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PubMed2002

Histological features and HLA class II alleles in hepatitis C virus chronically infected patients with persistently normal alanine aminotransferase levels.

OBJECTIVE: A significant proportion of individuals with chronic hepatitis C virus (HCV) infection have persistently normal alanine aminotransferase (ALT) levels. Although data are controversial, such patients usually have weaker histological damage and a lower progression rate of fibrosis. The aims of this study were: (1) to compare demographic, virological, and histological parameters of HCV patients with normal ALT values with those of HCV patients with elevated ALT levels; and (2) to determine whether HLA class II alleles contribute to the persistence of normal ALT levels in HCV patients. PATIENTS AND METHODS: Eighty three patients with chronic HCV infection and persistently normal ALT values (group 1) and 233 patients with chronic HCV infection and elevated ALT levels (group 2) were studied. Histological features were expressed using Knodell and Metavir scores. HLA DRB1* and DQB1* genotyping was performed using hybridisation with sequence specific oligonucleotides after genomic amplification. The kappa2 and Fisher's exact tests were used to compare discrete variables and phenotype frequencies between the two groups, and Wilcoxon's test was used for continuous variables. A multivariate logistic regression model was used to determine which variables predicted normal ALT values. RESULTS: ALT levels were correlated with the severity of liver damage. In group 1, 93% of patients had an F0 or F1 Metavir index of fibrosis compared with 47% of patients in group 2 (p<0.001). A longer duration of infection (p<0.001) and increased DRB1*11 phenotype frequency (pc=0.03) were observed among patients with normal ALT. The two groups did not differ with regard to the mode of contamination or viral genotype. After logistic regression, young age (p=0.0008), female sex (p=0.01), long duration of infection (p=0.0001), and HLA DRB1*11 (p=0.050) were more strongly associated with persistence of normal ALT. CONCLUSIONS: Our study confirms that patients with chronic hepatitis C and normal ALT levels have less severe liver disease than those with elevated ALT levels. This particular biochemical outcome may be explained, at least in part, by host immunogenetic factors such as the presence of HLA-DRB1*11.

Adult↗
PubMed1991

Organization of the human HLA-class-II region.

A detailed map of the class-II region of the human MHC has been established by pulsed-field-gel-electrophoresis (PFGE) mapping and cloning in yeast-artificial-chromosome (YAC) vectors. The map revealed CpG islands, which are frequently associated with genes, in the gaps between the known HLA-class-II genes. Using cosmid walking and chromosome jumping, we have cloned 3 of these islands and have identified 5 novel genes, named RINGI-5. This brief report summarizes our present knowledge of these genes.

Chromosome Mapping↗
PubMed1992

A gp120 HIV peptide with high similarity to HLA class II beta chains enhances PPD-specific and autoreactive T cell activation.

The recent report that anti-gp120 antibodies can be induced by allogeneic stimuli in experimental animals in the absence of HIV, has focused attention on the structural similarities between gp120 and MHC. Here we report that some HIV+ individuals develop antibodies which similarly react with the gp120 HIV sequence (aa 254-263) and with the HLA-DR beta chains (aa 142-151). As these two peptides share a high level of similarity, we have investigated the role of this gp120 region on HLA class II mediated T cell recognition. The synthetic peptide corresponding to the gp120 HIV sequence aa 254-263 has been tested on T cell line (TCL) activation. Both the PPD-specific and the self-HLA reactive TCL proliferation increased in the presence of this peptide. Prepulsing experiments indicate that this enhancing effect carried out by HIV peptide is exerted at the level of antigen presentation. Moreover, the specificity of this interaction is supported by the fact that a MoAb specific for this HIV peptide blocked the autoreactive TCL proliferation, similarly to the inhibition carried out by anticlass II antibody. These data support the hypothesis that the functional homology between the HIV peptide and the HLA beta chain described may be involved in the pathogenesis of AIDS.

Amino Acid Sequence↗
PubMedDate not supplied

[Soluble HLA class I and HLA class II antigens in the blood of HIV infected patients].

