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PubMed1995

[Usefulness of the DNA-HLA class II typing in corneal transplantation].

DNA-HLA (human leukocyte antigen) typing was performed for ocular tissues in order to determine the usefulness of the method in corneal transplantation. Each type of ocular tissue was dissected from eye bank eyes (n = 3). DNA was extracted, and HLA-DRB1, DQB1, and DPB1 genes were amplified using PCR (polymerase chain reaction) method. DNA can be extracted and amplified from each ocular tissue except for the crystalline lens, but DNA from iris and choroid can be amplified only after diluting the samples 10 to 100 times. HLA class II antigens were successfully determined in these ocular tissues by the RFLP (restriction fragment length polymorphism) method. The method was applied to the corneal tissues of donor and recipient used for the corneal transplantation (n = 7). HLA class II antigens can be determined in both the donor and recipient corneal samples, and the results of recipients' HLA typing were the same as those determined using the blood samples. These results indicate that the DNA-HLA typing can be used for ocular tissues. Since DNA-HLA typing is more accurate than the conventional serological typing, the method is promising for the study of HLA class II typing in corneal transplantation.

Aged↗
PubMed2000

CD4(+) T cells kill HLA-class-II-antigen-positive melanoma cells presenting peptide in vitro.

PURPOSE: Most melanoma cell lines express HLA class II antigens constitutively or can be induced to do so with interferon gamma (IFNgamma). We have previously demonstrated that peptide-specific CD4(+) T cells proliferate in response to HLA-class-II-antigen-mediated peptide presentation by melanoma cells in vitro and produce interleukin-10 (IL-10) and (IFNgamma). We asked whether the responding T cells kill the tumor cells and, if so, whether direct cell contact was required. METHODS: Two HLA class II(+) melanoma cell lines derived from metastases were co-cultured with a human CD4(+) T cell clone specific for influenza hemagglutinin peptide (HA). T cells, melanoma, and HA were co-cultured for 48 h. Melanoma cells with and without HA and/or T cells served as controls. After 36 h, the medium was removed for cytokine analysis by enzyme-linked immunosorbent assay (ELISA). Twelve hours later non-adherent cells were washed away and the adherent melanoma cells were trypsinized and counted. Dual-chamber culture plates were used to determine whether cell contact and/or exposure to cytokine were required for tumor cell death. RESULTS: Melanoma cell counts were over 80% lower in wells containing T cells than in wells with melanoma and peptide alone (P < 0.05). ELISA of supernatants revealed production of IFNgamma and IL-10 by the responding T cells. Direct T cell contact with tumor cells was not required for tumor cell death, as melanoma cells were killed when they shared medium but had no contact with T cells responding to peptide presentation by HLA-class-II-antigen-positive melanoma cells in a separate chamber. Blocking antibody to IFNgamma but not IL-10 prevented melanoma cell death at levels of cytokine similar to that present in co-culture assays. CONCLUSIONS: Peptide-specific CD4(+) T cells kill melanoma cells in vitro when they recognize peptide presented by the tumor cell in the context of HLA class II antigen. Direct cell contact is not required, suggesting that it is a cytokine-mediated event. Immunotherapy, using primed CD4(+) T cells and peptide, may be beneficial in patients whose tumors express HLA class II antigens or can be induced to do so with IFNgamma.

Amino Acid Sequence↗
PubMed1993

[Expression of HLA class II antigen-associated invariant chain on renal cell cancer].

Major histocompatibility complex (MHC) antigens play important roles in immune responses. MHC class II molecules serve as restriction elements for cells presenting antigens to CD4-positive helper T-cells. They also function as histocompatibility antigens responsible for graft rejections by stimulating allogenic reaction. Furthermore, it was reported that the expression of class II antigen on tumor cells increases immunogenicity in mice by a mechanism involving class II molecule positive tumor cells which present tumor associated antigens to host immune cells or induce allogenic reactions against tumor cells. Class II molecules associate with the HLA class II antigen-associated invariant chain (Ii) as soon as class II molecules are produced in the rough endoplasmic reticulum. Ii is considered to block the binding of endogenous peptides to class II molecules, and to be a signal for transporting class II molecules to endosomes. Both functions of Ii are essential for the function of class II molecules. To investigate the association between renal cell cancer (RCC) and the host's immune system, we immunohistochemically examined 60 RCCs for the expression of Ii, class II and class I antigens on RCC and the degree of lymphocytic infiltration. We detected Ii to varying degrees on 53 out of 60 RCC tissues but none on normal renal tubular cells. Compared with class II antigens, they were detected in the order DR > or = Ii > or = DP not equal to DQ. A significant correlation was found between the expression of Ii and the degree of lymphocytic infiltration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

