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PubMed1988

Molecular studies of a rare DR2/LD-5a/DQw3 HLA class II haplotype. Multiple genetic mechanisms in the generation of polymorphic HLA class II genes.

A cDNA library was constructed from a homozygous B lymphoblastoid cell line (REM) obtained from an individual of a long isolated American Indian tribe, the Warao. The REM cell line expresses serologically defined determinants, DR2 and DQw3, and the T lymphocyte-defined (Dw/LD) specificity, LD-5a. T cells can recognize differences between FJO (a DR2/DQw1 cell line that expresses the Dw specificity MN2) and REM for both DR and DQ molecules. cNDA clones encoding the polymorphic DR beta 1-, DR beta 2-, DQ beta-, and DQ alpha-chains were sequenced and compared with other DR and DQ gene sequences. The DR beta 1-sequence of REM is identical to the DR beta 1-sequence of FJO; the DR beta 2-sequence is also identical to that of FJO except for one amino acid difference at position 67 in the polymorphic first domain (Leu in REM, Phe in FJO) due to a single point mutation. The DQ beta-sequence is identical to that of DR4/DQw3 haplotype; the DQ alpha is different from the DQ alpha of DR4/DQw3 haplotype and identical to the DQ alpha of both the DR3/DQw2 haplotype of a Raji cell line and the DR5/DQw3 haplotype in deduced amino acid sequence. Taken together, these findings suggest that: 1) a single amino acid difference (position 67) in the third hypervariable region of the first domain of the DR beta 2-chain in the DR2 haplotype is apparently sufficient for stimulating T cell responses; 2) the DQw3 serologic specificity may be defined mainly by the DQ beta-rather than DQ alpha-chain; and 3) multiple genetic events have probably occurred to generate the rarely found REM (DR2/LD-5a/DQw3) haplotype.

Amino Acid Sequence↗
PubMed1990

Cytokine-mediated modulation of HLA-class II, ICAM-1, LFA-3 and tumor-associated antigen profile of melanoma cells. Comparison with anti-proliferative activity by rIL1-beta, rTNF-alpha, rIFN-gamma, rIL4 and their combinations.

Nine different human melanomas and 16 clones, isolated from 2 of them, were characterized for susceptibility to rIL1-beta-, rIL4-, rTNF-alpha- and rIFN-gamma-mediated effects on proliferation and surface expression of class-II HLA (DR and DP), ICAM-1 and LFA-3 molecules and of 3 tumor-associated antigens (recognized by MAb 763.74T, 149.53 and R24). In spite of marked inter- and intra-tumor heterogeneity for susceptibility to the effects of each cytokine, the most frequent upregulation was induced on the HLA class-II antigens by rIFN-gamma and on adhesion molecules by rIFN-gamma, rTNF-alpha and rIL1-beta, while tumor-associated antigens were often down-modulated by rIFN-gamma. Tumor heterogeneity was also evident on tumor-cell proliferation with an apparent hierarchy in the frequency and extent of inhibitory effects: rIFN-gamma greater than rTNF-alpha greater than rIL1-beta = rIL4. Combinations of 2 cytokines resulted in rare and limited changes in the antigenic profile in comparison to the effects seen with single factors, while the combination of rTNF-alpha and rIFN-gamma resulted in significant synergistic antiproliferative effects on most tumor cells and clones. Taken together, these results indicate that single cytokines can profoundly affect the antigenic profile of melanoma cells, while strong tumor-growth inhibition is often achieved by combinations of 2 cytokines acting in synergism.

Antigens, Neoplasm↗
PubMed1989

[Recent aspects of the pathogenesis of endocrine autoimmune diseases in the human: what role does expression of class II HLA molecules in the endocrine target cell play?].

The inappropriate expression of HLA Class II molecules by the target cells of endocrine autoimmune diseases is a recent observation that has been intensively studied in thyroid autoimmunity and type I diabetes mellitus. In vitro studies have shown that interferon-gamma can induce Class II expression, either alone, as in thyrocytes, or in combination with other mediators like tumour necrosis factor or lymphotoxin, as in islet cells, pointing to possible mechanisms operating in vivo. Endocrine cells expressing Class II molecules are able to present their autoantigens to helper T cells, thus possibly inducing the autoimmune process. However, until now it is still unclear if the expression of Class II molecules by the target cells is the primary immune phenomenon, which might possibly be triggered by a latent viral infection of the endocrine cell. Alternatively, it might be a secondary response in an ongoing autoimmune process. Particularly data obtained in the diabetic pancreas favour the first possibility, but only progress in our understanding of the role of HLA antigens in immunoregulation will make it possible to interpret the phenomenon properly.

