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PubMed1990

HLA-class II antigens on hemopoietic and stromal cells in human micro long-term bone marrow cultures.

Using a complement-dependent cytotoxicity assay (CDC), we analyzed the presence of HLA-class II antigens on both stromal and hemopoietic cells in a miniaturized human long-term bone marrow culture system. 4-Hydroperoxycyclophosphamide (4-HC)-resistant hemopoietic stem cells capable of restoring in vitro hemopoiesis on irradiated stromal cell layers were HLA-DR, -DP, and -DQ negative. In addition, these cells failed to bind the monoclonal antibody (mAb) Tü 39, previously proposed as a candidate for the recognition of a novel class II antigen, "-DY." On the other hand, the formation of confluent stromal cell layers was inhibited by HLA-DR- or -DP-specific mAbs, but not by the HLA-DQ-specific mAb Tü 22. This suggests the presence of HLA-DR- and/or HLA-DP-positive, but HLA-DQ-negative stromal precursor cells.

Antibodies, Monoclonal↗
PubMed1997

HLA class II DR-DQ amino acids and insulin-dependent diabetes mellitus: application of the haplotype method.

Insulin-dependent diabetes mellitus (IDDM) HLA class II DRB1-DQA1-DQB1 data from four populations (Norwegian, Sardinian, Mexican American, and Taiwanese) have been analyzed to detect the amino acids involved in the disease process. The combination of sites DRB1#67 and 86; DQA1#47; and DQB1#9, 26, 57, and 70 predicts the IDDM component in these four populations, when the results and criteria of the haplotype method for amino acids, developed in the companion paper in this issue of the Journal, are used. The following sites, either individually, or in various combinations, previously have been suggested as IDDM components: DRB1#57, 70, 71, and 86; DQA1#52; and DQB1#13, 45, and 57 (DQB1#13 and 45 correlates 100% with DQB1#9 and 26). We propose that DQA1#47 is a better predictor of IDDM than is the previously suggested DQA1#52, and we add DRB1#67 and DQB1#70 to the HLA DR-DQ IDDM amino acids. We do not claim to have identified all HLA DR-DQ amino acids-or highly correlated sites-involved in IDDM. The frequencies and predisposing/protective effects of the haplotypes defined by these seven sites have been compared, and the effects on IDDM are consistent across the populations. The strongest susceptible effects came from haplotypes DRB1 *0301/DQA1 *0501/ DQB1*0201 and DRB1*0401-5-7-8/DQA1*0301/ DQB1*0302. The number of strong protective haplotypes observed was larger than the number of susceptible ones; some of the predisposing haplotypes were present in only one or two populations. Although the sites under consideration do not necessarily have a functional involvement in IDDM, they should be highly associated with such sites and should prove to be useful in risk assessment.

Amino Acids↗
PubMed1992

Analysis of HLA class II genes in Japanese patients with idiopathic membranous glomerulonephritis.

Thirty unrelated Japanese adult patients with idiopathic membranous glomerulonephritis (IMG) and 50 unrelated Japanese normal controls were examined for HLA class II genes. Both the 3.0 kb DQB and the 6.2 kb DQA restriction fragments were simultaneously identified in 86.7% of the patients. These were significantly different from the 14% frequency of the fragments in controls (relative risk = 39.9; P = 1.7 x 10(-10)). The haplotype DR2-DQwl associated with IMG seemed to be Dw2 which was essentially different from the haplotype common to the normal Japanese population. Dw12. This was because most of the restriction fragment length polymorphism (RFLP) of DQB and DQA of the patients coincided with that of homozygous cell lines with Dw2. The DRB probe showed no significant differences in the hybridization patterns between the patient group and HLA-matched controls. These findings indicate that the specific HLA-DQ polymorphism correlates primarily with Japanese IMG.

Adult↗
PubMed2003

DQ 65-79, a peptide derived from HLA class II, mimics p21 to block T cell proliferation.

