NetMHCIIpan-3.0, a common pan-specific MHC class II prediction method including all three human MHC class II isotypes, HLA-DR, HLA-DP and HLA-DQ

AbstractHLA-DRB1 alleles have been associated with several autoimmune diseases. In anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), HLA-DRB1 shared epitope (SE) alleles are the major genetic risk factors. In order to investigate whether expression of different alleles of major histocompatibility complex (MHC) Class II genes influence functions of immune cells, we investigated transcriptomic profiles of a variety of immune cells from healthy individuals carrying different HLA-DRB1 alleles. Sequencing libraries from peripheral blood mononuclear cells, CD4+ T cells, CD8+ T cells, and CD14+ monocytes of 32 genetically pre-selected healthy female individuals were generated, sequenced and reads were aligned to the standard reference. For the MHC region, reads were mapped to available MHC reference haplotypes and AltHapAlignR was used to estimate gene expression. Using this method, HLA-DRB and HLA-DQ were found to be differentially expressed in different immune cells of healthy individuals as well as in whole blood samples of RA patients carrying HLA-DRB1 SE-positive versus SE-negative alleles. In contrast, no genes outside the MHC region were differentially expressed between individuals carrying HLA-DRB1 SE-positive and SE-negative alleles. Existing methods for HLA-DR allele-specific protein expression were evaluated but were not mature enough to provide appropriate complementary information at the protein level. Altogether, our findings suggest that immune effects associated with different allelic forms of HLA-DR and HLA-DQ may be associated not only with differences in the structure of these proteins, but also with differences in their expression levels.

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Supernatants of human leukocytes contain mediator, different from interferon gamma, which induces expression of MHC class II antigens.

Journal of Experimental Medicine ◽

10.1084/jem.164.1.131 ◽

1986 ◽

Vol 164 (1) ◽

pp. 131-143 ◽

Cited By ~ 28

Author(s):

G Groenewegen ◽

M de Ley ◽

G M Jeunhomme ◽

W A Buurman

Keyword(s):

Mhc Class Ii ◽

Antigen Expression ◽

Class Ii ◽

Ifn Gamma ◽

Human Leukocytes ◽

Hla Dr ◽

Hla Dq ◽

Mhc Class Ii Antigens ◽

Class Ii Antigen ◽

Mhc Class Ii Antigen

In this report, data are presented on the regulation of MHC class II antigen expression by a mediator present in supernatants of human mixed leukocyte cultures (MLC-SN), and which is different from IFN-gamma. The capacity of supernatants to induce antigen expression did not correspond to titers of IFN-gamma. Removal of IFN-gamma using either dialysis against pH 2 or neutralizing mAb against human IFN-gamma did not abrogate the MHC class II antigen expression-inducing capacity of MLC-SN when tested on adenocarcinoma cell lines, kidney epithelial cells, and fibroblasts in vitro in an indirect immunofluorescence assay. Therefore, supernatants of human leukocytes contain a mediator, different from IFN-gamma, which induces expression of MHC class II antigens. Dose-response studies revealed that the mediator is produced after allogeneic and lectin stimulation of human leukocytes, and by unstimulated leukocytes. Activation of leukocytes resulted in increased titers of the mediator. The mediator markedly enhances expression of both HLA-DR and HLA-DQ antigens, whereas IFN-gamma had a similar effect on HLA-DR antigens, and only a minor effect on HLA-DQ antigens. Interaction of the mediator and IFN-gamma resulted in a potentiating effect of these two factors on MHC class II antigen expression. Biochemical analysis revealed a mediator, distinguishable by FPLC from IL-1, IL-2, and human IFN-gamma, and which has a molecular mass of 32 kD.

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Faculty Opinions recommendation of MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726086459.793522584 ◽

2016 ◽

Author(s):

Seth Orlow

Keyword(s):

Mhc Class Ii ◽

Cytokine Production ◽

Surface Expression ◽

Class Ii ◽

Super Enhancer ◽

Hla Dr ◽

Hla Dq ◽

Autoimmune Vitiligo

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An Isotype-specific Activator of Major Histocompatibility Complex (MHC) Class II Genes That Is Independent of Class II Transactivator

Journal of Experimental Medicine ◽

10.1084/jem.185.11.1885 ◽

1997 ◽

Vol 185 (11) ◽

pp. 1885-1895 ◽

Cited By ~ 22

Author(s):

John Douhan ◽

Rebecca Lieberson ◽

Joan H.M. Knoll ◽

Hong Zhou ◽

Laurie H. Glimcher

Keyword(s):

