Expression levels of HLA-DRB and HLA-DQ are associated with MHC Class II haplotypes in healthy individuals and rheumatoid arthritis patients

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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Haplotype-Specific Expression Analysis of MHC Class II Genes in Healthy Individuals and Rheumatoid Arthritis Patients

Frontiers in Immunology ◽

10.3389/fimmu.2021.707217 ◽

2021 ◽

Vol 12 ◽

Author(s):

Miranda Houtman ◽

Espen Hesselberg ◽

Lars Rönnblom ◽

Lars Klareskog ◽

Vivianne Malmström ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Gene Expression ◽

T Cells ◽

Mhc Class Ii ◽

Immune Cells ◽

Mononuclear Cells ◽

Class Ii ◽

Differentially Expressed ◽

Healthy Individuals ◽

Hla Dq

HLA-DRB1 alleles have been associated with several autoimmune diseases. For anti-citrullinated protein antibody positive rheumatoid arthritis (RA), HLA-DRB1 shared epitope (SE) alleles are the major genetic risk factors. In order to study the genetic regulation of major histocompatibility complex (MHC) Class II gene expression in 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, thus HLA-DRB1 SE alleles have a strong cis effect on gene expression. 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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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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Abstract 095: CD74 Deficient Mice are Resistant to Toll-Like Receptor-Induced Preeclampsia

Hypertension ◽

10.1161/hyp.64.suppl_1.095 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Mohamad Hatahet ◽

Olga Y Gasheva ◽

Valorie L Chiasson ◽

Piyali Chatterjee ◽

Kelsey R Bounds ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Endothelial Dysfunction ◽

Mhc Class Ii ◽

Immune Cells ◽

Immune Cell ◽

Class Ii ◽

Poly I:C ◽

Hypertensive Disorder ◽

Toll Like Receptor

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder characterized by vascular endothelial dysfunction and excessive immunity and inflammation. Activation of the dsRNA receptor Toll-like receptor 3 (TLR3) or the ssRNA receptor TLR7 elicits a pregnancy-dependent PE-like syndrome in mice by inducing a pro-inflammatory immune response. CD74 (MHC Class II invariant chain) acts as a chaperone for MHC Class II surface expression on immune cells during antigen presentation and is cleaved into Class II-Associated Invariant Peptide (CLIP) following polyclonal activation of immune cell TLRs. The presence of CLIP in the groove of MHC Class II prevents T cell-dependent death leading to persistent immune cell activation. We hypothesized that genetic deletion of CD74 and subsequent depletion of CLIP on immune cells prevents TLR-induced immune responses and the development of PE in mice. Pregnant WT and CD74 KO mice were given i.p. injections of normal saline (P), poly I:C (TLR3 agonist; P-PIC), or R837 (TLR7 agonist; P-R837) on gestational days 13, 15, and 17 and euthanized on day 18. P-PIC and P-R837 WT mice had significantly increased splenic levels of pro-inflammatory CD3+/gd T cells and plasma levels of the gd T cell-derived cytokines IFNg, TNFa, and IL-17 compared to P WT mice whereas P-PIC and P-R837 CD74 KO mice had significantly increased anti-inflammatory CD3+/gd T cells and no significant increases in plasma IFNg, TNFa, and IL-17 levels. P-PIC and P-R837 CD74 KO mice did not develop the hypertension (gd17 SBP in mmHg: P WT=102±3, P CD74 KO=100±3, P-PIC WT=147±4*, P-PIC CD74 KO=95±3, P-R837 WT=133±2*, P-R837 CD74 KO=97±1; *p<0.05 vs. P WT), endothelial dysfunction, proteinuria, or placental necrosis seen in P-PIC and P-R837 WT mice. In conclusion, CD74 is crucial for the development of TLR-induced PE-like symptoms in mice and CD74/CLIP depletion may be a promising therapeutic target for women with PE.

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Hyperactivation of gp130-mediated STAT3 signaling induces a rheumatoid arthritis-like disease that is dependent on MHC class II restricted CD4+ T cells

International Congress Series ◽

10.1016/j.ics.2005.07.096 ◽

2005 ◽

Vol 1285 ◽

pp. 207-211

Author(s):

Masaaki Murakami ◽

Shin-ichiro Sawa ◽

Daisuke Kamimura ◽

Hokuto Kamon ◽

Hidemitsu Kitamura ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Mhc Class Ii ◽

Cd4 T Cells ◽

Class Ii ◽

Stat3 Signaling

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Comprehensive Analysis of CD4+ T Cell Response Cross-Reactive to SARS-CoV-2 Antigens at the Single Allele Level of HLA Class II

Frontiers in Immunology ◽

10.3389/fimmu.2021.774491 ◽

2022 ◽

Vol 12 ◽

Author(s):

