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PubMed1992

Effect of an anti-HLA class I monoclonal antibody on the antigenic and transcriptional expression of HLA class I genes in U937 cells.

The phenomenon of antigenic modulation was studied in the histiocytic lymphoma line U937. A redistribution of cell surface HLA antigen after incubation of U937 cells with the monomorphic anti-HLA class I monoclonal antibody W6/32 was demonstrated by immunofluorescence analysis. As assessed by hybridization of RNA obtained from W6/32-treated U937 cells with a probe corresponding to the alpha 3 domain of HLA Cw3, prolonged W6/32 incubation (24 to 72 hours) induced a decrease in HLA class I transcript abundance. This decrease was about 25% as compared with untreated control cells. These data indicate that W6/32 incubation can induce changes in HLA class I gene expression not only at the antigenic but also at the transcriptional level. Possible implications for the molecular basis of antigenic modulation are discussed.

Antibodies, Monoclonal↗
PubMed1994

Soluble HLA class II concentrations in normal individuals and transplant recipients. Comparison with soluble HLA class I concentrations.

We developed an ELISA to quantify soluble HLA class II (S-HLA-II) in 702 sera obtained from normal subjects, patients with end-stage renal disease, and recipients of renal, hepatic, and cardiac transplants. Concentrations of S-HLA-II were detectable in 124 of 126 normal individuals. The distribution of normal values described a monophasic curve with a skewed distribution. In transplant recipients, there were no differences between preoperative and posttransplant values, but values in liver patients were significantly higher than in kidney patients, and values for heart patients were lowest of all groups. There were periodic variations in concentrations in individual patients, but these were unrelated to rejection, infection, or any other apparent clinical event. S-HLA-II was consistently present in the urine. All of these observations contrast with previous observations concerning soluble HLA class I (S-HLA-I) molecules, which were almost the precise reverse. It seems likely that these clear differences in S-HLA-II and S-HLA-I concentrations relate to different physiologic processes in either production, function, or elimination.

Graft Rejection↗
PubMed1997

Inhibitor (IK) of IFN-gamma induced HLA class II antigens expression also inhibits HLA class II constitutive expression in the human Raji B cell line.

The expression of major histocompatibility complex (MHC) class II antigens is constitutive in professional antigen presenting cells (APCs) but can also be induced by interferon-gamma (IFN-gamma) on the majority of the non professional APCs (e.g. fibroblasts). We have recently characterised a new factor called IK which is an efficient inhibitor of IFN-gamma induction of MHC class II antigens expression. Here, we demonstrate a novel role for IK in MHC class II expression since over-expression of this protein by stable transfection into human B cells led to a total disappearance of constitutive MHC class II mRNA expression. The class II transactivator (CIITA) is necessary for both constitutive and IFN-gamma induced MHC class II expressions. Examination of CIITA mRNA in IK stably transfected clones revealed a marked reduction of CIITA mRNA transcription. Taken together these results demonstrate that the IK protein plays a key role in the constitutive expression of MHC class II antigens and that inhibition induced by IK is upstream of CIITA in this regulatory pathway.

B-Lymphocytes↗
PubMed1995

Alternative splicing of HLA class I transcripts induced by IFN-gamma and TNF in fibroblasts: release of soluble HLA class I heavy chain and an associate protein.