The levels of HLA, class I, antigen and HLA-DR antigen in the blood sera of HIV-infected persons were determined by the enzyme immunoassay. The levels of soluble antigens HLR-DR and of HLA, class I, in serum samples containing only antibodies to HIV were elevated, respectively, 1.8- and 1.3-fold in comparison with the norm. The level of soluble HLA-DR antigen in samples containing the markers of other infections (HBsAg, antibodies to hepatitis C virus, anti-IgM antibodies to cytomegalovirus) was significantly higher in comparison with samples containing only antibodies to HIV and serum samples from healthy donors (p < 0.05). The concentration of soluble HLA antigen, class I, in the samples containing antibodies to HIV and markers of other infections was also elevated, but the statistically authentic increase in comparison with the normal level was observed only in the presence of the markers of HIV infection, hepatitis C and cytomegalovirus infection.

Cytomegalovirus Infections↗
PubMed1996

HLA class II alleles in Ainu living in Hidaka District, Hokkaido, northern Japan.

The Ainu people are considered to be the descendants of preagricultural native populations of northern Japan, while the majority of the population of contemporary Japan (Wajin) is descended mainly from postneolithic migrants. Polymorphisms of the HLA-DRB1, DRB3, and DQB1 alleles were investigated in DNA samples of 50 Ainu living in Hidaka district, Hokkaido. Unique features of the Ainu in this study were high incidences of DRB1*1401, DRB1*1406, and a newly described allele, DRB1*1106 (20%, 17%, and 5%, respectively). On the other hand, several common alleles in Wajin (DRB1*1502, 1302, 0803, and 1501) were found at relatively low frequencies (1-2%) in Ainu. Previously DRB1*1406 was described as a characteristic allele of some Native American or northeast Asian ethnic groups, and DRB1*1106 had been found in only two Singapore Chinese and one Korean. Principal component analysis of various populations based on HLA class II allele frequencies places the Ainu population midway between other east Asian populations, including Wajin, and Native Americans. These observations may support the hypothesis that the Ainu people are the descendants of some Upper Paleolithic populations of northeast Asia from which Native Americans are also descended.

Alleles↗
PubMed2005

Maternal HLA class II compatibility in men with systemic lupus erythematosus.

OBJECTIVE: Maternal-fetal cell transfer during pregnancy can lead to long-lasting microchimerism, which raises the question of whether microchimerism sometimes contributes to autoimmune disease later in life. In an experimental model, transfusion of parental lymphocytes homozygous for major histocompatibility complex alleles results in systemic lupus erythematosus (SLE). We identified male patients with SLE and healthy male subjects and their mothers in order to investigate the mother-son HLA relationship in SLE risk. Male subjects were selected in order to avoid confounding due to fetal microchimerism, which may occur in women. METHODS: HLA genotyping for DRB1, DQA1, and DQB1 was conducted for sons and their mothers. Thirty men with SLE and their mothers were compared with 76 healthy men and their mothers. RESULTS: Sons with SLE were HLA-identical with their mothers (bidirectionally compatible) for the basic HLA-DRB1 groups encoded by DRB1*01 through DRB1*14 more often than were healthy sons (odds ratio [OR] 5.0, P = 0.006). Each DRB1 group contains multiple allelic variants; male patients with SLE and their mothers often were identical for both DRB1 allelic variants (OR 3.2, P = 0.08). For DQA1 and DQB1, the ORs were 2.3 (P = 0.08) and 2.0 (P = 0.21), respectively. When analysis was limited to male subjects with SLE-associated HLA genes (encoding HLA-DR2 or HLA-DR3), the differences further increased for DRB1 basic groups (OR 7.2, P = 0.01), DRB1 alleles (OR 15.0, P = 0.018), DQA1 6.4 (P = 0.006), and DQB1 (OR 5.7, P = 0.027). No increase in (unidirectional) compatibility of the mother from the son's perspective was observed at any locus. CONCLUSION: We observed increased bidirectional HLA class II compatibility of male SLE patients and their mothers compared with healthy men and their mothers. This observation implies that maternal microchimerism could sometimes be involved in SLE and therefore merits further investigation.