T cells from patients with chronic liver diseases: abnormalities in PHA-induced expression of HLA class II antigens and in autologous mixed-lymphocyte reactions.

The expression of HLA Class II antigens by resting and phytohemagglutinin (PHA)-activated T cells and their functional properties in autologous mixed-lymphocyte reactions (MLR) were investigated in patients with chronic active hepatitis, with alcoholic cirrhosis, and with primary biliary cirrhosis. In all groups of patients the percentage of resting T cells expressing HLA Class II antigens was significantly higher than that in controls. The percentage of T cells which acquired HLA Class II antigens following PHA stimulation was reduced in patients with chronic active hepatitis, serum hepatitis B surface antigen (HBsAg) positive, and in those with alcoholic cirrhosis, HBsAg negative, although the level of [3H] thymidine incorporation was within normal limits. The degree of proliferation in autologous MLR with PHA-T cells was significantly reduced in patients with chronic active hepatitis, HBsAb positive, and in those with alcoholic cirrhosis, HBsAg positive. A reduced proliferation was also detected in autologous MLR with non-T cells, in patients with chronic active hepatitis, HBsAg positive. The abnormalities of autologous MLR are selective, since the proliferative and stimulatory activities of cells from patients with chronic liver diseases in allogeneic MLR were within normal ranges. The immunoregulatory role of HLA Class II antigens and of autologous MLR suggests that the abnormalities we have identified may play a role in the immunological dysfunctions underlying chronic liver diseases.

Adult↗
PubMed1990

Multiple sclerosis and HLA class II susceptibility and resistance genes.

Probes to the HLA class II genes DR beta, DQ beta, and DQ alpha were used to study DNA from unrelated Caucasian multiple sclerosis (MS) patients by sequential restriction fragment length polymorphism (RFLP) analysis in Taq 1 restriction enzyme digests. Comparison of 104 patients and 108 controls, who were not matched for DR type, has identified for the first time a linked series of allele-specific RFLPs or allogenotypes which form an extended haplotype that is preferentially associated with MS. These allogenotypes include DRw15 or DR2(15); DQ beta lb, which corresponds at the DNA level to the DQwl(DQw6) serotype; a DQA1 allogenotype termed DQ alpha lb; and a 2.2 kb DX (DQA2) allogenotype termed DX alpha U (DQA2U). The role of HLA class II genes in susceptibility to MS was found to be complex. First, 23 of 104 MS patients showed DR-DQ linkages which were not observed in our control population. We suggest these anomalous associations may be important in the pathogenesis of MS. Second, homozygosity of a 2.0 kb DX (DQA2) gene, termed DX alpha L (DQA2L), showed a strong negative association with MS. DX alpha L (DQA2L) is in strong linkage disequilibrium with DR1, 5(w11) 7, and a subset of DR4, all of which also showed a negative association with MS. Since DX alpha L (DQA2L) does not code for any known product, DR1, 5(11), 4, and 7 become candidates for disease resistance genes.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic Linkage↗
PubMedDate not supplied

Monocytes of distinct clinical types of leprosy are differentially activated by cross-linking class II HLA molecules to secrete IL-12.

