A public HLA antigen associated with HLA-A9, Aw32, and Bw4

The HLA complex codes for three distinct 44000 dalton molecules associated with beta2 microglobulin--HLA-A, B and C--each with its own multiallelic series of private antigens. The HLA-B molecule is exceptional in that it also carries a diallelic system, Bw4 and Bw6. One of these, Bw4, is often associated with the A-locus specificity A9. This finding has usually been ascribed to linkage disequilibrium between A- and B-locus antigens. We have shown, however, that an epitope called LHe is actually shared by A-locus and B-locus molecules. This epitope is found on all HLA-B molecules bearing the Bw4 determinant and is also found on all HLA-A molecules carrying the A9 (Aw23 and Aw24) or Aw32 specificities. We consider this a "public" HLA antigen; the possible molecular basis for both subtypic and public antigens on a single glycoprotein is discussed.     

Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium?

The major histocompatibility complex (MHC) shows a remarkable conservation of particular HLA antigens and haplotypes in linkage disequilibrium in most human populations, suggesting the existence of a convergent evolution. A recent example of such conservation is the association of particular HLA haplotypes with the HFE mutations. With the objective of exploring the significance of that association, the present paper offers an analysis of the linkage disequilibrium between HLA alleles or haplotypes and the HFE mutations in a Portuguese population. Allele and haplotype associations between HLA and HFE mutations were first reviewed in a population of 43 hemochromatosis families. The results confirmed the linkage disequilibrium of the HLA haplotype HLA-A3-B7 and the HLA-A29 allele, respectively, with the HFE mutations C282Y and H63D. In order to extend the study of the linkage disequilibrium between H63D and the HLA-A29-containing haplotypes in a normal, random population, an additional sample of 398 haplotypes was analyzed. The results reveal significant linkage disequilibrium between the H63D mutation and all HLA-A29-containing haplotypes, favoring the hypothesis of a co-selection of H63D and the HLA-A29 allele itself. An insight into the biological significance of this association is given by the finding of significantly higher CD8(+) T-lymphocyte counts in subjects simultaneously carrying the H63D mutation and the HLA-A29 allele.     

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.     

Frequency of HLA alleles in a sample population from Campania

The authors present their findings on the HLA A and B antigens frequent in Campania by means of a 127 random people sample. Only the HLA 1-8 aplotype shows a clear crossing-over disequilibrium.     

Maternal-Fetal Interactions and the Maintenance of Hla Polymorphism

There is some empirical evidence that a fetus with an HLA antigen not present in its mother has a higher survival than a fetus sharing antigens with its mother. We have developed both single locus and two-locus theoretical models to examine this mode of selection. First, this immunologically based model appears to have the potential to maintain many alleles at a single locus and to result in an excess of heterozygotes when selection is strong. Second, substantial gametic disequilibrium is maintained between alleles at two loci for this selection mode when recombination is that observed between HLA loci A, B, and DR. Overall, it appears that this mode of selection has the potential to strongly affect genetic variation in the HLA region.     

Selection, Hitchhiking and Disequilibrium Analysis at Three Linked Loci with Application to Hla Data

The HLA system has been extensively studied from an evolutionary perspective. Although it is clear that selection has acted on the genes in the HLA complex, the nature of this selection has yet to be fully clarified. A study of constrained disequilibrium values is presented that is applicable to HLA and other less polymorphic systems with three or more linked loci, with the purpose of identifying selection events. The method uses the fact that three locus systems impose additional constraints on the range of possible disequilibrium values for any pair of loci. We have thus examined the behavior of the normalized pairwise disequilibrium measures using two locus (D'), and also three locus (D"), constraints on pairwise disequilibria in a three locus system when one of the three loci is under positive selection. The difference between these measures, delta = magnitude of D' - magnitude of D", has a distribution for the two unselected loci differing from that for the selected locus with either of the unselected loci (the hallmark is a high positive value of delta for the two unselected loci). An examination of genetic drift indicates that positive delta values are unlikely to be found in human populations in the absence of selection when recombination is greater than about 0.1%. This measure can thus provide insight into which allele of several linked loci might have been subject to selection. Application of this method to HLA haplotypes from a large French population study (Provinces Francaise) identifies selected alleles on particular haplotypes. Application of a complementary method, disequilibrium pattern analysis also confirms the action of selection on these haplotypes.     

Participation of Indo-European tribes in ethnogeny of the mongoloid population of Siberia: analysis of the HLA antigen distribution in mongoloids of Siberia.