DQ 65-79, a peptide derived from residues 65-79 of the alpha-chain HLA class II molecule DQA03011, blocks T cell proliferation and induces T cell apoptosis. Using a yeast two-hybrid assay, we previously identified proliferating cell nuclear Ag (PCNA) as an intracellular ligand for DQ 65-79. In this study, we show that three regions of PCNA, residues 81-100, 121-140, and 241-261, interact with DQ 65-79. Residues 241-261 of PCNA also interact with the C terminus (residues 139-160) of the cell cycle regulator, p21, suggesting that DQ 65-79 and p21 might function similarly. We show here that DQ 65-79 competitively inhibits binding of p21 to PCNA and that both DQ 65-79 and p21 139-160 induce T cell apoptosis, suggesting that DQ 65-79 and p21 act similarly to inhibit cell growth.

3T3 Cells↗
PubMed1987

Determination of the HLA-DR profile of an HLA class II negative carcinoma cell line by restriction fragment length polymorphism (RFLP) analysis.

The human colonic adenocarcinoma cell line HT-29 does not normally express HLA class II molecules. By restriction fragment length polymorphism (RFLP) analysis of DNA with a DR beta-probe, we analysed the genomic DR beta polymorphism of this cell-line, and compared it with the RFLP patterns seen in DNA from a reference panel of different DR homozygous and heterozygous cells. The HT-29 cell-line expressed DR beta fragments similar to the sum of the fragments expressed by DR4 and DR7 homozygous cells. The DR4 and DR7 haplotypes of HT-29 was further confirmed by comparing the RFLP patterns of four DR4/7 heterozygotes with that of HT-29. Furthermore, the HT-29 cell line expressed a Hind III 9.3 kb fragment previously found to be strongly associated to DRw53. Following treatment with gamma-interferon, the HT-29 cells could be induced to express class II molecules. Serological typing revealed the presence of the DR4, DR7 and DRw53 antigenic determinants.

Adenocarcinoma↗
PubMed1982

Both DR and MT class II HLA molecules may restrict proliferative T-lymphocyte responses to antigen.

Antigen-primed T-cell blasts may be separated from alloreactive T cells on Percoll gradients. By means of this method, HLA restriction of antigen-specific proliferative T-cell responses may be studied, using allogeneic antigen-presenting cells carrying foreign D/DR antigens. The reported data confirm that the D/DR molecules as such are major restriction elements in the T-cell response to herpes simplex virus (HSV) and purified protein derivative (PPD). However, evidence is presented that other Class II HLA molecules, the MT molecules, may also function as restriction elements for the HSV response.

Antigens↗
PubMed1998

Highly polarized HLA class II antigen processing and presentation by human intestinal epithelial cells.

The high concentration of foreign antigen in the lumen of the gastrointestinal tract is separated from the underlying lymphocytes by a single cell layer of polarized epithelium. Intestinal epithelial cells can express HLA class II antigens and may function as antigen-presenting cells to CD4(+) T cells within the intestinal mucosa. Using tetanus toxoid specific and HLA-DR-restricted T lymphocytes, we show that polarized intestinal epithelial cells directed to express HLA-DR molecules are able to initiate class II processing only after internalization of antigen from their apical surface. Coexpression of the class II transactivator CIITA in these cells, which stimulates highly efficient class II processing without the characteristic decline in barrier function seen in polarized monolayers treated with the proinflammatory cytokine gamma-IFN, facilitates antigen processing from the basolateral surface. In both cases, peptide presentation to T cells via class II molecules was restricted to the basolateral surface. These data indicate a highly polarized functional architecture for antigen processing and presentation by intestinal epithelial cells, and suggest that the functional outcome of antigen processing by the intestinal epithelium is both dependent on the cellular surface at which the foreign antigen is internalized and by the underlying degree of mucosal inflammation.

Anti-Bacterial Agents↗
PubMed1992

Intracellular localization of the HLA class II gene products in transfected mouse L cells.

