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PubMed2006

HLA-class II haplotype associations with ovarian cancer.

The development of cancer is a multistep process that is characterized by the accumulation of genetic alterations in cells and changed cellular interactions with the surrounding healthy tissues. The human immune system is believed to be intrinsically involved in this process. The correlation of certain human leukocyte antigen (HLA)-class I and II haplotypes with tumorigenesis is documented in a variety of tumors. However, few data exist on the possible association of specific HLA-class II alleles or haplotypes with ovarian cancer. In our sample of 52 Caucasian patients with primary ovarian carcinoma and 239 female healthy local controls, we observed a significantly increased incidence of the HLA-class II haplotypes DRB1*0301 - DQA1*0501 - DQB1*0201 (p < 0.001) and DRB1*1001 - DQA1*0101 - DQB1*0501 (p < 0.001) in the patients. Our data suggest that HLA-class II loci or individual HLA-class II haplotypes may be involved in the pathogenesis of ovarian cancer.

Adult↗

PubMed1991

Distribution of Langerhans cells and HLA class II molecules in prostatic carcinomas of different histopathological grade.

We have investigated Langerhans cell (LC) distribution in 38 prostatic carcinomas, of various degrees of differentiation, by immunohistochemistry with a polyclonal anti-S-100 serum, furthermore evaluating the expression of HLA class II-DR by neoplastic cells using a monoclonal antibody (MoAb) that reacts with a monomorphic determinant in formalin-fixed paraffin-embedded tissue. Antiserum to S-100 protein identified LCs mostly in carcinomas ranging from grade 1 to grade 2, while LCs were inconspicuous in grade 4 and virtually absent in grade 5 cancers. Moreover, sections stained with the anti -HLA-DR MoAb displayed an immunoreactivity, both cytoplasmic and apical, especially confined to neoplastic glands of low grade (1-2) carcinomas. Although we did not find a direct correlation between the two parameters under investigation and lymphoid infiltrate, we were able to document an increased number of HLA class II-positive interstitial cells in low-grade carcinomas, corresponding mostly to macrophages. Our results indicate that LC number is inversely correlated to the histopathological grade and directly to the expression of HLA class II-DR molecules by tumor cells; we believe that this might be important in understanding the more favorable biological behavior of low-grade prostate carcinomas as opposed to the higher grades, since LCs and HLA class II molecules may provide a means of eliciting the immune response, both LCs and epithelial cells expressing HLA class II molecules being capable of direct antigen presentation to immune cells. In this context macrophages might play a primary role in controlling tumor progression. To the best of our knowledge this is the first time that an attempt is made to correlate LCs and HLA class II expression to histopathological grading of prostatic carcinomas. We would also suggest that the presence of LCs and HLA class II molecules, either singly or in combination, in carcinoma of the prostate represents a good prognostic indicator, being constantly associated with the clinically less aggressive low-grade tumors. The evaluation of these two parameters might prove useful in the assessment of intermediate grades where no valid histologic criteria have been found to predict the clinical course of the disease.

Aged↗

PubMed1999

Immunohistochemical analysis of HLA class II antigens and tumor infiltrating mononuclear cells in renal cell carcinoma: correlation with clinical and histopathological data.

Cryostat sections of 37 renal cell carcinomas (RCC)--25 clear cell type, 10 granular and 2 chromophobe--were studied with indirect immunoperoxidase method applying monoclonal antibodies (MoAb) to HLA-DR, -DP and -DQ antigens for analysis of HLA class II antigens, and anti-CD14, -CD3, -CD4 and -CD8 MoAb for tumor infiltrating mononuclear cells (TIM). Number of positive cells was estimated semiquantitatively and results of immunohistochemical investigation were correlated with clinical (patient age and sex, tumor size and TNM stage) and histopathological (cytology, histology, grade) characteristics of RCC. All RCC expressed HLA-DR, 92% -DQ and 73% -DP antigens with level of expression in hierarchy- DR>-DQ>-DP, but no statistically important correlation could be established with any of the histopathological or clinical parameters analyzed. Monocytes were more abundant than T lymphocytes and CD4+ than CD8+ T cells, whereas tumors with T lymphocyte predominance and approximately equal number of CD4+ and CD8+ T cells had greatest average diameter. Inadequate activation of T lymphocytes by tumor cells (despite capability of antigen presentation) could be the reason for association of parameters which indicates more aggressive tumor behavior with aberrant HLA class II antigen expression on RCC.