Leprosy is characterized by a wide spectrum of clinical features depending on the individual differences in Th1-type immunity. The objective of this study was to evaluate whether monocyte activation by stimulus via class II HLA molecules would be correlated with the differences in cellular immune responses among diverse clinical forms of leprosy. IL-1beta and IL-12 productivity in monocyte preparations obtained from PBMCs was estimated in patients with lepromatous- and tuberculoid-type leprosy. We found that monocytes from lepromatous patients produced significantly higher (about 4-fold higher) amounts of IL-12 as compared to in patients with tuberculoid type of leprosy when class II HLA molecules were cross-linked with anti-HLA class II antibodies, whereas almost equal amounts of IL-1beta were produced from each monocyte preparation by stimulus via class II HLA molecules regardless of the clinical form of leprosy. These results suggest that monocyte activation differs between lepromatous and tuberculoid patients in terms of IL-12 secretion, which might be related to individual differences in the cellular immune responses according to the clinical type of leprosy.

Cytokines↗
PubMed1990

Study of monomorphic determinants on DR molecules of HLA class II antigens.

The properties of monomorphic antigenic determinants on DR molecules of HLA class II antigens were analyzed with a panel of mouse monoclonal antibodies (mabs). Competition assays and immunoblottings showed that these mabs recognize three distinct antigenic sites. The cluster of antigenic determinants specified by mabs Bra30, Bra38, HL-39, MEM-12 and L243 belongs to the first antigenic site. The second antigenic site was demonstrated only with mab Bra20. The first two antigenic sites were detected only on DR molecules and they both depended on conformation and/or association of heavy and light chains of HLA class II molecules. Finally, the third cluster of antigenic determinants recognized by mabs Bra13, Bra22, Bra70, HL-38, and HL-40 is localized on light chains of both, DR and DP, molecules of HLA class II antigens. On the contrary to the mabs against the first two antigenic sites, reactivity of mabs with the third antigenic site was not affected by denaturation of HLA class II molecule.

Antibodies, Monoclonal↗
PubMed1988

A novel HLA class II molecule.

Molecular evidence has been obtained for a novel monomorphic HLA class II molecule distinct from HLA-DP/DQ/DR using a panel of lymphoblastoid cells which include HLA-loss mutants. The expression of this molecule was investigated using monomorphic affinity-purified mouse monoclonal antibodies (mAbs), including one of the IgG2a subclass designated EDU-1. This antibody reacts strongly in a cell-binding radioimmunoassay with HLA-DR and -DQ loss mutants derived from a lymphoblastoid parental cell. The EDU-1 mAb also reacted with a local panel of homozygous Epstein-Barr virus-transformed cell lines. The reactive molecules were further detected on allostimulated T-cell clones and various leukemic cells including those of myeloid origin which lack surface expression of HLA-DQ molecules. Thus the class II molecule described in this study corresponds to a monomorphic HLA class II determinant expressed on a variety of cells of different origin and HLA phenotypes. Moreover, this antigen structure is distinct from that of HLA-DP/DQ/DR as shown by direct immunoprecipitation, serial immunodepletion experiments, and two-dimensional gel electrophoresis. The molecule could be specified by new class II genes between DP and DQ. An alternative explanation for the genetic basis of the novel molecule is the existence of isotypic associations between alpha and beta chains of various class II molecules (DP, DX, DZ, and DO) but not DR and DQ as the mutant cells tested lack the latter genes.

Antibodies, Monoclonal↗
PubMed1990

Class II HLA antigen expression in familial polyposis coli is related to the degree of dysplasia.

Class II HLA antigen expression was studied in 30 polyps from 3 patients who were diagnosed with familial polyposis coli. The highest levels of this expression were associated with the most severe grades of dysplasia (p less than 0.00001), the sequence of positivity being HLA-DR greater than DQ greater than DP. No association was observed between the expression of these antigens and the presence of a specific inflammatory leukocytic infiltrate. Our results imply that HLA class II molecule expression is somehow related to malignant transformation in familial polyposis coli in accordance with the adenoma-dysplastic adenoma-adenocarcinoma sequence. Thus these antigens may be useful markers to tumoral progression.

Adenocarcinoma↗
PubMed1987

Constitutive functional heterogeneity without detectable somatic mutation of antigen receptor genes in helper T cell clones: possible regulation by novel HLA class II "DY" determinants.

