HLA class II diversity in Australian aborigines: unusual HLA-DRB1 alleles.
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Alleles↗
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Southern blot analysis of HLA class II beta genes in relation to HLA-D, DR specificities.
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Cell Line↗
Neonatal lupus erythematosus: analysis of HLA class II alleles in mothers and siblings from seven Japanese families.
BACKGROUND: Neonatal lupus erythematosus (NLE) is a syndrome characterized by dermatitis and congenital heart block. The disease is mostly associated with transplacental passage of maternal anti-Ro(SS-A) or anti-La(SS-B) antibodies. Maternal HLA-DR3 and DQ2 alleles are associated with NLE in white and North American black populations. OBJECTIVE: We sought evidence of a potential genetic disposition to NLE in mothers with a relatively homogeneous ethnic background. METHODS: Class II human major histocompatibility complex HLA-DRB1, DQA1, DQB1, and DPB1 alleles were determined by polymerase chain reaction-restriction fragment length polymorphism in anti-Ro(SS-A)-positive mothers as well as in infants from seven Japanese families with siblings concordant or discordant for disease expression of NLE. RESULTS: All seven mothers had two or three DQ alleles of DQA1 and DQB1 possessing specific amino acid residues, which are reportedly associated with anti-Ro(SS-A) autoantibody response in white and black populations. There was no class II HLA profile that distinguished disease manifestations of NLE in infants. CONCLUSION: The HLA class II allele associations with anti-Ro(SS-A) autoantibodies that have been noted in other ethnic groups were also found in Japanese anti-Ro(SS-A)-positive mothers whose infants had NLE, suggesting shared susceptibility factors across racial barriers in maternal predisposition to Ro(SS-A) autoimmune response.
Disease Susceptibility↗
HLA class II DNA typing in two Brazilian populations.
Brazil constitutes a melting pot of populations arising from three major groups, including Amerindians, Africans, and Europeans predominantly from Portugal who were later supplemented by migrations from other European countries. Although every possible combination of racial mixture exists in Brazil, we have selected for this study two groups of subjects residing in Rio de Janeiro. A predominant White population, among whom some Amerindian admixture may exist, and a predominantly African population having little admixture from the other races. We have used the polymerase chain reaction (PCR) and hybridization with oligonucleotide probes to perform a complete typing of the HLA class II alleles. We report the allele frequencies for HLA-DRB1, DQA1, DQB1 and DPB1. We also report on the postulated DR-DQ haplotypes based on family studies and observations in homozygous B-cell lines. These results may serve as background for various types of clinical studies in Brazilian populations.
Alleles↗
Cytomegalovirus- and interferon-related effects on human endothelial cells. Cytomegalovirus infection reduces upregulation of HLA class II antigen expression after treatment with interferon-gamma.
Cultured human umbilical vein endothelial cells (HUVEs) were infected with human cytomegalovirus (HCMV) strain AD169. Up to 50% HUVEs proved to be positive for HCMV early nuclear antigens 24 hours after inoculation with virus. Following infection kinetics of surface expression of HLA class I and II, intercellular adhesion molecule (ICAM-1) and endothelial lymphocyte adhesion molecule (ELAM-1) on HUVEs were investigated by means of flow cytometry. A slight increase in HLA class I expression was observed, whereas expression of HLA class II (DR, DP, DQ) antigens was not induced by infection with HCMV. Furthermore, when compared with uninfected cells treated with interferon-gamma (IFN-gamma), reduced enhancement of HLA-DR expression was conspicuous in HCMV-infected cells treated with IFN-gamma. There is evidence that only a portion of HUVE is affected in its ability to upregulate HLA class II antigens. While expression of ICAM-1 was found to be enhanced between 8 and 20 hours after infection with a maximum at 12 hours after infection, no modulation of ELAM-1 was seen.
Cell Adhesion Molecules↗
Regulation of HLA class II molecule expressions by IFN-gamma. The signal transduction mechanism in glioblastoma cell lines.
