B-lymphocyte alloantigens associated with systemic lupus erythematosus.

We examined B-lymphocyte alloantigens in 41 patients with systemic lupus erythematosus and 184 controls, using a panel of 47 pregnancy serums, and compared reaction frequencies of individual serums. One serum, la-715, reacted with B lymphocytes from 75.6 per cent of patients and 14.1 per cent of controls (Pc less than 0.005, relative risk 18.8). Twenty-eight of the patients were also typed with a panel of HLA-D-related serums from the Seventh International Histocompatibility Workshop, HLA-DRw types assigned, and compared to 490 Workshop controls. Both HLA-DRw2 (57.1 per cent vs. 26.4 per cent, Pc less than 0.004) and HLA-DRw3 (46.4 per cent vs. 22.2 per cent, Pc less than 0.03) were increased in systemic lupus erythematosus. This study demonstrates that select B-lymphocyte alloantigens, which are controlled by genes in the major histocompatibility complex, are present in increased frequency in systemic lupus erythematosus.     

HLA and Cancer in South African Indians

Two-hundred-and-forty-nine Indian cancer patients were tested for 39 HLA antigens and the antigen frequencies were compared with those of 603 control subjects. Comparisons were also made between cancer patients and controls for each ethnic group and for each site of cancer. There was an increase in the frequency of the HLA antigens A11 and Bw52 in patients with malignancies. Heterozygosity at the B locus was significantly increased in patients with cancer of the breast. The Aw24, B17 haplotype was also associated with breast cancer.     

HLA Antigens in South American Indians

New HLA data for the Tirio, Parakan?, Kayapo and Mapuche tribes, as well as supplementary data for the Wai?pi, are presented. Taken together with previously published information on South American Indians, these typings show a remarkably homogeneous gene pool with a restricted range of polymorphisms and a further restricted set of haplotypes.     

HLA and Insulin Dependent Diabetes in South African Indians

The HLA antigens of 44 Asian Indians with juvenile-onset, insulin-dependent diabetes were determined. The frequency of HLA-B8 was increased but that of HLA-B15 was not. There was a significant increase in the frequency of some of the subdivisions of B5.     

HLA antigens in Tlingit Indians with rheumatoid arthritis

HLA-DR4 has been described in association with rheumatoid arthritis (RA) in multiple populations. We have studied HLA antigens in Alaskan Tlingit Indians. HLA-DR4 was decreased in the RA group (n = 32) compared with controls (n = 62) (6% vs 21% p = 0.07). The predominant DR4 allele observed was DRB1*0403 (Dw13.1). The most striking observation in these studies was a marked predominance of the DRB1*1402 allele encoding Dw16 (DRw14). This allele was present in 91% of RA cases, but was also highly prevalent in controls (80%, OR = 2.4 p = 0.20). DRB1*1402 only was observed in 47% of cases and 31% of controls. The DRB3*0101 (DRw52), and the DQA*0501 and DQB*0301 alleles encoding a subset of DQw3 were associated with DRB1*1402 in cases and in controls. HLA-Bw62 was increased in RA cases (28%) compared with controls (8%) (OR = 4.5, p = 0.01, corrected p = ns).     

New HLA class I-like alloantigens expressed on blast cells

New beta 2-microglobulin (beta 2-m)-associated, HLA-linked alloantigens, selectively expressed on phytohaemagglutinin (PHA)-activated lymphocytes, were identified using human alloantisera. Reactivity of the antisera against activated cells correlated with HLA-A2, A10 and A28 specificities. The new alloantigens were undetectable on peripheral blood mononuclear cells, B lymphocytes and platelets using either the lymphocytotoxicity or the absorption techniques, and appeared on lymphocytes upon PHA activation, with time-dependent kinetics. They were found on some, but not all, acute leukaemias of B, T and myeloid origin, being absent from chronic B lymphocytic leukaemias. The presence of the new beta 2-microglobulin-associated allospecificities was not correlated with the quantity of classical class I antigens present, as analysed on different cell types by flow cytometry. Thus, these antigenic determinants appear to be different from the classical HLA class I antigens and could be the human counterpart of the murine Qa system or of the second H-2K gene.     

