antigens). We assessed overall outcome at 5 years and during three periods after transplantation at: 0-3 months, 3-36 months, and after 36 months. The following factors were significantly associated with graft outcome in the multifactorial analysis: year of graft, age of donor, age of recipient, whether the recipient had diabetes, cause of donor's death, cold ischaemic time, transport of kidneys, transplant centre, and matching for HLA. The best outcome was achieved with kidneys that had no mismatches at HLA-A, HLA-B, and HLA-DR loci (000 mismatches). The next most favourable outcome was achieved with one mismatch at either A or B loci or one mismatch at both the A and B , but no mismatch at the DR locus (100, 010, or 110 mismatches). Age of the donor and recipient had a significant effect on transplant outcome: older age was associated with increased risk of graft failure. Various factors affect the outcome of primary cadaveric renal transplantation, particularly the age of the donor and the recipient. However, the effect of matching for HLA remains a strong one and fully justifies the continuing policy in the UK of exchanging kidneys on the basis of HLA matching, especially to recipients when there is a 000 mismatch for HLA between donor and recipient. On the basis of this analysis, a new allocation scheme for kidneys was introduced in the UK in 1998. During the first 9 months of the scheme, there has been a doubling of the number of HLA-000 mismatched kidneys transplanted.

2 Genes and environment

Many other autoimmune and chronic diseases exhibit marked geographic variation in incidence, which has been attributed to environmental differences across populations (Hutt and Burkitt, 1986). The results of our international IDDM research have provided evidence for the importance of large genetic variations in the frequency of HLA susceptibility genes between racial groups and countries. One may speculate that differences in the prevalence of susceptibility genes for other chronic diseases exist and significantly contribute to the geographic patterns of incidence of these disorders. Other autoimmune diseases are known to have epidemiological features similar to those described for IDDM. Although they are also characterized by an underlying HLA-related susceptibility, environmental factors are known to play an important aetiological role (Tiwari and Terasaki, 1985). DNA polymorphisms of the DR, DQ and DP locus antigens are associated with various autoimmune diseases (Todd et al, 1988; Thorsby et al, 1989). These molecular variations are similar to those described for IDDM, in that they are typically related to the hypervariable regions of the molecule and, thus, affect the peptide binding ability of the antigen. Based on the evidence for IDDM, population differences in the frequency of other HLA susceptibility genes are likely to be major determinants of the geographic distribution of diseases such as rheumatoid arthritis and multiple sclerosis. The epidemiological approach outlined in this review is, thus, applicable to other autoimmune diseases and will significantly contribute to our knowledge of the aetiology of these disorders. The emerging field of molecular epidemiology represents a new research approach which will lead to a better understanding of the relationships between specific risk factors and the aetiology of chronic diseases within populations and across the world.

HLA and multiple sclerosis in Italy: a review of the literature

HLA antigens of locus A, C, B, DR and DQ were typed in 104 Italian multiple sclerosis patients and in 905 healthy controls; the results have been compared with those published in the Italian literature. The Italian studies have been reviewed regarding the ethnic origin of the typed population and the corresponding prevalence of the disease. The data suggest a lack of association between A3 and B7 antigens and Italian multiple sclerosis and a relevance of other DR locus antigens (mainly DR4 and DR5), in addition to DR2, in the susceptibility to the disease.

Prenatal Effects of Maternal-Fetal HLA Compatibility

Both retrospective studies of idiopathic aborters, as well as prospective studies of normal couples, have shown reduced fertility among couples sharing HLA antigens. However, the effects of maternal-fetal histocompatibility on surviving embryos are largely univestigated. We thus prospectively studied 53 healthy, fertile women whose timed pregnancies were verified within 21 days of conception. Maternal-fetal histocompatibility status was determined for HLA-A,-B, and -DR locus antigens. Fetal growth rates were monitored by ultrasound at 8, 12, and 20 weeks gestation. Neonates were weighed, measured (birthlength, chest circumference, head circumference), and examined within 72 h of delivery (116 major and minor anomalies) in standardized fashion by one of two geneticists. Although no significant differences were found between infants compatible and incompatible at the HLA-A or HLA-B locus, significant differences were observed between HLA-DR compatible and incompatible infants for sex ratios (p less than .003) and minor anomaly rates (p less than .05). Although differences in mean birthweights between HLA-DR compatible and incompatible infants were not significant in this sample, HLA-DR compatible infants were on average 200 grams smaller than HLA-DR incompatible infants. We interpret these findings as evidence for selection against histocompatible fetuses throughout gestation, particularly with respect to HLA-DR compatibility. Potential immunologic and genetic mechanisms are discussed.