We examined the signal transduction mechanism responsible for the IFN-gamma-induced HLA class II molecule expressions on glioblastoma cell lines, T98G and A172. A series of experiments demonstrated that the activation of protein kinase C (PKC) is involved in the DR and DP molecule expressions on T98G cells. In addition to the activation of PKC, calcium influx appeared to be involved in the DR and DP molecule expressions on T98G. Northern blot analyses with actinomycin D or cycloheximide revealed that these second messengers induce the transcription of DRA and B and DPA and B genes without de novo protein synthesis. Furthermore, we examined the region of the DPB gene that is responsible for IFN-gamma-induced gene transcription by gene transfer of a series of 5' and 3' deletion mutants in which the upstream region of the DPB was linked to a reporter gene, chloramphenicol acetyltransferase. By using these deletion mutants, it appeared that the region between -152 and -126 bp contains a critical IFN-gamma-responsive element. Taken together, these results suggest that IFN-gamma activates PKC and stimulates calcium influx, resulting in the induction of transcription of DRA and B and DPA and B genes without de novo protein synthesis. In DPB gene, we speculate that preexiting protein(s) phosphorylated by PKC in the presence of Ca2+ might directly bind or indirectly interact with the region between -152 and -126 bp of the upstream sequence, leading to the induction of the transcription (possibly in concert with other nuclear protein(s) bound to the promoter sequences).
Biological Transport↗
Antagonists of cyclic nucleotide phosphodiesterase (PDE) isozymes PDE 3 and PDE 4 suppress lymphoblastic response to HLA class II alloantigens: a potential novel approach to preventing allograft rejection?
As a potential novel approach to preventing renal allograft rejection, we investigated whether the proliferative response of lymphocytes to mismatched HLA class II antigens in mixed lymphocytic culture (MLC) can be suppressed by antagonists of cyclic nucleotide phosphodiesterase (PDE) isozymes. Cilostamide, an antagonist of isozyme PDE3 and, to an even greater extent, in combination with rolipram, an antagonist of isozyme PDE4, markedly suppressed (delta = -60%; p < 0.01) the mitogenic proliferative response of lymphocytes in MLC to HLA-DR alloantigens from unrelated donors. These observations suggest that the selective PDE isozyme antagonists might have potential as novel drugs in "signal transduction-targeted" pharmacotherapy of renal transplant rejection.
3',5'-Cyclic-AMP Phosphodiesterases↗
Comprehensive analysis of class I and class II HLA antigens and chronic hepatitis B virus infection.
Following an acute hepatitis B virus (HBV) infection, clearance or persistence is determined in part by the vigor and breadth of the host immune response. Since the human leukocyte antigen system (HLA) is an integral component of the immune response, we hypothesized that the highly polymorphic HLA genes are key determinants of viral clearance. HLA class I and II genes were molecularly typed in 194 Caucasian individuals with viral persistence and 342 matched controls who had cleared the virus. A single class I allele, A*0301 (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.30 to 0.72; P = 0.0005) was associated with viral clearance. The class II allele DRB1*1302 was also associated with clearance (OR, 0.42; 95% CI, 0.19 to 0.93; P = 0.03), but its significance decreased in a multivariate model that included other alleles associated with disease outcome as covariates. B*08 was associated with viral persistence both independently (OR, 1.59; 95% CI, 1.04 to 2.43; P = 0.03) and as part of the conserved Caucasian haplotype A*01-B*08-DRB1*03. The B*44-Cw*1601 (OR, 2.23; 95% CI, 1.13 to 4.42; P = 0.02) and B*44-Cw*0501 (OR, 1.99; 95% CI, 1.22 to 3.24; P = 0.006) haplotypes were also associated with viral persistence. Interestingly, both the B*08 haplotype and DR7, which forms a haplotype with B*44-Cw*1601, have been associated with nonresponse to the HBV vaccine. The associations with class I alleles are consistent with a previously implicated role for CD8-mediated cytolytic-T-cell response in determining the outcome of an acute HBV infection.
Adult↗
Conversion of a melanoma cell line from an HLA class II positive to negative phenotype after treatment with anti-mycoplasma drugs.
