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PubMed1999

HLA-B27 subtypes and HLA class II alleles in Japanese patients with anterior uveitis.

PURPOSE: Some patients with anterior uveitis (AU) have ankylosing spondylitis (AS) and are HLA-B27 class I-positive. The purpose of this study was to investigate whether there are differences in HLA at the allele level among each group of patients with AU. METHODS: Seventy-three patients with AU were studied. They were classified into three groups: 31 with AS-associated AU, 14 with HLA-B27-associated AU, and 28 with idiopathic AU. Three control groups without AU were used: 138 random subjects, 33 HLA-B27-positive healthy subjects, and 19 HLA-B27-positive patients with AS. DRB1 and DQB1 genotyping was performed using polymerase chain reaction (PCR)-single-strand conformation polymorphism (PCR-SSCP) and PCR-restriction fragment length polymorphism. HLA-B27 subtype was determined by PCR-SSCP. RESULTS: There was no difference in the frequency of any class I antigen except HLA-B27 among the patients studied. The frequencies of HLA-DR12 in AS-associated AU and HLA-DR1 in HLA-B27-associated AU showed an increase. In HLA-B27-associated AU, DRB1*0101 and DQB1*0501 were increased compared with HLA-B27-positive control subjects. When HLA-B27 subtype distribution was compared among the groups, the proportion of B*2704 was significantly lower in HLA-B27-associated AU (P = 0.037), however, such a difference was not present in AS-associated groups. CONCLUSIONS: These results indicated that B*2704 seemed to be less susceptible to AU compared with B*2705 in Japanese subjects. The increase of HLA-DR12 and HLA-DR1 in AU may be caused by linkage disequilibrium with B*2704 and B*2705, respectively.

Adult↗
PubMed1997

Mannose receptor mediated uptake of antigens strongly enhances HLA-class II restricted antigen presentation by cultured dendritic cells.

Dendritic cells (DCs) use macropinocytosis and mannose receptor mediated endocytosis for the uptake of exogenous antigens. Here we show that the endocytosis of the mannose receptor and mannosylated antigen is distinct from that of a non-mannosylated antigen. Shortly after internalization, however, both mannosylated and non-mannosylated antigen are found in an MIIC like compartment. The mannose receptor itself does not reach this compartment, and probably releases its ligand in an earlier endosomal structure. Finally, we found that mannosylation of peptides strongly enhanced their potency to stimulate HLA class II-restricted peptide-specific T cell clones. Our results indicate that mannosylation of antigen leads to selective targeting and subsequent superior presentation by DCs which may be useful for vaccine design.

Antigen Presentation↗
PubMed2000

Identification of HLA-class-II-restricted epitopes of autoantigens in transgenic mice.

The past year has seen a spate of research in the use of HLA transgenic mice in the identification of self antigens associated with autoimmunity. Dominant T cell determinants - and, in a few cases, B cell determinants - have been characterized in the context of disease-predisposing HLA DR and DQ genes for at least three prominent and devastating autoimmune diseases: rheumatoid arthritis, multiple sclerosis and insulin-dependent diabetes mellitus.

Animals↗
PubMed1993

HLA class II polymorphism and IDDM susceptibility in the Greek population.

The frequencies of HLA-DQA1, DQB1 and DRB1 alleles were compared between 50 Insulin-Dependent Diabetes Melitus (IDDM) patients and 49 healthy controls in the Greek population. Statistically significant difference in the frequencies of HLA-DQA1*0501-DQB1*0201 (P = 10(-4)), DQA1*0301-DQB1*0201 (P = 0.01) and DQA1*0301-DQB1*0302 (P = 0.001) were observed. The DRB1*0405-DQA1*0301-DQB1*0201 was the only DR, DQ combination significantly associated with the disease. The unexpected increase of DRB1*0405 observed in the Greek IDDM may suggest as reported in Chinese and Japanese IDDM a contribution of DR beta and DQ alpha in susceptibility. Moreover, in contrast to the Asians, in the Greek, the DR beta, DQ alpha are found with the usual DQ beta 57-ve.

Adolescent↗
PubMed1996

Polymerase chain reaction--based sequence-specific oligonucleotide hybridization analysis of HLA class II antigens in pulmonary tuberculosis: relevance to chemotherapy and disease severity.

