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At least 991 records · Page 55Linked to original sources
PubMed1984

Cell-mediated PPD-specific cytotoxicity against human monocyte targets: evidence for restriction by class II HLA antigens.

Human Purified Protein Derivative of tuberculin- (PPD-) specific cytotoxic cells have been detected in cultures of peripheral blood mononuclear cells stimulated for 6 days with PPD. These cytotoxic cells are demonstrated by their ability to lyse PPD-pulsed autologous monocyte target cells, but not unpulsed targets. In a series of checkerboard experiments each involving 3-5 randomly combined donors, effector cells from 35 donors have been tested in autologous and 130 allogeneic combinations. Analysis of results from the pooled allogeneic combinations reveals that HLA-B - and even more pronounced HLA-DR - antigen sharing correlates positively to high lysis. No effect of HLA-A antigen sharing is found. A more detailed analysis shows that the effect of HLA-B sharing may be fully accounted for by HLA-B-DR linkage disequilibrium. The results thus indicate that cell-mediated PPD specific cytotoxicity is HLA-restricted. Further, the correlation to HLA-DR sharing indicates that the restriction element in this system in all probability is a class II antigen.

Cytotoxicity Tests, Immunologic↗
PubMed1998

Distribution of HLA class II alleles among Spanish patients with pemphigus vulgaris.

Twenty-six unrelated Spanish Caucasian individuals affected by pemphigus vulgaris (PV) were HLA typed and frequencies compared with those of 200 ethnically matched healthy controls. Twenty-three out of 26 patients were HLA-DR4. The frequency of HLA-DR14 was also increased (31%; controls: 4%). Of the 23 patients positive for HLA-DR4, 21 carried the DRB1*0402 allele. Therefore, the frequency of HLA-DRB1*0402 among patients was 81% (4% in controls; P=4.7x10(-27), OR=100.8). Interestingly, HLA-DR13, a frequent HLA-DR specificity in the Spanish general population (27%), was absent among the PV patients (P=0.009; Pc=0.1; OR=0.05). Taking together these data, we can conclude that, in the Spanish population, PV is preferentially and strongly associated with HLA-DRB1*0402, whereas DRB1*13 seems to confer a protective effect in our population.

Alleles↗
PubMed1996

The regulation mechanism of HLA class II gene expression at the level of mRNA stability.

The number of major histocompatibility complex (MHC) class II antigens may be regulated at different levels. Although transcriptional regulation has been studied most intensely, evidence for control mechanisms acting on the stability of MHC class II mRNAs has been reported. We have previously shown, in fact, that the half-life of MHC class II mRNA rapidly decreases in Raji cells upon inhibition of translation by cycloheximide; further data indicated that this effect was not correlated with the inhibition of the synthesis of trans-acting protein(s) required for mRNA stability. In the present work, we developed an in vitro mRNA decay assay system to measure HLA-DRA mRNA stability and used inhibitors of protein synthesis affecting different steps of the process of translation in order to discriminate among possible mechanisms determining controlled MHC class II mRNA hydrolysis. We found that HLA-DRA mRNA associated with polysomes derived from cells treated with either puromycin (which causes dispersion of polysomes and accumulation of monosomes) or cycloheximide (which slows down translation causing ribosome stalling) is more rapidly degraded than in the absence of protein synthesis inhibitors. On the basis of our findings, we suggest that arrest of protein synthesis per se exposes the HLA-DRA mRNA molecules to degradative activities co-sedimenting with the polysomal fraction.

Actins↗
PubMed1997

Formation of a regulatory factor X/X2 box-binding protein/nuclear factor-Y multiprotein complex on the conserved regulatory regions of HLA class II genes.

Coordinate regulation of MHC class II genes occurs in a tissue-specific and cytokine-inducible manner. While the upstream regulatory sequences are conserved among all MHC class II genes, multiple base pair changes are found, even within the essential X box region. Analysis of all class II X boxes reveals differential binding between two transcription factors known to interact with the X box region, regulatory factor X and X2 box-binding protein (RFX and X2BP) of the HLA-DRA gene. These data presented a paradox with regard to the coordinate regulation of the class II genes if the factors though to regulate the HLA-DRA gene do not bind to the homologous sequence of all class II genes. Previous results suggested that cooperative interactions between the DNA binding proteins may be the key to understanding this paradox. Here RFX/X2BP/DNA complexes were formed on all class II isotypes regardless of the ability of the X box region to bind either factor individually. To further determine the role of the interactions between the X and Y factors, multiprotein/DNA complexes containing RFX, X2BP, NF-Y, and X-Y box DNA of the DRA and DRB genes were formed. This quaternary complex was extremely stable to competitor DNA, with a half-life > 4 h. These results suggest that the conserved X and Y boxes of class II genes function similarly and define a single multiprotein regulatory complex for class II expression in B cells.