An HLA class II-positive melanoma cell line, DU-Mel 17, expressing both DR and DQ was shown to be contaminated with Mycoplasma hyorhinis. After treatment of the cell line with anti-mycoplasma drugs (a tetracycline derivative and a pleuromutilin), both DR and DQ expression on the cell surface, as well as DR alpha mRNA, were greatly decreased and the cells were rendered mycoplasma-free. Interestingly, drug-treated cells became resistant to geneticin, an unrelated drug. To test whether drug treatment or elimination of mycoplasma caused the abolition of class II expression, contaminated DU-Mel 17 cells were inoculated into peritoneal cavities of nude mice and later removed upon growth of a solid tumor. The cells were shown to be mycoplasma-free, and they expressed DR alpha mRNA, as well as DR and DQ proteins on their surfaces. Although it appears that the drugs were responsible for abating class II molecule expression in DU-Mel 17 cells, the identical drug-treatment regimen on a class II-positive, mycoplasma-free B cell line did not alter DR alpha mRNA or class II protein levels. Based on restriction fragment lengths, the DR alpha gene appeared to be grossly intact after drug treatment, and alterations in methylation patterns were not observed. These studies indicate that anti-mycoplasma treatment of DU-Mel 17 cells resulted in selection of a class II-negative, drug-resistant clone(s). Such treatment may result in a phenotype that is divergent from the parental cell line in one or more characteristics.
Anti-Bacterial Agents↗
[Expression of HLA-class II antigens in malignant melanoma].
Sixteen primary and ten metastatic melanoma lesions were stained in indirect immunoperoxidase with HLA-DR, DP and DQ monoclonal antibodies. In primary lesions, HLA-DR, DQ and DP antigens were much more expressed in nodular melanoma lesions than in acral lentiginous melanoma lesions. In metastatic lesions HLA-DR, DQ and DP antigens were expressed more than in primary lesions, but there were no significant differences between ALM and NM. In primary melanoma, 82%, 75%, and 75% of lesions tested were stained by anti HLA-DR, DP and DQ monoclonal antibodies, respectively. In metastatic melanoma, 90% of the lesions tested were stained by anti HLA-DR, DP and DQ monoclonal antibodies. HLA-class II antigens on melanoma cells were much more expressed in cases of high levels of invasion, high degrees of lymphocyte infiltration, and lower melanin content.
Adult↗
Major histocompatibility complex class II (HLA-DRB and -DQB) allele frequencies in Botswana: association with human immunodeficiency virus type 1 infection.
Southern Africa is facing an unprecedented public health crisis due to the high prevalence of human immunodeficiency virus type 1 (HIV-1). Vaccine development and testing efforts, mainly based on elicitation of HIV-specific T cells, are under way. To understand the role of human leukocyte antigen (HLA) class II alleles in HIV pathogenesis and to facilitate HLA-based HIV-1 vaccine design, we analyzed the frequencies of HLA class II alleles within the southern African country of Botswana. Common HLA class II alleles were identified within the Botswana population through the molecular genotyping of DRB and DQB1 loci. The DRB1 allele groups DRB1*01, DRB1*02/15, DRB1*03, DRB1*11, and DRB1*13 were encountered at frequencies above 20%. Within the DQB1 locus, DQB1*06 (47.7%) was the most common allele group, followed by DQB1*03 (39.2%) and DQB1*04 (25.8%). We found that DRB1*01 was more common in HIV-negative than in HIV-positive individuals and that those who expressed DRB1*08 had lower median viral loads. We demonstrate that the frequencies of certain HLA class II alleles in this Botswana population differ substantially from those in North American populations, including African-Americans. Common allele groups within Botswana cover large percentages of other African populations and could be targeted in regional vaccine designs.
AIDS Vaccines↗
Evidence of HLA class II association with antibody response against the malaria vaccine SPF66 in a naturally exposed population.