Prenatal Effects of Maternal-Fetal HLA Compatibility

Both retrospective studies of idiopathic aborters, as well as prospective studies of normal couples, have shown reduced fertility among couples sharing HLA antigens. However, the effects of maternal-fetal histocompatibility on surviving embryos are largely univestigated. We thus prospectively studied 53 healthy, fertile women whose timed pregnancies were verified within 21 days of conception. Maternal-fetal histocompatibility status was determined for HLA-A,-B, and -DR locus antigens. Fetal growth rates were monitored by ultrasound at 8, 12, and 20 weeks gestation. Neonates were weighed, measured (birthlength, chest circumference, head circumference), and examined within 72 h of delivery (116 major and minor anomalies) in standardized fashion by one of two geneticists. Although no significant differences were found between infants compatible and incompatible at the HLA-A or HLA-B locus, significant differences were observed between HLA-DR compatible and incompatible infants for sex ratios (p less than .003) and minor anomaly rates (p less than .05). Although differences in mean birthweights between HLA-DR compatible and incompatible infants were not significant in this sample, HLA-DR compatible infants were on average 200 grams smaller than HLA-DR incompatible infants. We interpret these findings as evidence for selection against histocompatible fetuses throughout gestation, particularly with respect to HLA-DR compatibility. Potential immunologic and genetic mechanisms are discussed.

The distribution of HLA-A, B, C, DR antigens in Chinese patients with hepatocellular carcinoma in Taiwan.

To evaluate the role of genetic factor in hepatocellular carcinoma, HLA-A, B, C and DR locus antigens were typed in 170 Chinese patients. Forty-three HLA-A, B, C, DR-related antigens were assayed by the conventional method. No significant risk antigen can be identified among these antigens. The distribution of each antigen was not related to sex. HBsAg, and alpha-fetoprotein status. The results suggest that there are no specific HLA-A, B, C and DR antigens patterns or frequencies associated with the development of hepatocellular carcinoma.

HLA antigens in patients with unexplained hepatitis following halothane anesthesia.

We examined HLA-A,B,C and DR locus antigens in 38 Japanese patients who had recovered from halothane hepatitis. The patients were divided into two subgroups, i.e. jaundice and non-jaundice groups, because the clinical features were quite different in each. DR2 was positive in 14 (58.3%) of 24 patients with jaundice, compared with 281 (33.6%) of the 837 Japanese healthy controls (chi-square with Yates' correction = 5.30, relative risk = 2.77, P less than 0.025). Conversely, Bw44 was increased in non-jaundice patients (50.0%), compared with 157 (12.7%) of the 1234 Japanese healthy controls (chi-square with Yates' correction = 13.75, relative risk = 6.86, P less than 0.001). The haplotype frequency (Hf) of Aw24-Bw52-DR2 was high in the patients with jaundice (Hf = 0.2362), while it was zero in the patients without jaundice (P less than 0.0042). These data suggest that the two groups of halothane hepatitis have different genetic backgrounds.

Clinical, immunologic, and genetic definitions of primary and secondary recurrent spontaneous abortions

Fifty couples with repeated pregnancy failures were grouped by clinical history as being primary (no children) or secondary (abortions subsequent to having children or stillbirths) aborters. Human leukocyte antigen (HLA) sharing between husband and wife and maternal antipaternal immunity were studied in both groups. Analyses showed significantly more HLA-A, B, and DR locus antigens shared in the primary abortion group than in the secondary abortion group (P = 0.01). The number of couples sharing two to five HLA antigens was higher for those couples with primary abortions than for secondary abortions (P = 0.009). Antipaternal immunity as measured by visual complement-dependent lymphocytotoxicity (CDCE), by 51Cr release (CDC51Cr), and by complement-independent, antibody-dependent cell-mediated cytotoxic (ADCC) assays was different between the two groups. CDCE was not present in the primary aborters' sera but was found in 13 of the 15 secondary aborters' sera (P = 0.0001). Similarly, ADCC was not apparent in primary aborters but was present in 14 of the 15 secondary aborters (P = 0.0001). CDC51Cr was detected in 3 of the 11 primary aborters and in 13 of the 15 secondary aborters (P = 0.008). Such differences in HLA sharing and immune reactivities between these two groups strengthen the idea that either inadequate or inappropriately vigorous maternal antipaternal immunity can be related to spontaneous abortions. These results uphold a central role for immunology in human reproduction and provide further support for the use of immunotherapy to prevent pregnancy losses in certain abortion-prone women.