Three hundred forty-three Yakuts (mongoloids of central Asian type living in Siberia) were tested for HLA-A, -B, and -C loci. The HLA antigen distribution corresponds on the whole to a mongoloid population with high frequency of the HLA-A9, -B15, and -B40 antigens (phenotype frequencies .533, .367, and .405, respectively). At the same time a strikingly high frequency for the "Indo-European" HLA-A1 antigen (phenotype frequency .282) was detected, which in Yakuts is found exclusively with HLA-B17 (haplotype frequency x 1,000 = 87.0; linkage disequilibrium value x 1,000 = 63.8). The present paper deals with a new hypothesis of the Yakut ethnogenesis according to which ancient Aryan tribes formed the substratum which was later assimilated by the mongoloid and Turkic populations. Another hypothesis that I have advanced argues that from analysis of the HLA system the ancient Aryans formed, a local group within the Indo-European entity, with high frequency for HLA-A1 and -B17 antigens and for the HLA-A1,B17 haplotype and with a complete absence of or very low frequency for the HLA-B8 antigen and for the HLA-A1,B8 haplotype. Significant linkage disequilibrium, as it is found in Indians and Yakuts, etc., could have resulted from mixing of the Aryans with non-Indo-European tribes. No significant linkage disequilibrium between A1 and B8 characteristic of the European caucasoids was produced in the mixing.     

Linkage analysis of human leukocyte antigen (HLA) markers in familial psoriasis: strong disequilibrium effects provide evidence for a major determinant in the HLA-B/-C region.

Although psoriasis is strongly associated with certain human leukocyte antigens (HLAs), evidence for linkage to HLA markers has been limited. The objectives of this study were (1) to provide more definitive evidence for linkage of psoriasis to HLA markers in multiplex families; (2) to compare the major HLA risk alleles in these families with those determined by previous case-control studies; and (3) to localize the gene more precisely. By applying the transmission/disequilibrium test (TDT) and parametric linkage analysis, we found evidence for linkage of psoriasis to HLA-C, -B, -DR, and -DQ, with HLA-B and -C yielding the most-significant results. Linkage was detectable by parametric methods only when marker-trait disequilibrium was considered. Case-control association tests and the TDT identified alleles belonging to the EH57.1 ancestral haplotype as the major risk alleles in our sample. Among individuals carrying recombinant ancestral haplotypes involving EH57. 1, the class I markers were retained selectively among affecteds four times more often than among unaffecteds; among the few affected individuals carrying only the class II alleles from the ancestral haplotype, all but one also carried Cw6. These data show that familial and "sporadic" psoriasis share the same risk alleles. They also illustrate that substantial parametric linkage information can be extracted by accounting for linkage disequilibrium. Finally, they strongly suggest that a major susceptibility gene resides near HLA-C.     

A Two-Locus Neutrality Test: Applications to Humans, E. COLI and Lodgepole Pine

The expected disequilibrium between two loci with k alleles at one locus and l alleles at the other is given for a sample of size n drawn from a population under neutrality equilibrium. Three different measures of disequilibrium with 95% intervals are tabulated for combinations of n, k, l and 4Nc, where N is the effective population size and c is the amount of recombination between the loci. The extent and pattern of disequilibrium are strongly dependent upon 4Nc and are somewhat dependent on n, k and l. The 95% intervals are large, particularly for low numbers of alleles and low values of 4Nc. As examples, observed disequilibrium from histocompatibility loci in humans (HLA) and electrophoretic data in E. coli and lodgepole pine were compared to these theoretical values. Using information about recombination rates, the HLA data showed more disequilibrium than neutrality expectations, whereas electrophoretic data from E. coli and lodgepole pine had somewhat less disequilibrium than neutrality expectations.     

Differential expression of HLA-DR, -DQ, and -DP antigens on malignant B cells

HLA class II antigens mediate interactions among cells involved in the immune response and play an important role in the process of self recognition. We made use of conventional alloantisera and six well-characterized monoclonal antibodies (MoAb) to study the HLA class II antigens on CALLA-positive malignant B cell populations and autologous normal B cell lines. Forty additional HLA class II-specific MoAb were also tested for their ability to bind to these cells. By using indirect immunofluorescence and immune precipitation assays, we find that malignant B cells often fail to express one or more of the three known types of HLA class II antigens. Cell lines with the following five phenotypes have been identified: HLA-DR+, -DQ+, -DP+; HLA-DR+, -DQ-, -DP+; HLA-DR-, -DQ+, -DP+; HLA-DR-, -DQ-, -DP+; and HLA-DR-, -DQ-, -DP-. These cell lines have been used to characterize the subregion specificity of MoAb that react with HLA class II antigens. This work confirms the existence of complicated patterns of serologic cross-reactivity between the three different types of HLA class II molecules. It also increases our understanding of the specificity of individual MoAb, thereby facilitating future investigation of the distribution and function of individual antigens. Our studies are consistent with the proposal that altered expression of HLA antigens on tumors might impair recognition of these cells by the immune system of the host, thereby contributing to the proliferation of a malignant clone.     