Adolescent↗
PubMed2006

Association of HLA class II DRB1, DPA1 and DPB1 polymorphism with genetic susceptibility to idiopathic dilated cardiomyopathy in Chinese Han nationality.

Although the aetiology of idiopathic dilated cardiomyopathy (IDC) remains unclear, many immunological abnormalities involving changes in cell-mediated and humoral immunity may be associated with cardiac impairment in IDC. Autoimmune mechanisms are likely to participate in the pathogenesis of at least a subgroup of IDC and components of the major histocompatibility complex may serve as markers for the propensity to develop immune-mediated myocardial damage. Human leukocyte antigen (HLA) class II genes, which are highly polymorphic, play an important role in the activating of immune responses and thus control the predisposition for or protection from IDC. This study explores the possible contribution of HLA-DRB and DP polymorphisms to IDC susceptibility. DNA genotyping for HLA-DRB1, DPA1 and DPB1 was performed using polymerase chain reaction-sequencing based typing (PCR-SBT) method in 198 IDC patients and 136 random selected healthy Han ethnic individuals living in Northern China. IDC patients were, sub-grouped into asymptomatics (subgroup A), with arrhythmia (subgroup B) and with overt congestive heart failure (subgroup C) according to the clinical manifestations and electrocardiogram or echocardiographic characteristics. ADP/ATP autoantibody was detected in IDC group by immunoblot analysis. The results revealed that HLA-DR15, -DPB*0601 frequencies were significantly elevated in IDC group compared with normal control. The DPB1*0601 allele in homozygous form or in combination with allele DPB1*2301 or *3901, was found present more often in IDC patients. The predominance of HLA-DR4 allele was observed in subgroup B after stratification. However, the frequency of DPB1*0101 allele increased in the control than in the IDC group. The frequency of HLA-DPB1*0601 allele was significantly higher in IDC patients with positive autoantibody against ADP/ATP carrier of myocardial mitochondria in contrast to those with negative autoantibody. We conclude that HLA-DR4, -DR15, -DPB1*0601 alleles confers susceptibility to, while DPB1*0101 allele confers protection from IDC among individuals of northern Chinese Han nationality. The glutamate at position 69 in the second exon of DPB1*0601, as a key residue for special conformation of HLA-DP, may confer predisposition to IDC. HLA-DR and -DP alleles polymorphisms may serve as genetic markers for IDC and be involved in the regulation of the immune specific response to auto or exterior anti-myocardium antibodies.

Alleles↗
PubMed1993

Surface expression of secretory component and HLA class II DR antigen on glandular epithelial cells from human endometrium and two endometrial adenocarcinoma cell lines.

The expression of secretory component (SC) by human glandular endometrial cells cultured in vitro was significantly increased by estradiol in the medium. Interferon-gamma and interleukin-4 stimulated the expression of SC only in the presence of estrogen. Tumor necrosis factor-alpha plus estrogen also caused a significant increase in the number of cells expressing SC. HLA class II antigen DR was detected on few glandular epithelial cells of human endometrium cultured in control medium, whereas interferon-gamma and interleukin-4, but not tumor necrosis factor-alpha, caused significant increases in the expression of DR. Estrogen in the culture medium did not significantly affect DR expression. The human endometrial adenocarcinoma cell lines, HEC and RL-95, expressed SC in approximately 50 and 20% of the cells. Also, approximately 20% of the RL-95 cells stained for DR antigen. Interferon-gamma did not influence the degree of expression of either surface marker of the two cell lines. Cells of both lines bound polymeric IgA and IgM but showed little to no binding of monomeric IgA, IgG, or an IgM previously shown not to bind SC.

Adenocarcinoma↗
PubMed2002

Improved flow cytometric detection of donor-specific HLA class II antibodies by heat inactivation.

Flow cytometry is a powerful technique for T-cell crossmatching but is prone to false-positive reactions with B cells. In this study the flow cytometry crossmatch (FCXM) was performed in 319 cases, using the patient's serum untreated and incubated at 56 degrees C for 30 minutes. Heat treatment inhibited B-cell reactivity in 30 of 39 cases. Flow cytometry testing with latex beads coated with human leukocyte antigen (HLA) class II antigens showed no class II antibodies in sera that were completely inhibited by heat treatment. There was no inhibition of class I antibodies to either T or B cells, or of class II antibodies to B cells. Experiments with aggregated IgG showed that inhibition by heat treatment is likely due to the prevention of complement binding to aggregates or dissociation of aggregates, or both. We conclude that heat inactivation is a simple step that eliminates false-positive reactions in the B-cell flow cytometry crossmatch.