The majority of interleukin 2-dependent HLA class II alloreactive human CD4-positive helper T-cell clones (TCC) presented the phenomenon of constitutive intraclonal heterogeneity, as reflected by limiting dilution analysis of changing frequencies of autonomously proliferative cells within the monoclonal population. Moreover, at 30-35 population doublings, these TCC lost their allospecific proliferative and helper capacity (phase I) and instead acquired strong antigen-non-specific suppressive activity (phase II). The TCR was still expressed at the same level on the cell surface. As shown by stable and identical rearrangement profiles of their T-cell receptor beta- and gamma-chain genes in both phases I and II, this constitutive change of function was probably not due to somatic mutation of the genes coding for the antigen-specific receptor. Moreover, antigen specific reactivity was retained in phase II TCC by the criterion of specifically stimulated secretion of granulocyte/macrophage colony stimulating factor. The preprogrammed intra-clonal functional flexibility is explained here by invoking a novel regulatory mechanism mediated by a fourth group of HLA class II determinants. When TCC were used as stimulators with the appropriate primed responders, it could be demonstrated that phase I autonomously proliferative non-suppressive T-helper lines failed to express certain novel lymphocyte activating determinants (LADs), whereas after their acquisition of suppressive function (phase II) these LADs were present. These stimulatory moieties appeared to represent a novel class II-like structure as established by serology, immunochemistry and functional characterization employing monoclonal antibodies to block stimulation. These operationally designated "DY" determinants are primarily and thus far exclusively involved in the induction of antigen non-specific suppressor cells. It is proposed that the intra-clonal changes of T-cell function described here are mediated by a switch in the utilization of qualitatively distinct class II-like restriction elements. The functional status of the phase I TCC can be altered by a switching over to the engagement of "DY" determinants in phase II. Thus, an autostimulatory and self-maintaining suppressive network may operate in extended inductive phases of human HLA restricted T-cell responses.

Cell Membrane↗
PubMedDate not supplied

[Association of class II HLA antigens and insulin-dependent diabetes mellitus in the population of Vojvodina].

INTRODUCTION: Class II HLA antigens were investigated in a group of 28 patients with insulin-dependent diabetes mellitus (IDDM) and 218 healthy unrelated persons (control group) from Vojvodina. MATERIAL AND METHODS: We used a modified two-colour immunofluorescence method (serologic technique) to determine the phenotype of DR and DQ locus HlA antigens. Phenotype frequencies of class II HLA antigens were determined in both investigated groups and were used for calculating relative risk (RR). If RR was higher than 1, we calculated the population attributable risk (EF), and if RR was lower than 1, we calculated the preventive fraction (PF). Investigation of statistically significant differences in frequencies of class II HLA antigens in patients and control group was performed by using chi 2 test. RESULTS: Results of investigation showed that values of RR were higher than 1 for HLA DR4 (2,808), DR10 (1,116) and DQ3 (1,386), while we noticed a statistically significant difference in frequencies of HLA DR4 (chi 2 test: 4,805) in patients regarding control group. HLA DQ1 antigen has a preventive role in development of IDDM due to highest value of PF (0,314). CONCLUSION: Results of our investigation confirm that there is an association of HLA DR4 with IDDM in population of Vojvodina. High values of relative risk of IDDM, noticed in persons with HLA-DR4 antigen, point to the degree of risk of IDDM, which is a disease with great socioeconomic importance in Vojvodina.

Adolescent↗
PubMed1987

HLA class II DNA analysis by RFLP reveals novel class II polymorphism.

Polymorphism of the HLA-D/DR region has been defined by serologic and cellular methods. Additionally, protein and DNA analyses not only confirmed and refined the definition of the established polymorphisms but also revealed further polymorphisms for which no serologic or cellular correlate are known (yet). To study these in more detail, we analyzed the banding patterns obtained from Southern blot hybridizations with DR beta and DQ alpha cDNA probes. Specific fragments reflecting already defined polymorphisms could be identified. A refined HLA-D/DR definition based upon the presence of DNA subtypes could be introduced. Fragments have also been identified that are associated with the DR/Dw specificities. Moreover, individuals with different DR types may also share fragments in hybridization assays. These shared hybridizing fragments (SHFs) are, for instance, found in individuals typed as DR4, DR5, DR7, and DRw8. In total, 20 SHFs were found using two restriction enzymes and the DR beta and DQ alpha cDNA probes. Some of these SHFs correlate with antigenic determinants defined by broad reacting alloantisera, such as DRw52, but for 14 of these SHFs, no serologic equivalent has been found so far. Thus, SHFs reflect a conservation at the DNA level of the HLA class II region, which suggests that the polymorphic class II genes may be more conserved than previously thought. The possible biologic implications of conserved sequences in the HLA class II genes will be discussed.