Autoimmune Diseases↗
PubMed1993

Rapid DNA typing of class II HLA antigens using the polymerase chain reaction and reverse dot blot hybridization.

A nonisotopic oligotyping method using reverse dot blot hybridization was developed for HLA class II DQA1, DQB1, DPB1, DRB1, DRB3, DRB4, DRB5 alleles. The polymorphic second exon of the different genes was amplified by the polymerase chain reaction (PCR). For each gene the amplified DNA was hybridized at stringent conditions to membrane-bound sequence-specific oligonucleotides (SSOs) and visualization of positive signals was done by chemiluminescence. A combination of 11, 18, 23 and 31 SSOs was designed to identify 9/13 DQA1, 16/17 DQB1, 23/24 DPB1 and 50/55 DRB1, 4 DRB3, 1 DRB4, 3/4 DRB5 alleles respectively. For the DRB1 locus, an additional DRB1*04 group-specific PCR was developed to make discrimination between the DR4 alleles possible in different heterozygous combinations. The procedure described here provides rapid and nonisotopic genotyping of heterozygous samples from a variety of sources and can be applied for tissue typing, disease susceptibility studies and forensic medicine.

Alleles↗
PubMed1987

Precise specificity of induced tubular HLA-class II antigens in renal allografts.

HLA-class II antigen expression is induced in the tubules of renal allografts, but it is unclear whether all three class II products--HLA-DR, DQ, and DP--are induced, and whether the induced product is of donor origin. A pretransplant (n = 14) and serial transplant biopsies (n = 45) were obtained from 14 transplant recipients in whom induced HLA-class II antigen was detected after transplantation with a monoclonal antibody reactive with HLA-DR, DP, and possibly DQ antigens. Cryostat sections were stained with locus-specific or polymorphic monoclonal antibodies in an indirect immunoperoxidase assay. In pretransplant biopsies intracellular HLA-DR antigen was expressed on proximal tubules, whereas all tubules were negative for HLA-DQ and DP products. After transplantation grafts with induced tubular HLA-class II antigen had induced HLA-DR, DQ and DP antigens expressed both within the cytoplasm and on the cell membranes. The donor or recipient origin of induced HLA-class II expression was determined using polymorphic antibodies specific for either donor or recipient antigens. This approach demonstrated that the induced class II antigen is of donor origin--and, furthermore, that the renal parenchyma remains of donor HLA-type, even one year after transplantation, and thus remains a source of antigenic stimulus to the recipient.

Antibodies, Monoclonal↗
PubMed1983

Involvement of class II HLA molecules in T cell activation by antigen. Implications for the autologous mixed lymphocyte reaction.

Our recent studies on the involvement of HLA Class II molecules in T cell activation by antigen are briefly reviewed. Both DR and MT Class II molecules were found to be able to function as restriction elements. The allotypic parts of DR molecules appeared to be most important in this respect, and were also found to influence the spectrum of antigen-specific responses. Both blood derived monocytes and Langherhans' dendritic cells were able to function as antigen-presenting cells, and expressed the same restriction elements. The relevance of these findings for the autologous mixed lymphocyte reaction (AMLR) is briefly discussed.

Antigen-Presenting Cells↗
PubMed1986

Cell mediated PPD specific cytotoxicity against human monocyte targets: III. Cellular typing with CTLs restricted by class II HLA antigens.