The antibody response against the malaria vaccine SPf66 and against circumsporozoite (CS) protein has been tested in immune adults from a malaria endemic area in Papua New Guinea. All individuals were genotyped for the HLA class II DQB1 and DRB1 loci, and the humoral response was analyzed with respect to the identified class II alleles. At each locus, only three alleles were frequent, namely DRB1*11, *15, and *16, and DQB1*0301, *0502, and *0601. Antibodies against SPf66 and CS protein were found in 84% and 79% of the individuals, respectively. A strong negative association was detected between the humoral response against SPf66 and DRB1*15 and DQB1*0601. A positive association of the response was observed with DRB1*11 and DQB1*0301. After analysis with a multiple regression model in which all alleles were included simultaneously, only DRB1*15 remained significantly associated with low antibody responses. This suggests that nonresponders may be expected after immunization with SPf66 in certain populations.
Adolescent↗
Direct detection of PCR products for HLA class II typing.
Direct detection of the PCR, or DD-PCR is proposed as an efficient method for performing PCR assays. Following the PCR reaction, ethidium homodimer dye is added to the reaction mixture and read by fluorescence. The dye step circumvents the necessity of running reactions on agarose gel electrophoresis, which is the current standard. This simple modification should find wide application for assays utilizing the PCR reaction. Here we show the ready detection of HLA class II polymorphism.
Base Sequence↗
The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity.
AIMS/HYPOTHESIS: The aim of this study was to explore the contribution of genetic factors to the emergence of beta-cell-specific humoral autoimmunity. SUBJECTS AND METHODS: We analysed the effect of HLA class II, insulin (INS; -23 HphI variant) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4 [+49 and CT60]) genes on the appearance of beta-cell-specific autoantibodies in a large population-based birth cohort recruited in Finland. Infants carrying increased risk HLA DQB1 genotypes were monitored for the appearance of autoantibodies (islet cell autoantibodies [ICA], insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA] and islet antigen 2 antibodies [IA-2A]). Those who developed beta-cell-specific autoantibodies were studied (n=574, mean follow-up time: 4.9 years; range 0.5-9.3). RESULTS: IAA emerged at a higher rate in children with the -23 HphI AA INS genotype than in those carrying AT or TT variants (hazard ratio 2.1, 95% CI 1.4-2.9, p<0.001). This effect of the INS locus was present in both HLA DQB1 risk groups. The appearance of IAA showed a strong association also with the HLA DRB1*0401 allele (hazard ratio 13.1, 95% CI 1.8-93.4, p<0.001). The development of IA-2A was also somewhat accelerated by the DRB1*0401 variant (p=0.03). Isolated ICA positivity was independent of the HLA and INS genotypes. None of the humoral immune markers showed association with the CTLA4 gene. CONCLUSIONS/INTERPRETATION: The INS and the DRB1 loci appear to contribute to the pathogenesis of type 1 diabetes by initiating/modifying insulin-specific autoimmunity. The emergence of IAA represents a crucial step in the development of beta cell autoimmunity in young children, in whom the appearance of GADA and IA-2A is linked to IAA.
Antibody Formation↗
Influence of genetic factors (HLA class II genes, insulin-gene region polymorphisms) and metabolic control on the development of diabetic nephropathy.
Both metabolic and genetic factors may contribute to the etiology of diabetic nephropathy. We selected 2 different groups of Type I diabetic patients in an attempt to evaluate both factors. HbA1c values and urinary albumin excretion were examined in 114 selected Type I diabetes patients with disease duration of more than 15 yr. We found signs of late renal complications in 28% of these patients. A clear difference in blood glucose control appeared between the 2 groups; the mean HbA1c value during the last 3 yr was 9.5% in the group with microalbuminuria or nephropathy, compared to 8.5% in the normoalbuminuric group (p < 0.0001). With the aim of studying genetic markers alone, we selected a group of 30 Type I diabetes patients with microalbuminuria and a control group of patients without microalbuminuria, but with very similar blood glucose control (e.g. similar mean 1 yr HbA1c values), age and disease duration. All individuals in both patient groups were genomically typed for HLA-DR, -DQ genes and insulin-gene region (INS) polymorphisms. We found no association between HLA class II alleles and microalbuminuria. Neither did we find any association with particular INS polymorphisms. This data indicates that neither genes in the HLA nor in the insulin region are of importance for development of diabetic microalbuminuria. However, all 11 patients with overt nephropathy carried a given INS polymorphism, suggesting an influence of this region for progression to overt nephropathy.