FS-4 fibroblasts were found to produce 37-kDa HLA class I heavy chain in response to IFN-gamma or TNF in a time- and dose-dependent fashion, and a synergism between IFN-gamma and TNF was observed. Immunoprecipitation of IFN-gamma- or TNF-induced FS-4 cell culture supernatants by mAb A1.4 revealed an additional 33-kDa protein in association with the 37-kDa heavy chain. The 33-kDa protein appeared to be expressed in a 38-kDa form on the membrane of FS-4 cells induced by IFN-gamma or TNF, as A1.4 immunoprecipitated the 38-kDa band in association with the 44-kDa transmembrane HLA class I heavy chain. Release of the 37-kDa heavy chain could well be due to an alternative RNA splicing with the deletion of exon 5 encoding the hydrophobic transmembrane region of membrane-anchored HLA class I heavy chain. Northern blot analysis and S1 nuclease protection assay suggested the existence of HLA class I heavy chain mRNA lacking exon 5 in IFN-gamma- or TNF-induced FS-4 cells. Southern blot analysis on the products of reverse transcription-polymerase chain reaction amplification from cytoplasmic RNA confirmed induction of alternative splicing by these cytokines. Our results suggest that cytokine-induced production of soluble HLA class I molecules may play important roles in the regulation of T cell interaction with antigen-presenting cells.

Alternative Splicing↗
PubMed1999

HLA class II genotype, HLA-DR B cell surface expression and allergen specific IgE production in atopic and non-atopic members of asthmatic family pedigrees.

HLA class II polymorphism is variably associated with sensitization to specific allergens, but few convincing HLA associations with asthma or the general state of atopy have been demonstrated. In this study we investigated HLA class II genotype associations with asthma, atopy and specific IgE (sIgE) production to six allergen extracts and six purified major allergens (Der p 1, Der p 2, Fel d 1, Can f 1, Alt a 1 and Phl p 5) in 176 individuals from 20 asthmatic family pedigrees. In selected individuals, cell surface HLA-DR peripheral B-cell expression was correlated with HLA-DRB1 genotype and atopic status. Results showed that HLA-DRB1*08 was negatively associated with asthma (2% vs 17%; Pc = 0.02; OR = 0.08) and atopy (0% vs 16%; Pc = 0.04; OR = 0.1), while DRB1*15 was positively associated with asthma (36% vs 13%; Pc = 0.02; OR = 3.6). Analysis of DRB1 sequences showed that only 29% of individuals with GAG TAC TCT ACG at codons 9-12 in one or both alleles were atopic, compared with 53% of individuals without this sequence (P = 0.002; OR = 0.36). DPA1*0201 was negatively associated with sIgE to both grass pollen mix and Phl p 5 (0% vs 23%; Pc = 0.02; OR = 0.14). A non-significant trend towards higher HLA-DR B-cell expression was seen in both non-atopic and DRB1*08 individuals. In conclusion, this single centre study has demonstrated a number of HLA class II genotype associations with asthma, atopy and sIgE to grass pollen mix and Phl p 5, including hitherto unreported DRB1*08, DRB1 codon 9-12 and DPA1*0201 associations. No significant associations between HLA-DR expression and DRB1 genotype or atopy were demonstrated, although a trend towards higher expression was seen in non-atopic individuals and individuals of DRB1*08 genotype.

Allergens↗
PubMed1995

HLA class II and HLA-B27 oligotyping in two Siberian native population groups.

It was the purpose of this study to better define the frequency of HLA-B27 subtypes and HLA class II alleles among indigenous populations from the eastern tip of the Chukotka Peninsula of Siberia, Russia, which have higher frequencies of HLA-B27 (40%) and spondyloarthropathies (2%) than Caucasian populations and test the hypothesis that these populations are more closely related to Orientals. Siberian Eskimos and Chukchi residing in four coastal villages on the Chukotka Peninsula inhabited by Siberian Eskimos and Chukchi people were examined using oligotyping of the polymerase-chain reaction-amplified second and third exons of the HLA-B27 gene. HLA-class II alleles (DRB1, DQA1 and DQB1) were similarly determined. Of 88 HLA-B27 positive individuals from these villages, all had HLA-B*2705, including the four patients with Reiter's syndrome and the five ankylosing spondylitis, except one Eskimo control who had HLA-B*2702. None had HLA-B*2704, a frequent subtype in Orientals. HLA-class II typing in 70 Siberian Eskimos and 71 Siberian coastal Chukchi revealed HLA-DRB1*0401, DRB1*0802, *0901 and *1402 to account for nearly all the DRB1 alleles found in this population, similar to what has been described in Eskimos in Alaska, but different from Chinese or native Americans in the U.S. The overwhelming majority of the individuals examined had HLA-DQB1*0301, similar to what has been observed in Native Americans. The Siberian Eskimos differed from the coastal Chukchi only in the occurrence of HLA-DRB1*0701, DQA1*0201, DQB1*0201 alleles, which occurred only in the former group. These data suggest that the Chukotka population is genetically more closely related to Caucasians and native Americans and less to other Oriental populations.