To investigate the impaired cell surface expression of human major histocompatibility antigen (HLA) in transfected L cells, we examined their intracellular localization by immunocytochemistry. HLA class II molecules produced in transfected L cells were mainly detected in the intracellular vesicles and in the nuclear envelope as granular precipitates. The results suggest that the intracellular transport of the newly synthesized molecules in transfected L cells is impaired at some point along the pathway from the rough endoplasmic reticulum (RER) to the medial-, trans-Golgi apparatus.

Animals↗
PubMed1999

HLA class II favors clearance of HCV infection and progression of the chronic liver damage.

BACKGROUND/AIMS: This study was aimed to determine whether host-dependent genetic factors modulate the outcome of HCV infection. METHODS: HLA class II DRB and DQB typing was performed in 184 infected patients and 200 healthy volunteers. Among the patients, 149 subjects had persistent HCV viremia (Group 1) and 35 subjects underwent spontaneous viral clearance (Group 2). Group 1 included cirrhotic patients with transfusion-acquired infections (n = 79), asymptomatic HCV carriers (n = 42), and patients with chronic hepatitis C responsive to interferon therapy (n = 28). RESULTS: Spontaneous viral clearance was associated with HLA DRB1*1104 (pc = 0.054, OR = 4.51, 95% C.I. 2.02-10.1) and HLA DQB1*0301 (pc = 0.0039, OR = 4.52, 95% C.I. 2.15-9.51). In Group 1 the haplotype DRB1*1104/DQB1*0301 was less frequent (4.8%) than in Group 2 (18.3%) (pc = 0.009, OR = 7.38, 95% C.I. 2.58-21.59). At the HLA level, cirrhotic patients were not different from asymptomatic HCV carriers and patients with interferon-induced viral clearance. In cirrhotic patients infected with genotype 1b, the DQB1*0502 allele was more frequently found in those with rapidly progressive liver damage (OR = 8.15, 95% C.I. 1.49-44.44), but the corrected p-value was not significant (pc = 0.09). CONCLUSIONS: The HLA haplotype DRB1*1104/DQB1*0301 appears to contribute to the spontaneous clearance of HCV infection. The predominance of the DQB1*0502 allele in cirrhotic patients with a rapidly progressive disease possibly reflects an influence of this allele on the progression of the HCV-related liver disease.

Adult↗
PubMed1998

HLA class II allele associations in Korean patients with pemphigus.

BACKGROUND: Studies at the population level have demonstrated associations between pemphigus (pemphigus vulgaris, PV, and pemphigus foliaceus, PF) and particular HLA haplotypes, which suggests that there may be a genetic predisposition for the disease. OBJECTIVE/METHODS: The aim of the present study was to examine the distribution/frequency pattern of HLA class II alleles (DRB1, DQA1 and DQB1) from a group of 30 Korean patients with pemphigus (15 PV and 15 PF) by PCR amplification with sequence-specific primers. RESULTS: In PV, the frequency of DRB1*01 allele was found to be significantly high (pc = 0.0014); in PF, DRB1*01, DQA1*0302 and DQB1*0603 alleles showed positive associations with statistical significances (pc = 0.0002, 0.0007 and 0.0067, respectively), when compared with those found in Korean controls. CONCLUSIONS: In this small-sample study, findings of allelic frequencies among Korean patients with pemphigus are somewhat different from those found in other populations.

Alleles↗
PubMed1997

HLA class II antigens DR4 and DQ8 are associated with allergy to hevein, a major allergen of Hevea latex.

