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PubMed1989

Restriction fragment length polymorphism in HLA class II genes of Latin-American Caucasian celiac disease patients.

In the present study Latin-American celiac disease patients were analyzed for the frequency of certain HLA class II restriction fragment length polymorphisms in order to investigate whether they exhibited the normal associated alleles or showed unusual class II variants. A DPB/RsaI 4.0-kb fragment that was shown to be significantly increased among North Americans celiac disease patients of the DR3,DQw2 haplotype was found with similar frequency in Latin-American control and celiac disease individuals. A DPA/BglII 3.7-kb fragment previously shown to be increased among British celiac disease patients was also present with similar frequency among Latin-American control and celiac disease individuals. These results show that the frequency of the HLA-DP region-derived restriction fragment length polymorphisms linked to celiac disease differs between Caucasian populations of different ethnic backgrounds (Anglo-Saxon and Latin-American). On the other hand, DNA samples from 13 patients and 14 controls bearing the DR5/DR7 phenotype (which is significantly associated with celiac disease in Latin populations) were investigated for the presence of particular restriction fragment length polymorphisms disproportionally present in celiac disease individuals. No significant differences were found between controls and patients when the DNA was analyzed with 10 different restriction enzymes and probes for DRB, DQA, DQB, and DPB HLA class II sequences.

Alleles↗
PubMed1987

IL-2 receptor and HLA class II antigens on cerebrospinal fluid cells of patients with multiple sclerosis and other neurological diseases.

The presence of IL-2 receptor and HLA class II antigens as detected by monoclonal antibodies on mononuclear cells from both cerebro-spinal fluid (CSF) and peripheral blood was examined by cytofluorographic analysis in patients with multiple sclerosis (MS) and other neurological diseases. CSF as compared to blood was enriched in cells expressing IL-2 receptor and HLA class II molecules both in MS patients and in other inflammatory diseases of the central nervous system suggesting that activated T-cells concentrate within the central nervous system.

Antigens, Surface↗
PubMed1995

Increased and decreased relative risk for non-insulin-dependent diabetes mellitus conferred by HLA class II and by CD4 alleles.

Non-insulin-dependent diabetes mellitus has been recognized to be heterogeneous in etiology, with multiple subgroups. Several genes or chromosomal regions have been implicated in the development of the disease. In this study the association of HLA class II alleles and genotypes and the association of CD4 and CD3 polymorphisms were assessed in a large number of Belgian non-insulin-dependent diabetes mellitus patients. Furthermore, the importance of the DQ alpha 1Arg52/DQ alpha 1Arg52 and the DQ beta 1Asp57/DQ beta 1Asp57 genotypes and the combination of both genotypes were examined. Our results show that in the HLA class II genes only the DQ alpha 1Arg52+/DQ alpha 1Arg52+ genotype was significantly associated with non-insulin-dependent diabetes mellitus compared with controls (p = 0.011, RR = 2.02). We also observed that the frequency of the CD4*A4/*A8 genotype and the CD4*A7 allele was significantly increased and decreased respectively in non-insulin-dependent diabetes mellitus patients as compared with the controls (p = 0.018, RR = 2.16 and p = 0.0003, RR = 0.49 respectively). These results therefore suggest that HLA class II and CD4 genes might independently contribute to the susceptibility for non-insulin-dependent diabetes mellitus and that these alleles and genotypes might identify subgroups of patients with different susceptibilities.

Adult↗
PubMed1998

Influence of the HLA class II polymorphism in chronic Chagas' disease.

Chagas' disease or American trypanosomiasis due to Trypanosoma cruzi has existed at least since the time of the Inca empire and contributes significantly to cardiovascular morbidity and mortality in several countries of this continent. Due to the fundamental role of human class II molecules polymorphic residues in the control of the immune response, a study was designed to define by DNA typing HLA class II alleles in a sample of 67 serologically positive individuals with and without cardiomyopathy and in 156 healthy controls of similar ethnic origin. Genomic DNA extraction, PCR amplification of the HLA-DRB1 and DQB1 second exon regions and hybridization to labelled specific probes were carried out following the 11th International Histocompatibility Workshop reference protocol. Comparison of DRB1 and DQB1 allele frequencies among the patients and control subjects showed a decreased frequency of DRB1*14 and DQB1*0303 in the patients, suggesting independent protective effects to the chronic infection in this population. Allele frequencies comparison between patients with and without cardiomyopathy showed a higher frequency of DRB1*01, DRB1*08 and DQB1*0501 and a decreased frequency of DRB1*1501 in the patients with arrhythmia and congestive heart failure. The results suggest that HLA Class II genes may be associated with the development of a chronic infection and with heart damage in Chagas' disease.

