摘要:

The functional significance of polymorphism among MHC class II promoters in man and mouse is here reviewed, mainly in terms of the hypothesis of differential expression. The hypothesis proposes that differences between antigen‐presenting cells in MHC class II expression exert a co‐dominant effect on the Th1 ‐ Th2 cytokine balance, such that class II molecules of one type come to control to a greater extent the production of one group of cytokines, and those of another type the production of the alternative group. The survey deals with the influence of signal strength and antigen‐presenting cell type on T‐cell subset differentiation; functional differences between MHC class n molecules not obviously related to determinant selection; disease protection mediated by HLA alleles; mechanisms possibly responsible for allotypic and isotypic bias; overdominance (heterozygous advantage) in selection for expression of class II alleles; MHC class II promoter structure and function; inter‐locus and inter‐allele variability within human MHC class II gene upstream regulatory regions; a comparison of these polymorphisms in mouse and man; read‐out of class II promoter function; and a comparison with expression of MHC class I. We conclude that the evidence that this variation is functionally active (i.e. controls expression) is increasing, but is not yet compelling. The crucial test still to come, we suggest, is whether or not the biological effects attributable to this polymorphism will line up with molecular studie

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02684.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

CD50 (ICAM‐3) has been identified as the third CD 11a/CD 18 (LFA‐1) counter receptor. We investigated the expression and possible role of this molecule in the induction of early and late activation events in human thymocytes. We observed that CD50 expression is acquired by early T cell progenitors (CD34+) and maintained during thymic development, reaching the highest levels in the most mature population of thymocytes (CD3high). Neither basal nor cytokine‐induced expression of CD50 was observed on untransformed human thymic epithelial cell lines. Cross‐linking of CD50 expressed on the surface of human thymocytes, by using mAbs recognizing epitopes not related to the CD1 la binding site, transduced transmembrane signals leading to an increase of intracellular calcium concentration. This calcium mobilization was inhibited when CD50 was co‐cross‐linked with CD45, suggesting that tyrosine phosphorylation is also involved in CD50 signaling. The same anti‐CD50 mAbs that were able to affect intracellular calcium levels were shown to induce CD69 but not CD25 expression on human thymocytes. This effect was preferentially observed on CD3low/CD3highthymocyte subpopula‐tions. Cross‐linking of CD50 also significantly increased activation‐induced cell death of human thymocytes. These results support the idea that CD50 molecule can play a role in developing functionally m

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02685.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Molecular genetic techniques were used to type nine loci in the HLA class II region in 241 unrelated African‐Americans from New York City (NYC). Several effects attributable to recent genetic admixture were evident: the number of distinct class II alleles and haplotypes was larger in the African‐Americans than in people of African or European origin, the allele frequencies were more consistently even, and linkage disequilibrium was present across the entire class II region. The African‐American DRB1 allele frequencies almost always fell between frequencies among samples from northern Europe and the Gambia, two possible founding populations. The exceptions are attributed to the contribution of other genetically dissimilar African groups to the African‐American gene pool. DRB1 allele frequencies (specifically DRB 1*1501) and some haplotypes of DRB 1‐DPB1 were different in our NYC and the 11th International Histocompatibility Workshop (IHW) samples of African‐Americans. The high level of allele and haplotype diversity found in African‐Americans has important implications for the construction of pools of unrelated potential donors for tissue tr

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02686.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Psoriatic arthritis (PA) is an immune disease associated with HLA‐A2 in the Japanese population. To investigate mechanisms the association between HLA‐A2 and PA, we examinedin vivoimmune responsiveness toStreptococcus pyogenes. Recombinant M proteins for the subtype specific N‐terminal half (AB region) and conserved C‐terminal half (C region) were produced separately. IgG antibody level against each region was measured by ELISA in 31 PA patients, 88 patients with psoriasis vulgaris, 6 patients with rheumatoid arthritis and 77 healthy controls. We found that IgG antibody levels against the C region were markedly higher in the PA patient group than in the other disease groups or controls. Further, IgG antibody levels were higher in PA patients with spondylitis and polyarticular arthritis than in PA patients with rheumatoid‐like arthritis and arthritis mutilans. In contrast, no significant difference in the IgG antibody levels against the AB region was observed among the tested groups. HLA‐A2 DNA typing showed that HLA‐A*0207 was associated with PA (RR= 17.6; Pcorr<0.01) and the IgG antibody responses to the C region correlated well with the presence of HLA‐A*0207. These results suggest that streptococcal infection may be involved in the pathogenesis of PA by participating in the HLA‐linked immu