Adult↗
Expression of HLA-class II antigens and proliferative capacity in autologous mixed lymphocyte reactions of human T lymphocytes exposed in vitro to alpha-endorphin.
alpha-Endorphin (aEP) inhibited the expression of HLA-Class II antigens by PHA-primed T lymphocytes and reduced mitogen-induced T-cell proliferation up to 35%. This action was time related and not naloxone sensitive. When aEP was added to autologous and allogeneic lymphocyte cultures (both of non-T/T and T/T type), it inhibited lymphocyte blastogenesis up to 40%. These findings, indicating that aEP can influence some functions of immunocompetent cells, provide evidence for the functional interrelationship between the neuroendocrine and the immune systems.
Adult↗
The study of HLA class II and autoimmune diabetes.
Many autoimmune diseases have genetic associations with the Major Histocompatibility Complex (MHC) class II loci. Susceptibility to Type 1 diabetes mellitus (TIDM) is particularly associated with Human Leucocyte Antigen (HLA) DR3, 4 and associated DQ2, 8 alleles and this is well documented in genetic association studies. These molecules play an important role in presentation of peptide antigens after intracellular processing to CD4 T lymphocytes. During the last decade, a number of approaches have been used to elucidate the molecular basis for the association of particular alleles with susceptibility to or protection from TIDM. These studies have focused on investigating the structure of the antigen presenting molecules, together with their peptides. Through binding studies, peptide elution, molecular modelling and crystallization of the peptide MHC complex, it has been possible to define the peptide binding regions and examine the stability of binding of peptides from putative autoantigens. This knowledge has also facilitated the development of reagents such as multimeric MHC-peptide complexes that will help to track the low frequency, potentially pathogenic antigen specific cells. Recently, HLA transgenic mice have been generated and used to study T cell epitopes. In addition, although it is clear that the presence of HLA molecules alone does not by itself cause disease, these transgenic mice will develop diabetes when there is an islet "insult", even if the islet "insult" is, itself, not sufficient to precipitate disease in the absence of the HLA class II transgene. These mice will allow further study of the role of these HLA molecules in vivo. We now have a much greater general understanding of the possible reasons why particular molecules may encode susceptibility to or protection from disease. All these studies will provide information to ultimately define a rational basis for the development of targeted immunotherapy.
Animals↗
Combination of HLA-A and HLA class II alleles controls the susceptibility to rheumatoid arthritis.
Two hundred and four unrelated Japanese patients with rheumatoid arthritis (RA) were typed for HLA by serological typing and DNA typing. The serological typing revealed that frequencies of HLA-A11, DR4, DR53 and DQ4 were increased and those of DR8 and DQ1 were decreased in the patients. The DNA typing has precisely defined the disease-associated HLA class II alleles; DRBl*0405, DQAl*03 and DQBl*0401 showed positive associations, while negative associations were found with DRBl*0803, DQAl*0103 and DQBl*0601. The risk for RA was found to be closely associated with particular amino acid sequences of DR-beta chain, including glycine residue at the 86th position in addition to those between 70 and 74, which are known to confer binding specificity and affinity to antigenic peptides. The observation that the frequency of HLA-A11 was increased in the DRBl*0405-positive patients suggested the interaction of these two alleles in the susceptibility to RA. On the other hand, the frequency of DPB1*0201 was increased in the DRBl*0405-negative patients and the frequency of HLA-A2 was increased in the DPBl*0201-positive patients, especially in the younger onset group. These findings suggested that the combination of HLA-A2 and DPBl*0201 may confer the susceptibility in the DRBl*0405-negative patients. Our results suggested the possibility that the susceptibility to RA is controlled by the interaction of HLA-A and DRBl genes or by that of HLA-A and DPBl genes in different patient subgroups.
Adult↗