Arthritis, a chronic immune-mediated disease involving painful destruction of the joints, presents a considerable medical challenge to our US Veteran population due to incomplete understanding of its pathogenesis. An emerging paradigm proposes that self-reactive (or autoreactive) T cells influenced by genetic-environmental interactions initiate and perpetuate disease. Understanding how these factors contribute to generation of autoreactive T cells and their subsequent expansion and ability to cause disease is centrally important in determining the etiology of arthritis. This project aims to address this critical question in the field of autoimmunity by focusing on the relationships between autoreactive T cells, the epithelial cells within the thymus, and the innate immune receptor Nod2. T cell development and ?education? occurs within the thymus, a primary lymphoid organ that serves a critical role in eliminating self-reactive T cells and preventing autoimmune disease. In the unfortunate event that autoreactive T cells leave the thymus and enter the periphery, they can become activated and differentiate into IL-17-secreting T cells (Th17 cells), a subset of cells known to cause arthritis. The proposed studies utilize a unique experimental mouse model of arthritis in SKG mice, which are genetically predisposed to produce autoreactive T cells (due to impaired selection within the thymus). We have expanded on the SKG model by genetically-modifying mice to also lack expression of Nod2, which has uncovered an entirely novel role for the innate immune receptor Nod2 in protection against of arthritis. This discovery bears clinical relevance to humans, as patients with mutations in NOD2 develop an inherited form of arthritis called Blau syndrome. Nod2 is a member of the cytosolic NOD-like receptor (NLR) family of innate immune receptors known to directly sense microbial, or foreign, motifs within the body. By understanding how Nod2 regulates autoreactive T cells in arthritis, we hope to better understand how extrinsic, or environmental, signals can contribute to clinical arthritis; thereby specifically investigating how a genetically determined shift of T cell-repertoire coupled with environmental stimuli facilitates the differentiation of autoreactive Th17 cells and drives disease. These findings, in both humans and rodents, underscore an essential homeostatic role for Nod2 in joint disease; the key observation we have made linking Nod2 specifically with control over T cell responses in arthritis, is the basis of this application. The goal of this application is two-fold: (1) To determine whether Nod2 influences development arthritogenic T cells within the thymus; and (2) To elucidate the immunoregulatory effects of Nod2 on peripheral activation of arthritogenic Th17 cells that cause arthritis. Experiments have been designed to examine T cell-intrinsic functions of Nod2 at the cellular and molecular level as well as in vivo functionality of peripheral versus thymic control over Nod2- mediated protection against autoimmune arthritis. The proposed studies provide us with a solid framework to test the central hypothesis that: Nod2 is an important immunomodulator of autoreactive T cells that cause arthritis. By studying how Nod2 suppresses arthritis, we hope to identify endogenous immune-control mechanisms that can be harnessed to control autoreactive T cell responses in patients suffering from arthritis. Ultimately, this project could yield findings that make a meaningful impact on future development of treatment strategies to improve the health of veterans.
Arthritis is a painful and chronic immune-mediated disease that progressively destroys joints and is the leading cause of disability in the US. One in three veterans is affected by arthritis, with more veterans reporting arthritis than nonveterans within most sociodemographic classifications. Thus, our veterans, who already face unique challenges upon re-entering civilian life, can also suffer substantial personal, social, and economic burdens associated with arthritis. Furthermore, the comorbidity of ophthalmic disease, cardiovascular risk, and interstitial lung disease in arthritic patients presents additional medical and life challenges throughout veterans? lifespans. This research application seeks to probe basic fundamental mechanisms of how T cells ?turn rogue? and cause arthritis, with the hope that our novel perspective will produce findings that ultimately have a meaningful impact on the future development of therapies for patients suffering from arthritis. If successful, such therapeutics could improve the overall health of our veterans.
|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|