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PubMed2004

Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis.

OBJECTIVE: The functional role of HLA class II molecules in the pathogenesis of rheumatoid arthritis (RA) is unclear. HLA class II molecules are involved in the interaction between T and B lymphocytes required for long-lived B cell responses and generation of high-affinity IgG antibodies. We undertook this study to investigate the relationship between HLA class II gene polymorphisms and RA-specific IgG antibodies against cyclic citrullinated peptides (anti-CCP antibodies). METHODS: High-resolution HLA-DR and DQ typing and anti-CCP-2 antibody testing were performed on 268 RA patients from the Early Arthritis Clinic cohort at the Department of Rheumatology of the Leiden University Medical Center. The presence of anti-CCP antibodies was analyzed in carriers of the different DR and DQ alleles. Disease progression was measured over a period of 4 years by scoring radiographs of the hands and feet using the Sharp/van der Heijde method. RESULTS: Carriership of the individual alleles HLA-DRB1*0401, DRB1*1001, DQB1*0302, and DQB1*0501 was associated with the presence of anti-CCP antibodies. Carriers of DQ-DR genotypes containing proposed RA susceptibility alleles were significantly more often anti-CCP antibody positive. Carriership of one or two HLA-DRB1 shared epitope (SE) alleles was significantly associated with production of anti-CCP antibodies (odds ratio [OR] 3.3, 95% confidence interval [95% CI] 1.8-6.0 and OR 13.3, 95% CI 4.6-40.4, respectively). An increased rate of joint destruction was observed in SE+, anti-CCP+ patients (mean Sharp score 7.6 points per year) compared with that in SE-, anti-CCP+ patients (2.4 points per year) (P = 0.04), SE+, anti-CCP- patients (1.6 points per year) (P < 0.001), and SE-, anti-CCP- patients (1.6 points per year) (P < 0.001). CONCLUSION: HLA class II RA susceptibility alleles are associated with production of anti-CCP antibodies. Moreover, more severe disease progression is found in RA patients with both anti-CCP antibodies and SE alleles.

Adolescent↗
PubMed1990

Monoclonal antibody OKT3-induced T cell proliferation: differential role of HLA class II determinants expressed by T cells and monocytes.

Monoclonal antibodies (MAb) to monomorphic determinants of HLA Class II antigens inhibit monocyte-dependent T cell proliferation induced by MAb OKT3 to a different extent, suggesting a differential regulatory role of the corresponding determinants in T cell proliferation. To elucidate the mechanism(s) underlying this pattern, the MAb CR10-343 and Q5/6 with high inhibitory effect and MAb CR11-462 and CR12-356 with low inhibitory effect were characterized. Cross-inhibition studies showed that the four MAb recognize distinct determinants. The determinants recognized by MAb CR10-343 and CR12-462 are spatially close. The determinants recognized by the four MAb appear to be functionally independent in MAb OKT3-induced T cell proliferation, since the inhibitory effect of the combination of MAb CR10-343 and Q5/6 and of the MAb CR11-462 and CR12-356 was additional but not synergistic. To compare the functional activity of HLA Class II determinants expressed by monocytes and by activated T cells in MAb OKT3-induced T cell proliferation, the effect of the four MAb on MAb OKT3-induced T cell proliferation in a monocyte-dependent and in a monocyte-free system was studied. Dose-response and proliferation kinetics studies showed that the four MAb display a similar inhibitory effect on MAb OKT3-induced T cell proliferation in a monocyte-free system. These results suggest fine differences in the role played by monocyte- and T cell-bound HLA Class II determinants in the regulation of MAb OKT3-induced T cell proliferation. This functional heterogeneity may enhance the flexibility of HLA Class II antigens to mediate cell-cell interactions involved in the proliferative response to a variety of mitogenic stimuli.

Antibodies, Monoclonal↗
PubMed1990

T-cell recognition of HLA class II molecules induced by gamma-interferon on a colonic adenocarcinoma cell line (HT29).

HLA class II molecules may be induced on non-lymphoid cells by gamma-interferon (IFN-gamma). We investigated if HLA class II molecules induced by IFN-gamma on the HT29 colonic carcinoma cell line are functional, i.e. if they may be recognized by allogeneic T cells. We found that IFN-gamma-treated HT29 (HT29IFN) cells could not induce primary proliferative responses of peripheral blood T lymphocytes, nor were they able to induce proliferation in T-lymphocyte clones (TLC) specific for HLA class II molecules found on HT29IFN. However, in the presence of exogenous interleukin 2 (IL-2), 1 of 5 DQw8-specific TLC proliferated when restimulated with HT29IFN, and 3 of these 5 TLC could very effectively inhibit the growth of HT29IFN, probably due to a cytotoxic effect. Both the proliferative response and the cytotoxicity were inhibited by anti-DQ MoAb. We conclude that T cells may recognize HLA-DQ molecules on non-lymphoid cells, which may be of relevance for autoimmune diseases, graft-versus-host disease, and possibly for the recognition of malignant cells.