Adult↗

PubMed1995

T cell proliferation restricted by HLA class II molecules in patients with hen's egg allergy.

We investigated the synergistic effect of anti-HLA class II monoclonal antibodies on proliferative responses to ovalbumin (OA) of T cell line (TCL) cells from five hen's-egg-sensitive patients. Among the five patients, the proliferation of the TCL cells from two patients with AD who have a low immune reaction was restored by the anti-HLA-DQ monoclonal antibodies, and the proliferation of the TCL cells from the other three patients was inhibited by the anti-HLA-DP monoclonal antibodies. These results suggest that a component of the T cell repertoire reactive with OA in hen's-egg-sensitive patients may be restricted by HLA-DP molecules. Furthermore, in hen's-egg-sensitive patients with AD who have a low immune reaction, low responsiveness may be regulated by HLA-DQ molecules.

Animals↗

PubMed1990

HLA class II glycoprotein expression by monocytes from HIV-infected individuals: differences in response to interferon-gamma.

The expression of HLA class II glycoproteins by monocytes from HIV-infected individuals was evaluated. We found no differences in HLA-DR, HLA-DQ, or HLA-DP expression by freshly isolated monocytes from patients with clinical AIDS, HIV-infected patients without AIDS or from uninfected individuals. However, monocytes from HIV-infected individuals without AIDS responded better to stimulation with recombinant human interferon-gamma (IFN-gamma) than did monocytes from patients with clinical AIDS or from uninfected individuals. The response to IFN-gamma stimulation by monocytes from patients with clinical AIDS was different. Thus, the largest increases in the percentage of cells expressing HLA-DR was associated with the smallest changes in the fluorescence intensity of the population that is observed following stimulation of monocytes from other patient populations.

Acquired Immunodeficiency Syndrome↗

PubMed2006

HLA class II allele frequencies in type 1A diabetes mellitus Slovak patients.

BACKGROUND: Diabetes mellitus type 1A (DM-1A) is an autoimmune disease in which the immune response is directed to pancreatic islet cells. DM-1A occurs in genetically predisposed individuals. Among type 1A diabetes associated genes, those of the HLA region have the greatest effect. OBJECTIVES: The aim of our study was to obtain a comprehensive survey of the HLA-DRB1 and HLA-DQB1 allele frequencies in Slovak patients suffering from DM-1A. METHODS: HLA class II genotyping was performed on genomic DNA by the PCR-SSP method according to the 12th Workshop protocol. RESULTS: Our report gives the first presentation of the distribution of HLA-DRB1 alleles (including complete DRB1*04 subtypes) and that of HLA-DQB1 alleles in the Slovak diabetic patients diagnosed at 0-18 years of age. Susceptibility is significantly associated with the alleles DQB1*0302 (OR = 7.8), DRB1*04 (OR = 4.9), DRB1*0301 (OR = 4.2) and DQB1*02 (OR = 2.2), whereas the alleles DQB*0602 (OR = 0.05), DRB1*11 (OR = 0.2), DRB1*15 (OR = 0.2) and DQB1*0301 (OR = 0.3) were found to be protective. CONCLUSIONS: Our results, consistent with other studies, show increased frequencies of known positively associated HLA class II alleles in our type 1A diabetes mellitus patients compared to the general (nondiabetic) population. The protective effect of previously reported alleles was confirmed as well. Results of our population-based study serve in clinical practice for the identification of subjects at risk of developing DM-1A among the first-degree relatives (Tab. 2, Ref. 12).