The HLA system in Italy

4,902 Italians were typed for HLA-A antigens, 4,721 for HLA-B and 1,503 for HLA-C. The samples, which were composed of unrelated, healthy individuals born in Italy, were used for estimating HLA-A, HLA-B and HLA-C gene frequencies with the maximum-likelihood method. Different Italian regions showed significant differences in the HLA alleles, providing further evidence for the genetic heterogeneity of the Italian population. HLA gene frequencies place continental Italy and Sicily in a position which is similar to that of other Mediterranean populations, whereas the genetic isolation of Sardinia is quite evident. The most significant linkage disequilibrium values found in the Italian population (except for Sardinia) were in agreement with those observed in other Caucasian populations. The difference between Northern and Southern Italy and between continental Italy and Sardinia was emphasized by the linkage disequilibrium values and by the principal-component analysis as well.     

Variation of HLA-ABC surface antigen expression on adenocarcinoma of the colon in correlation with the degree of differentiation

The expression of HLA class I antigens was tested on biopsy specimens originating from 90 patients suffering from adenocarcinoma of the colon. Three different samples were examined from each specimen: one from the tumor and the other two from the neighboring surrounding surgical margins. Twenty-seven out of 27 well-differentiated carcinomas were found highly positive for the presence of HLA class I antigens. Most of the moderately well differentiated tumors (37 out of 46) were weakly positive. None of the poorly differentiated tumors (n = 11) nor the mucin-producing tumors (n = 6) expressed HLA class I antigens. In 180 histologically normal colonic epithelia from patients suffering from adenocarcinoma of the colon (surgical edges free from tumorous tissue of the same specimens) no positive expressions were found. These results tend to suggest that class I HLA-ABC deficient, poorly differentiated tumors may possibly evade lethal immune aggression by HLA-restricted cytotoxic T cells and thus progress to overt malignancy. This negative expression may provide an explanation for the poorer prognosis observed among patients afflicted by a poorly differentiated adenocarcinoma or mucin-producing adenocarcinoma of the colon. Furthermore, these results tend to suggest that enhanced expression of HLA class I antigens on colonic epithelium could serve as a clinical laboratory indication for further examination looking for the possible emergence of neoplasm. If further verified, this may prove to serve as a predictive diagnostic tool for screening populations at risk.     

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 antigens in a sample of the Spanish population: Common features among Spaniards,Basques, and Sardinians

Summary Frequencies of recently described HLA-A,-B (antigens or splits) and HLA-C and HLA-DR antigens are studied in a 450 normal Spaniards sample. The linkage disequilibria are also calculated. HLA-DR7 is more frequent than in any other population studied. Aw30-B18 and Aw33-B14 associations are common and specific Spanish, Basque, and Sardinian HLA features. A11-B27 association is found in our Spanish sample and also in Basques.HLA-Bw4,-Bw6 antigens are analyzed by family mating and segregation and also using unrelated individuals. It shows a good fit as a genetic system. HLA-B antigens are included either in Bw4 or Bw6 according to expectations from other Caucasoid population results. The possibility of a common and North African origen (Iberians) for Spaniards, Basques, and Sardinians is discussed on the basis of presently available HLA data.     

The HLA system and the analysis of multifactorial genetic disease

The human leukocyte antigen (HLA) system comprises closely linked genes controlling highly polymorphic proteins involved in the presentation of peptides to the T-cell receptor. Specific alleles at HLA loci are associated with diseases, often those suspected to be of autoimmune aetiology. Many of these associations result from linkage disequilibrium between the HLA gene studied and other HLA genes or non-HLA gebes close by. Owing to its high level of polymorphism and its candidate role in many diseases, HLA was the first system used in many techniques of genetic mapping, such as affected-sib-pair analysis and association (linkage disequilibrium) studies. Much remains unknown about the reasons why diseases are associated with HLA. Experience gained from HLA has, however, shown how other loci involved in complex traits can be identified by studying families with multiple affected cases or sib pairs, followed by linkage-disequilibrium mapping and then analysis of candidate genes.     