Adenocarcinoma↗
PubMed2000

Molecular aspects of HLA class II alphabeta heterodimers associated with IDDM susceptibility and protection.

HLA-DQ alleles are strongly associated with IDDM susceptibility and protection. Studies assessing the molecular properties of HLA-DR, a HLA class II locus in linkage disequilibrium with HLA-DQ, have made substantial contributions toward elucidating the structure and function of HLA class II molecules. Reports on the molecular properties of HLA-DQ are now following and have revealed interesting observations regarding the stability of HLA-DQ alphabeta heterodimers. Future work is expected to provide an understanding of the mechanism by which HLA-DQ is associated with IDDM susceptibility and protection.

Animals↗
PubMed1988

HLA class II antigen expression and the autoimmune thyroid response in patients with benign and malignant thyroid tumors.

To further understand the relationship between the immune system and the neoplastic human thyroid cell we investigated the degree of intrathyroidal lymphocytic infiltration and thyroid HLA class II expression in 17 patients with thyroid tumors. In another 60 thyroid tumor patients the association of thyroidal lymphocytic infiltration with thyroid autoantibody production was analyzed. In total 117 thyroid tissues were examined including tissue obtained at autopsy (n = 28), fetal thyroid tissue (n = 4), thyroid samples obtained from areas distant from benign follicular adenomas (n = 5), and 80 abnormal thyroids including patients with benign (n = 53) or malignant (n = 24) thyroid tumors and Hashimoto's thyroiditis (n = 3). Normal adult and fetal thyroid tissue had no significant lymphocytic infiltration and no detectable HLA-DR, -DP, or -DQ antigens on their thyroid follicular epithelial cells. The degree of lymphocytic infiltration in the nonneoplastic thyroid tissue of thyroid glands with benign and malignant thyroid tumors varied considerably and correlated with the presence and titer of serum thyroid autoantibodies measured by sensitive ELISA techniques. However, all but one of the benign follicular adenomas had thyroid cells negative for HLA class II determinants despite the presence of infiltrating lymphocytes, while 7 of 10 thyroid carcinomas expressed class II antigen (principally HLA-DR) even when only minor degrees of lymphocytic infiltration were present. These data indicate a correlation between lymphocytic infiltrates and serum thyroid autoantibody titers but the relationship with HLA class II expression is more complex. Since we have previously shown that HLA class II antigen expression can be induced by local interferon-gamma secretion, presumably from activated T cells, we conclude that estimates of simple thyroid lymphocytic infiltration and serum autoantibody secretion do not correlate with the degree of intrathyroidal T-cell activation. Furthermore, our observation of increased expression of HLA class II antigens in thyroid cancer suggests considerable cellular heterogeneity in susceptibility to HLA class II antigen induction in human thyroid disease.

Adenoma↗
PubMed1993

Differences in HLA class II alleles of isolated South American Indian populations from Brazil and Argentina.

We have studied the HLA class II alleles in 277 South American Indians, which included Argentinian tribes from the Gran Chaco: Toba (n = 135), Toba-Pilaga (n = 19), Mataco-Wichi (n = 49), and Xavantes, a tribe from Central Brazil (n = 74). In the Brazilian tribe, only four DR groups were found: DRB1*1602 (gf = 0.303), DRB1*04 including DRB1*0404 (gf = 0.070) and DRB1*0407 (gf = 0.077), DRB1*0802 (gf = 0.265), and DRB1*1402 (gf = 0.303). The HLA class II allele frequencies were similar among the different Argentinian tribes, and 90% of DRB1 alleles belonged to three families: DRB1*04 (including DRB1*0403, DRB1*0404, DRB1*0407, DRB1*0411, and DRB1*0417), DRB1*0802, and DRB1*14 (including DRB1*1402 and DRB1*1406). At the DPB1 locus, we found only seven alleles, the most frequent being DPB1*0402. Comparison of HLA class II alleles with those of North American Indians that we have previously studied shows that the frequency of some HLA class II alleles in Brazilian Xavantes resembles that of North American Indians more than that of the Argentinian Indian tribes. The allele DRB1*0417 was found exclusively in this population.