Adult↗
PubMed1992

HLA class II sequence polymorphisms and susceptibility to rheumatoid arthritis in Greeks. The HLA-DR beta shared-epitope hypothesis accounts for the disease in only a minority of Greek patients.

OBJECTIVE: In Northern Europeans, rheumatoid arthritis (RA) is strongly associated with a relatively conserved pentapeptide sequence of HLA-DR beta found notably in the HLA-DR4 subtypes Dw4 and Dw14 and in DR1. A previous serologic study of HLA class II polymorphism in a Greek population with RA failed to show significant associations with any antigen. METHODS: We characterized HLA-DRB polymorphisms in Greek patients with RA and in control subjects by restriction fragment length polymorphism analysis. Allelic DRB subtypes were examined by polymerase chain reaction amplification and oligonucleotide hybridization. RESULTS: DNA analysis in the RA patients showed that although individual HLA-DR allelic associations were weak, a relatively conserved HLA-DR beta motif was significantly associated with RA in this population of Greek patients. The third hypervariable region amino acid sequences QRRAA, QKRAA, or RRRAA were found in the HLA-DR beta 1 of 43.5% of the RA patients versus 15.5% of the controls (uncorrected P = 0.00004). CONCLUSION: Sequences shown to influence susceptibility to RA in patients in the UK also play a role in patients in Greece. However, 57% of Greek patients lack the putative HLA-DR beta motif, which suggests that considerable immunogenetic heterogeneity underlies disease susceptibility in this population.

Amino Acid Sequence↗
PubMed1988

Constitutive expression of HLA class II antigens on EBV positive malignant cells from nasopharyngeal carcinoma: possible involvement in T cell infiltration.

Undifferentiated nasopharyngeal carcinoma (NPC) was originally referred to as "lymphoepithelial carcinoma." Two main cell types are constantly associated within these tumors: the malignant epithelial cells which harbor the Epstein-Barr virus (EBV) genome, and the nonmalignant lymphocytes mostly of the T lineage. Three characteristic features of malignant NPC cells might explain T cell migration within NPC tumor tissue: HLA class II molecule expression, IL-1 production, and presence of EBV antigens. Homogeneous suspensions of malignant NPC cells were derived from a nude-mouse transplantable tumor in order to specify the status of HLA class II molecules in these tumors. These suspensions were stained for HLA class II antigens and analyzed by flow cytometry in comparison with other carcinoma cell lines. Three characteristics of transplantable malignant NPC cells were demonstrated: constitutive and coordinate expression of DR, DP, and DQ molecules, and concomitant expression with the CDw40 antigen ("B lymphocyte carcinoma cross-reacting antigen").

Adolescent↗
PubMed1995

Lp(a) lipoprotein, IgG, IgA and IgM antibodies to Chlamydia pneumoniae and HLA class II genotype in early coronary artery disease.

The associations previously found between lipoprotein(a) (Lp(a)) levels and atherosclerotic disorders, diabetes, rheumatoid arthritis and renal diseases suggest that Lp(a) may be involved in autoimmune reactions. The relation found between Lp(a) levels and the HLA class II genotype in males with early coronary artery disease (CAD) further support that assumption. It was suggested that an autoimmune process, perhaps triggered by a concomitant intracellular infection may occur especially in patients with inherited high Lp(a) levels in combination with certain inherited HLA class II genotypes. In this study a Chlamydia pneumoniae IgG titer > or = 32 was significantly more common (P = 0.036) in CAD patients than in matched controls. This is in agreement with previous reports by other investigators. In addition, an IgG titer > or = 256 in combination with an Lp(a) level > or = 120 mg/l was found to occur significantly more often (P = 0.011) in male patients than in male controls. Certain HLA class II DR genotypes in combination with high Lp(a) levels and C. pneumoniae titers occurred more frequently in both male and female patients than in controls. Some combinations were very common in male patients, and the difference in comparison with male controls was highly significant.