Base Sequence↗
PubMedDate not supplied

Serological and structural analysis of HLA class I molecules: beta 2-microglobulin interacts with the two external domains of the HLA class I heavy chain.

The serological reactivities of HLA class I molecules were studied in relation to structural modifications of these molecules, including shuffling of external exons and exchange of human beta 2-microglobulin for beta 2-microglobulin from different species. Two major clusters (I and II) of monomorphic and polymorphic antigenic determinants could be delineated. beta 2-Microglobulin participates in the formation of the two clusters, indicating that the light chain interacts tightly with the two external domains of the HLA class I heavy chain. However, external molecules can modify these interactions and alter the antigenic structure of the overall molecule. Thus, fixation on HLA class I molecules of the Fab fragment of a monoclonal antibody directed at antigenic determinants associated with cluster II resulted in enhanced fixation of a monoclonal antibody (B10.6) related to cluster I. The structural and functional implications of these results are discussed.

Antibodies, Monoclonal↗
PubMed1999

Genetics and specific immune response in allergy to birch pollen and food: evidence of a strong, positive association between atopy and the HLA class II allele HLA-DR7.

BACKGROUND: In some geographic areas birch pollen represents the most prominent cause for airborne allergic diseases. Up to 70% of patients allergic to birch pollen are hypersensitive to fruits, especially apples. Associations have been found, in some instances, with a sensitivity to aeroallergens and HLA class II genes. OBJECTIVES: We investigated whether susceptibility or resistance to birch pollen allergy with and without food allergy was associated with HLA class II genes. METHODS: Blood samples were obtained from 2 groups of unrelated European-born white adults: 42 atopic patients (31 of them with asthma) and 42 healthy control subjects with no personal or familial history of asthma or atopy. Their antibody responses to birch pollen, apples, grass, and weed pollens were evaluated by skin tests, RASTs, and immunoprints. Genomic DNA was extracted from PBLs. The exons of DQA1, DQB1, DRB1, and DPB1 genes were selectively amplified by using the PCR method. Genotyping was carried out by digestion of the amplified DNA products with allele-specific endonucleases (PCR-RFLP), which recognize allelic variations in the polymorphic exon. RESULTS: We found no significant differences in the frequency of DPB1 alleles between patients and control subjects. HLA class II DR4 and/or DR7 alleles were present in 42.6% of the patients and in only 2.4% of the healthy subjects. These results confirm a previous study of a group of polysensitized atopic patients, which showed that DR4 and DR7 alleles were rare in healthy control subjects and frequently observed in atopic subjects with or without concomitant asthma. CONCLUSION: We conclude that the allele HLA-DR7 is significantly involved in the presentation of apple and pollen allergens. However, we suggest that this susceptibility is more related to atopy than to specific responses to allergens.

Adult↗
PubMedDate not supplied

Ultrastructural immunocytochemical demonstration of HLA class I antigens in human pathological liver tissue.