The HLA-restriction specificity of a set of Cytotoxic T-Lymphocytes (CTLs) derived from 20 different individuals and with specificity for antigenic components in Purified Protein Derivative of tuberculin (PPD) were examined against a panel of 50 unrelated target cell donors. PPD pulsed monocytes were used as antigen presenting target cells. CTLs were generated by Interleukin-2 (IL-2) expansion of in vitro PPD activated Peripheral Blood Mononuclear Cells (PBM). The results confirm our previous finding that PPD-specific CTLs are restricted by HLA-class II - and not by class I antigens. The 20 CTLs used together provide reliable cellular typing reagents for the antigens HLA-DR2, -3, -4 and -7 and less so for the antigens HLA-DR1 and -5. In contrast, sharing between CTL- and target cell donors of HLA-DRw6 and -w8 correlates poorly to PPD-specific cytotoxicity. A few consistent exceptional patterns were observed. In one case lack of lysis in spite of HLA-DR antigen sharing could be explained by a split of HLA-DR2 into a normal and a short variant. Positive reactions in combinations, where no HLA-DR antigens are shared, were only few and evenly distributed among CTLs. Thus our findings indicate that our bulk CTLs predominantly contain clones restricted by determinants strongly associated to the serologically defined HLA-DR antigens.

Antigens, Surface↗
PubMed1986

Dissection of HLA class II haplotypes in HLA-DR4 homozygous individuals.

In order to identify better markers for HLA-DR4-associated autoimmune disorders, we have studied the complexity of the HLA class II region in DR4-positive cells at the DNA level and compared the DNA polymorphism with that defined by serology, mixed lymphocyte culture (MLC) reactivity, and protein chemistry. At the DNA level, HLA-DR4 can be characterized by a homogeneous pattern of bands hybridizing to HLA class II cDNA probes. Besides, subtypes can be defined within DR4 using HLA-DR beta, -DQ alpha, and -DQ beta cDNA probes in Southern blot analysis. Three subtypes are found using the DR beta cDNA probe. One of these subtypes correlates with the cellularly defined Dw15 specificity, another with the serologically defined LB4 and LB14 specificities. None of the restriction fragment length polymorphism (RFLP) patterns coincide with the MLC-defined DR4 subtypes Dw4, Dw10, Dw13, and Dw14 separately. Variation of two fragments hybridizing to the DQ alpha cDNA probe obtained after either Pvu II or Taq I digestion yields three subtypes. Pvu II- and Eco RI-digested DR4 DNA give rise to three DQ beta detectable subtypes. Correlation between these subtypes, isoelectric point variation of DQ molecules, and the DQ-related allelic system TA10/2B3 are demonstrated. Some of the patterns obtained with DQ alpha and DQ beta cDNA probes display heterozygosity in the DQ region, as demonstrated by family segregation. No correlation was observed between DQ and the cellularly defined Dw determinants. A new polymorphism has been obtained with the DQ alpha probe, probably due to DX polymorphism. DR beta RFLP divides the LB14 supertypic specificity into two new subtypes. A combination of the four different techniques applied to a panel of 16 DR4 homozygous cell lines reveals at least nine different haplotypes in DR4. These newly defined haplotypes may be of help in further studies concerning the relationship of micropolymorphism with several diseases.

Cell Line↗
PubMed1994

Cellular mechanisms of exogenous peptide binding to HLA class II molecules in B cells.

We have investigated the ability of APC Class II molecules to bind and release exogenous peptides, two phenomena that are still poorly understood. In order to investigate the half-life of the complex of an exogenous peptide with DR molecules we have evaluated the uptake and release of the radiolabeled peptide 17-29-Tyr of influenza virus matrix protein (MA 17-29-Y) by a B-EBV cell line at different times and under different conditions. We have found that the kinetics of both binding and release of the peptide are very fast in living cells; using glutaraldehyde-fixed cells, the kinetics of the two phenomena are slow, closely resembling those observed with the same peptide and purified, immobilized DR molecules. As confirmed by the study of a specific T-cell clone activation, the Class II-MA 17-29-Y complexes are short-living ones, with an average half-life of 55 min, and the DR molecules that bind exogenous peptides continuously undergo peptidic exchange. These data, taken together, suggest that the APC are endowed with cellular mechanisms that increase the efficiency of both the loading and the unloading of Class II HLA with exogenous peptides. These mechanisms do not appear to require ATP or to involve newly synthesized Class II molecules, intracellular acidic compartments, or the microtubule-microfilament system. On the other hand, an undamaged cell membrane appears to be crucial for an efficient binding.