Antibodies, Bacterial↗
PubMed1993

Defective HLA class II expression in monocytes of type 1 diabetic patients. The Childhood Diabetes in Finland Study Group.

Activation of T-helper cells is modulated by the intensity of HLA class II expression on antigen-presenting cells. We evaluated whether any abnormalities could be found in the expression of HLA-DR and -DQ molecules on monocytes in type 1 diabetic subjects. DR and DQ molecules were induced by human recombinant interferon-gamma on cultured peripheral blood monocytes obtained from children with type 1 diabetes (N = 28), their siblings (N = 18) and unrelated healthy controls (N = 21). The response in DQ induction varied considerably between different individuals, but the average responsiveness was significantly lower in patients compared to siblings and unrelated controls. In addition to the diabetic subjects deficient DQ induction was also observed in three siblings. One of them had high levels of islet cell antibodies and presented with diabetes 6 months later, and another had active rheumatoid arthritis. The response in DR induction was also slightly lower in patients than in siblings, but did not differ from that in unrelated controls. The results suggest abnormalities in the regulation of HLA class II expression in type 1 diabetic subjects possibly reflecting the ongoing autoimmune process.

Adolescent↗
PubMed1998

HLA class II DRB1, DQB1 and DPB1 genotypic associations with peanut allergy: evidence from a family-based and case-control study.

BACKGROUND: Peanut is one of the most common foods provoking allergic reactions and is the most frequent cause of fatal and near-fatal food-induced anaphylaxis. However, as yet, little is known of the genetic and immunological mechanisms which underly peanut allergy. OBJECTIVE: Based on findings in other allergic diseases, we have investigated whether particular human leucocyte antigen (HLA) class II genetic polymorphisms contribute to the development of peanut allergy. METHODS: All individuals from 37 families each containing one or more peanut allergic individuals, plus nine unrelated patients (161 individuals in total, defined as the study group) were typed for the HLA class II DRB1, DQB1 and DPB1 loci, by PCR-based techniques. Genotype frequencies were compared with those found in 293 unrelated controls. RESULTS: Four class II genotypes (DRB1*08 (13.7% vs 4.8%; Pc = 0.026), DRB1*08/12 tyr 16 (22.4% vs 8.2%; Pc = 0.021), DQB1*04 (12.2% vs 2.7%; Pc = 0.0026) and DPB1*0301 (49.1 vs 22.5%; Pc = 0.00062)) were present at a significantly higher frequency in the study group compared with controls. Three of these genotypes (DRB1*08 (18.0%; Pc = 0.027), DRB1*08/12 tyr16 (24.0%; Pc = 0.029) and DQB1*04 (16.7%; Pc = 0.0029)) were also significantly increased in peanut allergic individuals compared with controls. In addition, two genotypes (DPB1*0101 and 0201) were significantly decreased in frequency in the overall study group, but not specifically in peanut allergic individuals. CONCLUSION: While other genetic factors may be important, results from this study indicate that HLA class II genetic polymorphism may play a role in determining susceptibility to peanut allergy.

Arachis↗
PubMed1992

Analysis of HLA class II allogenotyping in Australian aborigines and Papua New Guinea populations.

Human leukocyte antigen (HLA) class II allogenotyping has been applied to investigate the polymorphism of the DRB, DQB1, DQB2, DQA1, and DQA2 genes in Aborigines from the East Coast of Australia and in Melanesians from the Papua New Guinea North-East Coast and Highlands. Three new DR/DQ arrangements were observed, DRw14/DQB1-2b/DQA1-1a and DRw5Nauru/DQB1-3a/DQA1-2 (n Australian Aborigines), and DRw5Nauru/DQB1-1a/DQA1-1b (in Madang). DQA2 and DQB2 allogenotyping with TaqI and PstI digested genomic DNA revealed little polymorphism among the Papua New Guineans, with DQA2-Xa1 and DQB2-Xb1 the most common alleles in all the groups. However, the presence of DQA2-Xa2 in Papuans and Australian Aborigines reflects the degree of admixture with Caucasoids while the DQA2-Xa4 allele in Madang is probably a marker of Mongoloid origin.

Asian People↗
PubMed2005

Molecular genetic studies on the compatibility of HLA class II alleles in patients with unexplained recurrent miscarriage in the Japanese population.