Discordant patterns of linkage disequilibrium of the peptide-transporter loci within the HLA class II region.

Disequilibrium between genetic markers is expected to decline monotonically with recombinational map distance. We present evidence from the HLA class II region that seems to violate this principle. Pairwise disequilibrium values were calculated from six loci ranging in physical separation from 15 kb to 550 kb. The histocompatibility loci DRB1, DQA1, and DQB1, located on the distal end of the class II region, behave as a single evolutionary unit within which extremely high linkage disequilibrium exists. Lower but still significant levels of disequilibrium are present between these loci and DPB1, located at the proximal edge of the HLA complex. The peptide-transporter loci TAP1 and TAP2, located in the intervening region, reveal no disequilibrium with each other and low or negligible disequilibrium with the flanking loci. The action of two genetic process is required to account for this phenomenon: a recombinational hotspot operating between TAP1 and TAP2, to eliminate disequilibrium between these loci, and at the same time selection operating on particular combinations of alleles across the DR-DP region, to create disequilibrium in the favored haplotypes. The forces producing the patterns of disequilibrium observed here have implications for the mapping of train loci and disease genes: markers of TAP1, for example, would give a false impression as to the influence of DPB1 on a trait known to be associated with DQB1.     

Phorbol ester effect in platelets, lymphocytes, and leukemic cells (HL-60) is associated with enhanced phosphorylation of class I HLA antigens. Coprecipitation of myosin light chain

Phorbol-12-myristate-13-acetate (PMA) is a potent tumor promoter. However, the mechanism of its effect is still unknown. In the present study we use two dimensional gel electrophoresis to show that the PMA effect on platelets is associated with enhanced phosphorylation of a series of polypeptides at 44K which migrate close to but distinct from a previously reported 47K protein. We identified these proteins as the class I molecules of the human histocompatibility antigens (HLA A,B). We further demonstrate that the PMA effect is also associated with a dramatic phosphorylation of HLA antigens in HL-60 leukemic cells and in human lymphocytes, showing that an increase in phosphorylation of HLA antigens is intimately related to the signal of PMA in various cellular systems. Immunoprecipitation of HLA proteins resulted in coprecipitation of phosphorylated myosin light chain (20K). HLA antigens are transmembrane proteins which interact with cytoskeletal elements, probably via their intracellular region, which has been previously shown to be phosphorylated. It is suggested that phosphorylation of HLA membrane proteins may represent an important mechanism in the effects induced by PMA.     

HLA complex genes in type 1 diabetes and other autoimmune diseases. Which genes are involved?

The predisposition to develop a majority of autoimmune diseases is associated with specific genes within the human leukocyte antigen (HLA) complex. However, it is frequently difficult to determine which of the many genes of the HLA complex are directly involved in the disease process. The main reasons for these difficulties are the complexity of associations where several HLA complex genes might be involved, and the strong linkage disequilibrium that exists between the genes in this complex. The latter phenomenon leads to secondary disease associations, or what has been called 'hitchhiking polymorphisms'. Here, we give an overview of the complexity of HLA associations in autoimmune disease, focusing on type 1 diabetes and trying to answer the question: how many and which HLA genes are directly involved?     

Separation and comparison of human TL-like antigens and HLA(A,B, C) antigens expressed on Cultured T cells

Beta₂-microglobulin-bound T-cell membrane components containing both human TL-like antigens and HLA(A, B, C) antigens were partially purified from Renex 30-solubilized membrane material of cells of a human T-cell-type leukemia cell line, HPB-ALL. The radioiodinated preparation was subjected to limited papain digestion; the HLA(A, B, C) antigens split, whereas a large portion of the human TL-like antigens remained intact. The antigen molecules were recovered by lentil-lectin affinity chromatography and separated by gel filtration on the basis of the induced difference in molecular size. The human TL-like-antigen preparation thus obtained was essentially free of HLA(A, B, C) antigens. The human TL-like antigens were immunospecifically precipitated and the component polypeptide, heavy and light, chains were separated by acid dissociation followed by gel filtration. The component chains were compared with the corresponding chains of HLA(A, B, C) antigens obtained similarly from the same HPB-ALL cells with respect to their fragmentation patterns on chemical or enzymatic cleavage. The results provided convincing evidence for the identity of the light chains of human TL-like antigens and HLA(A, B, C) antigens, and also evidence suggesting the presence of substantial differences in the fundamental structure of the heavy chains of human TL-like antigens and HLA(A, B, C) antigens.A unit of the New York State Department of Health.