Major histocompatibility complex products Class I (HLA Class I) antigens are not expressed on the surface of normal human hepatocytes but become so in pathological conditions. The purpose of this study was to specify the ultrastructural topography of HLA Class I antigens expression. Nine human liver specimens, known from light microscopic investigation to display membranous positivity for HLA Class I antigens, were processed for immunoelectronmicroscopy using monoclonal anti-HLA Class I in an indirect immunoperoxidase procedure. HLA Class I antigens were detected on the basolateral membrane of hepatocytes and bile duct cells; some cisternae of the endoplasmic reticulum were also positive. The membranes of normal bile canaliculi of hepatocytes and the apical border of bile duct cells were negative. In one case of presumably drug-induced cholestasis, abnormal cholestatic canaliculi displayed HLA Class I antigens. These results indicate that HLA Class I antigens are synthesized by the hepatocytes and bile duct cells and incorporated into the plasma membrane; the basolateral expression follows the pattern as in other polarized cells. The expression in cholestatic canaliculi suggests a disturbed polarity of the hepatocyte.

Bile Ducts↗
PubMed1996

Invariant chain association with MHC class I: preference for HLA class I/beta 2-microglobulin heterodimers, specificity, and influence of the MHC peptide-binding groove.

MHC class I molecules require the assembly of heavy chain with beta2-microglobulin (beta 2m) and peptide in order to present Ag on the cell surface. Endoplasmic reticulum resident proteins associate with class I molecules and aid assembly. Free class I heavy chains associate with calnexin, which may facilitate association with beta 2m. Invariant chain (Ii) also associates with MHC class I molecules, but its role in class I assembly is not clear. We report here that Ii strongly associates with HLA class I/beta 2m heterodimers, but weakly with free class I heavy chains in HLA-B7-transfected T2 cells. Ii/HLA class I complexes persist stably within the endoplasmic reticulum/cis-Golgi compartment in peptide-processing deficient cells, but are much less prominent in normally processing cells. Furthermore, Ii differentially associates with variant HLA-B7 molecules that have peptide-binding groove mutations, and the degree of association correlates with HLA-B7 variant cell surface expression. Ii also shows HLA class I molecule specificity, associating to a greater degree with HLA-B7 than HLA-A2. Together these observations suggest that Ii stabilizes particular HLA class I/beta 2m heterodimers until peptide is loaded, and that this association may enhance class I cell surface expression.

Antigens, CD↗
PubMed1988

Phenotypic and genetic analysis of HLA class I and HLA-DR antigen expression on human melanomas.

Class I and HLA-DR antigen expression were studied with histochemical techniques involving monomorphic monoclonal antibodies in 49 cases of human malignant melanomas, 20 primary and 29 metastatic. A large percentage (90%) of primary melanomas were positive for HLA class I, while those primary lesions showing lowest levels of class I antigen expression were at the upper end of the range of invasiveness and possessed a higher metastatic potential. Expression of HLA-DR molecules on primary melanomas was low (25% of all cases) and HLA-DR-positive melanomas were among the most aggressive. In metastatic melanomas, HLA class I expression was less common than in primary lesions. The lowest percentage of cases positive for HLA class I was found for cutaneous metastases. HLA-DR molecules were more frequently expressed by lymph node metastases than on primary melanomas. The comparison of the expression of HLA class I and HLA-DR molecules by primary melanomas and their autologous metastases revealed a high degree of heterogeneity. Class I genes were further studied by Southern blot assays. No differences were found in restriction fragments for class I genes among 4 melanomas and their autologous lymphocytes, 2 of which were positive and 2 negative for class I expression.

Blotting, Southern↗
PubMed1994

A HLA class I cis-regulatory element whose activity can be modulated by hormones.