B-Lymphocytes↗
PubMed1996

HLA class II is associated with the frequency of glutamic acid decarboxylase M(r) 65,000 autoantibodies in Japanese patients with insulin-dependent diabetes mellitus.

Autoantibodies to glutamic acid decarboxylase (GAD65Ab) are common in both caucasian and Japanese patients with insulin-dependent diabetes mellitus (type 1), while the type 1-associated HLA haplotypes differ. In the present study, we analyzed GAD65Ab in relation to HLA-DQ and -DR alleles in Japanese type 1 patients. GAD65Ab were found in 58% short-duration (less than 5 years) type 1, 23% long-duration type 1, 56% slowly progressive type 1, 3% type 2 patients, and 1.7% healthy individuals. In 75 HLA-typed type 1 patients, the GAD65Ab frequency was higher in short-duration patients with DRB1*08 allele (100%, Pc < 0.05). GAD65Ab frequencies in DQB1*0302, DQB1*0303, and DRB1*09-positive, long-duration type 1 patients were lower than those in short-duration type 1 patients (14%, 19%, and 20%, Pc < 0.02 compared with short-duration type 1, 90%, 75%, and 71%, respectively), while the frequency varied less in DQB1*04 individuals (44% and 30% in short- and long-duration type 1 patients, respectively). These findings were also observed among patients with DRB1*04, i.e., the haplotype DRB1*0405-DQB1*0401 showed less variation in frequency of GAD65Ab (44% and 35% in short- and long-duration type 1 patients, respectively), while DRB1*04xx-DQB1*0302 showed lower frequency in long-duration type 1 than short-duration (13% and 100%, respectively). Thus, HLA class II is associated with frequency GAD65Ab, and this association might be affected by disease duration in Japanese type 1 patients.

Adolescent↗
PubMed1992

Comparison of HLA class II alleles in Gypsy and Czech populations by DNA typing with oligonucleotide probes.

Czechs (CZ) and Gypsies (GY) have lived in the same country for several centuries but seem to have different migratory origins. We have studied 99 CZ and compared them with 34 GY from an isolated group living in Czechoslovakia. DRB1, DRB3, DRB4, DRB5, DQA1, DQB1 and DPB1 alleles were determined by PCR followed by oligonucleotide hybridization. DRB1*0701 was the most frequent DR allele in CZ (af = 36.3%). In GY, after DRB1*0701, DRB1*1404 was the second most frequent allele (af = 29.4%), while in CZ this allele was not found. Both groups differed also in the distribution of DR4 subtypes. In CZ, DRB1*0401 was the most frequent subtype (50.0%) of DR4. In GY, DRB1*0408 was the predominant type (44.4%). A new DQB1 pattern was found in GY, which we have called DQB1*3.4. This allele was similar to DQB1*0301 in codon 26, but in codon 57 it resembled DQB1*0302. All cells having this new allele were also positive for DRB1*0408. Four-locus associations in CZ showed haplotypes similar to those previously found in other Caucasoid populations. In GY we observed more unusual haplotypes, some previously seen in the Orient, possibly reflecting GY ancestry.

Alleles↗
PubMed2006

Polymorphism of HLA class II genes in Miao and Yao nationalities of Southwest China.

In the present study, the polymorphism of human leucocyte antigen class II genes was investigated by the sequence-based typing method in two Chinese populations: the Miaos (n = 85) from Guizhou province and the Yaos (n = 66) from Yunnan province. These two populations exhibited certain similarity in their allelic distributions. Among 24 DRB1 alleles detected, DRB1*150101, DRB1*140101, DRB1*160201 and DRB1*090102 in Miao and DRB1*120201, DRB1*140101, DRB1*150101 and DRB1*090102 in Yao were highly predominant. Sixteen DQB1 alleles in total were found in these two populations among which DQB1*050201, DQB1*060101/060103 and DQB1*030101/0309 in both Miao and Yao and DQB1*050301 in Yao were commonly observed. In the 13 DPB1 alleles detected, the most frequent allele was DPB1*0501 in Miao and Yao followed by DPB1*02 and DPB1*1301. Frequent comparisons with other Chinese populations suggested the southern Chinese feature for both the Miao and Yao nationalities.