Adult↗
PubMed1992

HLA class II specificities in vasculitis with antibodies to neutrophil cytoplasmic antigens.

HLA class II genes were examined in patients with small vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA) using restriction fragment length polymorphism and allele specific oligonucleotide typing. Fifty-nine patients were studied, 34 with Wegener's granulomatosis and 25 with microscopic polyarteritis, and their results were compared with those from 1103 British Caucasoid controls. The frequency of HLA-DQw7 was significantly increased in patients with vasculitis (patients 53%; controls 27.8%, chi 2 17.8, Pc less than 0.0025, relative risk 2.9), and all the DQw7 bearing haplotypes commonly found in Caucasoid populations contributed to the increase. By contrast, the frequency of HLA-DR3 bearing haplotypes was decreased in the patients (patients 6.8%; controls 21.6%, chi 2 6.7, P less than 0.01). HLA specificities were similar in the groups of patients presenting with Wegener's granulomatosis and microscopic polyarteritis and with different types of ANCA assessed by indirect immunofluorescence. However, patients with the DQw7, DR4 haplotype were significantly more likely to have transiently positive tests for ANCA than patients with other DQw7 bearing haplotypes, whereas patients with DR2 bearing haplotypes were more likely to have persistently positive ANCA. These results show that HLA class II genes are associated with small vessel vasculitis and may influence the duration of the associated autoimmune response.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1993

Haplotypic variation of the transporter associated with antigen processing (TAP) genes and their extension of HLA class II region haplotypes.

Stable cell surface presentation of HLA class I molecules requires active transport of antigenic peptides across the endoplasmic reticulum by products of two genes, TAP1 and TAP2, which map in the major histocompatibility complex class II region. Alleles of each gene are derived from a combination of variable sites at each locus. In this study, TAP1 and TAP2 alleles were identified in homozygous typing cell (HTC) lines, allowing resolution of specific haplotypes in conjunction with the highly polymorphic HLA class II region haplotypes. Three alleles at each TAP locus were found from which eight haplotypes could be assigned. Determination of TAP1 and TAP2 alleles in cell lines homozygous at DR, DQ, and DP created eight additional haplotypes beyond the number observed with these class II genes alone. Complete analysis of DR, DQ, TAP, and DP genotypes in 66 HTCs resulted in the following groups: 1) 46 homozygotes; 2) nine homozygous at DR, DQ, and TAP, but heterozygous at DP; 3) four homozygous at DR, DQ, and DP, but heterozygous at one or both TAP genes; 4) four homozygous at DR and DQ, but heterozygous at TAP and DP; and 5) three complex genotypes heterozygous at DP, TAP, and at least one of DQA1, DQB1, or DRB1 loci. TAP1 and TAP2 genes map in an area of frequent recombination. TAP alleles were determined in five DQB1, DPB1 recombinant individuals, three of which were informative. Recombination was found between DQB1 and the TAP loci in two individuals and between TAP and DPB1 in the other individual.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1987

Effect of interferon gamma on expression of HLA-class II molecules on blood-derived dendritic cells.

T4 cells recognize antigen together with HLA class II molecules in the membrane of antigen-presenting cells (APC). The magnitude of the induced T cell response is in part dependent upon the quantitative expression of HLA-class II molecules in the cell membrane of the APC. We report here that recombinant interferon gamma (IFN-gamma) may enhance the expression of HLA class II molecules on the surface membrane of blood-derived dendritic cells by 30-90%.

Dendritic Cells↗
PubMed1997

A preliminary study of HLA class II alleles in Thai patients with non Hodgkin's lymphoma.

The HLA class II alleles were analyzed by the PCR-SSP technique in the DNA samples obtained from 27 Thai patients with non Hodgkin's lymphoma (NHL). It was found that (1) the incidence of HLA-DRB1*15 and HLA-DRB1*09 was slightly decreased (P > 0.05). On the other hand, the incidence of HLA-DQB1 alleles was the same as control. However, further study is suggested in order to conclude the close relationship between the presence of certain HLA class II alleles and susceptibility to NHL in Thai patients.

Adult↗
PubMed1992

Local immunosuppression determined by class II HLA antigen expression in patients with preclinical cervical carcinoma.

Class II HLA antigen expression was investigated in biopsy material from patients with preclinical cervical carcinoma. Class II molecules were determined immunohistochemically by MoAb against HLA-DR antigens. A significant reduction of class II positive cells was established in the tumor tissue compared to the normal cervical epithelium. A correlation between the tumor progression and the inhibition of the class II antigen expression was found.