Base Composition↗
PubMed2002

Real-time sequence-specific primer polymerase chain reaction amplification of HLA class II alleles: a novel approach to analyze microchimerism.

The careful assessment of microchimerism is essential to investigate the effects of donor bone marrow-derived cells in transplantation. We have developed a protocol to assess microchimerism based on the HLA mismatch between the recipient and the donor. Our approach combines real-time polymerase chain reaction (PCR) with sequence-specific primer PCR (SSP-PCR) to selectively amplify and measure the abundance of donor HLA alleles in DNA samples extracted from the recipient after transplant. To optimize and validate the reliability of this method at different levels of microchimerism, we tested serial dilutions of donor DNA into recipient DNA. We demonstrate that donor alleles can be readily detected and reliably measured at concentrations as low as 0.1%. This method is simple and rapid and could find practical application in the assessment of microchimerism in patients receiving organ or cellular transplants in conjunction with donor bone marrow cells infusion.

Alleles↗
PubMed1992

Effects of localized HLA class II beta chain polymorphism on binding of antigenic peptide and stimulation of T cells.

The relationship between HLA-DR1 polymorphism and recognition of antigen by T cells was investigated. Two allelic variants of HLA-DR1, which differ by amino acid substitution at positions 85 and 86 of the beta chain, were characterized for the effect of substitution on recognition of foreign antigen by DR1-restricted T cells. Substitution of alanine and valine for valine and glycine residues at positions 85 and 86 of the DR1 beta chain resulted in deficient T-cell stimulation as demonstrated by the requirement for higher concentrations of antigen to induce maximal levels of T-cell proliferation, induction of lower levels of proliferation at optimal antigen concentrations, and slower kinetics of formation of stimulatory peptide-DR1 complexes. Direct binding studies employing both biotinylated and radioiodinated forms of antigenic peptide demonstrated quantitatively lower levels of peptide bound to substituted DR1 molecules and low levels of site-specific binding as assessed by competitive inhibition analyses. The effect of MHC class II polymorphism on peptide-binding affinity as opposed to induction of appropriate peptide conformation and the impact of polymorphism at DR1 beta chain positions 85 and 86 on allorecognition of HLA-DR1 are discussed.

Alleles↗
PubMed1998

HLA class II antigens are associated with resistance or susceptibility to hepatosplenic disease in a Chinese population infected with Schistosoma japonicum.

The major histocompatibility Class II alleles of 108 individuals living in an area endemic for schistosomiasis japonica in China were determined to identify possible immunogenetic associations with advanced schistosomiasis. Two alleles, HLA-DRB1*1202 (P = 0.002) and HLA-DQA*0601 (P = 0.001) were strongly associated with resistance to advanced disease. In contrast, HLA-DQB1*05031 (P = 0.02) was associated with susceptibility to advanced schistosomiasis. The remaining alleles showed no association with advanced disease. Allele DRB1*1202 co-occurred with allele DQA1*0601; therefore, their independent protective effects could not be ascertained. In contrast, alleles DQA1*0601 and DQB1*05031 never co-occurred and had opposite and significant effects on the occurrence of disease.

Alleles↗
PubMed1990

Rapid nonlysosomal degradation of assembled HLA class II glycoproteins incorporating a mutant DR alpha-chain.

Gamma irradiation followed by antibody and complement selection was used to isolate a human B-lymphoblastoid cell line that no longer expresses HLA-DR molecules on its cell surface. Cell surface expression in the mutant (HMy2.DRN) was restored by transfecting a wildtype DRA but not a DRB cDNA, suggesting that a structural mutation in the DRA mRNA or protein was responsible for the lack of cell surface expression. Nucleotide sequence analysis of the DRA mRNA from HMy2.DRN revealed a 75 nucleotide deletion corresponding to the start of the alpha 2 domain and involving one of two cysteines that are involved in the formation of an intrachain disulfide bond. At the biochemical level, only minute quantities of HLA-DR could be precipitated from this cell line after a 4-h continuous label with 35S-methionine. HLA-DR beta and the class II-associated invariant chain could be seen coprecipitating with the mutant DR alpha-chain, suggesting a limited accumulation of normally assembled molecules. However, by carrying out the labeling at 16 degrees C instead of 37 degrees C, equivalent amounts of HLA-DR could be precipitated from parent and mutant alike. The mutant DR alpha chain was found in association with the beta-chain, but with reduced association with the invariant chain under these conditions. Pulse chase analysis in the parent and mutant cell lines indicated that this mutant DR alpha beta I complex undergoes a process of degradation at 37 degrees C. Inhibitors of intracellular transport such as monensin were ineffective in blocking this process of degradation. This work is consistent with published reports implicating the involvement of a pre-Golgi or an early Golgi compartment in the proteolysis of aberrantly folded or assembled multisubunit proteins.

