Herpesvirus Entry Mediator-Ig Treatment during Immunization Aggravates Rheumatoid Arthritis in the Collagen-Induced Arthritis Model

Pierer, Matthias; Schulz, Anja; Rossol, Manuela; Kendzia, Eva; Kyburz, Diego; Haentzschel, H; Baerwald, C.; Wagner, Ulf

doi:10.4049/jimmunol.0713715

Cited by 30 publications

(23 citation statements)

References 37 publications

(41 reference statements)

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“…This study demonstrated the stimulatory role of HVEM in EAU through the induction of Th1-and Th17-type T cell responses and suggested its potential as a therapeutic target. This finding is not necessarily consistent with previous studies, because HVEM has been reported to mediate suppressive effects, serving as a ligand to deliver BTLA inhibitory cosignals, in autoimmune models including EAE, hepatitis, and rheumatoid arthritis (23,24). In order to exclude the possibility that HVEM-KO mice in our animal facility exhibited variable phenotypes for undetermined reasons such as microbiomes, we examined EAE severity in HVEM-KO mice in our facility.…”

Section: Discussionsupporting

confidence: 49%

“…Thus, severity of these diseases is attenuated by knockout of the HVEM gene or by treatment with anti-HVEM-neutralizing mAbs. However, deficiency or blocking of HVEM exacerbates severity of ConA-induced hepatitis, experimental autoimmune encephalomyelitis (EAE), and collageninduced arthritis (23,24), indicating inhibitory functions of HVEM in these autoimmune diseases. Thus far, it remains unexplored whether HVEM plays a stimulatory or inhibitory role in the pathogenesis of uveitis and, if any, how it regulates the pathology.…”

mentioning

confidence: 99%

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Pathogenic Function of Herpesvirus Entry Mediator in Experimental Autoimmune Uveitis by Induction of Th1- and Th17-Type T Cell Responses

Sakoda

Nagai

Murata

et al. 2016

The Journal of Immunology

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Herpesvirus entry mediator (HVEM), a member of the TNFR superfamily, serves as a unique molecular switch to mediate both stimulatory and inhibitory cosignals, depending on its functions as a receptor or ligand interacting with multiple binding partners. In this study, we explored the cosignaling functions of HVEM in experimental autoimmune uveitis (EAU), a mouse model resembling human autoimmune uveitis conditions such as ocular sarcoidosis and Behcet disease. Our studies revealed that EAU severity significantly decreased in HVEM-knockout mice compared with wild-type mice, suggesting that stimulatory cosignals from the HVEM receptor are predominant in EAU. Further studies elucidated that the HVEM cosignal plays an important role in the induction of both Th1- and Th17-type pathogenic T cells in EAU, including differentiation of IL-17–producing αβ+γδ− conventional CD4+ T cells. Mice lacking lymphotoxin-like, inducible expression, competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT), B- and T-lymphocyte attenuator (BTLA) or both LIGHT and BTLA are also less susceptible to EAU, indicating that LIGHT–HVEM and BTLA–HVEM interactions, two major molecular pathways mediating HVEM functions, are both important in determining EAU pathogenesis. Finally, blocking HVEM cosignals by antagonistic anti-HVEM Abs ameliorated EAU. Taken together, our studies revealed a novel function of the HVEM cosignaling molecule and its ligands in EAU pathogenesis through the induction of Th1- and Th17-type T cell responses and suggested that HVEM-related molecular pathways can be therapeutic targets in autoimmune uveitis.

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Section: Discussionsupporting

confidence: 49%

mentioning

confidence: 99%

Pathogenic Function of Herpesvirus Entry Mediator in Experimental Autoimmune Uveitis by Induction of Th1- and Th17-Type T Cell Responses

Sakoda

Nagai

Murata

et al. 2016

The Journal of Immunology

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“…Inhibition via BTLA is known to compromise T cell-mediated immunity in mice (17,19,21,37,38). Our data demonstrate that BTLA inhibits T cell function in humans, as it does in mice, suggesting that BTLA may compromise T cell-mediated protection from infection and cancer in humans.…”

Section: Discussionmentioning

confidence: 55%

BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination

Derré¹,

Rivals²,

Jandus³

et al. 2010

J. Clin. Invest.

252

246

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The function of antigen-specific CD8 + T cells, which may protect against both infectious and malignant diseases, can be impaired by ligation of their inhibitory receptors, which include CTL-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1). Recently, B and T lymphocyte attenuator (BTLA) was identified as a novel inhibitory receptor with structural and functional similarities to CTLA-4 and PD-1. BTLA triggering leads to decreased antimicrobial and autoimmune T cell responses in mice, but its functions in humans are largely unknown. Here we have demonstrated that as human viral antigen-specific CD8 + T cells differentiated from naive to effector cells, their surface expression of BTLA was gradually downregulated. In marked contrast, human melanoma tumor antigen-specific effector CD8 + T cells persistently expressed high levels of BTLA in vivo and remained susceptible to functional inhibition by its ligand herpes virus entry mediator (HVEM). Such persistence of BTLA expression was also found in tumor antigen-specific CD8 + T cells from melanoma patients with spontaneous antitumor immune responses and after conventional peptide vaccination. Remarkably, addition of CpG oligodeoxynucleotides to the vaccine formulation led to progressive downregulation of BTLA in vivo and consequent resistance to BTLA-HVEM-mediated inhibition. Thus, BTLA activation inhibits the function of human CD8 + cancer-specific T cells, and appropriate immunotherapy may partially overcome this inhibition.

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“…Therefore, bidirectional signaling is possible for the HVEM-mediated signaling network, which can be involved in positive or negative immunological reactions under different contexts. [15][16][17] HVEM has been reported to influence diverse immune responses on mucosal surfaces and elsewhere, including models of airway inflammation, 18 autoimmune diabetes, 19,20 concanavalin A-mediated hepatitis, 21,22 autoimmune encephalopathy, 22 collagen-induced arthritis 23 and colitis models induced by either overexpression of a HVEM ligand in transgenic mice, 24 exposure to chemicals such as 2,4,6-trinitrobenzenesulfonic acid (TNBS) or dextran sodium sulfate (DSS) or transfer of naïve CD4 + CD45RB high T cells to immune deficient mice. [25][26][27] Depending on the context, the role of HVEM in these studies could be either pro-inflammatory, 18,19,25,26 or antiinflammatory.…”

Section: Hvemmentioning

confidence: 99%

“…[25][26][27] Depending on the context, the role of HVEM in these studies could be either pro-inflammatory, 18,19,25,26 or antiinflammatory. 22,23,26 This dichotomy in outcomes probably reflects the fact that HVEM has multiple molecules it can interact with. These HVEM interacting ligands include Ig superfamily proteins with inhibitory function such as the B and T Lymphocyte attenuator (BTLA or CD272) and CD160, as well as LIGHT, also known as TNF superfamily member 14 (TNFSF14) or CD258 (Fig.…”

Section: Hvemmentioning

confidence: 99%

Hvem

Shui

Kronenberg

2013

Gut Microbes

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Herpesvirus Entry Mediator-Ig Treatment during Immunization Aggravates Rheumatoid Arthritis in the Collagen-Induced Arthritis Model

Cited by 30 publications

References 37 publications

Pathogenic Function of Herpesvirus Entry Mediator in Experimental Autoimmune Uveitis by Induction of Th1- and Th17-Type T Cell Responses

Pathogenic Function of Herpesvirus Entry Mediator in Experimental Autoimmune Uveitis by Induction of Th1- and Th17-Type T Cell Responses

BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination

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