Antigens, Neoplasm↗
PubMed1991

Mutations in the D strand of the human CD4 V1 domain affect CD4 interactions with the human immunodeficiency virus envelope glycoprotein gp120 and HLA class II antigens similarly.

CD4, a cell surface glycoprotein expressed primarily by T lymphocytes and monocytes, interacts with HLA class II antigens to regulate the immune response. In AIDS, CD4 is the receptor for the human immunodeficiency virus, which binds to CD4 through envelope glycoprotein gp120. Delineation of the ligand-binding sites of CD4 is necessary for the development of immunomodulators and antiviral agents. Although the gp120 binding site has been characterized in detail, much less is known about the class II binding site, and it is as yet uncertain whether they partially or fully overlap. To investigate CD4 binding sites, a cellular adhesion assay between COS cells transiently transfected with CD4 and B lymphocytes expressing HLA class II antigens has been developed that is strictly dependent on the CD4--class II interaction, quantitative, and highly reproducible. Mutants of CD4 expressing amino acids with distinct physicochemical properties at positions Arg-54, Ala-55, Asp-56, and Ser-57 in V1, the first extracellular immunoglobulin-like domain, have been generated and studied qualitatively and quantitatively for interaction with HLA class II antigens, for membrane expression, for the integrity of CD4 epitopes recognized by a panel of monoclonal antibodies, and for gp120 binding. The results obtained show that the mutations in this tetrapeptide, which forms the core of a synthetic peptide previously shown to have immunosuppressive properties, affect the two binding functions of CD4 similarly, lending support to the hypothesis that the human immunodeficiency virus mimicks HLA class II binding to CD4.

Amino Acid Sequence↗
PubMed1993

[Molecular biological analysis of HLA class II gene in autoimmune hepatitis among Japanese].

The frequencies of HLA B54, DR4, DR53 and DQ4 were significantly higher in patients with autoimmune hepatitis than in healthy controls. HLA-DR4 was most frequently associated with autoimmune hepatitis. To define the HLA class II gene which has the susceptibility or resistance to autoimmune hepatitis, we performed HLA class II genotyping using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) method. The frequency of DRB1*0405 was significantly higher in autoimmune hepatitis than in controls. However, there was no significant difference in the frequency of the DR4 associated Dw-allele between the patients and the controls who were DR4-positive. Six DR4-negative patients had DR2, but there was no significant difference in the frequency of the DR2-associated Dw-alleles compared with the DR2-positive controls. Comparison of the amino acid residues of DRB1 chain suggested that the basic amino acid at position 13, which is present only on the DR2 and DR4 B1 molecules (Arg on DR2 and His on DR4), contributes to the susceptibility to autoimmune hepatitis among Japanese.

Asian People↗
PubMed2005

HLA class II antibodies in transfusion-related acute lung injury (TRALI). A case report.

TRALI, a serious complication of blood transfusion, is underdiagnosed. Anti-granulocyte and anti-HLA class I molecules in donors or recipients and very recently, lipids in stored blood as well as anti-HLA class II have been associated with the syndrome. We present a TRALI case which occurred in a 56 year old woman after plasma transfusion. HLA class II antibodies were identified in the donor and were correlated with the recipients' HLA antigens. The presence of HLA class II antibodies without anti-HLA class I has been reported in very few cases and may facilitate the understanding of the pathogenesis of the syndrome.

Blood Component Transfusion↗
PubMed1992

Extensive genetic diversity in the HLA class II region of Africans, with a focally predominant allele, DRB1*1304.

Molecular HLA class II typing of greater than 1700 individuals from The Gambia in West Africa and Malawi in South-Central Africa revealed a striking diversity of HLA DRB-DQB haplotypes as defined by restriction fragment length polymorphism (RFLP); this diversity is twice as extensive as that found in northern Europeans. Despite this diversity, sequence and PCR/oligonucleotide analysis showed that the recently described variant DRB1*1304 is the commonest DRB1 allele in The Gambia. The sequence, geographical distribution, and RFLP association of this allele, together with homozygosity test results, suggest that DRB1*1304 may have arisen from DRB1*1102 and have reached its remarkably high frequency as a result of recent directional selection. The prevalence of this unusual allele has implications for trials of subunit vaccines in this area. The extensive and distinctive HLA class II region polymorphism in sub-Saharan Africans is consistent with evidence from other genetic loci implying an African origin of modern Homo sapiens.

Alleles↗
PubMed1989

Differential susceptibility of HLA class II antigens induced by gamma-interferon in human neuroblastoma cell lines.

