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PubMed2003

Independent association of HLA-DR and FCgamma receptor polymorphisms in Korean patients with systemic lupus erythematosus.

OBJECTIVES: To determine the distribution of HLA-DR type and FcgammaRIIa/IIIa polymorphisms, and to analyse the combined effects of these genes for susceptibility in Korean systemic lupus erythematosus (SLE) patients. METHODS: A total of 299 SLE patients meeting 1982 ACR criteria and 144 Korean disease-free controls were enrolled. Genotyping for the FcgammaRIIa 131 R/H and FcgammaRIIIa 176 F/V was performed by polymerase chain reaction (PCR) of genomic DNA using allele-specific primers. HLA-DRB1 typing was performed by the PCR-SSOP method. RESULTS: There was significant skewing in the distribution of the three FcgammaRIIa genotypes between the SLE patients and the controls [P = 0.002 for R/R131 vs R/H131 and H/H131, relative risk (RR) 2.6 (95% CI 1.3-5.2)], but not in FcgammaRIIIa genotypes. HLA-DRB1*15 allele was significantly more prevalent among SLE patients than the control population [P < 0.02, RR = 1.7 (1.1-2.6)]. HLA-DRB1 genotypes or allele frequencies of the SLE patients with nephritis did not differ significantly from those of the SLE patients without nephritis. We analysed the combined effects of the two candidate genes on SLE susceptibility. HLA-DRB1*15 allele was a significant predictor of SLE in individuals who were not homozygous for FcgammaRIIa-R/R131 [RR = 2.1 (1.2-3.7), P < 0.008], and the FcgammaRIIa-R/R131 genotype vice versa [RR = 5.3 (1.9-15.4), P < 0.001]. However, an additive or synergistic effect of both susceptible genes on relative risk for SLE was not evident. CONCLUSIONS: Our results suggest that FcgammaRIIa-R/R131 homozygote and HLA-DRB1*15 allele are independent risk factors in Korean SLE patients without additive or synergistic effects.

Adult↗
PubMed1982

Polymorphism of properdin factor B in Japanese. Description of a rare variant and data of association with HLA and C2.

Polymorphism of the properdin factor B (BF) was investigated using an agarose gel immunofixation electrophoresis in 487 unrelated healthy adult Japanese who were already typed for HLA-A, -B, -C and C2. Besides the previously reported phenotypes in Japanese (S, FS, and F), a rare heterozygous phenotype (tentatively maned FTS) was observed once. The estimated allele frequencies for BS*S, BF*F, and FB*FT (F Tokyo) were 0.801, 0.198, and 0,001 respectively. The relative electrophoretic mobility of the variant band of type FTS was measured by Dr. G Mauff to be F 0.75. The conversion fragment Bb of the type showed a double-banded pattern. BF hemolytic activity of the FTS individual was at the same level as other phenotypes. Statistical tests for the phenotypic data of BF with HLA-A, -B, -C, and C2 indicated the presence of the following significant associations in Japanese: Aw33-BF*F, A11-BF*S, Aw24-BF*S, B15-BF*F, B17-BF*F, Bw44-BF*F, B7-BF*S, Bw52;-BF*S, BW54-BF*S, BW59-BF*S, Cw3-BF*F, C2*AT-BF*F, and C2*A'-BF*F.

Adult↗
PubMed2002

HLA-G exhibits low level of polymorphism in indigenous East Africans.

Human leukocyte antigen G (HLA-G) is a nonclassical HLA class I antigen that is predominantly expressed on invasive cytotrophoblastic cells, and is postulated to be a mediator of maternal-fetal tolerance. Almost all studies in Caucasian and Asian populations have consistently reported that HLA-G exhibits low levels of allelic polymorphism unlike the classical class I genes. However, the concept that HLA-G is nonpolymorphic has recently been challenged in a single study of African-American subjects. We have examined the DNA sequences of the first seven HLA-G exons by single-strand conformational polymorphism (SSCP) and DNA direct sequencing procedures in 45 healthy individuals from an indigenous African population. Overall, we detected 14 sequence variations: 3 in the signal peptide (exon 1); 2 in the alpha-1 domain (exon 2); 5 in the alpha-2 domain (exon 3); 2 in alpha-3 domain (exon 4); 2 in transmembrane domain (exon 5); and none in the cytoplasmic tail (exons 6 and 7). Of these variants, only three result in amino acid substitutions at the protein level. Of particular interest, we identified a novel nucleotide substitution (C727T), 56 bp before the HLA-G gene transcription start site, located in the putative binding site for polyomavirus enhancer-binding protein 2 (PEBP2) transcriptor factor. These data confirm previous reports describing HLA-G exhibiting limited allelic polymorphism. Further studies are needed to determine the impact of the C727T polymorphism on the level or developmental regulation of HLA-G expression.