Amino Acid Sequence↗
PubMed1997

HLA class II associations in juvenile Graves' disease: indication of a strong protective role of the DRB1*0701,DQA1*0201 haplotype.

Previous studies have shown that HLA-DRB1*0301 and DQA1*0501 are associated with susceptibility to Graves' disease. Ninety Danish patients with early onset of Graves' disease and 102-192 controls were analyzed for HLA-DR and -DQ to investigate if the same associations exist in the juvenile form of Graves' disease. Both DRB1*0301 and DQA1*0501 were highly significantly increased in the patients with relative risks of 8.0 and 4.6, which are higher than those seen in adults. Stratification showed that DRB1*0301 is more strongly associated than DQA1*0501. Surprisingly, the DRB1*0701,DQA1*0201 haplotype was completely absent from this group of patients, indicating a strong protective role of this haplotype in juvenile Graves' disease.

Adolescent↗
PubMed1992

Production of epitope specific monoclonal IgG antibodies to HLA class II molecules by combining in vivo and in vitro immunization.

To study the expression of HLA-DQ beta chain alleles associated with type 1 diabetes, mAbs were generated from mice immunized with synthetic peptides representing allelic HLA-DQw7 and HLA-DQw8 beta chain sequences. The splenocytes from immunized mice were fused with myeloma cells, either immediately after or following additional in vitro boosting with peptide. Peptide-specific mAbs, predominantly of the IgG isotype, were isolated only from in vitro boosted splenocytes. Immunoblot analysis showed that several of the mAbs cross-reacted with DQ beta chain molecules. One mAb to a peptide representing DQw8 beta position [49-60] specifically recognised the DQw8 beta chain. Three mAbs to a peptide representing DQw8 beta position [39-52] specifically recognised an epitope consisting of Gly-Val-Tyr in position 45-47, i.e., all DQ beta alleles except DQw7 beta (position 45-47: Glu-Val-Tyr) and DQw2 beta (position 45-47; Gly-Glu-Phe). In FACS analysis these mAbs bound lymphocytes with the same specificity as found by immunoblotting analysis. Thus, by combining in vivo and in vitro immunization we have generated a number of epitope specific monoclonal IgG antibodies that distinguish closely related HLA-DQ beta chain alleles in predetermined positions.

Alleles↗
PubMed2005

Association of Helicobacter pylori-related distal gastric cancer with the HLA class II gene DQB10602 and cagA strains in a southern European population.

BACKGROUND: Distinct human leukocyte antigen (HLA)-DQ genes have been associated with an increased or reduced risk for gastric cancer, but its association with Helicobacter pylori status is controversial. In the present study we evaluated the influence of host HLA DQA1 and DQB1 loci, H. pylori genotype, and socio-economic factors on predicting H. pylori-associated distal gastric cancer in a southern European population. MATERIAL AND METHODS: In a prospective case-control (1 : 2) study, 42 patients with H. pylori-associated distal gastric cancer were matched by age (+/-5 years) and gender to 84 patients with H. pylori-associated benign gastroduodenal disease (controls). The level of education received, smoking status, alcohol consumption, origin and familial history of gastric cancer were registered at inclusion. HLA DQA1 and DQB1 typing and H. pylori genotyping were determined from endoscopic gastric mucosal biopsies. RESULTS: Compared with control patients, a positive association with cagA(+) strains (p < .002) and a negative association with vacA-s2 strains (p < .02) was found in patients with distal gastric cancer. At the DQB1 locus, the (*)0602 allele was more frequent in distal gastric cancer than in controls (26.2% vs. 4.8%; p < .005). After correction for multiple comparisons (exact multiple regression analysis) the cagA(+) status and the DQB1(*)0602 allele were associated with an increased distal gastric cancer risk (OR 3.7; 95% CI = 1.33-12.26 and OR 4.82; 95% CI = 1.24-19.83, respectively) whereas the vacA-s2 status was associated with a decreased risk (OR 0.33; 95% CI = 0.10-0.94). CONCLUSION: Our findings suggest that in the H. pylori-infected southern European population, the cagA genotype and the HLA-DQB1(*)0602 gene confer an increased risk for distal gastric cancer.