Antigen Presentation↗
PubMed1995

HLA class II antigen associations help to define two types of alopecia areata.

BACKGROUND: Multiple HLA class I and class II antigen associations have been described for alopecia areata (AA). As in other immune-mediated diseases, the HLA antigens associated with AA could influence the patient's ability to respond to immune challenge from both self- and non-self-antigens and may offer clues to the cause and prognosis of and potential therapy for the disease. OBJECTIVE: Our purpose was to determine which HLA class II antigens are associated with two forms of long-standing AA, which we define to be long-standing patchy AA and long-standing alopecia totalis (AT) and alopecia universalis (AU). We also examined other factors such as age at onset of disease and familial and patient histories of autoimmune disease for correlation with the two groupings. METHODS: Patients were typed for HLA class I and class II antigens by serologic methods and were typed by molecular methods for the subtypes of the HLA class II antigens. RESULTS: HLA-DR11 (DRB1*1104) and HLA-DQ7 (DQB1*0301) were found to be highly significantly increased in frequency in patients with long-standing AT/AU (group III) but not in patients with long-standing patchy AA (group II); both patient groups showed increased frequencies of HLA-DQ3 (DQB1*03). Group III patients were unique in their early age at onset of disease. Familial incidence of AA was 37% in patients who had their first patch by 30 years of age and 7.1% with the first patch after 30 years of age. CONCLUSION: The data support the differential association of two well-defined clinical forms of AA, namely long-standing AT/AU and long-standing patchy AA, with specific HLA antigens and age at onset; they also suggest that the broad antigen HLA-DQ3, DQB1*03, is a likely candidate for general susceptibility to AA. Our findings also suggest a bimodal pattern of disease with an early-onset form associated with greater severity, long duration, and family history of the disease and a late-onset form characterized by milder severity, shorter duration, and low family incidence.

Alleles↗
PubMed1984

Possible involvement of the T4 molecule in T cell recognition of class II HLA antigens. Evidence from studies of CTL-target cell binding.

The present study examines the potential role of the T4 molecule in functional cell-cell interactions between target cells and human cytotoxic T lymphocyte (CTL) clones that are specific for HLA class II alloantigens encoded by the SB locus. There were marked differences (greater than 30-fold) between the seven SB-specific clones studied with respect to their susceptibility to inhibition by anti-T4 as well as anti-T3 antibodies. We wished to test the hypothesis that such variation among the clones would be due to differences in clonal "affinity" for antigen. To quantitate differences among the CTL clones in the tightness with which they bind target cells, the clones were analyzed using a previously published assay of susceptibility of CTL-target cell conjugates to dissociation in the presence of unlabeled targets. The results revealed that the clones that were most susceptible to inhibition by anti-T4 and anti-T3 were the weakest target cell binders, and vice versa. Anti-T4 antibody could partially induce dissociation of functional CTL-target cell conjugates in the absence of any added cold targets. For the "highest affinity" clone such anti-T4 antibody-induced dissociation could be observed at 4 degrees C but not 23 degrees C. These results indicate that the T4 molecule is functionally involved in target cell binding by CTL, and raise the possibility that although it is easiest to demonstrate the function of the T4 molecule in "low affinity" clones, that function may also be operative in the "high affinity" clones.

Adult↗
PubMed1988

Analysis of the molecular specificities of anti-class II monoclonal antibodies by using L cell transfectants expressing HLA class II molecules.

Expressible HLA class II alpha- and beta-chain cDNA were used for DNA-mediated gene transfer to produce L cell transfectants expressing single types of human class II molecules. Cloned transfectants expressing nine different class II molecules were isolated: DR alpha: DR1 beta I, DR alpha: DR4 beta I, DR alpha: DR5 beta I, DR alpha: DR5 beta III (DRw52), DR alpha: DR7 beta I, DR alpha: DR4/7 beta IV (DRw53), DQ7 alpha: DQw2 beta, DQ7 alpha: DQw3 beta, and DPw4 alpha: DPw4 beta. These class II-expressing transfectants were used to analyze by flow cytometry the molecular specificities of 20 anti-class II mAb. These analyes indicate that some mAb are more broadly reactive than was previously thought based on immunochemical studies. In contrast, the narrow molecular specificities of other anti-class II mAb were confirmed by this approach. Transfectants expressing human class II molecules should be valuable reagents for studies of B cell and T cell defined epitopes on these molecules.