Africa, Eastern↗
PubMed2003

The polymorphisms of intron1 sequences of HLA-A and -B.

Human leucocyte antigen (HLA) class I antigens are highly polymorphic membrane glycoproteins present on most nucleated cells. The polymorphism region is mainly located in exons 2 and 3 of HLA class I genes, which is flanked by introns 1 and 3. Thus, the sequence information of introns 1 and 3 is important for the genotyping of HLA. However, the information about them has not been extensively reported by now. In this work, the intron 1 sequences of HLA-A and -B of 51 standard genomic DNAs provided by the 13th International Histocompatibility Work Group (IHWG) were cloned and sequenced. The polymorphism of the intron sequences were also analyzed by the software Clustal W 1.82. Some sequences were chosen to compare with the standard sequences published in National Center for Biotechnology Information (NCBI). The comparison showed that all the sequences matched exactly with the standard sequences. The knowledge of intron 1 sequences could be very important not only for developing DNA-based typing strategies for the HLA-A and -B alleles but also for establishing an understanding of the evolutionary mechanisms involved in the polymorphism generation of HLA class I alleles.

HLA-A Antigens↗
PubMed1997

HLA class II allele frequencies in northern Thais (Kamphaeng Phet).

The polymorphism of HLA class II genes (HLA-DRB1, -DQA1, -DQB1 and -DPB1) was investigated in 97 normal Northern Thais (NT) from Kamphaeng Phet province using PCR-SSO typing. Allele frequencies (AF) have been determined. DRB1*1202 (17.5%), DRB1*1502 (16.5%), DQA1*0101 (25.8%), DQA1*0102 (21.7%), DQB1*0502 (22.7%), DPB1*0501 (23.2%) and DPB1*1301 (22.7%) showed the highest frequencies in each locus. These results were more similar to those observed in Present-day Thais (PDT) and Central Thais (CT) than Northern Thais from Chiang Mai (CM) and Dai Lue (DL). However, the data presented in this population study should be useful in many fields, such as anthropology, organ transplantation, disease susceptibility and evolutionary genetics.

Alleles↗
PubMed1995

A subset of HLA-DR9 molecules is detected by a polymorphic monoclonal antibody on lymphoblastoid cell lines but not on peripheral blood lymphocytes.

Some mAbs recognizing polymorphic epitopes of HLA-DR molecules exhibit striking differences of reactivity with the same HLA-DR molecules expressed by different cell types. In this study, we investigated the basis for the differential reactivity of the polymorphic anti-DR mAb OHA TM901 with HLA-DR9 molecules expressed by human PBLs or LCLs. By immunoprecipitation experiments we showed that OHA TM901 recognizes a subset of HLA-DR9 molecules from LCLs. This subset corresponds to HLA-DR9 molecules containing immature-type oligosaccharides. The absence of OHA TM901 reactivity with HLA-DR9 PBLs, as revealed by cytofluorometry analysis, suggests that this subset is either not expressed or expressed at a very low level on PBLs. These results indicate that overexpression of HLA-DR molecules in immortalized LCLs could lead to cell-surface expression of underglycosylated forms which are generally not found on the cell surface of PBLs.

Antibodies, Monoclonal↗
PubMed1999

HLA and tumour necrosis factor (TNF) polymorphisms in ocular Behçet's disease.