HLA antigens were studied by serology and polymerase chain reaction-based sequence-specific oligonucleotide hybridization techniques in 153 patients with pulmonary tuberculosis (PTB) and 289 healthy controls. HLA-DR2 was present more frequently in PTB patients than in controls (51% vs. 36.3%; corrected P[Pc]=.029, relative risk [RR] = 1.8). The DR2 association was stronger in patients in the drug-failure group (n=56; Pc=.000012, RR=3.7) than in healthy controls and in patients in the drug-responder group. No significant deviation was observed in HLA allelic frequencies in various patient groups, as determined by radiographs of lung lesions. Molecular subtyping of DR2 revealed that the bulk of the allele was DRB1*1501 and DRB1*1502 in patients and controls. There was no skewing of the frequency of these molecular subtypes of DR2 in patients, suggesting that the whole DR2 molecule or its closely linked gene(s) may be involved in governing patient susceptibility to PTB and, particularly, development of the severe drug-resistant form of the disease.

Adult↗
PubMed2000

The HLA class II locus DPB1 can influence susceptibility to type 1 diabetes.

HLA-DPB1 genotypes were determined for samples from 269 multiplex Caucasian families from the Human Biological Data Interchange. DRB1 and DQB1 loci were also characterized, allowing assignment of DPB1 alleles to haplotypes and calculation of linkage disequilibrium values. Frequencies for several DPB1 alleles differed significantly between patients and affected family-based control subjects. Some differences were attributable to linkage disequilibrium with DR and DQ alleles, whereas others were not. DPB1*0301 and DPB1*0202 alleles are predisposing for type 1 diabetes in these data, not only in analyses of individual alleles, but also in genotype analyses. DPB1*0402 appears protective; however, stratification analysis indicates that its protective effect is specific for DR3 haplotypes. A protective role for DPB1*0401 is suggested by genotype analysis. For increased statistical power, DPB1 alleles were pooled into three categories: susceptible, neutral, and protective after removal of effects due to linkage disequilibrium with DR-DQ. Analysis of these pools suggests that DPB1 primarily affects susceptibility to, rather than protection from, type 1 diabetes in a dominant fashion. This effect is more apparent in patients with genotypes other than the highest risk DR3/DR4-DQB1*0302 genotype. These data support a role for the DPB1 locus in conferring susceptibility to type 1 diabetes.

Alleles↗
PubMed1998

Donor-recipient sharing of HLA class II alleles predicts earlier recurrence and accelerated progression of hepatitis C following liver transplantation.

Both direct viral cytopathic effects and host immune responses appear to be important in the pathogenesis of hepatitis C virus (HCV) infection. Liver transplantation provides a means to explore the role of the immune system in the development of HCV-related liver damage through comparing the natural history of HCV in patients with different degrees of donor-recipient human leukocyte antigen (HLA) matching. We evaluated 36 patients with recurrent hepatitis C viremia following liver transplantation to determine whether hepatocellular injury or progression to bridging fibrosis occur more rapidly when donor and recipients share HLA alleles. HLA typing for the HLA-A and HLA-B loci was performed by serological techniques and PCR-based oligotyping was used to type alleles of the DRB1, DRB3, DQA1, and DQB1 loci. A median of eight liver biopsies, obtained during a median follow-up of 36 months, were reviewed per patient. Donor-recipient sharing of alleles of HLA-DQB1 or DRB1 was associated with more rapid development of recurrent hepatitis by univariate analysis (chi2=5.7, P=0.02 and chi2=5.54, P=0.02 respectively). However, only sharing of HLA-DRB1 alleles was identified as an independent predictor of reduced time to recurrent histologic injury by multivariate analysis (chi2 =5.74, P=0.02). Furthermore, sharing of HLA-DRB3 and histologic evidence of rejection were associated with more rapid progression to bridging fibrosis both by univariate methods (chi2=4.12, P=0.04 and chi2=4.66, P=0.03 respectively), and by multivariate analysis (chi2=13.01, P=0.001). These findings suggest that HLA class II-restricted immune responses may contribute to the pathogenesis of HCV-related liver injury in liver transplant recipients.

Adult↗
PubMed1990

Detection and quantitation of HLA class II molecules on keratinocytes by quantitative immunofluorescence.

The paper describes measurements of HLA-DR antigen expression on normal human keratinocytes in culture using anti-HLA-DR antibodies and fluorescent Protein A or fluorescent second antibody methods and a low-light level video camera and image analysis program to quantitate the fluorescence output. The measurements are ultimately quantitated in terms of molecules of Ia antigen reacting material per cell. The method has a sensitivity at a S/N ratio of 10:1 of 180 molecules/micron2. The results show that normal keratinocytes do indeed express class II antigens on their surfaces at levels well above background. We confirm that treatment of the cells with gamma-interferon produces enhanced expression of DR antigens within 4 days. The method of quantitation is applicable to fluorescence and other low light level images.