To elucidate the basis of the down-regulation in major histocompatibility complex (MHC) class I gene expression and to identify possible DNA-binding regulatory elements that have the potential to interact with class I MHC genes, we have studied the transcriptional regulation of class I HLA genes in human breast carcinoma cells. A 9 base pair (bp) negative cis-regulatory element (NRE) has been identified using band-shift assays employing DNA sequences derived from the 5'-flanking region of HLA class I genes. This 9-bp element, GTCATGGCG, located within exon I of the HLA class I gene, can potently inhibit the expression of a heterologous thymidine kinase (TK) gene promoter and the HLA enhancer element. Furthermore, this regulatory element can exert its suppressive function in either the sense or anti-sense orientation. More interestingly, NRE can suppress dexamethasone-mediated gene activation in the context of the reported glucocorticoid-responsive element (GRE) in MCF-7 cells but has no influence on the estrogen-mediated transcriptional activation of MCF-7 cells in the context of the reported estrogen-responsive element (ERE). Furthermore, the presence of such a regulatory element within the HLA class I gene whose activity can be modulated by hormones correlates well with our observation that the level of HLA class I gene expression can be down-regulated by hormones in human breast carcinoma cells. Such interactions between negative regulatory elements and specific hormone trans-activators are novel and suggest a versatile form of transcriptional control.

Base Sequence↗
PubMed1993

Molecular mapping of the HLA class II region in HLA-DR3 associated idiopathic membranous nephropathy.

Susceptibility to IMN is associated, in European Caucasoids, with the extended HLA haplotype in A1, B8, and DR3. It is unclear from previous investigations of HLA class II genes whether the association with A1, B8, DR3 is due to an HLA-DR or -DQ locus, or both, or to another locus linked to HLA class II. To examine genetic polymorphism over a more extensive area of DNA than previously, we carried out long range mapping of the HLA class II region of A1, B8, DR3 patients and healthy controls to discover if new markers of disease could be identified at this level of organization. Large fragments of genomic DNA were cut using enzymes with infrequent restriction sites, and were separated by pulsed field gel electrophoresis (PFGE) and analyzed using a series of probes which cover the HLA class II region. In several different DR3 haplotypes examined, the overall content of DNA and organization of the class II region were similar. However, both patient and control B8, DR3 haplotypes contained an extra Pvul site in the DRB region, compared to the disease-neutral B18, DR3 haplotype. Further, the DP region of the patient B8, DR3 haplotypes contained an additional partial BssHII cutting site which was not identified in the control B8, DR3 haplotypes. This structural heterogeneity in the vicinity of DP could have implications for genetic susceptibility to IMN and for linkage disequilibrium.

Chromosomes, Human, Pair 6↗
PubMed1988

Isolation and nucleotide sequence of a cDNA clone encoding a novel HLA class I gene.

A cDNA clone, designated JTW15, has been isolated and found to encode a novel, divergent class I HLA gene transcript. The clone was identified by its ability to hybridize with a pan-HLA class I nucleotide probe while failing to bind probes specific for the 3' untranslated exons of the HLA-A, -B, and -C genes. JTW15, 1665 nucleotides in length, represents a full length copy of an approximately 1.7-kb mRNA detected in Northern blot analyses. Comparison of the derived amino acid sequence with those of other HLA class I proteins showed JTW15 to be the most divergent HLA class I gene identified so far, the level of sequence homology being lowest for the alpha 1 and alpha 2 domains. The JTW15 gene transcript was found in a broad variety of cell types and was inducible in cells treated with IFN-gamma. JTW15 is the first isolated full length cDNA clone defining a non-HLA-ABC class I gene.

Amino Acid Sequence↗
PubMed2003

Differential effects of US2, US6 and US11 human cytomegalovirus proteins on HLA class Ia and HLA-E expression: impact on target susceptibility to NK cell subsets.