Adolescent↗

PubMed1991

HLA class II (DR, DQ, DP) in patients with sarcoidosis: evidence of an increased frequency of DRw6.

The distribution of HLA class II (DR, DQ, and DP) antigens was studied in 41 patients with symptomatic sarcoidosis (SA) and ethnically matched healthy controls. HLA-DR, -DQw1 and -DQw3 typings were performed with alloantisera in the conventional microcytotoxic test, whereas -DP typings were done using primed lymphocyte typing. The frequencies of DRw6 were 41.5% in SA patients and 17.9% in controls (relative risk, RR = 3.2, p = 0.00087, p less than 0.05 when corrected). DR3 was decreased to 14.6% in SA patients compared to 25.9% in controls (RR = 0.49, p = 0.07, i.e., not statistically significant). The decreased frequency of DR3 was only seen in patients with severe, long-standing disease. In contrast, the DRw6 increase was most pronounced in patients with severe disease (RR = 6.4; p = 0.003). There were no statistically significant deviations in the frequencies of DQ and DP alleles between patients and controls. In conclusion, our data suggest that DRW6 confers susceptibility and DR3 resistance to severe, long-standing disease.

Female↗

PubMed1993

HLA class II alleles and susceptibility and resistance to insulin dependent diabetes mellitus in Mexican-American families.

The role of HLA class II alleles in genetic predisposition to insulin dependent diabetes mellitus (IDDM) was examined by PCR/oligonucleotide probe typing of 42 Mexican-American IDDM families derived from Hispanic Caucasians and Native Americans. All high risk haplotypes (HLA-DR3 and DR4) were of European origin while the most strongly protective haplotype (DRB1*1402) was Native American. Of the 16 DR-DQ DR4 haplotypes identified, only those bearing DQB1*0302 conferred risk; the DRB1 allele, however, also markedly influenced IDDM risk. The general pattern of neutral and protective haplotypes indicates that the presence of Asp-57 in the HLA-DQ beta chain does not confer IDDM protection per se and indicates that both DRB1 and DQB1 influence IDDM susceptibility as well as protection.

Alleles↗

PubMed1990

The X boxes from promoters of HLA class II B genes at different loci do not complete for nuclear protein-specific binding.

Expression of HLA class II genes is coordinately regulated by cis-acting elements present in their promoter regions immediately upstream from the 5' end of their transcription start sites. Trans-acting factors from the nuclear proteins of the cell are able to positively or negatively regulate transcription of these genes by binding to highly conserved sequences, called boxes. After cloning the promoter regions of all the transcribed class II B genes present in the cell line Priess, we were able to identify certain protein-box complexes and to determine the affinity of these proteins for their respective boxes by comparing promoter boxes of each gene to those of the other genes. Different nuclear proteins seemed to bind to the X boxes of the different class II B genes tested. In the case of the Y box-protein complexes, the various Y boxes competed with similar affinities. The protein(s) which specifically bound to the DRB1-CCAAT box also bound to DPB1-CCAAT box, but completely failed to bind the homologous box from DQB1. Further, CCAAT box-specific protein(s) did not bind to the Y box of the same gene, excluding the possibility that these proteins just recognize the reverse CCAAT box (ATTGG) present within Y.

Amino Acid Sequence↗

PubMed1988

Sequence analysis of HLA class II genes from insulin-dependent diabetic individuals.