Major Histocompatibility Complex ◽

Cell Line ◽

Mhc Class Ii ◽

Ectopic Expression ◽

Class Ii ◽

Major Histocompatibility ◽

Class Ii Transactivator ◽

Histocompatibility Complex ◽

Hla Dr ◽

Hla Dq

Patients with one type of major histocompatibility complex class II combined immunodeficiency have mutations in a gene termed class II transactivator (CIITA), which coordinately controls the transcription of the three major human class II genes, HLA-DR, -DQ, and -DP. However, the experimentally derived B-lymphoblastoid cell line, clone 13, expresses high levels of HLADQ in the absence of HLA-DR and HLA-DP, despite its mapping by complementation analysis to this group. It was possible that one of the clone 13 CIITA alleles bore a mutation that allowed HLA-DQ, but not HLA-DR or -DP transcription. Alternatively, another factor, distinct from CIITA, might control HLA-DQ expression. We report here that ectopic expression of CIITA cDNAs derived by reverse transcriptase polymerase chain reaction from clone 13 do not restore expression of HLA-DQ in another CIITA-deficient cell line, RJ2.2.5. In addition, no CIITA protein is detectable in clone 13 nuclear extracts. In contrast, somatic cell fusion between clone 13 and RJ2.2.5 restored expression of the HLA-DQ haplotype encoded by the RJ2.2.5 DQB gene. Taken together, these data demonstrate the existence of an HLA-DQ isotype-specific trans-acting factor, which functions independently of CIITA.

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MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1523482113 ◽

2016 ◽

Vol 113 (5) ◽

pp. 1363-1368 ◽

Cited By ~ 54

Author(s):

Giulio Cavalli ◽

Masahiro Hayashi ◽

Ying Jin ◽

Daniel Yorgov ◽

Stephanie A. Santorico ◽

...

Keyword(s):

High Risk ◽

Mhc Class Ii ◽

Surface Expression ◽

Class Ii ◽

Low Risk ◽

Risk Haplotype ◽

Super Enhancer ◽

Hla Dr ◽

Hla Dq ◽

Autoimmune Vitiligo

Genetic risk for autoimmunity in HLA genes is most often attributed to structural specificity resulting in presentation of self-antigens. Autoimmune vitiligo is strongly associated with the MHC class II region. Here, we fine-map vitiligo MHC class II genetic risk to three SNPs only 47 bp apart, located within a predicted super-enhancer in an intergenic region between HLA-DRB1 and HLA-DQA1, localized by a genome-wide association study of 2,853 Caucasian vitiligo patients. The super-enhancer corresponds to an expression quantitative trait locus for expression of HLA-DR and HLA-DQ RNA; we observed elevated surface expression of HLA-DR (P = 0.008) and HLA-DQ (P = 0.02) on monocytes from healthy subjects homozygous for the high-risk SNP haplotype. Unexpectedly, pathogen-stimulated peripheral blood mononuclear cells from subjects homozygous for the high-risk super-enhancer haplotype exhibited greater increase in production of IFN-γ and IL-1β than cells from subjects homozygous for the low-risk haplotype. Specifically, production of IFN-γ on stimulation of dectin-1, mannose, and Toll-like receptors with Candida albicans and Staphylococcus epidermidis was 2.5- and 2.9-fold higher in high-risk subjects than in low-risk subjects, respectively (P = 0.007 and P = 0.01). Similarly, production of IL-1β was fivefold higher in high-risk subjects than in low-risk subjects (P = 0.02). Increased production of immunostimulatory cytokines in subjects carrying the high-risk haplotype may act as an “adjuvant” during the presentation of autoantigens, tying together genetic variation in the MHC with the development of autoimmunity. This study demonstrates that for risk of autoimmune vitiligo, expression level of HLA class II molecules is as or more important than antigen specificity.

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Cytokines in chronic inflammatory arthritis. IV. Granulocyte/macrophage colony-stimulating factor-mediated induction of class II MHC antigen on human monocytes: a possible role in rheumatoid arthritis.

Journal of Experimental Medicine ◽

10.1084/jem.170.3.865 ◽

1989 ◽

Vol 170 (3) ◽

pp. 865-875 ◽

Cited By ~ 98

Author(s):

J M Alvaro-Gracia ◽

N J Zvaifler ◽

G S Firestein

Keyword(s):