It is hypothesized that patients having unexplained recurrent miscarriage lack an appropriate immune reaction against their partner's antigens, which means possible compatibility of HLA antigens between the patient couples. The conclusion, however, has not yet been achieved, so the purpose was to determine whether significant compatibility of HLA class II exists between the couples. The HLA-DRB1 and -DQB1 genotypes were determined using PCR-RFLP method in 91 patient couples and in 72 normal couples. The number of patient couples with zero-allele mismatch was not significantly different compared with that of control couples regarding HLA-DRB1 genotype and phenotype, as well as regarding HLA-DQB1 genotype and phenotype. While the number of patient couples with zero- and one-allele mismatch was significantly higher compared with that in control as to HLA-DR and -DQ phenotype (P=0.029 by Chi-square test). In conclusion, it is suggested that the compatibility of HLA class II antigens between couples might be involved in the genesis of unexplained recurrent miscarriage.

Abortion, Habitual↗
PubMed2005

HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri.

Human papillomavirus (HPV) infection is the most important risk factor for development of cervical carcinoma. Carriers of certain HLA class II alleles, e.g., DRB1*1501 and DQB1*0602, are more prone to HPV 16 infection and cervical carcinoma, whereas other alleles, e.g., DRB1*1301 and DQB1*0603, render carriers less susceptible to the disease. In our study comprising 484 cases and 601 controls, we examine the effect of HLA class II alleles on viral load of the oncogenic types HPV 18/45 and HPV 31 and risk of developing cervical carcinoma in situ. We find that carriers of the commonly reported protective DRB1*1301 and DQB1*0603 alleles have lower HPV 18/45 load compared to noncarriers and a lower risk of developing HPV 18/45-positive cervical carcinoma. This provides further evidence that the HLA class II-mediated immune response to HPV is important for controlling viral load and outcome of an infection.

Adult↗
PubMed1992

Regulation of HLA class II antigen expression on cultured corneal epithelium by interferon-gamma.

The effect of recombinant human interferon gamma (IFN-gamma) on the induction of HLA class II (HLA-DR, -DP, -DQ) antigen expression on human corneal epithelial (HCE) cells was examined in different stages of culture. Primary cultures were established with limbal explants without endothelium. HCE cells in Stage 1 and Stage 2, with cells negative and positive for the 64K corneal keratin (the marker for advanced corneal epithelial differentiation), respectively, were prepared. HCE cells in both stages were treated with IFN-gamma at a concentration of 0 to 1000 U/ml for two to six days and were stained by the avidin-biotin peroxidase complex method. Class II antigens were not detected on HCE cells in either stage without IFN-gamma treatment. IFN-gamma induced three class II antigens on HCE cells in both stages in a dose- and time-dependent manner but at different levels for each antigen (DR greater than DP greater than DQ). In addition, DQ expression was related to cell differentiation, with DQ extremely rare at Stage 1 and more frequent at Stage 2 (5% vs. 20%). These findings indicate that the induction of class II antigens on HCE cells may be regulated by IFN-gamma independently for each of the antigens and that DQ induction may depend upon the differentiation of HCE cells in culture.

Cell Differentiation↗
PubMed1993

Molecular analysis of HLA class II genes in primary Sjögren's syndrome. A study of Israeli Jewish and Greek non-Jewish patients.

In an attempt to define the role of HLA class II genes in predisposition to primary Sjögren's syndrome, patients of two different ethnic groups (Israeli Jews and Greeks of non-Jewish origin) suffering from this disorder were studied. Oligonucleotide genotyping revealed the majority in both groups to carry either DRB1*1101 or DRB1*1104, alleles that are in linkage disequilibrium with DQB1*0301 and DQA1*0501. The high frequency of the two alleles in these SS patients is in contrast with the accepted association of primary SS with HLA-DR3 in Italian and American individuals. Molecular analysis of DQB1 and DQA1 alleles found in American Caucasian and American black SS (or SLE) patients demonstrated high frequencies of DQB1*0201 and DQA1*0501. The fact that the majority of SS patients, across racial and ethnic boundaries, carry a common allele, DQA1*0501, implies its involvement in the predisposition to primary SS. Based on sequence analysis and the computer imaging of the HLA class II molecule structure, a hypothetical model for the role of the DQ molecule in promoting primary SS is proposed.