Calibration↗
PubMed1989

Are HLA class II genes controlling susceptibility and resistance to Brazilian pemphigus foliaceus (fogo selvagem)?

In order to investigate the possible association between Brazilian pemphigus foliaceus and HLA, we studied 48 patients and 74 matched controls, all Brazilian Caucasoids, for HLA-A,B,C; DR1 to DRw8 and DQw1 to DQw3. The frequencies of DR1, DR4 and B16 were significantly increased, while DR7 was significantly decreased among the patients. Furthermore DQw2, likewise the DR specificities associated with it - DR3 and DR7 - never occurred among the patients in the absence of the susceptibility markers DR1, DQw1 or DR4, DQw3. Acting on these findings, we suggest that at least two MHC-class II genes are involved in the pathogenesis of Brazilian pemphigus foliaceus: at least one gene, associated to DR1,DQw1 and to DR4,DQw3, confers susceptibility and at least one gene, associated to DR7,DQw2 and DR3,DQw2, confers resistance. The susceptibility gene(s) seem(s) to be epistatic to or dominant over (if allelic) the resistance gene(s). Both are dominant over other alleles at their locus (or loci).

Adolescent↗
PubMed1991

Two B cell factors bind the HLA-DRA X box region and recognize different subsets of HLA class II promoters.

The class II genes of the human Major Histocompatibility Complex (MHC) encode three isotypes of alpha/beta heterodimeric proteins, HLA-DR, -DQ, and -DP, which are responsible for presenting processed antigens to T helper lymphocytes. These MHC class II genes are expressed in a coordinate manner. The promoter regions of all MHC class II genes share a set of highly conserved elements that mediate different levels of tissue-specific and inducible transcription. One element, the X box, appears to be the major positive element in B cell-specific expression, and nuclear protein binding studies have subdivided this region into the X1 and X2 boxes. Regulatory Factor X (RFX) binds to the X1 box whereas several other factors have been described that bind to the X2 box. In this report, we further characterize the X1 binding protein RFX and show that RFX binds poorly to beta chain gene promoters. In particular, RFX does not bind to the DRB gene, which is expressed at the highest levels of all beta chain genes. In addition, we have identified an X2 box binding activity in human B cell extracts that binds with high affinity to the HLA-DRA promoter. This X2 binding protein, X2BP, binds to a different subset of class II promoters than does RFX. These findings suggest that coordinate regulation of class II expression may involve different combinations or arrangements of transcriptional elements and factors instead of a common set.

Autoradiography↗
PubMed1986

A quantitative dot immunobinding assay for human HLA class II antigens using nitrocellulose membrane filters.

A quantitative method for the evaluation of human HLA-DR antigen expression has been developed. Cell membrane proteins were solubilized in Nonidet P-40 or deoxycholic acid detergent and diluted in a Triton X-100 containing sample buffer. The samples were subsequently spotted on a nitrocellulose membrane filter and fixed by immersion in isopropyl alcohol-acetic acid solution. The membrane was saturated in a 5% BSA blocking buffer and sequentially incubated with specific monoclonal anti-HLA-DR antibody, and 125I-labelled protein A. Each spot was then assayed for radioactivity in a gamma scintillation counter. Immunoadsorbant purified HLA-DR antigen was used to standardize the method and a reference dosage curve was established with serial dilutions of the purified HLA-DR antigen. The method permitted the detection of HLA-DR antigens with reproducibility in the ng range, in cellular extracts, physiological and pathological fluids, and in fractions eluted from affinity columns.

Cell Line↗
PubMed1999

Sequencing of HLA class II genes based on the conserved diversity of the non-coding regions: sequencing based typing of HLA-DRB genes.