We compared in an inducible expression system the individual effect of US2, US6 and US11 human cytomegalovirus (HCMV) proteins on HLA-E and HLA class Ia surface expression, assessing in parallel their influence on target susceptibility to NK cell clones. To this end, the RPMI 8866 B lymphoma cell line (HLA-A2, HLA-A3, HLA-B7, HLA-Cw7, HLA-E(R), HLA-E(G)) was stably cotransfected with the ecdysone receptor, together with the US sequences under the control of an ecdysone-inducible promoter. Biosynthesis of viral proteins was turned on by incubating transfectants with Ponasterone A. US6 down-regulated expression of all class I molecules, hampering target resistance to NK cell clones controlled by the CD94/NKG2A, KIR2DL2 and/or CD85j (ILT2 or LIR-1) inhibitory receptors. By contrast, US11 reduced the surface levels of class Ia molecules but preserved HLA-E; this rendered US11(+) cells sensitive to NK clones under the control of KIR2DL2 and/or CD85j, while their resistance to CD94/NKG2A(+)KIR2DL2(-) effector cells was maintained. US2 preserved as well HLA-E expression but selectively targeted class Ia molecules; in fact, HLA-A and HLA-C allotypes were down-modulated whereas HLA-B7 remained unaltered. US2(+) targets became sensitive to KIR2DL2(+) cells but remained resistant to CD94/NKG2A(+)CD85j(+) NK clones. The differential effects of US proteins on HLA class Ia and HLA-E likely reflect the evolutionary adaptation of HCMV to counteract NK-mediated surveillance.

Cytotoxicity, Immunologic↗
PubMed2007

Dual selection pressure by drugs and HLA class I-restricted immune responses on human immunodeficiency virus type 1 protease.

To determine the influence of human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells on the development of drug resistance mutations in the HIV-1 protease, we analyzed protease sequences from viruses from a human leukocyte antigen class I (HLA class I)-typed cohort of 94 HIV-1-positive individuals. In univariate statistical analyses (Fisher's exact test), minor and major drug resistance mutations as well as drug-associated polymorphisms showed associations with HLA class I alleles. All correlations with P values of 0.05 or less were considered to be relevant without corrections for multiple tests. A subset of these observed correlations was experimentally validated by enzyme-linked immunospot assays, allowing the definition of 10 new epitopes recognized by CD8+ T cells from patients with the appropriate HLA class I type. Several drug resistance-associated mutations in the protease acted as escape mutations; however, cells from many patients were still able to generate CD8+ T cells targeting the escape mutants. This result presumably indicates the usage of different T-cell receptors by CD8+ T cells targeting these epitopes in these patients. Our results support a fundamental role for HLA class I-restricted immune responses in shaping the sequence of the HIV-1 protease in vivo. This role may have important clinical implications both for the understanding of drug resistance pathways and for the design of therapeutic vaccines targeting drug-resistant HIV-1.

Alleles↗
PubMed2005

Total soluble HLA class I and soluble HLA-G in multiple myeloma and monoclonal gammopathy of undetermined significance.

Serum beta2-microglobulin, the light chain of the HLA class I molecular complex, remains one of the best survival prognostic factors in multiple myeloma, but other HLA class I molecules might be of interest in monoclonal gammopathies. In this study, we evaluate total soluble HLA class I (HLA-Is) and soluble HLA-G (HLA-Gs) in 103 patients with newly diagnosed multiple myeloma, 30 patients with monoclonal gammopathy of undetermined significance (MGUS), and 30 healthy subjects, studying their prognostic value in multiple myeloma. In multiple myeloma patients, HLA-Is and HLA-Gs median values were 0.8 microg/mL and 28 ng/mL, respectively. Median HLA-Is concentration was higher in stage II and III multiple myeloma patients than in stage I multiple myeloma, MGUS, and control patients. Median HLA-Gs was significantly lower in healthy controls than in MGUS and multiple myeloma patients. A high level of HLA-Is (> or =2.1 microg/mL) was predictive of short survival (P = 0.017). For each given level of beta2-microglobulin, the relative risk of death was higher for patients with HLA-Is > or = 2.1 microg/mL than in patients with a lower level (P = 0.047). HLA-Gs, a marker of monoclonal gammopathy, was of no prognostic value, but the addition of HLA-Is to beta2-microglobulin produced an efficient prognostic score (P < 0.0001). HLA-Is is a new marker of multiple myeloma tumor load and provides additional survival prognostic information to beta2-microglobulin.

Aged↗