Alleles↗
PubMed1994

Both class I and class II HLA antigens are thyroid cancer susceptibility factors.

It has been established that HLA antigens are susceptibility factors for different cancers, including thyroid tumors. However, the diversity and sometimes weak and contradictory associations found have frequently led to the view that the HLA and tumorigenesis links might be the result of statistical errors. However, it has recently been established that it is indeed a currently complex and unexplained but real phenomenon, which may be crucial in preventing several types of cancer. In the present work we have found in a relatively large series of thyroid cancer patients (n = 161) that both HLA class I (B35) and class II (DR11) antigens are susceptibility factors only in the papillary tumor group of patients, B35 association p value is found at the limit of significance (pc(120) = 0.05); the follicular group did not show any HLA association, suggesting that the etiopathogenesis of each type of cancer is different. HLA-B35 and DR11 are not working together to induce tumorigenesis and each of them seems to confer susceptibility by using different pathways or by being markers of distinct neighboring susceptibility genes. DR4 has also been found in 86% (n = 6) of Hürthle cell carcinoma. No association has been found between HLA and disease activity. HLA mechanisms of association to cancer are discussed and a world-wide HLA/tumorigenic study is proposed to obtain a clear picture of the puzzling and controversial susceptibility markers found in different tumors and in different ethnic groups.

Disease Susceptibility↗
PubMed1996

Genetic susceptibility and anti-human platelet antigen 5b alloimmunization role of HLA class II and TAP genes.

Platelet alloimmunization may result in post-transfusion purpura, and during pregnancy may cause neonatal alloimmune thrombocytopenia (NAIT), with a frequency estimated at 1.3 per 1000 live births. The risk of morbidity is significant: 20% of affected infants have neurologic sequelae and the death rate is about 10%. A better understanding of the immune response to platelet alloantigens would allow for a better definition, and thus better management of pregnant women at high risk. Limited data are available on the immune response against HPA-5b, the second most frequent antigen, after HPA-1a, implicated in NAIT. We studied HLA class II and TAP gene polymorphism in 50 women immunized against HPA-5 system antigens. Our results suggest a strong association of alloimmunization with a cluster of HLA DR molecules sharing a particular polymorphic amino acid sequence at position 69-70 (Glu-Asp encoded by GAA-GAC nucleotide sequence) of the DR beta 1 chain (RR = 2.95, RR = 5.70 when patients were homozygous for this sequence), and a negative association with the DRB1*0301 allele (2.1% vs. 28%; RR = 0.08). Furthermore, increased frequency of a TAP2 dimorphism at position 379 was observed in immunized women against the HPA-5 antigens (RR = 4.7).

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

HLA class II DPB1, DQA1, DQB1, and DRB1 genotypic associations with occupational allergic cough to Bunashimeji mushroom.

We previously reported that two-third of workers in a Bunashimeji mushroom (Hypsizigus marmoreus) farm complained of respiratory allergic symptoms, but one-third workers did not suffer from such symptoms even when working for a long period. CD4+ T-helper (Th) cells increased, and Th2/Th1 ratio increased in the allergic workers. To address these immunological backgrounds, we have investigated whether there is any relationship between mushroom allergy and human leukocyte antigen (HLA) class II alleles of DPB1, DQA1, DQB1, and DRB1 by using the polymerase chain reaction-restriction fragment length polymorphism (RFLP) and sequencing-based typing methods. We observed that the allele frequencies of DQA1*0103, DQB1*0601, and DRB1*0803 were significantly higher in the workers having no allergic symptoms than allergic workers (DQA1*0103: 57 vs 25%, DQB1*0601: 49 vs 14%, and DRB1*0803: 29 vs 0%). However, this phenomenon was not seen in workers producing another kind of mushroom, Honshimeji (Lyophyllum aggregatum). The HLA-DRB1*0803 allele alone, the DRB1*0803, DQA1*0103, DQB1*0601 haplotype, or both were negatively associated with allergy to Bunashimeji, and these alleles might be involved in the prevention of Bunashimeji mushroom-specific respiratory allergy.

