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

Abstract

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.

Inflammatory pathway genes associated with inter-individual variability in the trajectories of morning and evening fatigue in patients receiving chemotherapy

“…Only one SNP (i.e., TNFRSF14 rs2234163) was associated with initial levels of both morning and evening fatigue. TNFRSF14 , encodes for a protein that both activates and inhibits T-cells based on the cellular environment [133]. TNFRSF14 rs2234163 is a missense mutation that substitutes threonine for alanine.…”

Herpesvirus Entry Mediator and Ocular Herpesvirus Infection: More than Meets the Eye

“…Recently, lymphoma B cells from patients with mutations in the HVEM gene (TNFRSF14) were found to have increased alloantigen-presenting capacity in comparison to controls, corresponding to higher levels of GVHD in patients undergoing allogeneic hematopoietic stem cell transplantation (143). In murine experimental autoimmune uveitis (EAU), a model of human autoimmune conditions with ocular manifestations such as Behçet disease and sarcoidosis, HVEM was shown to increase disease severity by inducing pathogenic Th1-and Th17-type T cell responses (144). Similarly to HVEM KOs, LIGHT and BTLA KOs are protected from severe disease during EAU, suggesting that these ligands, in combination with HVEM, promote pathogenesis in EAU (144).…”

“…In murine experimental autoimmune uveitis (EAU), a model of human autoimmune conditions with ocular manifestations such as Behçet disease and sarcoidosis, HVEM was shown to increase disease severity by inducing pathogenic Th1-and Th17-type T cell responses (144). Similarly to HVEM KOs, LIGHT and BTLA KOs are protected from severe disease during EAU, suggesting that these ligands, in combination with HVEM, promote pathogenesis in EAU (144). If LIGHT and/or BTLA are the ligands involved in HSK as well, targeting HVEM signaling with antibodies or small-molecule inhibitors could produce novel therapies applicable to a variety of ocular inflammatory conditions.…”

Modern Therapeutic Approaches for Noninfectious Ocular Diseases Involving Inflammation

“…[4,204,205] The most common EAU models utilize mice and rats by actively immunizing them with retinal antigens (S-Ag or IRBP), which are recognized by lymphocytes of uveitis patients. [206] Some of the characteristics of EAU in animals are retinal vasculitis, photoreceptor damage, retinal and/or choroidal inflammation, and loss of vision function, thus reproducing the main clinical-pathological features of human uveitis.…”