You-Seok Hyun ◽

Yong-Hun Lee ◽

Hyeong-A Jo ◽

In-Cheol Baek ◽

Sun-Mi Kim ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

Class Ii ◽

Hla Class Ii ◽

T Cell Response ◽

Hla Dr ◽

Hla Dq ◽

Single Allele ◽

Human Coronaviruses

Common human coronaviruses have been circulating undiagnosed worldwide. These common human coronaviruses share partial sequence homology with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); therefore, T cells specific to human coronaviruses are also cross-reactive with SARS-CoV-2 antigens. Herein, we defined CD4+ T cell responses that were cross-reactive with SARS-CoV-2 antigens in blood collected in 2016–2018 from healthy donors at the single allele level using artificial antigen-presenting cells (aAPC) expressing a single HLA class II allotype. We assessed the allotype-restricted responses in the 42 individuals using the aAPCs matched 22 HLA-DR alleles, 19 HLA-DQ alleles, and 13 HLA-DP alleles. The response restricted by the HLA-DR locus showed the highest magnitude, and that by HLA-DP locus was higher than that by HLA-DQ locus. Since two alleles of HLA-DR, -DQ, and -DP loci are expressed co-dominantly in an individual, six different HLA class II allotypes can be used to the cross-reactive T cell response. Of the 16 individuals who showed a dominant T cell response, five, one, and ten showed a dominant response by a single allotype of HLA-DR, -DQ, and -DP, respectively. The single allotype-restricted T cells responded to only one antigen in the five individuals and all the spike, membrane, and nucleocapsid proteins in the six individuals. In individuals heterozygous for the HLA-DPA and HLA-DPB loci, four combinations of HLA-DP can be expressed, but only one combination showed a dominant response. These findings demonstrate that cross-reactive T cells to SARS-CoV-2 respond with single-allotype dominance.

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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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Differences of IL-1βReceptors Expression by Immunocompetent Cells Subsets in Rheumatoid Arthritis

Mediators of Inflammation ◽

10.1155/2015/948393 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 7

Author(s):

Alina A. Alshevskaya ◽

Julia A. Lopatnikova ◽

Nadezhda S. Shkaruba ◽

Oksana A. Chumasova ◽

Aleksey E. Sizikov ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Immune Cells ◽

Cell Subset ◽

Receptor Expression ◽

Healthy Individuals ◽

Relative Percentage ◽

Before And After ◽

Anticytokine Therapy ◽

Membrane Bound

IL-1βis involved in the induction and maintenance of chronic inflammation in rheumatoid arthritis (RA). Its activity is regulated and induced by soluble and membrane-bound receptors, respectively. The effectiveness of the cytokine depends not only on the percentage of receptor-positive cells in an immunocompetent subset but also on the density of receptor expression. The objective of this study was to investigate the expression of IL-1βmembrane-bound receptors (IL-1R1 and IL-1R2) in terms of the percentage of receptor-positive cells and the number of receptors per cell in different subsets of immune cells in RA patients before and after a course of basic (excluding anticytokine) therapy and in healthy individuals. The resulting data indicate differences in the expression of IL-1βreceptors among T cells, B cells, and monocytes in healthy volunteers and in rheumatoid arthritis patients. The importance of determining both the relative percentage of cells expressing receptors to immunomodulatory cytokines and the number of membrane-bound receptors per cell is highlighted by evidence of unidirectional or multidirectional changing of these parameters according to cell subset and health status.

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HLA-DR alleles differ in their ability to present staphylococcal enterotoxins to T cells.

Journal of Experimental Medicine ◽

10.1084/jem.172.3.709 ◽

1990 ◽

Vol 172 (3) ◽

pp. 709-717 ◽

Cited By ~ 156

Author(s):

A Herman ◽

G Croteau ◽

R P Sekaly ◽

J Kappler ◽

P Marrack

Keyword(s):

T Cells ◽

Mhc Class Ii ◽

Class Ii ◽

Human Class ◽

Staphylococcal Enterotoxins ◽

Histocompatibility Complex ◽

Hla Dr ◽

Specific Manner ◽

Class Ii Antigens ◽

Mhc Class Ii Molecules

Staphylococcal enterotoxins (SEs) have been shown to bind to major histocompatibility complex (MHC) class II proteins and stimulate T cells in a V beta-specific manner, and these V beta specificities for various SEs have been well documented in mice and humans. This study was undertaken in order to examine the ability of human class II molecules to present SEs to human and murine T cell hybridomas. Using a panel of transfectants expressing individual HLA class II antigens, we have shown that HLA-DR alleles differ in their ability to bind and present SEs. Since the HLA-DR proteins share a common alpha chain, these results indicate that the polymorphic beta chain plays an important role in SE binding and presentation to T cells. In addition, we have shown that human class II isotypes markedly differ in their ability to present SEs. The results of this study should provide information on the region of MHC class II molecules that interacts with foreign, and perhaps self, super-antigens.

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HLA-DR polymorphism affects the interaction with CD4.

Journal of Experimental Medicine ◽

10.1084/jem.182.3.733 ◽

1995 ◽

Vol 182 (3) ◽

pp. 733-741 ◽

Cited By ~ 25

Author(s):

S Fleury ◽

J Thibodeau ◽

G Croteau ◽

N Labrecque ◽

H E Aronson ◽

...

Keyword(s):

T Cells ◽

Mhc Class Ii ◽

Cd4 T Cells ◽

Class Ii ◽

Functional Assay ◽

Allelic Polymorphism ◽

Potential Contribution ◽

Hla Dr ◽

Peptide Binding Groove ◽

Mhc Class Ii Molecules

Major histocompatibility complex (MHC) class II molecules are highly polymorphic and bind peptides for presentation to CD4+ T cells. Functional and adhesion assays have shown that CD4 interacts with MHC class II molecules, leading to enhanced responses of CD4+ T cells after the activation of the CD4-associated tyrosine kinase p56lck. We have addressed the possible contribution of allelic polymorphism in the interaction between CD4 and MHC class II molecules. Using mouse DAP-3-transfected cells expressing different isotypes and allelic forms of the HLA-DR molecule, we have shown in a functional assay that a hierarchy exists in the ability of class II molecules to interact with CD4. Also, the study of DR4 subtypes minimized the potential contribution of polymorphic residues of the peptide-binding groove in the interaction with CD4. Chimeras between the DR4 or DR1 molecules, which interact efficiently with CD4, and DRw53, which interacts poorly, allowed the mapping of polymorphic residues between positions beta 180 and 189 that can exert a dramatic influence on the interaction with CD4.

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