In this paper, we present a novel sequencing based typing strategy for the HLA-DRB1, 3, 4 and 5 loci. The new approach is based on a group-specific amplification from intron 1 to intron 2 according to the serologically-defined antigens. For this purpose, we have determined the 3' 500 bp-fragment of intron 1 and the 5' 340 bp-fragment of intron 2 of all serological antigens and their most frequent subtypes. We discovered a remarkably conserved diversity characterized by lineage-specific sequence motifs. This lineage-specificity of non-coding motifs in the 1st and 2nd intron offered the possibility to establish a clear serology-related amplification strategy. The method allows the complete analysis of the 2nd exon and the definition of the cis/trans linkage of sequence motifs by intron-mediated polymerase chain reaction (PCR)-based separation of the haplotypes in nearly all serologically heterozygous samples. In particular, the non-coding variabilities between the DR52-associated DRB1 groups made their independent amplification possible. Thus, compared to the standard procedures using exon-based amplification primers, the groups DR3, DR12, some DR13 alleles (1301, 1302) and the DR14 group could be amplified by specific primer mixes. The DR8 could be amplified with an individual primer mix not co-amplifying the DR12. The DR11 and DR13 did not show any individual motif in intron 1 or intron 2. In order to achieve a separate amplification, they had to be amplified by multispecific primer mixes (DR3/11/13/14; DR3/11/13 or DR11/13/14) excluding the other haplotype. Thus, exclusively the alleles in rare DR11,13 heterozygosities without a DRB1*1301 or 1302 could not be amplified separately. Fourteen primer mixes are used to amplify the specificities DR1-14, and 6 primer mixes for the specificities DR51-53. The sequence homology of the 3' end of intron 1 facilitated the application of only three different sequencing primers for all DRB alleles.

Alleles↗
PubMed1997

HLA class II genes in Latvian patients with juvenile rheumatoid arthritis.

PCR-based HLA genotyping was used to analyze the association of HLA-DR and -DQ genes in 127 juvenile rheumatoid arthritis patients and 111 population-based controls from Latvia. The results show DQA1*03 to be positively associated in overall patients and DRB1*01-DQA1*0101-DQB1*0501 to be negatively associated with JRA in overall patients and in polyarthritis patients compared to controls. These data indicate the immunogenetic heterogeneity in the JRA patients, in the disease subgroups and in different ethnic groups. Rheumatoid factor (RF) was assayed in patients (n = 119) and controls (n = 98). RF was present in patients (7/119, 6%) compared to controls (5/98, 5%). None of the DQA1, DQB1 alleles, DQ and DR-DQ haplotypes was associated in seropositive patients compared to seropositive controls. DR1-DQ5 (DQA1*0101-B*0501) was decreased in seronegative patients (11/111, 10%) compared to seronegative controls (24/105, 23%), but the difference was not significant after correction of the p value.

Alleles↗
PubMed2006

HLA class II gene polymorphism in Parsees and Zoroastrians of Iran.

Extensive polymorphism of the HLA genes in different ethnic groups has been used as an invaluable tool for anthropological studies. In this study, HLA-DRB1, DQA1 and DQB1 allele frequencies and haplotypes were determined in 72 Parsees and 65 Zoroastrians living in Iran. The predominant DRB1 allele was *1103 = 4 in Parsees and *0701 in Zoroastrians. DQA1*0501 was the most common alleles in both spopulations. The most frequent DQB1 allele was *0301 in Parsees and *0201 in Zoroastrians. DRB1*1103 = 4-DQA1*0501-DQB1*0301 and DRB1*0701-DQA1*0201-DQB1*0201 were the most prevalent haplotypes in Parsees and Zoroastrians, respectively. Significant deviation from Hardy-Weinberg equilibrium was observed in DQA1 and DQB1 loci of Zoroastrians. The former locus also departed from neutrality due to balancing selection. All pairs of the studied loci in this study showed significant linkage disequilibrium. Analysis of molecular variance indicated that the main variation was confined to individuals within the studied populations. Neighbour-joining tree based on Nei's genetic distances according to DRB1 and DQB1 allele frequencies showed that Parsees and Zoroastrians of Iran were located in the same cluster of the phylogenetic tree. Furthermore, Zoroastrians of Iran and Pakistan are very close to each other. This study will serve as a reference for further anthropological studies when the HLA profile of all ethnic groups of Iran is investigated.

Ethnicity↗
PubMed1990

HLA class II and T cell receptor gene polymorphisms in psoriatic arthritis and psoriasis.

HLA-DRB, DQA and DQB genes as well as the T cell receptor (TcR) alpha, beta, and gamma genes were studied by Southern blot analysis of genomic DNA from patients with psoriatic arthritis (PsA) and psoriasis alone (Ps). A subtype of DR7, DR7a, was found in 38.8% of patients with PsA, 41.5% of patients with Ps, and in 8% of healthy individuals (N) (PsA vs N: pc = 0.0002, RR = 7.1; Ps vs N: pc = 0.0002, RR = 7.9). No association with TcR genes was found. Our findings suggest either that the DR7a allele may be in linkage disequilibrium with HLA-Cw6 or that it may be an important susceptibility factor for PsA and Ps.

Adult↗