Rheumatoid Arthritis ◽

Class Ii ◽

Tnf Alpha ◽

Blood Monocytes ◽

Ifn Gamma ◽

Normal Peripheral Blood ◽

Gm Csf ◽

Hla Dr ◽

Class Ii Mhc ◽

Hla Dq

Granulocyte/macrophage CSF (GM-CSF) has recently been identified in rheumatoid arthritis (RA) synovial effusions. To study a potential role for GM-CSF and other cytokines on the induction of HLA-DR expression on monocytes and synovial macrophages, we analyzed the relative ability of recombinant human cytokines to induce the surface expression of class II MHC antigens on normal peripheral blood monocytes by FACS analysis. GM-CSF (800 U/ml) (mean fluorescence channel 2.54 +/- 0.33 times the control, p less than 0.001) and IFN-gamma (100 U/ml) (5.14 +/- 0.60, p less than 0.001) were the most potent inducers of HLA-DR. TNF-alpha and IL-4 also increased HLA-DR expression, although to a lesser degree [1.31 +/- 0.06 (p less than 0.02) and 1.20 +/- 0.03 (p less than 0.01), respectively]. IL-1 (40 U/ml), IL-2 (10 ng/ml), IL-3 (50 U/ml), IL-6 (100 U/ml), and CSF-1 (1,000 U/ml) did not affect surface HLA-DR density. GM-CSF also increased HLA-DR mRNA expression and surface HLA-DQ expression, but decreased CD14 (a monocyte/macrophage antigen) expression. The effect of GM-CSF on HLA-DR was not mediated by the generation of IFN-gamma in vitro because it was not blocked by anti-IFN-gamma mAb. GM-CSF was additive with IL-4 and low amounts (less than 3 U/ml) of IFN-gamma and synergistic with TNF-alpha. Because we have recently reported that supernatants of cultured RA synovial cells produce a non-IFN-gamma factor that induces HLA-DR on monocytes, we then attempted to neutralize this factor with specific anti-GM-CSF mAb. Four separate synovial tissue supernatants were studied, and the antibody neutralized the HLA-DR-inducing factor in each (p less than 0.01).

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Congenital immunodeficiency with a regulatory defect in MHC class II gene expression lacks a specific HLA-DR promoter binding protein, RF-X

Cell ◽

10.1016/s0092-8674(88)90389-3 ◽

1988 ◽

Vol 53 (6) ◽

pp. 897-906 ◽

Cited By ~ 142

Author(s):

W. Reith ◽

S. Satola ◽

C. Herrero Sanchez ◽

I. Amaldi ◽

B. Lisowska-Grospierre ◽

...

Keyword(s):

Gene Expression ◽

Mhc Class Ii ◽

Binding Protein ◽

Class Ii ◽

Hla Dr ◽

Congenital Immunodeficiency ◽

Regulatory Defect

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Expression of MHC class II antigens (HLA-DR, -DP, and -DQ) on human gastric epithelium

Gastroenterologia Japonica ◽

10.1007/bf02775060 ◽

1992 ◽

Vol 27 (1) ◽

pp. 23-28 ◽

Cited By ~ 10

Author(s):

Nobuaki Ishii ◽

Mitsuro Chiba ◽

Masahiro Iizuka ◽

Hiroyuki Watanabe ◽

Tomonori Ishioka ◽

...

Keyword(s):

Mhc Class Ii ◽

Class Ii ◽

Gastric Epithelium ◽

Hla Dr ◽

Mhc Class Ii Antigens ◽

Class Ii Antigens

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Sequential loss of CD34 and class II MHC antigens on purified cord blood hematopoietic progenitors cultured with IL-3: characterization of CD34-, HLA-DR+ cells

Blood ◽

10.1182/blood.v74.4.1287.1287 ◽

1989 ◽

Vol 74 (4) ◽

pp. 1287-1294 ◽

Cited By ~ 33

Author(s):

C Caux ◽

C Favre ◽

S Saeland ◽

V Duvert ◽

P Mannoni ◽

...

Keyword(s):

Cord Blood ◽

Class Ii ◽

Human Cord Blood ◽

Mhc Antigens ◽

Differentiated Cells ◽

Hla Dr ◽

Class Ii Mhc ◽

Hla Dq ◽

Class Ii Mhc Antigens ◽

Cd34 Expression

Abstract The expression of class II MHC and CD34 antigens on human cord blood hematopoietic progenitor cells (HPC) was investigated upon culturing in the presence of interleukin-3 (IL-3). HPC isolated by “panning” according to their expression of CD34 coexpressed HLA-DR and HLA-DP, and the majority of the CD34+ HPC also expressed HLA-DQ. In the presence of IL-3, the expression of CD34 and class II MHC antigens was found to be gradually lost in culture. Loss of CD34 expression preceded loss of HLA-DR expression. After eight days of culture, CD34-, HLA-DR+ blast cells were obtained that strongly proliferated in response to IL- 3, GM-CSF, G-CSF, and M-CSF, and that had the capacity to generate macrophage and granulocyte colonies. After ten days of culture in IL-3, a population of CD34- cells that expressed low levels of HLA-DR (HLA- DRlo) was obtained by FACS-sorting. These CD34-, HLA-DRlo cells lacked colony-forming activity while the population expressing high levels of HLA-DR (HLA-DRhi) contained great numbers of colony-forming cells, and proliferated stronger in response to CSFs than the HLA-DRlo fraction. Finally CD34-, HLA-DR- cells that appeared later in the cultures (14 to 16 days) represented more differentiated cells with only marginal proliferative and no clonogenic capacity. These data indicate that whereas CD34 expression is associated with the multilineage potential of the HPC, HLA-DR expression correlates with overall proliferative capacity of hematopoietic cells during culture in IL-3.

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