Aged↗
PubMed2006

HLA class II DRB1 polymorphism in Argentinians undergoing chronic Trypanosoma cruzi infection.

DNA typing of human lymphocyte antigen (HLA)-dicloro-1-[beta]-D-ribofuranosyl-benzimidazole 1 (DRB1) alleles in 35 individuals serologically positive for T. cruzi and in 41 healthy controls was performed. DRB1*0409 allele was significantly more prevalent in seropositive individuals, with a trend being also observed for the DRB1*0701 and DRB1*1503 alleles. Although statistically insignificant, the latter was found more frequent in cases with cardiomyopathy.

Animals↗
PubMed1991

[Expression of class II HLA antigens on cryopreserved isolated mononuclear splenic cells].

The human spleen presents a rich source of class 2 HLA-positive mononuclear cells. After cryopreservation in liquid nitrogen and storage during 18 months these cells retain high viability and continue expressing class 2 HLA antigens on their membrane. Cryopreserved cells react specifically with antibodies to particular determinants of class 2 HLA-DR molecules. This permits their using as target-cells in serological reactions, and serves the basis for creation of banks of well-characterized "standard" class 2 HLA-positive cells with the known phenotype.

Cell Membrane↗
PubMed1984

Antigen-specific T cell clones restricted by DR, DRw53 (MT), or DP (SB) Class II HLA molecules. Inhibition studies with monoclonal HLA-specific antibodies.

T lymphocyte clones (TLCs) specific for Chlamydia trachomatis were obtained after limiting dilution of activated T cells from a single donor, BS (HLA-A3; B7,15; DR1, 4; DRw53; DPw4). Most of the proliferative TLCs obtained apparently used restriction elements on DR1 or DR4 molecules, expressed in the antigen-presenting cells (APC). The restriction pattern of two TLCs, however, closely followed the DRw53 specificity, while one TLC seemed to be restricted by elements on DPw4 molecules. A panel of murine monoclonal antibodies (Mabs) was employed to further dissect the restriction specificities. The proliferative capacity of some of the TLCs was studied with and without Mabs directed against different HLA molecules, using non-T cells, monocytes, and peripheral blood dendritic cells as APC. Two Mabs, 7.2 and D-54, which seem to detect monomorphic determinants on HLA-DR, inhibited both DR- and DRw53-restricted TLCs. One Mab, 109d6 which reacts with DRw53 determinants, selectively inhibited the DRw53-restricted TLCs. The DP-restricted TLC was not inhibited significantly by any tested Mabs, including two Mabs with putative specificity for monomorphic determinants on the DP molecule.

Antibodies, Monoclonal↗
PubMed2002

Increased frequency of homozygosity for HLA class II loci in female patients with chronic lymphocytic leukemia.

The etiology of chronic lymphocytic leukemia (CLL) appears to be influenced by genetic factors which may contribute to its differential, gender- and age-specific incidence. The presented study is the first, which investigated the frequencies of DNA-typed alleles of all relevant human leukocyte antigens (HLA) loci in CLL patients with regard to gender and age at disease onset. The most remarkable result was the higher frequency of homozygosity for MHC class II loci in female patients. Particularly, an increased frequency of overall homozygosity for the DRB3/4/5 loci was observed in female patients compared to gender matched controls (RR = 2.8) and male patients. The previously demonstrated association of DQB1 homozygosity with CLL in general was found to be specific for female patients (RR = 4.4). Considering the lack of an a priori hypothesis which made it virtually impossible to obtain statistical significance it was not unexpected that none of the observed differences remained significant after correction for multiple comparisons. However, these results suggest a recessive, gender-specific susceptibility factor for CLL within or in vicinity of the human MHC class II region and should serve as an a priori hypothesis for future studies focusing on these gene loci. Furthermore, an increased frequency for HLA-Cw*06 was seen in patients with an early onset age (RR = 2.7) but lost significance after correction for multiple comparisons. The previously reported association of HLA-DRB4*0103 with CLL in general was observed in all groups irrespective of gender and age. Conclusively, our study supports the concept, that CLL represents a disease with a complex etiology and genetic susceptibility which appears to be influenced by the human MHC.

Adult↗