HLA-A,B,C and DR antigens in Asaro speakers of Papua New Guinea

The HLA profile of the Asaro speakers of Papua New Guinea exhibits restricted polymorphisms. Antigens like AW24, MT1, and MB1 were present in almost every individual assayed. A CW6-related antigen and a DR locus antigen FT19 (a split of DRW6), not previously found in Pacific populations, were observed in a significant number of individuals. Ancestral HLA-B,C haplotypic combinations, such as B13, CW4 and BW60, CW3, were frequently found. Preliminary evidence is provided for an association between BW62 and CW6 in this population. The observed distributions of multiple-locus heterozygosities are similar to those expected under the null hypothesis of linkage equilibrium. The results indicate that the Asaro, among other highland populations, have been isolated long enough for pre-existing linkage disequilibria at recombinational distances of 0.8% or more (such as occur with HLA-A,B and HLA-B,DR haplotypes) to have broken down.

HLA antigens in uveitis

HLA antigens are associated with a number of inflammatory eye diseases, most notably HLA B27 with anterior uveitis (AU). This association varies between different populations and ethnic groups. The aim of this study was to investigate the relationship between uveitis and HLA A, B and DR locus antigens in an Australian population. Seventy-two consecutive patients with uveitis were studied (37 males and 35 females) over a 6 month period. Thirty-two percent of the AU patients were HLA B27 +, as were 42% of males (19% females) with their first attack of AU compared with 60% of males (23% females) with recurrent AU. The only significant difference in etiology between males and females was the greatly increased incidence of rheumatic diseases in males, in whom 77% (10/13) had radiological evidence of sacroiliitis. Additional findings included a lack of association between the HLA B7 cross reactive group and DR locus antigens in AU as well as the lack of any HLA associations in the 13 patients with posterior uveitis (PU).

HLA antigens in intestinal cow's milk allergy.

The histocompatibility antigens of one hundred patients with a severe form of cow's milk allergy were studied. HLA-A and B locus antigens were identified in all patients, C locus antigens in 62 patients and DR locus antigens in 41 patients. The A, B and C locus antigen frequencies were compared with those of healthy blood donors, and DR locus antigen frequencies with those of healthy unrelated volunteers and cadaver kidney donors. The series included six patients with concomitant coeliac disease, who were treated as a separate group. No statistically significant differences between the patients and controls were observed, but suggestive differences became apparent when the patient group was divided into subgroups according to the presence or absence of certain co-existing conditions, and the severity of the initially observed intestinal lesion. It is concluded that several factors contribute to the pathogenesis of intestinal cow's milk allergy, and that in some cases genes linked to the HLA region may play a role.

Regulatory effect of monocytes on T cell proliferative responses to oral microbial antigens.

Mononuclear cell preparations isolated by Ficoll-Hypaque centrifugation from human peripheral blood were found to vary considerably in the number of monocytes they contained (mean, 20.3%; range, 13 to 33%). The regulatory role of monocytes in T cell proliferative responses to sonic extracts of a panel of oral microorganisms was therefore investigated. T cells were fractionated by anti-immunoglobulin chromatography and depleted of monocytes by treatment with a monoclonal anti-human Ia-like (DR locus antigen) antibody and complement. Purified populations of monocytes were obtained by extensive adherence procedures. The resultant cell populations were greater than 95% pure, as judged by indirect immunofluorescence on a fluorescence-activated cell sorter. Monocyte-depleted T cells failed to respond by proliferation to the nonoral antigen tetanus toxoid, as well as to any oral microorganism, but retained responsiveness to phytohemagglutinin. Readdition of monocytes in final concentrations of from 5 to 15% resulted in the restoration of maximal T cell proliferation. Monocytes in greater numbers suppressed T cell responses to all sonic extracts tested.