Alleles↗
PubMed2000

Association of MHC and rheumatoid arthritis. Regulatory role of HLA class II molecules in animal models of RA: studies on transgenic/knockout mice.

Human leucocyte antigen (HLA) class II molecules have been shown to be associated with predisposition to rheumatoid arthritis (RA). We generated HLA-DR and DQ transgenic mice that lacked endogenous class II molecules to study the interaction between the DR and DQ molecules and define the immunologic mechanisms in rheumatoid arthritis. Using collagen-induced arthritis (CIA) as an experimental model for inflammatory polyarthritis, we show that both DQ and DR are involved in predisposition or resistance to arthritis. Our studies suggest that polymorphism in DQB1 genes may determine predisposition to RA while the DRB1 polymorphism may dictate severity/protection of the disease. These mice provide powerful tools to develop immunotherapeutic protocols.

Animals↗
PubMed1998

HLA class II polymorphism in the Ticuna of Brazil: evolutionary implications of the DRB1*0807 allele.

The alleles at the HLA class II loci HLA-DRB1, DQA1, DQB1 and DPB1 were determined for 49 individuals of the Ticuna, a Native South American population living in Brazil, using PCR/SSO probe hybridization and DNA sequencing. A newly described DRB1*08 variant, DRB1*0807, which has previously been reported only in native Colombians and contemporary Brazilians of African and Caucasian descent, was identified in the Ticuna at a high frequency (f=0.225). Because *0807 has been observed only in South American populations, we propose that it was generated from a parental *0802 allele recently, after the isolation of various Native South American populations, and infer that the DRB1*0807 allele was generated by a C to T change at codon 57 (Asp-->Val, GAT-->GTT) from the ancestral *0802. This inference is supported by the sequence of a complex VNTR in the second intron of the DRB1 gene. The DPB1 alleles *0401, *0402 and *1401 constituted 76% of the observed Ticuna DPB1 alleles (f=0.166, 0.427 and 0.166 respectively). In addition, the DPB1 allele *3501, which has been observed in a few other Native South American groups, was observed at a frequency of 0.053 and may have been generated from the putative ancestral allele *1401 allele in South America. The DRB1 and DPB1 allele frequencies for the Ticuna deviate from expected Hardy-Weinberg equilibrium proportions, while DQA1 and DQB1 allele frequencies do not. When this deviation, which involves an observed excess of DRB1*0807 heterozygotes, is considered with the high frequency of the DRB1*0807 and DPB1*1401 alleles, we infer that native South American populations may have been under selection pressure for increased allele diversity.

Africa↗
PubMed1989

HLA class II mRNA accumulation by activated human T cells following growth in conditioned medium.

The expression of HLA Class II beta genes by seven CD4- or CD8-positive T cell clones grown in conditioned medium was examined on the mRNA and cell surface levels. Monoclonal antibodies directed against Class II glycoproteins demonstrated the presence of these molecules on the cell surface. In addition, Northern blot analysis demonstrated that cDNA probes for the DR, DP, and DQ beta genes hybridized to mRNA isolated from each clone. Because we were interested in differences in expression of relative levels of DR, DQ and DP, mRNA isolated from the clones was quantified by means of densitometry. Our results demonstrated that different ratios of DR, DQ and DP beta chain messages were expressed by the clones. Subsequent studies established the kinetics of the accumulation of DR beta mRNA messages by T cells during culture and showed that it could be regulated by factors contained within conditioned medium. Our results confirm that the accumulation of Class II mRNA following growth of T cells in conditioned medium appears to be a general feature.

Antigens, Surface↗
PubMed2004

Sequencing of two new HLA class II alleles: DRB3*0218 and DQB1*030202.

Two novel human leukocyte antigen (HLA) class II alleles for DRB3 and DQB1 genes detected in Caucasoid Spanish individuals are described: DRB3*0218 and DQB1*030202. Both alleles have been found during routine high-resolution typing by sequencing. DRB3*0218 shows a novel DRB3 gene polymorphic position, located at amino acid residue 58, alanine to glutamic acid. This residue is shared by several DRB1 alleles, including all described DRB1*11 subtypes. DQB1*030202 differs from DQB1*030201 by a point mutation at position 319 (T to C). This nucleotide change generates a new codon at amino acid position 75 that is not shared by any other DQB1 allele.

Amino Acid Sequence↗