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02687.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

HLA‐C antigens are expressed to the cell surface at roughly 10% the level of HLA‐B or ‐A, and their serological definition remains persistently difficult. To characterize the factors limiting surface expression, the processes of assembly and intracellular transport of HLA‐Cw4 molecules were investigated in the C1R cell line. When appropriate peptides were added to cultured cells or in cell lysates significant amounts of conformed HLA‐C molecules that associate with β2‐microglobulin (β2m) are detected, but are indeed not sufficient to restore expression to the level observed for HLA‐A or ‐B molecules. Furthermore, a precursor/product relationship exists between the free class I heavy chain and the mature conformation of HLA‐Cw4 molecules. Thus, HLA‐C assembly promotes the conversion of HC‐10‐reactive molecules (weakly‐β2m‐associated non‐ligand associated free HC form) into the β2m‐associated class I molecules recognized by W6/32. To further investigate the factors that regulate cell surface expression, intracellular transport of HLA‐Cw4 was studied in pulse chase analysis. In contrast to some HLA‐A and B, maturation of HLA‐Cw4 heavy chains and their export to the medial and trans‐Golgi compartments are quite inefficient. After 4 h of chase period, roughly half of the pulse‐labeled HLA‐Cw4 molecules have transited to the medial‐Golgi and acquired complex oligosaccharides characteristic of mature form. In addition, treatment with γ‐interferon does not appear to improve maturation of HLA‐Cw4 heavy chains, suggesting that increased supply of peptides does not influence intracellular transport. Moreover, only a small fraction in the pool of HLA‐Cw4 molecules was subsequently transported through the trans‐Golgi network, as indicated by their acquisition of sialic acids. Taken together these studies show that HLA‐Cw4 molecules are inefficiently transported through the Golgi apparatus and presumably re

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02688.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

HLA class II antigens and DRB1, DQA1, DQB1 alleles were studied in 16 Italian and in 16 Sardinian patients with pemphigus vulgaris (PV). In the last group the complete HLA A‐DQ haplotypes, including the complotypes, were defined by family studies. As in other populations, two PV susceptibility haplotypes were found: HLA‐DRB 1*0402, DQA1*0301, DQB1*0302 and HLA‐DRB 1*1401, DQA1*0104, DQB 1*0503. The first haplotype was largely prevalent in the Sardinian patients and was a part of the extended haplotype HLA‐A2, Cw4, B35, S31, DR4, DQ8. The strength of the allele associations to PV is in agreement with the view that the main PV susceptibility genes are the DRB 1*0402 and DQB 1*0503 alleles. A genetic resistance to PV seems to be conferred by the HLA‐DR3, DQ2 haplotype in the Sardinian p

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02689.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Pemphigus vulgaris (PV) is a blistering disease of the skin and mucous membranes characterized by an autoantibody response against a keratinocyte adhesion molecule, desmoglein 3, causing acantholysis and blister formation. We compared high resolution MHC class II alleles and haplotype frequencies (HLA‐DRB, DQA1 and DQB1) in 37 patients with PV to 89 haplotypes of normal relatives from New Delhi and Ahmedabad. We found that PV patients had significantly increased frequencies of DRB1*1404 (P<0.0001), DQA1*0101 (P=0.001), and DQB1*0503 (P<0.0001). These associations were due to the increased frequencies of the haplotype HLA‐DRB 1 * 1404, DRB3*0202, DQA1*0101, DQB1*0503 in patients compared to control haplotypes (p<0.0001). Also, patients from Ahmedabad had a significant increase in HLA‐DQB 1*0302 (p=0.03). An identical amino acid sequence (Leu‐Leu‐Glu‐Arg‐Arg‐Arg‐Ala‐Glu), in positions 67–74 of the P domain of DRB alleles is restricted to some DR14 alleles. Therefore, there are three possible explanations for class II allele involvement in autoantibody in PV patients with class II haplotypes marked by HLA‐DR14. First, the class II alleles could be markers for an unidentified susceptibility gene in linkage disequilibrium with them. Second, the primary association could be with DQB 1*0503 and the association with HLA‐DR14 alleles would be the result of linkage disequilibrium. Third, the HLA‐DRB 1 locus susceptibility could involve a specific amino acid sequence in the third hypervariable region shared