In this study we investigated the relationship between HLA class II alleles and the IgE-specific immune response to the 4.7 kDa polypeptide hevein of Hevea brasiliensis, a major latex allergen, 51 individuals with immediate-type latex allergy and 90 controls were examined for the polymorphisms in exon 2 of HLA-DRB1, 3, 4, 5 and DQB1 by sequence-specific oligonucleotide probe typing. 35 (69%) out of 51 latex-sensitized subjects showed positive hevein-specific IgE values. Analysis of the HLA data among these 35 subjects revealed increased phenotype frequencies for DR4 (22/35, 63%) and DQ8 (18/35, 51%) when compared with those in the 16 hevein-negative but latex-positive subjects (DR4: 2/16, 13%, p = 0.0009, Pc = 0.047; DQ8: 0/16, p = 0.0003, pc = 0.018) and with healthy controls (DR4: 22/90, 24%, p = 0.00012, pc = 0.013; DQ8: 16/89, 18%, p = 0.0003, pc = 0.036). Finally the DR4-DQ8 haplotype frequency was significantly elevated in hevein-positives when compared with hevein-negatives (51% vs. 0, p = 0.0003, pc = 0.034) or controls (51% vs. 18%, p = 0.0002, pc = 0.045) The present data suggest DR4 and DQ8 to be operating jointly as susceptibility factor for the allergy to hevein.

Adolescent↗
PubMed1989

Intracellular events associated with inhibition of B cell activation by monoclonal antibodies to HLA class II antigens.

We have investigated several aspects of the inhibitory effects of monoclonal antibodies (mAb) directed against MHC class II antigens in B cell activation/proliferation, using a panel of mAb specifically reactive with antigens encoded by HLA class II loci (DP, DQ, DR). All mAb except the anti-DP mAb inhibited significantly anti-mu plus B cell growth factor-induced DNA synthesis. Only one mAb, however, which was reactive with gene products of all three class II loci (DP, DQ, DR) inhibited anti-mu-induced DNA synthesis as well as c-myc mRNA expression. In addition, the same mAb inhibited the early events induced by anti-mu stimulation alone, including phosphatidylinositol turnover and elevation of [Ca2+]i. In contrast to previous findings in the murine system, none of the anti-MHC class II mAb used in this study increased the cAMP levels.

Antibodies, Monoclonal↗
PubMed1994

HLA class II antigens in rheumatic fever. Analysis of the DR locus by restriction fragment-length polymorphism and oligotyping.

We recently described an association of serologically defined HLA class II antigens DR7 and DR53 with RF. This study aimed at determining more precisely the class II gene associated with the disease. We studied patients and age- and race-matched controls. Genomic DNA was digested with four different enzymes and hybridized with HLA cDNA probes for DR beta, DQ beta, DQ alpha, and DP beta genes. RFLP analysis disclosed a fragment of 13,81 kb on Taq I DR beta blots, which correlates with HLA-DR53 and HLA-DR16, according to data from the Tenth International Histocompatibility Workshop. Of 24 patients, 20 (83.3%), were positive for the 13.81-kb/Taq I/DR beta allogenotope, compared with 16 (34%) of 47 healthy individuals (p = 0.000079, Fisher's exact test). Search for specific nucleotide sequences was performed using polymerase chain reaction technique. Oligonucleotides corresponding either to allele-specific DR7 and DR53 sequences, or shared by DRB1 and DRB3, DRB4, or DRB5 sequences were screened. Differences were tested throughout the second exon up to codon 100. Results were as expected by simple comparison with the published sequences of individual alleles. Although a clear association with DRB loci is shown, a susceptibility associated either with an allele or with a unique sequence was not found. A promiscuous presentation of the putative cross-reacting peptide or a heterogeneity of the causative agent might be the origin of these results. Genetic complementarity may be an additional factor defining inherited susceptibility to this disease.

Base Sequence↗
PubMed1986

Molecular localization and polymorphism of HLA class II restriction determinants defined by Mycobacterium leprae-reactive helper T cell clones from leprosy patients.

