Innate immunity, as the first line of defense against microbial pathogens, is a response that must be tightly regulated or excessive inflammation will ensue, causing disease. For an optimal therapeutic approach, we need to not only understand basic mechanisms of initiation and early events that lead to disease but importantly, how the body protects itself from aberrant immune responses that can trigger autoimmunity. Uveitis (intraocular inflammation), which occurs in association with a number of systemic immunological diseases, presents a considerable medical challenge due to incomplete understanding of its pathogenesis. The gene NOD2 may provide an important clue into uveitis because a single point mutation results in a rare, inflammatory disease called Blau syndrome, which manifests as granulomatous uveitis. NOD2 belongs to a family of innate immune receptors termed NOD-like receptors (NLRs), which are intracellular sensors involved in host defense against invading pathogens. Since no other single gene has been identified as a singular cause of uveitis, analysis of NOD2-pathways could offer important insight into the underlying mechanisms controlling ocular inflammation. To understand how the endogenous, innate immune receptor NOD2 participates in orchestration of autoimmune responses, we undertook studies using experimental autoimmune uveitis (EAU), a prototypical T cell-mediated autoimmune disease model of the eye. Our preliminary studies led us to the unanticipated discovery that NOD2 deficiency renders mice susceptible to EAU; thereby identifying NOD2 as a major genetic susceptibility factor in autoimmune uveitis. Objectives outlined in this grant will test the centra hypothesis of this proposal that NOD2 is important for maintaining ocular immunological homeostasis by preventing aberrant responses that predispose to autoimmune disease of the eye by: (1) Maintaining proper regulation of T cell effector responses and diverting a pathogenic Th17-effector response; (2) Interpreting microenvironment cues within the eye by controlling the physiological state of microglia; and (3) Minimizing tissue damage caused by hypersensitivity responses involving the Fc-gamma receptor (FcgR) and complement systems that occur in the context of antibody-related activation. The goal of this project is to address currently unanswered questions within the field pertaining to the influence of innate immune receptors and orchestration of autoreactive T cell-driven responses. By focusing on aspects of how NOD2 controls early and innate reactions that exist at the interface of innate and adaptive immunity we hope to identify ways to enhance protective innate defenses within the eye while avoiding maladaptive effects of inflammatory pathology, as a potential novel strategy for therapeutic intervention for uveitis and other potentially vision-threatening diseases.
The complexity of uveitis has presented considerable challenges towards understanding its pathogenesis and identification of novel therapeutic treatments. We propose studies based on our exciting discovery of a novel role for the innate immune sensor NOD2 in antigen-specific uveitis in mice, which support its role in maintaining immunological homeostasis of the eye. The goal of this project is to understand the endogenous protective mechanisms by which NOD2 mediates early events involved in orchestration of autoimmunity, and therefore have potential for innovative therapies designed to prevent vision-threatening disease in patients.
|Napier, Ruth J; Lee, Ellen J; Vance, Emily E et al. (2018) Nod2 Deficiency Augments Th17 Responses and Exacerbates Autoimmune Arthritis. J Immunol 201:1889-1898|
|Brown, B R; Lee, E J; Snow, P E et al. (2017) Fungal-derived cues promote ocular autoimmunity through a Dectin-2/Card9-mediated mechanism. Clin Exp Immunol 190:293-303|
|Lee, Ellen J; Brown, Brieanna R; Vance, Emily E et al. (2016) Mincle Activation and the Syk/Card9 Signaling Axis Are Central to the Development of Autoimmune Disease of the Eye. J Immunol 196:3148-58|
|Dugan, Jae; Griffiths, Eric; Snow, Paige et al. (2015) Blau syndrome-associated Nod2 mutation alters expression of full-length NOD2 and limits responses to muramyl dipeptide in knock-in mice. J Immunol 194:349-57|
|Lee, Ellen J; Allensworth, Jordan J; Clowers, Jenna S et al. (2015) Aberrant interleukin-1 signalling does not increase susceptibility of mice to NOD2-dependent uveitis. Clin Exp Ophthalmol 43:349-57|