Adult↗
PubMed1997

HLA class II restricted T-cell reactivity to a developmentally regulated antigen shared by leukemic cells and CD34+ early progenitor cells.

After allogeneic bone marrow transplantation (BMT), the beneficial graft-versus-leukemia (GVL) effect but also the life-threatening graft-versus-host disease (GVHD) are mediated by T cells of the grafted marrow. The identification of leukemia cell-reactive T cells and their ligands are, therefore, crucial for the development of new anti leukemia strategies. Here we describe a leukemia-reactive allo-HLA class II restricted CD4+ T-cell clone, 6.2, isolated from a healthy individual after stimulation with allogeneic leukemic cells. Clone 6.2 recognizes leukemic cells from several AML patients without showing reactivity to unfractioned peripheral blood mononuclear cells, monocytes, B cells, T-cell blasts, and proximal tubulus epithelial cells. Interestingly, clone 6.2 also recognizes BM cells derived from healthy individuals and inhibits the colony formation of myeloid and erythroid cell lineages. In the BM, clone 6.2 recognizes only CD34+ early precursor cells but not CD34-, more differentiated cells. Thus, the target antigen of clone 6.2 is developmentally regulated and expressed only by leukemic cells and CD34+ early progenitor cells in the hematopoietic system. We suggest that targeting the T-cell immune response to leukemia-associated, developmentally regulated antigens of the hematopoietic system can provide a basis for the separation of GVL from GVHD, and may lead to new therapeutic approaches for residual and relapsed leukemia.

Acute Disease↗
PubMed1998

Induction of HLA-unrestricted and HLA-class-II-restricted cytotoxic T lymphocytes against MUC-1 from patients with colorectal carcinomas using recombinant MUC-1 vaccinia virus.

We recently reported that immunization with a recombinant MUC-1 vaccinia virus (rVMUC-1) protected C57BL/6 mice from challenge with DF3/MUC-1-positive syngeneic tumors. To elucidate whether anti-MUC-1 tumor immunity, especially MUC-1-specific cytotoxic T lymphocytes (CTI), can be induced in cancer patients by rVMUC-1, we stimulated the peripheral blood lymphocytes from patients with DF3/MUC-1+ or DF3/MUC-1 colon carcinomas using the autologous monocytes infected with rVMUC-1 (rVAMN). The stimulated T lymphocytes from two patients with DF3/MUC-1-positive colorectal carcinomas (rVPY+T and rVPW+T) demonstrated HLA-unrestricted cytotoxicity against MUC-1, whereas those from the patient with DF3/MUC-1-negative colon carcinoma (rVPA-T) did not. The HLA-unrestricted cytotoxicity was demonstrated by the CD8+ T cells possibly recognizing an epitope present on the tandem repeats. Adoptive immunotherapy who performed three times with patient PY, at 4-week intervals. The adoptive transfer of the first stimulated lymphocytes, demonstrating a high level of HLA-unrestricted cytotoxicity against MUC-1, resulted in the significant reduction of the liver metastasis of patient PY. However, HLA-unrestricted cytotoxicity against MUC-1 was extremely reduced at the second transfer and finally eliminated at the third, whereas the CD4+ T cells demonstrating HLA-class-II-restricted cytotoxicity against MUC-1 predominantly proliferated at the third adoptive immunotherapy treatment. The liver metastasis and the serum levels of tumor markers (carcinoembryonic antigen CA19-9) demonstrated a rapid and marked increment after the second transfer and especially after the third. These results suggest that the HLA-unrestricted cytotoxic CD8+ T cells against MUC-1, induced in patients with DF3/MUC-1+ colorectal carcinomas using rVMUC-1, correlate with the antitumor activity in vivo.

Animals↗