The role of HLA-B*51 and other major histocompatibility complex (MHC) genes in Behçet's disease (BD) remains unknown. We have performed HLA and tumour necrosis factor (TNF) polymorphism analysis in BD and evaluated their contribution to ocular disease. In this study, 102 patients and 115 controls of Middle Eastern descent were investigated by HLA and B*51 subtyping using novel primers, and by LT alpha NCo 1 and TNF 308 promoter polymorphism analysis. The frequency of the HLA-B*51 family of alleles was raised in patients compared to controls (66% vs. 15%, Pc=2.5x10(-12), OR=10.9). The odds ratio (OR) of this group of alleles for subgroups of patients was as follows: non-ocular patients 7.8, all ocular patients 12.6, blind patients >22. HLA-B*51 subtyping detected B*5101, 07, 08 and 09 alleles, with a similar frequency among patients and controls. HLA-Cw*1602 was associated with B*5108, but was not an independent risk factor for disease. The LT alpha (TNFB*2) allele was associated with HLA-B*51 among patients and the frequency of this allele was significantly higher among completely blind patients compared to both non-ocular patients (P=0.048, OR >3.6) and to healthy controls (P=0.022, OR >4.3). The rare TNF-2 polymorphism at the TNF -308 promoter position was associated with HLA-B*50 (not B*51), and was not associated with BD. Thus, in this population the HLA*B51 family of alleles is a strong risk factor for BD, and in particular the development of ocular disease. HLA-B*51 subtyping did not define new markers for BD. A primary role for TNF gne polymorphisms in BD was not identified, but co-expression of the TNFB*2 allele with HLA-B*51 may contribute to severity of ocular disease.

Adolescent↗
PubMed1988

Genetic basis of cell surface polymorphisms encoded by the major histocompatibility complex in humans.

In this review, the authors have analyzed the relationship between molecularly defined HLA gene polymorphisms and the diversity of HLA antigens detected serologically and by T-cell allorecognition. Although many relevant publications were not included, examples of the studies described here provide evidence for the strong association between polymorphisms defined at the gene and at the cell surface product levels. The concordance between RFLP and alloantigenic reactivity patterns may represent strong linkage disequilibrium between specific restriction enzyme variations in the coding and noncoding regions. It has become apparent that the allelic variations detected by molecular techniques are far greater than those defined by serological and cellular typing. This observation provides an impetus to identify reagents which define additional cell surface polymorphisms potentially important in immunoregulation, disease susceptibility, and transplant immunity.

HLA Antigens↗
PubMed2003

HLA-G allelic variants are associated with differences in the HLA-G mRNA isoform profile and HLA-G mRNA levels.

During pregnancy, the human extra-villous trophoblast in the contact zone between maternal and fetal tissue in the placenta does not express the classical MHC class I and II molecules. Instead, HLA-G and -C, and possibly HLA-E, are expressed. HLA-G may modulate the immunological relationship between mother and fetus in several ways. Finally, the expression of membrane-bound HLA-G and soluble HLA-G has been proposed to influence the outcome of pregnancy, and an aberrant HLA-G expression in pre-eclamptic placentas and spontaneous abortions has been reported. Here, an association between certain HLA-G polymorphisms and the mRNA levels of the different alternatively spliced HLA-G isoforms in first trimester trophoblast cell populations is reported. Several alternatively spliced HLA-G mRNA isoforms, including a 14-bp polymorphism in the 3'UTR end (exon 8) of the HLA-G gene, are expressed at a significantly lower level than the corresponding HLA-G mRNA isoforms with the 14-bp sequence deleted. Furthermore, characteristic HLA-G mRNA isoform expression patterns were associated with specific HLA-G genotypes and alleles. In the HLA-G*01012 and - G*01013 alleles that include the 14-bp sequence, an additional alternative splicing was observed, with the first 92-bp of exon 8 spliced out. This was most pronounced in HLA-G genotypes with G*01013. These findings may have functional implications for the recent reports of aberrant HLA-G expression and reproductive success.

Alternative Splicing↗
PubMed1985

Polymorphisms within the HLA-DRw6 haplotype. II. Protein charge heterogeneity reflects MLC subtyping of HLA-DRw6 homozygous cells.