Animals↗
PubMed2001

Class II HLA associations with autoantibodies in scleroderma: a highly significant role for HLA-DP.

Scleroderma is a condition of variable phenotype characterised by fibrosis of the skin and internal organs. There is a range of disease-specific autoantibodies found in the sera of patients. The aims of this study were to: (1) investigate the role of the MHC and particularly HLA-DP in the production of autoantibodies; (2) investigate clinical associations with autoantibodies. We have performed HLA class II typing using PCR with sequence-specific primers on DNA samples from 202 scleroderma patients and 307 UK control subjects. All patients had well defined clinical phenotypes. Sera from patients were examined for the presence of disease specific autoantibodies in particular the anti-topoisomerase autoantibody (ATA), the anti-centromere autoantibody (ACA) and the anti-RNA polymerase autoantibody (ARA). There was a striking association between HLA-DPB1*1301 and ATA (Pcorr = 0.0001). In addition, ATA was associated with HLA-DRB1*11 and the anticentromere autoantibody (ACA) with HLA-DRB1*04, HLA-DRB1*08 (P = 0.001) and HLA-DQB1 alleles with a glycine residue at position 26. Very strong associations were detected between clinical phenotypes and autoantibodies. ATA was associated with pulmonary fibrosis (P = 0.00002), anti-RNA polymerase autoantibody (ARA) with renal involvement (P = 0.0000006) and diffuse skin disease (P = 0.00001), and ACA with limited skin involvement (P = 0.00002) and protection against pulmonary fibrosis (P = 0.0000003). We have identified a significant association between the ATA and HLA-DPB1*1301 which may provide an insight into how this autoantibody is formed. Patient clinical characteristics depend on the autoantibodies they carry.

Autoantibodies↗
PubMed1988

Role of HLA class II and cytokine expression in rheumatoid arthritis.

HLA class II expression is notable in rheumatoid arthritis. We have investigated the mechanism of HLA class II regulation in the joints and found local synthesis, as judged by mRNA levels to be high. The role of antigen presentation in maintaining class II mRNA was explored, and blocking presentation by using monoclonal antibodies to HLA class II inhibited synthesis of mRNA for HLA-DR alpha chain. HLA class II expression is maintained by cytokines and so cytokine production in rheumatoid joints was investigated. It was chosen to use mRNA analysis by slot blotting as a screening assay, and the expression of many cytokines was detected. Levels of these were maintained in culture in the absence of extrinsic stimulation.

Antibody Formation↗
PubMed2001

Identification of beta-lactoglobulin-derived peptides and class II HLA molecules recognized by T cells from patients with milk allergy.

BACKGROUND: Cow's milk allergy impairs the health and development of many infants since it deprives them of adequate nutrition. Cow's milk fractions contain many allergens, and beta-lactoglobulin (BLG) is one of the major allergens. OBJECTIVE: The purpose of this study was to determine T cell epitopes, antigen-presenting molecules and cytokine production by T cells in relation to BLG. The results can provide new therapeutic possibilities of using analogue peptides of BLG for infants with cow's milk allergy. METHODS: Using a mixture of a panel of overlapping synthetic peptides that cover the entire BLG molecule, we established polyclonal BLG-specific short-term T cell lines and clones from peripheral blood mononuclear cells of four patients with allergy to cow's milk carrying most of the common human leucocyte antigen (HLA) haplotypes seen in the Japanese population. We then identified the T cell epitopes and antigen-presenting molecules, and measured the production of cytokines interleukin (IL)-4, IL-5 and interferon-gamma in the culture supernatants. RESULTS: The T cell lines established from the four patients responded to seven different peptides. Three of the peptides stimulated the T cells of two donors, regardless of the HLA types. The patterns of inhibition of the proliferative responses of the cell lines by anti-HLA class II antibodies were heterogeneous; three were mainly inhibited by anti-HLA-DR mAbs, and the other was inhibited by anti-HLA-DQ mAbs. High levels of IL-5 were produced by these T cell lines. CONCLUSIONS: Patients' T cells recognized BLG in association with a variety of HLA-DR or -DQ as antigen-presenting molecules. Although some peptides did have a more potent T cell stimulatory activity than others, the T cell receptor ligands formed with the BLG molecule are heterogeneous. Peptides for the desensitization of T cells of the patients with cow's milk allergy need to be designed keeping in mind the different requirements in different ethnic groups.