Expression of HLA-A/B/C and -DR Locus Antigens on Epithelial, Stromal, and Endothelial Cells of the Human Cornea

ABSTRACT We studied class I (A/B/C) and class II (DR) HLA antigens on human corneal cells with monoclonal antibodies using immunofluorescence and immunoperoxidase techniques. Cryostat sections of freshly harvested human corneas expressed class I HLA antigens on the corneal epithelium. Class II antigens were not detected on these corneal specimens, except for occasional, scattered positive cells in the peripheral corneal epithelium and stroma near the corneoscleral limbus. Corneal endothelial whole flat mounts from freshly excised human corneas were negative for class I and class II HLA antigens. In tissue culture, however, growing human corneal endothelial cells expressed class I HLA antigens. Crowing human corneal fibroblasts in tissue culture similarly were shown, through immunofluorescent techniques using monoclonal antibodies, to express class I HLA antigens. Fibroblasts and endothelial cells in tissue culture were negative for class II HLA antigens. We believe the low-to-nondetectable HLA antigen expression on central corneal stroma and endothelium may partly explain the immunological tolerance enjoyed by most corneal allografts.

Human leukocyte anitgen in torticollis and other idiopathic dystonic syndromes.

Two groups totaling 67 patients with idiopathic focal, segmental, and generalized dystonia, including torticollis, were compared with normal controls to determine whether there was a difference in the frequency of A, B, and C locus human leukocyte (HLA) antigens. The results indicated no statistically significant deviations in HLA antigen frequencies between the patients and the normal controls. Thirteen of the patients with idiopathic torsion dystonia were compared with normal controls for DR locus antigens. A trend of increased DR3 antigens observed in the patients may be significant. HLA genotyping of parents and children in nine families was also studied to determine if an HLA-linked factor could be related to the dystonic syndrome in the children. The results were indeterminate, suggesting that further family studies are required to resolve this issue.

Allergy to murine antigens in a biological research insitute

Symptomatic and immunologic responses to allergens from laboratory mice were studied in a research institute. Subjects who had been exposed to mice and 50 unexposed subjects were studied by questionnaire and by prick tests with seven prevalent aeroallergens and allergens from mouse urine and pelts. Of the 121 exposed subjects. 39 (32.2%) had respiratory, ocular, or cutaneous symptoms after exposure to mice; occurrence of these symptoms correlted with positive skin tests to purified mouse urinary proteins (MUP) and pelt allergensfrom CBA/H mice. Serum levels of IgG antibodies correlated with the frequency of mouse exposure. In subjects with seasonal allergic rhinitis, nasal symptoms from exposure to mice, positive prick tests to MUP, and IgE antibodies to MUP were significantly more prevalent. The possibility of genetic influences on susceptibility to mouse allergy were also suggested by a negative association between the incidence of HLA-DRW6 and positive prick-test responses to urinary proteins from C57BL and BALB/c mice among the 54 subjects who were exposed to mice and tested for DR locus antigens (p = 0.05). However, no significant differences in any of the loci studied culd be shwn in subjects with and without nasal symptoms from exposure to mice.

Expression of HLA-ABC and -DR locus antigens on human kidney, endothelial, tubular and glomerular cells.

The distribution of the major histocompatibility complex antigens on the various cellular structures of the human kidney was analysed by using a modified Staphylococcus aureus Cowan 1 method. Conventional alloantisera and heterologous antisera raised against isolated molecules were used for the HLA-ABC antigens, whereas the HLA-DR (Ia) antigens were detected with heterologous antisera only. The HLA-ABC antigens were expressed on all types of kidney passenger leucocytes, on vascular endothelial cells, and on kidney tubular cells, but not substantially on the glomerular podocytes. The DR antigens were strongly expressed on (a fraction of) the passenger lymphocytes and on the kidney vascular endothelial cells, weakly on the passenger monocytes, but not measurably on the urine-producing apparatus of the kidney--that is, on the glomerular and tubular cells.