HLA antigens in Asian Indians: HLA-D-DR relationships

Fifty-nine Asian Indians were typed for HLA-A, B, D, and DR antigens. Peculiar to the population that we have tested was the absence of HLA-A25, B13, B14, DR1, DW1, LD13 (a DR1-associated HLA-D allele), and LD12 (a DR4-associated HLA-D allele). Certain haplotypes that exhibit high frequencies in Caucasians (such as A2-BW50, AW24-B18, B8-DR3, BW44-DR7, B18-DR5) or in Blacks (such as A29-B7) also show significant delta in Asian Indians. The HLA-D-DR associations previously described in European and North American Causcasians were also found in Asian Indians. Additionally, however, Asian Indians exhibited two new HLA-D antigens, one associated with DR5 and the other with DRw6. The genetic distance between Asian Indians and Caucasians, Blacks, or Mongoloids is of the same order of magnitude.     

HLA A*02 allele and B-associated haplotype diversity in Indians

Human leucocyte antigen (HLA) A2 is the most heterogeneous allele at the HLA A locus, with approximately 56 different subtypes. Substantial heterogeneity in A*02 distribution has been observed in populations worldwide. HLA A2 allele distribution varies (4-25%) in different Indian populations and castes. HLA B40 is the most common allele associated with A2 haplotypes. In this study, molecular A*02 subtyping in Maratha (western Indian--Aryan) and Nadar (south Indian--Dravidian) caste groups using high-resolution polymerase chain reaction/reverse line strip/sequence-specific oligonucleotide hybridisation (PCR-RLS-SSOP) indicates the presence of 10 subtypes (A*02011, A*0203, A*0205, A*0206, A*0207, A*0208, A*0209, A*0211, A*0222 and A*0236) in variable frequencies. Moreover, A*0211-B*4006 was commonly observed among the north Indian Maratha caste and A*02011-B*4006 among the south Indian Nadar caste groups. HLA A*0211 is found frequently in this population and in Asian Indians, and has been reported with low frequencies in many other populations worldwide. A*0222 has been observed among Hispanics, while A*0236 has been observed exclusively among members of the Maratha caste. The findings demonstrate a substantial heterogeneity among the groups studied that may be a consequence of founder effect, racial admixture or selection pressure due to environmental factors.     

Studies of HLA alloantigens of the Navajo Indians of North America. I. Variance of association between HLA-DRW (WIA) and HLA-DW specificities.

As a part of the 7th International Histocompatibility Workshop, 49 randomly selected Navajo Indians were B-cell (DR) typed. Thirty-three of these individuals were also HLA-D (L.D.) typed with the Caucasian derived Copenhagen homozygous testing cell panel. DRW 2, 7, and WIA 8 were clearly defined while DRW 3 and 4 were less well defined and DRW 1, 5, and 6 were not defined in this population by the Workshop antisera. There was highly significant correlation between DRW 7/DW 7 and WIA 8/DW 8 but no correlation at all between DRW 2/DW 2, DRW 3/DW 3 and DRW 4/DW4. These results, in part, were discordant with the finding of the 7th Workshop and suggest that either DRW (WIA) and DW alloantigens are the product of more than one gene locus or that these antigens are a product of one gene locus but that each antigen molecule has multiple factors.     

The interchange of derivatives of human B2-microglobulin in HLA alloantigens

Derivatives of human Beta 2 microglobulin (B2M) have been made by attaching various groups to amino groups in the peptide. In this way ¹²⁵iodine, dinitrobenzyl, and m-maleimidobenzoyl groups have been introduced. These derivatives of B2M were able to associate with HLA chains and could be displaced again by native B2M. The rate of dissociation of HLA chains and derivatives of B2M is comparable with the intrinsically labelled native dimer. In some cases, particularly with [¹²⁵I]-B2M, the rate of dissociation appears to be smaller than for native B2M.     

Study of HLA alloantigens of the Navajo Indians of North America: II. HLA–A, B, C, DR and other genetic markers

This report presents the antigen frequencies for HLA-A, B, C, DR, immunoglobulin, and red blood cell systems for the Navajo Indians of North America. HLA-A-B, B-C, and B-DR haplotype frequencies and significant delta values are given. These data are compared with similar data for other American Indians and major non-Indian ethnic groups. Very restricted HLA polymorphism is unique for the Navajo as well as American Indians in general and this feature has important implications with regard to disease association and transplantation.     