MHC class II molecules carry the restriction determinants (RDs) for antigen presentation to antigen-specific Th lymphocytes. This restriction of T cell activation endows those molecules with a key role in the induction and regulation of antigen-specific immune responses. Moreover, class II molecules are the products of class II immune response (Ir) genes. The polymorphism of these Ir genes leads to genetically controlled differences in immuneresponsiveness between different individuals. An important human example is leprosy, in which HLA class II-linked Ir genes determine the immune response against Mycobacterium leprae, the causative organism of the disease. Since the immune response against M. leprae is entirely dependent on Th cells, the HLA class II-linked Ir gene products may well regulate the immune response by controlling the presentation of M. leprae antigens to Th cells. We therefore have investigated the HLA class II RD repertoire of M. leprae-reactive Th cell clones (TLC) by means of extensive panel and inhibition studies with fully class II-typed allogeneic APCs and well-defined HLA class II-specific mAbs. The TLC studied (n, 36) proliferated specifically towards M. leprae, produced IFN-gamma upon activation, and had the CD3+CD4+CD8- phenotype. The results show in the first place that the majority of the RDs for M. leprae reside on DR and not on DP or DQ molecules. This indicates a major role for DR molecules in the immune response to M. leprae and suggests that these molecules are the main products of M. leprae-specific Ir genes. Furthermore, since the expression of DR molecules is much stronger than that of DP and DQ molecules, these findings suggest that the localization of RDs for M. leprae on class II molecules correlates with the quantitative expression of these molecules. The observation that the RDs on DR molecules coded by a DR4 haplotype were situated only on those DR molecules that are known to be highest in expression can be explained in the same way. Second, four distinct RDs related with but not identical to the Dw13 allodeterminant were carried by the DR+DRw53- (alpha beta 1) molecules of a DR4Dw13 haplotype. Since the known amino acid residue differences between the allelic DR4 related Dw beta 1 chains cannot explain the observed RD-polymorphism, this observation suggests that multiple distinct RDs unique for the DR4Dw13 haplotype are expressed by these molecules. Only 2 of 36 TLC were not restricted by DR.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed2005

An independent role of protective HLA class II alleles in rheumatoid arthritis severity and susceptibility.

OBJECTIVE: To prospectively investigate the effect of the DERAA-encoding HLA alleles on disease susceptibility and severity in a large cohort of patients with rheumatoid arthritis (RA), and to differentiate protective effects from non-predisposition by comparing subgroups of patients with an equal amount of predisposition alleles. METHODS: HLA class II alleles were determined in 440 patients with early RA and in 423 healthy controls. In order to study the effect of HLA on disease severity, radiographic joint destruction was evaluated, using the modified Sharp/van der Heijde method, during 4 years of followup. RESULTS: The presence of DERAA-encoding HLA-DRB1 alleles conferred a lower risk of developing RA for both the presence and absence of SE alleles (odds ratio 0.6). At all time points, radiographic destruction was significantly less severe in DERAA-positive patients with 1 SE allele compared with DERAA-negative patients with 1 SE allele. Additionally, a protective effect of DERAA was detected in the groups of patients who were prone to having more severe disease because of the presence of anti-cyclic citrullinated peptide antibodies or because of smoking. CONCLUSION: DERAA-encoding HLA-DRB1 alleles independently protect against RA and are associated with less severe disease.

Alleles↗
PubMed2000

Properties of HLA class II molecules divergently associated with Goodpasture's disease.

Goodpasture's disease provides an opportunity to analyse molecular mechanisms that may underlie MHC class II associations with autoimmune disease because it is caused by autoimmunity to a defined antigen [the 230 amino acid NC1 domain of the alpha3 chain of type IV collagen (alpha3(IV)NC1)] and has strong HLA class II associations. We compared the alpha3(IV)NC1 peptide binding of class II molecules with strong positive (DR15) and dominant negative (DR7/1) associations using an inhibition binding assay and short synthetic peptides spanning the sequence of alpha3(IV)NC1. DR15 in general bound the peptides with low affinity (three of 23 < 100 nM) compared to DR1 and DR7 (12 and 10 < 100 nM respectively), and no peptide bound DR15 with much higher affinity (>10-fold) than both DR1 and DR7. Thus DR15 molecules are unlikely to increase susceptibility to Goodpasture's disease by presenting a particular alpha3(IV)NC1-derived peptide uniquely well and DR1/7 are unlikely to protect by their inability to present particular peptides. However DR1/7 could protect by capturing alpha3(IV)NC1 peptides and preventing their display bound to DR15; the binding data suggest that all the major (biochemically detectable) alpha3(IV)NC1 peptides presented bound to DR15 by DR15 homozygous antigen-presenting cells (APC) would bind preferentially to DR1/7 in DR15, 1/7 heterozygote APC.