To examine the nature of HLA-linked genetic susceptibility to insulin-dependent diabetes mellitus (IDDM), we compared HLA class II gene sequences from IDDM patients and control individuals. Genomic libraries were constructed from two siblings with IDDM, typed serologically as DR3,w6 and DR3,4. These libraries represent the HLA haplotypes (DR3, DR4) most frequently associated with IDDM, as well as one haplotype found less often. Individual genomic clones were identified and assigned to specific loci and haplotypes. The nucleotide sequence was then determined from the variable second exon from the HLA-DQ alpha, DQ beta, and DR beta genes from all three haplotypes. Sequence variation within the DQ alpha genes could not be correlated with the disease. For all three haplotypes, the DQ alpha sequence from the IDDM patient was identical to the DR-matched control sequence. Similarly, for the DR3 haplotype, the DQ beta sequences matched all control DR3 alleles. The DQ beta sequence from the DR4 haplotype was identical to the predominant DR4 allele (DQ beta 3.2) but differed at four amino acid residues from the other major DR4 DQ beta sequence (DQ beta 3.1) found rarely among IDDM patients. Sequence analysis of the DQ beta gene from the DRw6 haplotype revealed a new allele that differed from the DQ beta allele from a control DR6 allele at two residues. The DR beta genes from these three haplotypes also did not show any sequence features uniquely associated with IDDM, although the frequency of certain allelic variants in all three of these haplotypes may be altered in the IDDM population. A particular group of amino acids was found to be shared between the DR beta-1 alleles from the DR4 and DRw6 haplotypes and may be involved in genetic susceptibility to IDDM.

Amino Acid Sequence↗

PubMed1987

HLA class II restriction of T helper cell response to cytomegalovirus (CMV). I. Immunogenetic control of restriction.

All three HLA class II families (DR, DQ, and DP) are involved in restriction of helper T cell (Th) recognition of nominal antigens including CMV. Only limited studies have been described previously to determine whether restricting determinants of DR and especially DQ are subtypic to the serologically defined DR and DQ specificities, and to what extent restricting determinants are associated with Dw specificities defined in alloresponses. In the present report, we describe a large number of CMV-specific Th clones derived from two different individuals who are seropositive for CMV. Clones were classified as being DR-, DQ-, or DP-reactive based on blocking with monoclonal antibodies. DR- and DQ-restricted clones were then examined in panel studies using antigen-presenting cells (APC) expressing the Dw subtype of the restricting DR-DQ haplotype, as well as APC expressing different Dw subtypes associated with the serologically defined specificity. Unrelated specificities were also included. Our findings show that not only for DR but for DQ as well, the primary restricting determinants appear to be subtypic to the serologically defined antigen; furthermore, subtype restriction for both DR and DQ is very closely associated with single Dw specificities. In several cases in which cross-reactivity among restricting Dw specificities was observed in association with a given DR or DQ haplotype, a molecular basis could be suggested to explain the cross-reacting determinants. A small minority of the clones appeared to be CMV specific, but was restricted by a determinant(s) that is either monomorphic or minimally polymorphic.

Antigen-Presenting Cells↗

PubMed1997

HLA class II antibodies recruit G-CSF activated neutrophils for treatment of B cell malignancies.

Monoclonal antibodies offer the potential to improve specificity of oncological therapy. However, future success in the clinic depends on enhancing antibody effector functions. Here, we suggest that target antigen selection may influence recruitment of effector cells for antibody therapy, and may improve the outcome of antibody treatment in patients. Comparing a wide range of antibodies to different B cell antigens, we found most were able to mediate antibody dependent cellular cytotoxicity (ADCC) with blood mononuclear cells (MNC). In direct contrast, however, polymorphonuclear granulocytes (PMN) from the same donors showed ADCC only with HLA class II antibodies. Based on this observation, we propose a therapeutic strategy with a combination of HLA class antibodies and G-CSF, the latter being required to increase number and activational state of neutrophils. In particular, we suggest using bispecific antibodies (BsAb) in which one arm binds to HLA class II on tumor cells, and the second to FcgammaRI on activated effector cells. The clinical potential of this approach for the treatment of B cell malignancies looks most attractive.

Animals↗

PubMed2002

The HLA class II transcriptional activator blocks the function of HIV-1 Tat and inhibits viral replication.