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02690.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

This study describes a comprehensive, easy to perform PCR‐SSOP typing approach suitable for complete genomic subtyping of HLA‐A*02. A single 1.6 kb PCR–amplificate spanning exons 2,3 and 4 of the HLA‐A*02 gene was used for hybridization with a panel of twenty‐four SSOPs. This allowed unequivocal assignment of all so far known HLA‐A2 subtypes, including A*0209 and A*0215N which differ for nucleotide substitutions in exon 4, without the need for two separate amplifications. Using this approach, HLA‐A*02 subtype distribution was analyzed in 218 samples from unrelated, healthy individuals from northern Italy enrolled in the Italian Bone Marrow Registry and typed as HLA‐A2 by serology or generic molecular analysis. As expected, A*0201 was found in the majority (92.6%) of samples. However, a significant number (6.8%) of individuals carried A*0205. Furthermore, A*0202, A*0208, A*0209 and A*0217, so far not described in Caucasians, were detected in a low number of samples (frequency ranging from 0.45% to 1.8%). Finally, a novel HLA‐A*02 subtype, A*0220, was detected in 0.9% of the samples. As confirmed by DNA sequencing of exons 2 and 3, this allele is identical to A*0201 except for a single nucleotide substitution in codon 66 which changes the predicted amino acid sequence form Lys to Asn. The findings of this study have implications for the selection of HLA‐A*02+ donors in unrelated bone marrow transplantation and of patients for specific immunotherapy with HLA‐A*02 restri

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02691.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Recent evidence indicates that HLA‐C molecules are biologically relevant by eliciting T‐cell responses and exerting control over NK cell function. In addition, HLA‐C is associated with susceptibility to various diseases, notably psoriasis vulgaris. Clarification of the full biological roles for HLA‐C has however proved difficult because detection of HLA‐C antigens by complement mediated cytotoxicity using alloantisera is inefficient. Up to 50% of individuals in every race have serologically undetectable HLA‐C locus antigens due to a combination of relatively low expression, lack of serological reagents and a lack of information about the distribution of the HLA‐C blank alleles. Recently, amplification of DNA using sequence‐specific primers (PCR‐SSP) has proved a reliable, accurate and rapid method for medium resolution HLA‐C typing. We have now developed high resolution HLA‐C typing by PCR‐SSP utilizing allele and group‐specific PCR‐SSP reactions which can identify all HLA‐C alleles (except non‐coding change alleles) in most heterozygous combinations. Using this system we have typed 604 unrelated United Kingdom Caucasoids to generate accurate frequency and linkage disequilibrium data. To assess the validity of serology for HLA‐C, PCR‐SSP typings for 527 out of the 604 individuals were compared to serology. We find that the frequency of many HLA‐C antigens has been underestimated by serology and some antigens such as Cw6 are consistently assigned incorrectly by serology. The overall discrepancy rate between serology and SSP was high at 37% (195/527). High‐resolution HLA‐C typing of 112 International Histocompatibility Wo

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02692.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

We have examined 56 unrelated individuals from Malaysian aborigines for their DNA polymorphism of the HLA‐B gene by sequence specific oligonucleotide probe (SSO) method. Using the SSO hybridization, we found that one specific DNA allele with a B*1513 like pattern of epitope combination (ECB1513) was dominant among the Melayu Asli (Af=41.9%) and the Senoi (Af=24%). To determine the nucleotide sequences of ECB1513, a DNA fragment spanning from the beginning of exon 1 to the middle of exon 4 of the HLA‐B gene was amplified by polymerase chain reaction (PCR) from two ECB1513 positive individuals, and the PCR products were cloned and sequenced. This sequencing analysis confirmed that ECB1513 was identical to HLA‐B*1513 in exon 1,2, 3, and 4. Amino acid sequence of this major allele, HLA‐B*1513, in the aborigines especially around the peptide binding groove (B and F pockets), was compared with that of African B*5301 that had been suggested to confer resistance to malaria infection in Africa. The amino acid residues composing of the F pocket were completely identical in B*1513 and B*5301. These observations suggest that acommon environmental factor, the malaria infection, might have independently enhanced the selection of functional change in the polymorphic portion of HLA‐B gene in Africa and in South

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02693.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY