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PubMed2000

Sequence-based typing of HLA class II DQB1.

Due to the expanding number of known HLA class II DQB1 alleles, high-resolution oligotyping is becoming ineffective, therefore a sequence-based typing (SBT) strategy was developed to provide rapid and definitive typing of HLA-DQB1. HLA-DQB1*02, *03, *04, *05, and *06 alleles were individually amplified by polymerase chain reaction (PCR) using exon 2 group-specific primers. Forward and reverse PCR primers were tailed with M13 universal and M13 reverse sequences, respectively. Subsequent bi-directional cycle-sequencing was carried out using Cy5.5-labeled M13 universal primer and Cy5.0-labeled M13 reverse primer. Automated sequencing was performed in 30 min using a Visible Genetics, Inc. (VGI) MicroGene Clipper Sequencer. Full concordance was observed between this SBT method and oligotyping among 151 individuals.

DNA Primers↗

PubMed2002

Differential presentation of group A streptococcal superantigens by HLA class II DQ and DR alleles.

Superantigens have been implicated as pivotal mediators of severe invasive group A streptococcal (GAS) infections, by virtue of their potent immunostimulatory activity. HLA polymorphism has been suggested to influence the susceptibility to severe invasive GAS infection. Here we studied the influence of allelic and isotypic variation of HLA class II molecules on GAS superantigen-induced immune responses using cells derived from patients with bare lymphocyte syndrome, untransfected or transfected with various HLA class II alleles. Significantly higher proliferative responses were detected when streptococcal pyrogenic exotoxin (Spe) A was presented by cells expressing DQA1*0101/DQB1*0302 (DQ3.2), as compared to cells expressing DR1, DR4, or DR5 alleles (p=0.0002-0.01). In contrast to SpeA, SpeC was preferentially presented by DR4 as compared to DQB1*03 (p=0.04). In agreement with the proliferation results, a significantly higher frequency of IL-2-, TNF-alpha-, TNF-beta-, and IFN-gamma-producing cells was detected when SpeA was presented by HLA class II DQB1*03 alleles as compared to DR4 (p=0.0002-0.04). Binding experiments showed a high affinitybinding of SpeA to both class II DR4 and DQB1*0302, and there was no significant difference in SpeA binding affinity between the two alleles. The data confirm the effect of allelic polymorphism in superantigen responses and show that different superantigens are preferentially presented by distinct class II alleles.

Alleles↗

PubMed1987

Defective HLA class II expression in a regulatory mutant is partially complemented by activated ras oncogenes.

The human B-cell line RJ2.2.5, derived by mutagenesis from a Burkitt lymphoma cell line and selected for loss of HLA class II antigen expression, was infected with recombinant retroviruses containing either the Harvey murine sarcoma virus oncogene v-Ha-ras or the human neuroblastoma homolog NRAS. Both activated ras genes partially complemented the regulatory defect in RJ2.2.5 and specifically increased the expression of the DR and DQ subsets of HLA class II genes. Blot-hybridization analysis and RNase mapping indicated that HLA-DQ alpha-chain mRNA in the infected cell lines was increased to a level at least 50% that of the parent B-cell line, Raji. The levels of HLA-DR and -DQ beta-chain RNA also were increased but to a lesser extent. In contrast, we detected no effect of ras on the quantities of other class II, class I, or invariant-chain mRNAs. Fluorescence-activated cell sorter analysis with antibodies recognizing HLA-DR, -DQ, and class I antigens supported these observations. Enhancement of HLA class II gene expression by ras genes may have important implications for regulation of the immune system in response to transformation.

Antigens, Surface↗

PubMed1996

Association of HLA class II genes with susceptibility to Crohn's disease.

BACKGROUND: Published studies on the association between HLA class II genes and inflammatory bowel disease are contradictory perhaps because of the limited size and ethnic heterogeneity of the populations studied. AIM: To compare the frequencies of HLA class II genes in a large number of French patients with Crohn's disease and in an ethnically matched control group. METHODS: 344 patients (196 F, 148 M, mean age 23.6 years) with Crohn's disease were molecularly genotyped for the HLA-DQB1 and DRB1 alleles. The results were compared with those for an ethnically matched control population of 488 white adults. RESULTS: There were two significant variations of alleles at the DQB1 locus: an increase in DQB1*0501 allele frequency (chi 2 = 10.6, corrected p value (pc) = 0.01, odds ratio (OR) = 1.61) and a decrease in DQB1*0602/0603 allele frequencies (chi 2 = 8.43, pc = 0.037, OR = 0.66). DRB1 analysis showed associations with three allelic variations: an increase in the frequencies of DRB1*01 (chi 2 = 12.86, pc = 0.003, OR = 1.75) and DRB1*07 alleles (chi 2 = 11.18, pc = 0.008, OR = 1.58) and a very significant decrease in that of the DRB1*03 allele (chi 2 = 19.7, pc = 9.10(-5), OR = 0.46). CONCLUSION: The alleles DRB1*01 and DRB1*07 are associated with susceptibility to Crohn's disease. The strong negative association between the DRB1*03 allele and Crohn's disease suggests that the HLA-DRB1*03 allele mediates 'resistance' to Crohn's disease.

Adolescent↗

PubMed1988

HLA class II sublocus expression in benign and malignant breast epithelium.

Using immunohistochemistry and a panel of five monoclonal antibodies, the epithelial expression of HLA class II sublocus products by benign and malignant breast has been studied. The magnitude of the stromal mononuclear inflammatory cell infiltrate was assessed. There was expression of HLA class II by 75 per cent of epithelial cells in the benign tissues, with little variation in intensity and between antibodies. There was coordinate expression of DR and DQW1. Epithelial expression by carcinomas was more complex and variable. Most (61 per cent) carcinomas exhibited variable loss of epithelial expression of class II products, as detected by three antibodies recognizing epitopes on DP, DQ, and DR together. Thirteen (28 per cent) carcinomas were completely negative or had very occasional positive cells. The extent of this loss was unrelated to the magnitude of the inflammatory infiltrate and axillary lymph node status. No well-differentiated carcinomas exhibited complete loss. Furthermore, non-coordinate expression of DR and DQW1 was present in 8 out of 40 carcinomas, with the proportion of DQW1 positive epithelium always being less than that of DR. Carcinomas exhibiting non-coordinate expression were never well differentiated; there was no relationship with the extent of the inflammatory infiltrate. This is the first study to detail HLA class II expression in breast, and our results suggest that alterations in expression of these products may modify or reflect tumour behaviour.

Antibodies, Monoclonal↗

PubMed2007

Generation of inflammatory cytokines and chemokines from peripheral blood mononuclear cells by HLA Class II antibody-containing plasma unit that was associated with severe nonhemolytic transfusion reactions.

BACKGROUND: HLA Class II antibodies are thought to be involved in severe transfusion reactions including transfusion-related acute lung injury (TRALI). The activation of monocytes by HLA Class II antibody may play an important role in the etiology of TRALI. CASE REPORT: An 81-year-old man with non-Hodgkin's lymphoma (Clinical Stage IIIA) received a plateletpheresis unit containing at least 4 x 10(11) platelets because of thrombocytopenia and a bleeding tendency. Approximately 30 minutes after the start of transfusion, he developed chills, tachycardia, dyspnea, lumber, and abdominal pain and then a fever (40.3 degrees C). His SaO(2) dropped to 70 percent. The transfusion was discontinued immediately. His symptoms disappeared after treatment with oxygen and the administration of corticosteroid and aminophyrine. A chest X-ray showed no sign of pulmonary edema. RESULTS: The donor serum sample had HLA-DR antibodies against multiple DR antigens including DR13, the recipient's HLA-DR type. The cross-match between the patient's lymphocytes and the donor serum was positive. The treatment of peripheral blood mononuclear cells from healthy subjects bearing DR13 antigen with the donor plasma caused the secretion of inflammatory cytokines (i.e., interleukin [IL]-1beta, IL-6, and tumor necrosis factor-alpha) and neutrophil-activating chemokines (i.e., IL-8 and CXCL1/GRO-alpha) in a cognate antigen-antibody relationship. In addition, the secretion of inflammatory cytokines appeared to require the involvement of CD32 and/or CD16. CONCLUSION: HLA-DR antibodies, detected in this case, had biologic functions to induce production of not only inflammatory cytokines but also neutrophil-attractant chemokines in vitro, which could contribute to the etiology of severe nonhemolytic transfusion reactions.

Acute Disease↗

PubMed1996

HLA class II genotyping of sarcoidosis patients in Hokkaido by PCR-RFLP.

To confirm the significant association of sarcoidosis with HLA-DR5, -DR6, and -DR8 associated DRB1 alleles, in sarcoidosis patients from the eastern Japan (Kanto) area found in our previous study, we used HLA class II genotyping of patients in another region-Hokkaido, in northern Japan. The annual incidence of sarcoidosis in Hokkaido is about three times that of eastern Japan, and Hokkaido has one of the world's highest incidences of this disease. For the HLA class II (HLA-DRB1, -DRB3, -DQA1, -DQB1) genotyping, we used the polymerase chain reaction restriction fragment polymorphism (PCR-RFLP) method with 150 subjects: 40 sarcoidosis patients and 110 healthy controls. The frequencies of DRB1*12, DRB1*14, DRB1*08, DQA1*0501, and DQB1*0301 were significantly increased in the patients, compared with the controls. Our finding of a high frequency of DRB1*08 (which lacks the DRB3 gene encoding the DR52 antigen) in patients living in both eastern Japan and in Hokkaido, confirms that it is the HLA-DRB1 locus, rather than that of the HLA-DRB3, -DQA1, or -DQB1, which determines the susceptibility to sarcoidosis.

Adolescent↗

PubMed1994

No association with HLA class II alleles in Swedish patients with cutaneous manifestations of Lyme borreliosis.

The possibility of an association between manifestations of Lyme borreliosis and HLA class II alleles has been investigated with varying results. In the present study, we used genomic typing techniques to determine the DR, DQ and DP allele frequencies in 29 patients with erythema migrans and 36 patients with acrodermatitis chronica atrophicans. We did not find a significant deviation from controls in the distribution of the HLA class II alleles in any of these disease manifestations, nor in the subgroup of 8 patients with acrodermatitis chronica atrophicans and long-standing arthritis. With the additional information obtained by the typing techniques used, our results are thus in accord with those studies where no association between the development of the late disease manifestation acrodermatitis chronica atrophicans and HLA class II alleles has been found.

Acrodermatitis↗

PubMed2004

Identification of two novel HLA class II alleles, DQB10311 and DQB10620.

Two novel HLA class II alleles have been identified in routine typing of a kidney transplant patient and a cord blood unit from the Australian Cord Blood Bank in Sydney. Sequence analysis of exon 2 of the DQB1 genes revealed the novel polymorphism. A substitution of A to C at nucleotide position 136 has been identified for the DQB1*0311 allele when compared to the closest-matched allele, DQB1*030201. An identical substitution has also been identified for the DQB1*0620 allele when compared to the closest-matched allele, DQB1*0602. The substitution results in an amino acid change from methionine to leucine at position 46 implicating different specificity and affinity of antigen binding.

Alleles↗

PubMed1987

Induction of various HLA class II molecules in a human colonic adenocarcinoma cell line.

The colonic carcinoma cell line HT-29 had no constitutive expression of HLA class II molecules. Gamma interferon (IFN-gamma) induced expression of HLA class II molecules in a dose-dependent manner with 100 U/ml as an optimal dose. The expression of HLA-DR, HLA-DP, and HLA-DQ molecules seemed to follow different kinetics. While DR and DP molecules were maximally induced after 2 days, DQ molecules appeared later with maximum percentage positive cells after 8 days. Treatment with a prostaglandin synthesis inhibitor (indomethacin) neither induced class II expression nor altered the dose-response curve for IFN-gamma; this indicated that possible endogenous production of prostaglandins in this cell line did not interfere with its class II expression. The lectins phytohaemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM), and wheat germ agglutinin (WGA) did not induce class II expression.

Adenocarcinoma↗

PubMed2002

HLA class II associated risk and protection against multiple sclerosis-a Finnish family study.

We analyzed the HLA class II haplotypes in 249 Finnish nuclear families and compared the frequencies of parental haplotypes transmitted or non-transmitted to multiple sclerosis (MS) patients. The most important predisposing haplotype was DRB1*15-DQB1*0602 (P<10(-6)) as expected and a weak predisposing effect of DRB1*04-DQB1*0302 was revealed after the elimination of DRB1*15-DQB1*0602. HLA-DRB1*01-DQB1*0501 and DRB1*13-DQB1*0603 were negatively associated with MS in transmission disequilibrium test, but only the DRB1*13-DQB1*0603 association remained significant (P=0.008) after the elimination of DRB1*15-DQB1*0602 haplotypes. Based on this study HLA class II haplotypes exhibit both predisposing and protective effects in MS.

Family Health↗

PubMed1995

Lack of correlation between HLA class II alleles and immune responses to Pf155/ring-infected erythrocyte surface antigen (RESA) from Plasmodium falciparum in Madagascar.

To investigate the relationships between predominant HLA class II alleles and immune responses to the Plasmodium falciparum ring-infected erythrocyte surface antigen (Pf155/RESA), 50 individuals from the highlands of Madagascar were followed-up from 1988 to 1991. The T cell reactivity and antibody responses to synthetic peptides (EENV)4, (EENVEHDA)4, and (DDEHVEEPTVA)3, representing major T and B epitopes of Pf155/RESA antigen, were assessed with an average of five determinations per individual over the four-year follow-up period. The T cell reactivity was investigated by lymphocyte proliferation and assays for interferon-gamma and interleukin-2 release. Antipeptide antibodies were measured using the Falcon assay screening test-enzyme-linked immunosorbent assay. The cumulative prevalence rates of cellular (range for the three peptides = 64-68%) and antibody responders (range = 70-74%) were similar for each peptide. The HLA class II typing was performed using polymerase chain reaction-restriction fragment length polymorphisms. The prevalent alleles or groups of alleles (frequency > 20%) were similar in responders and nonresponders, both for cellular and antibody responses to each peptide. These were HLA-DR 5 group and HLA-DQA1 *0601, *0101-0102-0104, HLA-DQB1 *0301, and HLA-DPB1 *0101-2601 alleles. Allelic distribution was similar in individuals presenting with (74%) or without (26%) a malaria attack during a 20-week follow-up conducted when malaria was hyperendemic (P > 0.05, by Fisher's exact test). Despite repeated immunologic measures that better identify the responders, no relationship was found between HLA class II alleles and the cellular or antibody responses to Pf155/RESA epitopes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1999

HLA class II transgenic mice as models of human diseases.

Predisposition to develop various autoimmune disorders has been associated with certain HLA class II molecules but there is a lack of information on the pathophysiological role of HLA genes in conferring susceptibility. Various experimental animal models of autoimmune disease have been studied to address the role of immune response genes. To study the interactions involved between class II molecules (DQ and DR) and define the immunologic mechanisms in various diseases, we generated HLA-DR and DQ transgenic mice that lacked endogenous class II molecules. The HLA molecules in these mice are expressed on the cell surface and can positively select CD4+ T cells expressing various V beta T-cell receptors (TCR). A peripheral tolerance is maintained to transgenic HLA molecules thus indicating that these molecules act as self. Mouse co-stimulatory and accessory molecules can interact with the HLA-peptide-TCR complex leading to efficient T-cell activation. In this review, we describe immunogenetic models for human diseases using these transgenic mice. Our studies show that HLA class II transgene-restricted T cells recognize the immunodominant antigens and peptide epitopes, similar to HLA class II-restricted human T cells. Thus these mice provide powerful tools to understand the role of HLA class II molecules in predisposition and onset of human diseases and to develop immunotherapy and vaccines.

Amino Acid Sequence↗

PubMed2003

HLA class II transgenic mice authenticate restriction of myelin oligodendrocyte glycoprotein-specific immune response implicated in multiple sclerosis pathogenesis.

Myelin oligodendrocyte glycoprotein (MOG) is a potential target antigen of the central nervous system (CNS), known to induce autoreactive T cell response and demyelinating anti-MOG antibodies in multiple sclerosis (MS) patients. Association of HLA class II genes with MS is well established. To better understand the role of HLA class II molecules in disease pathogenesis, we generated transgenic mice that express HLA-DR2, -DR3, -DR4, -DQB1*0601, -DQB1*0604 and -DQ8 without mouse class II (Abeta(0)). We have for the first time characterized the T and B cell epitopes of human MOG restricted by different HLA class II molecules. Immunization with recombinant MOG (rMOG) generated a strong CD4(+) T cell-mediated response in an HLA class II-restricted manner. Cytokine analysis revealed an increase in pro-inflammatory (IFN-gamma, IL-12 and IL-6) and anti-inflammatory (IL-10) cytokines. T cell autoreactivity to MOG was directed against peptides 1-20, 31-50, 61-80 and 91-110, of which three are also immunodominant epitopes for MOG in MS. A strong B cell response to MOG was observed in all transgenic mice, and major B cell epitopes recognized were located within amino acids 1-30, 51-80 and 101-120 of human MOG, which consists of two epitopes reported in MS. Transgenic mice used in this study recognized the immunodominant MOG epitopes similar to HLA class II-restricted human T cells, and would therefore be valuable in elucidating the roles of HLA class II genes and autoantigens in MS.

Animals↗

PubMed2006

In adult onset myositis, the presence of interstitial lung disease and myositis specific/associated antibodies are governed by HLA class II haplotype, rather than by myositis subtype.

The aim of this study was to investigate HLA class II associations in polymyositis (PM) and dermatomyositis (DM), and to determine how these associations influence clinical and serological differences. DNA samples were obtained from 225 UK Caucasian idiopathic inflammatory myopathy patients (PM = 117, DM = 108) and compared with 537 randomly selected UK Caucasian controls. All cases had also been assessed for the presence of related malignancy and interstitial lung disease (ILD), and a number of myositis-specific/myositis-associated antibodies (MSAs/MAAs). Subjects were genotyped for HLA-DRB1, DQA1 and DQB1. HLA-DRB1*03, DQA1*05 and DQB1*02 were associated with an increased risk for both PM and DM. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype demonstrated strong association with ILD, irrespective of myositis subtype or presence of anti-aminoacyl-transfer RNA synthetase antibodies. The HLA-DRB1*07-DQA1*02-DQB1*02 haplotype was associated with risk for anti-Mi-2 antibodies, and discriminated PM from DM (odds ratio 0.3, 95% confidence interval 0.1-0.6), even in anti-Mi-2 negative patients. Other MSA/MAAs showed specific associations with other HLA class II haplotypes, irrespective of myositis subtype. There were no genotype, haplotype or serological associations with malignancy. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype associations appear to not only govern disease susceptibility in Caucasian PM/DM patients, but also phenotypic features common to PM/DM. Though strongly associated with anti-Mi-2 antibodies, the HLA-DRB1*07-DQA1*02-DQB1*02 haplotype shows differential associations with PM/DM disease susceptibility. In conclusion, these findings support the notion that myositis patients with differing myositis serology have different immunogenetic profiles, and that these profiles may define specific myositis subtypes.

Adult↗

PubMed1991

Molecular HLA-class II typing: advantages and clinical application.

The major histocompatibility complex (HLA system in Man) is characterized by its extensive degree of allelic polymorphism. After the serological and cellular methods, the molecular biological methods appeared to be a powerful tool in detecting HLA-class II polymorphism. Restriction fragment length polymorphism (RFLP), using restriction endonucleases, represented an efficient method of HLA-DR, DQ, and DP genotyping. Recently, the polymerase chain reaction (PCR) permitted the development of two major class II genotyping techniques: the PCR allele specific oligonucleotide typing and the PCR-RFLP typing. By these new methods, a refined and accurate determination of DRB, DQB, DQA, and DPB alleles is possible. The major application of a refined HLA class II typing is in transplantation especially for unrelated bone marrow grafts. Moreover, it permits the identification of the amino acids implicated in the cellular response which by itself is important for the fundamental immunological studies.

Genotype↗

PubMed1999

Human RAGE GLY82SER dimorphism and HLA class II DRB1-DQA1-DQB1 haplotypes in type 1 diabetes.

Advanced glycation end products (AGEs) are believed to play an important role in the development of diabetic complications. AGEs increase in diabetes and modulate cellular functions through binding to a specific cell surface receptor (RAGE). The RAGE gene maps to chromosome 6p in the HLA class III area and is telomeric to the class II region at 250 kb from DRA. A recent report described the characterization of a major RAGE gene variant as a biallelic single base polymorphism (G/A 557) in the exon 3 sequence leading to a change of a glycine to a serine at position 82. Using DGGE and PCR-RFLP, we have investigated the distribution of this dimorphism in conjunction with HLA class II genes in large populations of type 1 diabetic patients and healthy subjects. Although no association of this RAGE gene polymorphism with disease susceptibility was found, we report a strong linkage disequilibrium between the variant carrying the serine amino acid at position 82 and two HLA-DR2 and HLA-DR4 specificities. In particular, we describe two major extensive HLA class II haplotypes associated with this serine variant and identified as DRB1*0401-DQA1*0301-DQB1*0301 in the diabetic group and DRB1*1501-DQA1*0102-DQB1*0602 in control individuals. These data were partially confirmed by family transmission analysis.

Diabetes Mellitus, Type 1↗

PubMed1993

Linkage disequilibrium between TAP2 variants and HLA class II alleles; no primary association between TAP2 variants and insulin-dependent diabetes mellitus.

The TAP1 and TAP2 genes, located in the HLA class II region, encode subunits of a peptide transporter. Both genes display limited genetic variability; four different nucleotide substitutions have been found in the TAP2 gene. Here studies on linkage disequilibrium between TAP2 variants and HLA class II alleles are reported, in an attempt to evaluate whether TAP2 variants are associated with insulin-dependent diabetes mellitus (IDDM). As reported previously, a significant decrease of homozygosity for TAP2 alleles encoding alanine at residue 665 (665 Ala) and glutamine at 687 (687 Gln) paralleled by an increase in homozygosity for TAP2 alleles encoding threonine at residue 665 (665 Thr) and a stop codon at 687 (687 Stop), was found in both Finnish and Norwegian IDDM patients compared to random controls. However, a strong linkage disequilibrium between these TAP2 polymorphisms and given HLA-DR and -DQ genes was observed among healthy controls. The frequent 665 Thr and 687 Stop variants were in linkage disequilibrium both with the DR4-DQ8 and the DR3-DQ2 haplotypes, haplotypes which are strongly associated with IDDM. In contrast, the DR1-DQ5 and DR13-DQ6 (e.g. DQB1*0603) haplotypes, which are decreased among IDDM patients, were associated with the 665 Ala and 687 Gln variants. Thus, when DR- and DQ-matched patients and controls were compared, associations of the investigated TAP2 variants and IDDM were no longer detectable. These data, therefore, indicate that the associations previously found between certain TAP2 variants and IDDM are secondary to a primary association between this disease and particular DQ alpha beta heterodimers.

ATP Binding Cassette Transporter, Subfamily B, Mem↗