The Distribution of HLA Antigens in the Motilones Indians of Venezuela

The HLA antigen profile of the Bari and Yupa Indians who live in the Motilones Valley on the border between Venezuela and Colombia was studied. Both groups showed very limited polymorphism. HLA-A1, A3, A11, Aw23. A25, A26, A29, Aw30, Aw32, and Aw33, and HLA-B7, B8, B12, B13, B14, B17, B18, Bw22, and B27 were not observed in either population.     

HLA A*02 allele frequencies and B haplotype associations in Western Indians

The population of Western India is described as Australoid or Proto-Australoid elements with admixture from Caucasian, Mongoloid, and Aryan races. We investigated the frequencies of human leukocyte antigen (HLA) A*02 alleles and their B* allele haplotype associations among 664 healthy unrelated Western Indians. Fifty-one of 204 serologically typed A2 individuals were analyzed for 56 molecular A*02 subtypes using high resolution polymerase chain reaction-reverse line strip-sequence-specific oligonucleotide hybridization (PCR-RLS-SSOP). A total of seven different A*02 alleles were identified, A*02011 (16%), A*0203 (16%), A*0205 (2%), A*0206 (2%), A*0211 (52.9%), A*0222 (4%), and A*0236 (8%). The most common HLA B allele associated with A*02 was B*40. Among the 42 subtypes HLA B*4006 (37.22%) was the most frequent subtype. HLA A*0211 was highly frequent in this population, A*0206 and A*0203 are common alleles observed among Asian populations, whereas A*0205 occurs in Caucasians and Africans and A*0222 has been observed among Hispanics. A*0236 has been observed among the western Indians exclusively. Most of the HLA A*02 subtypes observed were associated with B*4006 haplotype, although A*0236 was with B*0702 or B*1302 among the western Indians. The prevalence of A*0211 at high frequencies, A*0222, A*0236 novel alleles along with A*02 related haplotypes, demonstrate a substantial heterogeneity, which may be a consequence of founder effect, racial admixture, or selection pressure due to environmental factors.     

Codominant expression of the polymorphic MICA alloantigens encoded by genes in the HLA region

The HLA‐related, polymorphic MHC class I‐related chain A (MICA) gene encodes a 383‐amino acid polypeptide, with three extracellular domains (α1, α2 and α3), a transmembrane region and a cytoplasmic tail. We have previously shown that freshly isolated endothelial cells, fibroblasts, keratinocytes and monocytes express MICA, while peripheral blood CD4⁺, CD8⁺ or CD19⁺ lymphocytes do not. This polymorphic MICA molecule is a target for specific alloantibodies in sera from kidney, heart and lung transplant recipients, although its possible role during graft rejection remains to be demonstrated. In this study we investigated whether there is codominance in the expression of MICA. We isolated RNA from a heterozygous cell line (HCT116), previously shown by sequencing‐based typing to be MICA*001/MICA*00902, as well as 12 clones derived from it. Thereafter, we retrotranscribed the RNA into cDNA, and performed a molecular typing using MICA‐sequence specific oligonucleotides (SSOP). Using this approach, we detected the RNA encoding MICA*001 and MICA*00902 in all the clones and in the parental cell line, indicating that MICA is codominantly expressed. This codominant expression was further confirmed by cloning and sequencing plasmids encoding these two alleles produced from the same HCT116 RNA preparation. We also produced the two recombinant MICA proteins (MICA*001 and MICA*00902). They reacted with rabbit anti‐MICA polyclonal antibodies by ELISA and Western blot, indicating that the plasmids carrying the cDNA inserts probably encode functional MICA proteins. This strongly suggests that, like the HLA class I and class II proteins, MICA is codominantly expressed. The codominant expression of the polymorphic, HLA‐like MICA alloantigens may have implications for the immune response elicited by the allograft in organ transplantation.     

HLA class II variation in the Gila River Indian Community of Arizona: alleles, haplotypes, and a high frequency epitope at the HLA-DR locus.