Cell Line↗
PubMed1985

Evidence for a new HLA class II determinant present on cells from HLA-DR1 and/or -DR4 individuals.

Evidence for a new HLA class II specificity is presented. It is recognized by LE serum, which reacts with most DR1 and/or DR4 individuals (r = 0.86). Its frequency in the French population is 0.33. Absorption-elution experiments showed that the serum reactivity was not due to a mixture of anti-DR1 and anti-DR4 antibodies, but to a single antibody population which could be absorbed on and eluted from both DR1(+) or DR4(+) cells. LE specificity seemed to be expressed on DR but not on DQ molecules since the serum reacted with and could be absorbed by DR+,DQw- cells; it did not react with a DR-,DQw+ mutant cell, but did react with the DR+,DQw+ parental cell. The relationship between LE specificity and MC1 and Te23 specificities remains to be determined.

Adult↗
PubMed1987

Regulation of HLA class II expression and its role in autoimmune disease.

Excessive HLA class II expression is found on the target tissues of the majority of human autoimmune diseases, together with activated (interleukin 2 receptor-expressing) T lymphocytes, suggesting that the target tissues act as antigen-presenting cells for infiltrating autoreactive cells, which in turn produce molecules that maintain class II expression. This vicious cycle has been shown to operate in Graves' thyroiditis, because interferon-gamma (IFN-gamma) induces class II expression on thyrocytes, and thyrocytes expressing class II antigens present their autoantigens to T cells cloned from thyroid tissue of Graves' disease patients. These results led us to consider whether the same mechanisms operate in other autoimmune diseases. In investigations into class II induction in other cell types we found that IFN-gamma is not the only regulator of HLA class II expression and that synergy exists among mediators regulating class II differentially on different cell types. This concept makes it possible to envisage selective diminution of class II antigens on target tissues without loss of class II on antigen-presenting cells. The study of mediators regulating class II expression on cells in vitro led us to ask whether the appropriate regulator molecules are important in disease states. To investigate this question we have developed the use of cDNA probes to analyse the expression of lymphokines, other cytokines, and receptors in small local biopsy samples of tissue from patients with autoimmune diseases. Results obtained so far indicate that mRNAs for many lymphokines are present in synovial fluid cell samples from patients with rheumatoid arthritis.

Autoimmune Diseases↗
PubMed1994

Epstein-Barr virus (EBV) latent membrane protein 1 increases HLA class II expression in an EBV-negative B cell line.

Transformation of normal resting B cells by the Epstein-Barr virus (EBV) leads to the establishment of permanent lymphoblastoid cell lines (LCL) which express high levels of HLA antigens and which are highly efficient in antigen presentation. Certain features of the LCL phenotype can be reproduced by transfecting EBV-negative B lymphoma (BL) cell lines with individual EBV latent genes under heterologous promoters. In this work we have analyzed a series of subclones derived from the EBV-negative cell line Louckes, stably transfected with constructs encoding EBV latent genes for their expression of HLA class II molecules. Louckes parental cells and control transfectants expressed detectable levels of HLA-DR, DQ and DP antigens on the cellular surface by cytofluorometry, but these levels were significantly increased in transfectants expressing the virus-coded latent membrane protein 1 (LMP-1). Northern blotting for the individual alpha and beta chain mRNA at each of the three HLA class II loci indicated correspondingly increased levels of HLA class II transcripts in the LMP-1 transfectants. Transfectants expressing the virus-coded nuclear antigens EBNA-1, EBNA-2 or EBNA-LP showed no significant changes in these parameters. These observations indicate that up-regulation of HLA-class II molecules can be a part of the changes induced by LMP-1 in B cells.