We have analyzed the HLA class II gene products from HLA-DRw6 homozygous cells. Epstein-Barr virus-transformed B-cell lines were internally labeled with [35S]-methionine. An NP-40 lysate of the cells was subjected to immunoprecipitation, first with a DRw52-like-specific monoclonal antibody and subsequently with a DR-specific framework antibody. The DR region-encoded gene products were analyzed by one-dimensional gel isoelectric focusing and two-dimensional gel electrophoresis. It is shown that DRw6 homozygous cell lines contain at least two nonallelic DR beta chains, one carrying a DRw52 determinant and one DRw52-negative population. Both chains appear to be polymorphic between the cellularly defined subtypes of DRw6. The determinant responsible for the differential mixed lymphocyte culture reactivity of Dw18 and Dw19 cells resides on the DRw52-positive population, whereas the Dw6-Dw9 differences are attributed to determinants on both populations of DR light chains. The Dw16-derived DRw52+ chain much resembles the Dw18 DRw52+ light chain whereas there is a clear-cut difference between these two subtypes in the DRw52- population. We conclude that, for DRw6 homozygous cells, the cellularly recognized D determinants are probably located on DR-encoded molecules, both DRw52+ and DRw52-, and that charge shift of these chains is at least partly responsible for differential recognition of these cells in mixed lymphocyte cultures.

Epitopes↗
PubMed1984

Complete nucleotide sequence of a gene encoding a functional human class I histocompatibility antigen (HLA-CW3).

The HLA-CW3 gene contained in a cosmid clone identified by transfection expression experiments has been completely sequenced. This provides, for the first time, data on the structure of HLA-C locus products and constitutes, together with that of the gene coding for HLA-A3, the first complete nucleotide sequences of genes coding for serologically defined class I HLA molecules. In contrast to the organisation of the two class I HLA pseudogenes whose sequences have previously been determined, the sequence of the HLA-CW3 gene reveals an additional cytoplasmic encoding domain, making the organisation of this gene very similar to that of known H-2 class I genes and also the HLA-A3 gene. The deduced amino acid sequences of HLA-CW3 and HLA-A3 now allow a systematic comparison of such sequences of HLA class I molecules from the three classical transplantation antigen loci A, B, C. The compared sequences include the previously determined partial amino acid sequences of HLA-B7, HLA-B40, HLA-A2 and HLA-A28. The comparisons confirm the extreme polymorphism of HLA classical class I molecules, and permit a study of the level of diversity and the location of sequence differences. The distribution of differences is not uniform, most of them being located in the first and second extracellular domains, the third extracellular domain is extremely conserved, and the cytoplasmic domain is also a variable region. Although it is difficult to determine locus-specific regions, we have identified several candidate positions which may be C locus-specific.

Amino Acid Sequence↗
PubMed1999

The cytoplasmic and the transmembrane domains are not sufficient for class I MHC signal transduction.

Class I MHC molecules deliver activation signals to T cells. To analyze the role of the cytoplasmic and the transmembrane (TM) domains of class I MHC molecules in T cell activation, Jurkat cells were transfected with genes for truncated class I MHC molecules which had only four intracytoplasmic amino acids and no potential phosphorylation sites or native molecules or both. Cross-linking either the native or the truncated molecules induced IL-2 production even under limiting stimulation conditions of low engagement of the stimulating mAb. Moreover, direct comparison of transfected truncated and native class I MHC molecules expressed on the same cell revealed significant stimulation induced by cross-linking the truncated molecules, despite low expression. In addition, truncated class I MHC molecules were as able to synergize with CD3, CD2, or CD28 initiated IL-2 production as native molecules. In further experiments, hybrid constructs made of the extracellular portion of the murine CD8 alpha chain and of the TM and the intracytoplasmic domains of H-2Kk class I MHC molecule were transfected into Jurkat T cells. The expression of the transfected hybrid molecules was comparable to that of the native HLA-B7 molecules. Cross-linking the intact monomorphic HLA-A,B,C epitope or the polymorphic HLA-B7 epitope induced IL-2 production upon costimulation with PMA. In contrast, cross-linking the hybrid molecules generated neither an increase in intracellular calcium concentration ([Ca2+]i) nor stimulated IL-2 production. By contrast, cross-linking intact murine class I MHC molecules induced [Ca2+]i, signal and IL-2 production in transfected Jurkat cells. The data therefore indicate that unlike many other signaling molecules, signaling via class I MHC molecules does not involve the cytoplasmic and the TM portions of the molecule, but rather class I MHC signal transduction is likely to be mediated by the extracellular domain of the molecule.

Animals↗