The expression of HLA class II genes is under the control of a transcriptional activator, CIITA, encoded by the AIR-1 locus. Here we show that CIITA inhibits HIV-1 LTR transactivation mediated by Tat. The inhibition occurred when CIITA and Tat were transiently expressed in cells after transfection and, most importantly, when tat cDNA was transfected in cells expressing CIITA in a constitutive fashion and at physiological levels. Furthermore, CIITA inhibited the HIV-1 LTR transactivation mediated by extracellular Tat protein. CIITA inhibition of Tat function could be reversed by overexpression of Cyclin T1, the cellular cofactor used by Tat to facilitate elongation of viral transcripts. CIITA inhibition of Tat function had a dramatic effect on HIV-1 productive infection of human T cells because CIITA(+) T cells supported very poorly, if any, viral replication. These results indicate that sustained expression of CIITA in HIV-1-susceptible targets may down-regulate viral expression both in cells actively replicating the virus and in silently infected cells requiring exogenous Tat to reactivate virus from latency.

Gene Products, tat↗

PubMed1999

IL-12 directly up-regulates the expression of HLA class I, HLA class II and ICAM-1 on human melanoma cells: a mechanism for its antitumor activity?

IL-12 enhances cytolytic activity and proliferation of NK and T cells, and induces cytokines such as IFN-gamma. No direct effects on non-hematopoietic cells have been shown. This study investigates the effects of IL-12 on melanoma cells in vitro. We analyzed 15 melanoma cell cultures and 1 melanoma cell line. Out of 16 samples 13 expressed the beta chain of the IL-12 receptor (IL-12Rbeta). Preincubation with IL-12 increased the surface levels of human leukocyte antigen (HLA) class I, HLA class II and intercellular adhesion molecule (ICAM)-1 of those cultures with IL-12Rbeta expression. The effects of IL-12 on HLA class I could be blocked by an IL-12-neutralizing monoclonal antibody (mAb), but not by an mAb against IFN-gamma. Melanoma cells transduced with IL-12 expressed enhanced levels of HLA class I, HLA class II and ICAM-1 compared to controls. Co-incubation of the melanoma cells with allogeneic peripheral blood mononuclear cells (PBMC) resulted in enhanced proliferation and increased production of IL-2 and IFN-gamma after pretreatment with IL-12. IL-12 pretreatment increased the susceptibility of melanoma cells to lysis by prestimulated autologous PBMC. Since IL-12 induced immunocritical surface molecules on melanoma cells, it might be beneficial during immune interventions in melanoma patients.

Antibodies, Monoclonal↗

PubMed1990

Human peripheral blood dendritic cells concentrate in contrast to monocytes intracellular HLA class II molecules in a juxtanuclear position.

The localization of histocompatibility antigens of the HLA-D locus in dendritic cells (DC) and monocytes (Mo) isolated from human peripheral blood was investigated. Functionally DC were characterized by their capacity to act as strong stimulators in an allogeneic mixed leucocyte reaction. In cytospins, DC were differentiated from Mo by dendritic morphology, strong HLA class II and moderate RFD1 expression on the plasma membrane and acid phosphatase activity in a juxtanuclear spot. Ultrathin cryosections showed that DC had a heavily labelled plasma membrane for HLA-D. In addition, these antigens were found in intracellular vesicles predominantly located in the juxtanuclear zone. This pattern of labelling was not seen in Mo. Obviously, DC concentrate intracellular class II antigens in the same area as lysosomal activity. These results may indicate that this juxtanuclear area is a center of antigen processing in DC.

Acid Phosphatase↗

PubMed1991

HLA class II specificities and haplotypes in South Africa detected using polymerase chain reaction and sequence-specific oligonucleotide typing.