Antigens, Viral↗
PubMed2003

Mutational analysis of the HLA class II interaction with Epstein-Barr virus glycoprotein 42.

Entry of Epstein-Barr virus (EBV) into B lymphocytes requires the binding of viral glycoprotein 42 (gp42), a C-type lectin family member, to HLA class II. Recently, the structure of the gp42:HLA-DR1 complex was determined. In order to confirm the interaction as determined in the structural study and to identify other potential interactive residues, a mutational analysis of HLA class II was performed. A secreted form of gp42 (sgp42) reacted with a conformation-specific monoclonal antibody and blocked EBV infection. The binding of sgp42 and EBV entry to two sets of HLA class II mutants were tested. The first set of mutants were based on the known interaction of the C-type lectin Ly49A with HLA class I, and the second set of mutants were based on the identified interface in the gp42:HLA-DR1 complex. As expected, none of the mutants that would be predicted to interfere with the interaction of Ly49A with class I affected the interaction of gp42 with HLA class II, whereas mutants in amino acids identified in the gp42:HLA-DR1 structure inhibited sg42 binding to class II. In general, sgp42 binding correlated with efficient entry of EBV, as demonstrated by the necessity of glutamic acid 46 or arginine 72 in class II molecules. Furthermore, other HLA class II residues buried within the interface of gp42 and HLA class II when mutated had either no effect or a decrease in both binding and entry and implicate a region of class II important in stabilizing the interaction with gp42. These studies provide insight into the entry and fusion processes of the critical interaction between gp42 and HLA class II.

Amino Acid Sequence↗
PubMed1995

Evidence of linkage between susceptibility to multiple sclerosis and HLA-class II loci in Italian multiplex families.

To verify whether multiallelic polymorphisms belonging to HLA class II genes are linked to multiple sclerosis (MS) in the Italian population, we studied 28 multiplex MS families originating from different areas of Italy. Allelic characterization was carried out by analysis of RFLPs and oligonucleotide typing. Evidence supporting the existence of linkage between MS susceptibility and the HLA class II loci DRB1, DQA1 and DQB1 was provided using two non-parametric tests, affected sib-pair analysis, and affected-pedigree-member (APM) analysis. The APM analysis also suggested the existence of genetic heterogeneity for the HLA class II loci and MS susceptibility in our series. Linkage disequilibrium between MS susceptibility and the haplotype DRB1*1501,DQA1*0102,DQB1*0602 was demonstrated by applying the transmission linkage disequilibrium test to our families. Finally, lod score analysis suggests that in our Italian families, MS susceptibility is conferred by HLA class II alleles according to a low-penetrance autosomal recessive mode of inheritance.

Alleles↗
PubMed1998

HLA class II allele and haplotype frequencies in Ethiopian Amhara and Oromo populations.

HLA class II alleles were identified in 181 healthy unrelated Ethiopian children of both sexes and in 350 European controls from the South of France. The Ethiopian individuals belonged to the two major ethnic groups of the country: Oromo (N=83) and Amhara (N=98). In both panels, genetic polymorphism of HLA class II alleles was analysed for the first time by molecular typing of DRB1, DQA1 and DQB1 loci. Allelic and phenotypic frequencies were compared with those of European controls and other African populations. Construction of HLA class II three-locus haplotypes was also performed. The study revealed some differences between the two groups. Characteristic features of Central and North African populations appeared on the Ethiopian HLA genotypes. Surprisingly, DRB1*11 presented one of the lowest gene frequencies in both Ethiopian ethnic groups in contrast to Europeans and West Africans. Furthermore, this decrease was more marked than those observed using serological techniques in other geographically close East African countries. Oromo and Amhara only showed minor differences in spite of their different origins and histories. One significant difference consisted of a lower DRB1*01 gene frequency in Oromo as reported in most West African people. Some new or rare haplotypes were also observed in the Oromo group. Our results underline the distinctive features of the Ethiopian populations among the few HLA genotyping data available for East African groups and emphasise the major interest of such investigations in this region of Africa.

Alleles↗