Amino Acid Sequence↗
PubMed1997

Identification of Dermatophagoides farinae-2-derived peptides and class II HLA molecules recognized by T cells from atopic individuals.

Der f2, the group 2 allergen of Dermatophagoides farinae, is one of the major inhalation allergens in Japan. Using the mixture of a panel of overlapping synthetic peptides that spread over the entire Der f2 molecule, we found that polyclonal Der f2-specific short-term T cell lines prepared from peripheral blood mononuclear cells of 5 individuals allergic to Der f who carry most of the common HLA haplotypes seen in the Japanese population can respond mainly to 7 different peptides. Distribution of the T cell epitopes on Der f2 was not identical with that on Der p2. Five of 7 peptides stimulated T cells of more than 2 donors, regardless of HLA types. Inhibition patterns by anti-HLA class II mAbs were heterogenous in proliferative responses of each cell line, three were mainly inhibited by anti-HLA-DR mAb, and the others were inhibited by anti-HLA-DQ mAb. One of these T cell lines, SM, of which the proliferative response was partially inhibited by anti-HLA-DQ mAb, was cloned. Indeed, the T cell clone SM4.6 was restricted by DQ6 molecules encoded for by an HLA-DRB1*1502-DRB5*0102-DQA1*0103-DQB1*0601 haplotype. These results indicate that patients' T cells recognize Der f2 in association with a variety of HLA-DR or HLA-DQ as antigen-presenting molecules. Thus, although some peptides do have a more potent T cell stimulatory activity than others, the TCR ligands formed with the Der f2 molecule are highly heterogeneous, a factor also noted in Der f1-specific T cell lines in our previous study.

Allergens↗
PubMed1991

Cross-ethnic group comparisons of HLA class II alleles and insulin dependent diabetes mellitus.

HLA class II associations with IDDM in populations of non-Caucasoid origin can provide important insights into the nature of the HLA and disease association. Firstly, HLA class II alleles that are rare in Caucasoids but common in other populations can be assessed for their contributory role in IDDM. Secondly, the different HLA class II gene linkage arrangements in different populations can help map the IDDM susceptibility determinants. This chapter reviews studies of HLA class II associations with IDDM in Asian Indians, Chinese, Japanese, Africans and black Americans. Most of these studies have been based on HLA-DR serology. However, DNA analyses, based on restriction fragment length polymorphism, sequence specific oligonucleotide hybridizations of polymerase chain reaction products and DNA sequencing, have made clear the identity of genes contributing to susceptibility or resistance to IDDM in populations of non-Caucasoid origin. DNA sequence analysis of the variable regions of the HLA-DQA, DQB and DRB genes has revealed at least eight alleles at HLA-DQA, 13 at HLA-DQB and 34 at HLA-DRB1. This chapter correlates HLA-DR and DQ allelic diversity with inherited predisposition to IDDM on a global basis. IDDM is strongly associated with the serological specificities of HLA-DQ, rather than with particular amino acid substitutions in class II alleles. DQw8 has a high risk for IDDM, DQw4, DQw5 and DQw9 have a lesser risk, while DQw6 and DQw7 are protective in IDDM. DQw2 is permissive for IDDM, depending on the presence of other HLA class II alleles. Increased heterozygosity at HLA is observed in Oriental patients, as it is in Caucasoid IDDM patients. The nature of this synergism is examined in terms of possible interactive effects between DQA and DQB alleles or DRB and DQB alleles; both effects could be operating. The conclusion from this genetic analysis is that molecular mimicry at HLA-DQ, with either foreign or autoantigens, may be an important mechanism in IDDM. Additionally, the anomalous role of DQw2 in IDDM suggests that a further mechanism, such as T cell activation, may control the ability to mount an immune response against autoantigens. Further studies, possibly with transfectant cell lines, are necessary to clarify the functional role of HLA class II genes in IDDM.

Alleles↗