Alleles↗
PubMed2000

HLA class II genotypes associated with chronic hepatitis C virus infection and response to alpha-interferon treatment in Poland.

AIMS/BACKGROUND: Recent evidence suggests that spontaneous clearance of hepatitis C virus (HCV) may be associated with the HLA DQB1*0301 allele but there is still some debate over the role of other alleles and HLA haplotypes in HCV infection. As this may best be resolved by studying genetically different populations, we have investigated HLA class II-encoded susceptibility and resistance to HCV infection in a relatively sedentary population of patients from northwestern Poland. METHODS: The distributions of HLA class II DRB1, DQA1, DQB1 and DPB1 alleles were determined by standard PCR-protocol in 129 unrelated patients with chronic hepatitis C (anti-HCV and HCV-RNA positive) and 103 healthy unrelated racially-matched control subjects. Fifty-five patients were treated with alpha-interferon (5 MIU thrice weekly for 6 months) out of whom 29 showed a complete response and 26 were non-responders. RESULTS: A significantly reduced frequency of the DQB1*0301 allele in the patients was observed (24.0% vs. 38.8%; p=0.015). Additionally, two different DR-DQ haplotypes were found to be associated with chronic HCV infection: DRB1*1501-DQA1*01-DQB1*0602 (24.0% vs. 12.6%; p= 0.027) and DRB1*0701-DQA1*0201-DQB1*02 (31.8 vs. 12.6%; p=0.0006), the latter difference being most pronounced in those patients who responded to alpha-interferon treatment (41.4% vs. 12.6%; p=0.00048). CONCLUSIONS: The results confirm the negative association between chronic HCV and DQB1*0301 and identify two novel genetic associations. In particular, the DRB1*0701-DQA1*0201-DQB1*02 haplotype is associated with both chronic infection and response to alpha-interferon. Interestingly, the same haplotype is reportedly associated with non-response to hepatitis B vaccination.

Adult↗
PubMedDate not supplied

HLA class II expression in normal and inflamed conjunctiva.

Conjunctival biopsy specimens from 8 OCP (ocular cicatricial pemphaigoid), 6 AKC (Atopic keratoconjunctivitis) patients, and 10 normal individuals were studied for the expression of HLA class II molecules. Immunohistochemical studies were performed using monoclonal antibodies specific for HLA DR, DP, and DQ molecules. Strong, diffuse staining in conjunctival epithelium was observed for HLA DR in the specimens of OCP and AKC patients with heavy staining in the superficial and basal epithelial layers, not observed with normal specimen. About 30% of the samples from OCP and AKC patients showed a similar pattern of the diffuse staining in the superficial epithelial cell layers for HLA DP with less intensity than for HLA DR, while the 50% of the samples had shown greater HLA DP positivity in the basal epithelial cell layers. Positive epithelial cells and positive inflammatory cells were also observed in these samples while normal epithelium had few HLA DP positive cells. The HLA DQ staining pattern was similar to that observed for the HLA DP. There were significant increases over normals in the numbers of HLA-DR positive cells within the substantia propria of OCP and AKC specimens with the majority of the positive cells located subepithelially and around vessels. Increased numbers of HLA DP and HLA DQ positive cells were seen in the substantia propria of CP and AKC specimens with the staining pattern similar to the HLA DR while normal specimens had little staining in this region. Vessel endothelial cell staining was observed for HLA DR, DP and DQ with different degrees of the staining in these three groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoimmune Diseases↗