Five neuroblastoma cell lines have been examined for the induction of HLA class II antigens by a recombinant gamma-interferon. The expression of HLA-DR and -DP was induced on up to 80% of cells in two of five neuroblastoma cell lines examined (KP-N-SI and KP-N-RT). Low expression of HLA-DR and -DP was induced on the SK-N-DZ line in the presence of recombinant gamma-interferon for 10 days. In contrast HLA-DQ was not induced on any of five neuroblastoma cell lines studied. HLA-DR and -DP antigen induction was reversible, falling to nondetectable levels when interferon was removed from the culture medium. The reinduction of interferon to the culture medium again induced HLA-DR and -DP antigen expression in a fashion similar to that originally observed. These results were confirmed by Northern blot analysis using a probe to HLA-DR alpha mRNA. Recombinant interferon appears to induce HLA class II expression at the level of gene transcription or posttranscription. The results also indicate that HLA-DR, -DP, and -DQ antigens are independently regulated. Treatment of neuroblastoma cell lines with gamma-interferon results in the induction of a differentiated phenotype. Although the cytokine gamma-interferon induces neurofilament expression in some of the cell lines, this was not the case for all lines studied. Thus no correlation could be established between the morphological differentiation and either HLA class II or neurofilament expression. In addition, no correlation between response to recombinant interferon and N-myc amplification was noted. The biological significance of HLA class II expression on neuroblastoma cell lines by gamma-interferon may be related to the differentiation stage of neuroblastoma cells or may enable gamma-interferon-treated neuroblastoma cells to be recognized by cytotoxic T-cells.

Dose-Response Relationship, Drug↗
PubMed2002

HLA class II haplotypic association and DQCAR microsatellite polymorphisms in Croatian patients with psoriasis.

The purpose of the present study was to investigate polymorphism of HLA class II haplotypic associations (HLA-DRB1, -DQA1, -DQB1) and DQCAR alleles in 78 Croatian patients with psoriasis. Patients were divided into two groups according to a family history of disease and age of onset: type I (positive family history and early onset) and type II (negative family history and late onset). The difference in frequency of HLA class II haplotypic associations between type I patients and controls was observed for the following combinations: HLA-DRB1*0701, -DQA1*0201, -DQB1*02 (23.6% vs. 7.2%; p < 0.001), HLA-DRB1*0701, -DQA1*0201, -DQB1*0303 (8.5% vs. 1.3%; p = 0.0018) and HLA-DRB1*1601, -DQA1*0102, -DQB1*0502 (2.8% vs. 9.3%; p = 0.06). The difference between type II psoriasis and controls for association: HLA-DRB1*1501, -DQA1*0102, -DQB1*0602 is not significant (20.0% vs. 8.9%; p = 0.06). The significantly higher frequency of DQCAR 113bp and 119bp alleles in patients with type Ipsoriasis is a result of linkage disequlibrium of these alleles with both HLA-DRB1*0701 haplotypic associations. Analysis ofDQCAR alleles in the HLA-DRB1*0701 haplotypic associations in patients with psoriasis vulgaris and matched controls did not reveal any difference in polymorphism of DQCAR alleles. These data suggest that HLA-DRB*0701 haplotypic combinations are associated with type I but not for type II psoriasis in the Croatian population. DQCAR polymorphism is not useful genetic marker to distinguish susceptible HLA class II haplotypic association.

Adult↗
PubMed2006

HLA class II disease associations in southern Africa.

Southern Africa harbors several population groups representing a diversity of gene pool origins. This provides a unique opportunity to study genetic disease predisposition in these populations against a common environmental background. Human leukocyte antigen (HLA) association studies of these populations could improve knowledge on inter-population variation and HLA-related disease susceptibility. The aim of this paper is to review HLA class II disease associations reported for southern African population groups, compare them with findings in other populations and identify those unique to southern Africa. A number of HLA class II disease associations appear to be unique to southern African populations. These include DRB1*14011 association with insulin-dependent diabetes mellitus susceptibility in the Xhosa and DRB1*10 and DQB1*0302 with rheumatoid arthritis susceptibility in the South African (SA) Indian and SA Coloreds, respectively. A noteworthy similarity in class II disease association was observed among southern African Caucasoid and their European parental populations. Unique HLA class II disease associations observed in southern Africa are consistent with the notion that unique environmental and natural selective factors have resulted in certain ethnic-specific HLA class II disease associations, while common HLA class II disease associations found across different populations support the notion that common diseases are caused by common, ancient alleles present in indigenous African populations.

Africa, Southern↗