Inflammatory arthritis is a highly debilitating and chronic immunological disease that results in pain and progressive destruction of the joints. Most arthritic syndromes are presumed polygenetic diseases with unknown etiologies. A prevailing theory is that in the context of genetic predisposition, environmental microbes trigger innate immunity in order to induce inflammatory disease. The preponderance of research to date has focused on adaptive and T cell responses in arthritis, with little being understood of what innate signals precede the activation of arthritis-causing T cells in the induction of disease. A recently identified gene NOD has unveiled important insight into the genetics involved in arthritis. A single base-pair change i NOD2 results in 100% penetrance of a disease called Blau syndrome wherein patients develop arthritis that is accompanied by inflammation of the eyes and skin. NOD2 belongs to the NOD-like receptor (NLR) family of pattern recognition receptors (PRRs) and is an important aspect of host defense against microbial pathogens, thereby suggesting an intriguing connection between microbial sensing and chronic inflammatory disease. To explore the role of NOD2 in arthritis, we chose to use disease modeled in the genetically susceptible SKG mouse strain because they develop a chronic, T cell-mediated arthritis that is induced by exposure to microbial triggers. In SKG mice, a spontaneous point mutation that perturbs T cell receptor signaling results in impaired positive and negative selection and enhanced production of autoreactive T cells. While arthritis in SKG mice is related to aberrant T cell responses, its initiation depends on innate immune mechanisms that activate the C- type lectin receptors (CLR), a class of PRRs known to be involved in host defense against fungal and mycobacterial infections. We crossed the NOD2 KO mice to the SKG mice and discovered that SKG mice deficient in NOD2 expression developed an exacerbated form of arthritis triggered by curdlan, which activates the CLR, Dectin-1. The three aims proposed relate to the hypothesis central of this application: NOD2 is an important determinant of arthritis susceptibility through regulation of immunological responses triggered by microbial activation of CLRs. We will: 1) Define how NOD2 expression influences the onset and development of arthritis triggered by curdlan in SKG mice, which includes how NOD2 expression influences inflammatory responses within the joint; 2) Elucidate the deleterious effects of NOD2-deficiency on arthritogenic T cell effector and regulatory responses that are involved in arthritis; 3) Determine whether the CARD9 pathway is essential for induction of arthritis in SKG mice and delineate the proximal CLRs central to arthritis regulated by NOD2 expression. That we have identified an innate immune receptor involved in a T cell- dependent disease may be an important clue into a powerful mechanism that has evolved to protect the joint from inflammation. Understanding the signaling mechanisms utilized by innate immune receptors such as CLRs and the effects of collaboration with NOD2, is an important question that needs to be addressed if the role of this receptor in arthritis is to be fuly understood. Results of the proposed studies delving into the mechanisms through which these innate immune pathways operate could open up new avenues for development of therapies for Blau syndrome and potentially also for other autoinflammatory, arthritic conditions.
The complexity of inflammatory arthritis has presented considerable challenges towards understanding its pathogenesis and identification of novel therapeutic treatments. Especially relevant to the VA patient care mission is that arthritis is on the rise in the armed forces with a much higher rate of incidence occurring at younger ages compared to civilians. We propose studies based on our exciting discovery of a novel role for the innate immune sensor NOD2 and the revelation of a previously unconsidered family of innate immune sensors, CLRs, in arthritis development in the genetically predisposed SKG mice. The knowledge gained from this proposed body of work could offer unique insights into the function of a gene, NOD2, that when mutated directly results in arthritis. Therefore, understanding gained in this application of the disease mechanisms through which environmental triggers and NOD2 operate could have important therapeutic potential in rheumatology and other disciplines.
|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|
|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|