A genetic distribution for the HLA class II loci is described for 349 "full-blooded" Pima and Tohono O'odham Indians (Pimans) in the Gila River Indian Community. A high frequency epitope in the *DRw52 family was defined by reactions with 31 alloantisera, which we have designated *DR3X6. It segregates as a codominant allele at HLA-DR with alleles *DR2, *DR4, and *DRw8, and has the highest frequency yet reported for an HLA-DR specificity, 0.735. It forms a common haplotype with *DRw52 and *DQw3 that is a valuable marker for genetic admixture and anthropological studies. Phenotype and allele frequencies, and haplotype frequencies for two and three loci, are presented. Variation at these loci is highly restricted, the mean heterozygosity for HLA-DR and HLA-DQ being 0.361. The Pimans represent a contemporary model for the Paleo-Indians who first entered North America 20,000 to 40,000 years ago.     

Codominant expression of the polymorphic MICA alloantigens encoded by genes in the HLA region.

The HLA-related, polymorphic MHC class I-related chain A (MICA) gene encodes a 383-amino acid polypeptide, with three extracellular domains (alpha1, alpha2 and alpha3), a transmembrane region and a cytoplasmic tail. We have previously shown that freshly isolated endothelial cells, fibroblasts, keratinocytes and monocytes express MICA, while peripheral blood CD4+, CD8+ or CD19+ lymphocytes do not. This polymorphic MICA molecule is a target for specific alloantibodies in sera from kidney, heart and lung transplant recipients, although its possible role during graft rejection remains to be demonstrated. In this study we investigated whether there is codominance in the expression of MICA. We isolated RNA from a heterozygous cell line (HCT116), previously shown by sequencing-based typing to be MICA*001/MICA*00902, as well as 12 clones derived from it. Thereafter, we retrotranscribed the RNA into cDNA, and performed a molecular typing using MICA-sequence specific oligonucleotides (SSOP). Using this approach, we detected the RNA encoding MICA*001 and MICA*00902 in all the clones and in the parental cell line, indicating that MICA is codominantly expressed. This codominant expression was further confirmed by cloning and sequencing plasmids encoding these two alleles produced from the same HCT116 RNA preparation. We also produced the two recombinant MICA proteins (MICA*001 and MICA*00902). They reacted with rabbit anti-MICA polyclonal antibodies by ELISA and Western blot, indicating that the plasmids carrying the cDNA inserts probably encode functional MICA proteins. This strongly suggests that, like the HLA class I and class II proteins, MICA is codominantly expressed. The codominant expression of the polymorphic, HLA-like MICA alloantigens may have implications for the immune response elicited by the allograft in organ transplantation.     

Comparison of the humoral and cytotoxic T-lymphocyte response to individual HLA class I alloantigens in highly immunized patients

In order to investigate the correlation between activation of cytotoxic T-lymphocyte precursor (CTLp) and the formation of antibodies to alloantigens, we studied 21 highly sensitized patients waiting for a kidney transplantation. Both antibody reactivity and CTLp frequencies of these patients were determined against 88 individual HLA class I alloantigens. A high or low CTLp frequency against a certain HLA-A or -B alloantigen was not correlated with the presence or absence of the antibodies to that antigen. Mismatched antigens, towards which the patient had not formed antibodies, can induce either a higher or a lower frequency of CTLp compared to mismatches towards which the patients had formed antibodies. The possible implications of this lack of correlation between the T- and B-cell allorepertoires with regard to donor selection for (highly immunized) patients is discussed.     

Differential immunogenicity of HLA class I alloantigens for the humoral versus the cellular immune response: "towards tailor-made HLA mismatching"

The immunogenicity of an individual human leukocyte antigen (HLA) class I mismatch is different for the cellular and the humoral alloimmune responses. The consequence is that the same antigen can induce a strong antibody response and no cytotoxic T lymphocyte reactivity, but the reverse can occur also. Exact knowledge of the immunogenicity of an HLA mismatch for an individual patient can lead to a strategy of tailor-made HLA mismatching if no HLA identical donor is available. Depending on the clinical situation, one should select a donor with HLA mismatches according to the humoral or cellular mismatch algorithm.