DNA sequencing of HLA class II alleles has revealed a degree of polymorphism much greater than was expected on the basis of the standard serological typing methods. Amplification of the polymorphic second exon of the class II genes using the polymerase chain reaction, followed by hybridization with sequence-specific oligonucleotide probes, allows the unambiguous identification of alleles which could not be detected previously. Using the protocols of the Eleventh International Histocompatibility Workshop, we have applied this procedure for the typing of several individuals and their families with suspected alleles that had been observed using serology, cellular typing and restriction fragment length polymorphism (RFLPs). These included an allele related to DRw8 and DRw14, which has only been observed in the mixed ancestral South African population. In addition, unusual combinations of class II genes forming unique haplotypic associations were seen.

Alleles↗

PubMed2000

Anti-ganglioside antibodies in a large cohort of European patients with systemic lupus erythematosus: clinical, serological, and HLA class II gene associations. European Concerted Action on the Immunogenetics of SLE.

OBJECTIVE: To assay anti-ganglioside antibodies (aGM1) in sera of a large cohort of European patients with systemic lupus erythematosus (SLE) to define the prevalence of these autoantibodies in SLE; to evaluate the association of aGM1 with clinical manifestations and other autoantibodies found in SLE; and to search for aGM1 association with HLA class II alleles. METHODS: Four hundred forty-eight patients with SLE were consecutively enrolled in 8 centers from 6 European countries. All sera were tested for antinuclear antibodies by immunofluorescence on HEp-2 cells as substrate, anti-dsDNA, aGM1, aCL, abeta2-glycoprotein I (abeta2-GPI) antibodies by ELISA, and antineutrophil cytoplasmic antibodies (ANCA) by immunofluorescence and by ELISA. Genomic typing for HLA class II loci was performed by polymerase chain reaction-sequence specific oligonucleotide probe method. Clinical assessment was done at the time of enrolment. RESULTS: We found 41.9% of patients with clinical signs of neuropsychiatric involvement; 15.5% of patients were positive for aGM1, 8% of the IgG isotype and 8.6% of the IgM isotype; aGM1-IgG were associated with neuropsychiatric manifestations (NPM) (RR = 3.7), with migraine (RR = 2.4), with OBS (RR = 7.3), and with peripheral neuropathy (RR = 8.5). aGM1-IgM were associated with NPM (RR = 4) and with depression (RR = 3.4). Furthermore, the genetic study showed that aGM1-IgG were associated with HLA-DQB1*0404 (RR = 7.2) while aGM1-IgM were associated with HLA-DQB1*0605 (RR = 33.3). No associations were found between aGM1 and anti-dsDNA, aCL, abeta2GP1, or ANCA. CONCLUSION: Our results show aGM1 can be found in patients with SLE. aGM1 may play a pathogenetic role for some NPM in this condition.

Adolescent↗

PubMed1995

Binding of peptides of the human acetylcholine receptor alpha-subunit to HLA class II of patients with myasthenia gravis.

MG is an autoimmune disease in which T cells specific to T-cell epitopes of the human acetylcholine receptor play a role. We have identified two peptides, p195-212 and p259-271, of the human acetylcholine receptor alpha-subunit, to which PBLs of MG patients responded by proliferation. Nevertheless, proliferation assays are relatively complicated to perform and might be affected by medications taken by the patients. Therefore, we tested the possibility of using a different assay to determine recognition of these peptides by MG patients. Thus, we performed a direct binding assay using biotinylated peptides and APCs from peripheral blood of MG patients and healthy controls. With this assay we detected the binding of the two peptides to the surface of intact APCs of both MG patients and control donors. Moreover, the presentation of peptide p259-271 by individuals with MG was significantly higher than that observed in healthy subjects. The peptides were specifically bound to HLA class II determinants on the APCs, as shown by inhibition with antibodies to the HLA class II haplotypes of the individuals investigated. Moreover, the binding of these peptides was in correlation with their ability to induce specific proliferative responses of peripheral blood T cells of these patients. The ability to screen for potentially pathogenic epitopes in each patient is of importance for the future design of specific inhibitory analogues that might be used to treat MG.

Amino Acid Sequence↗