Poster presenter: Ruth J. Napier, Ph.D, assistant professor, Oregon Health & Science University
Poster title: Card9 Promotes Th17-mediated Arthritis and Spondylitis via Control of Acute Pathogenic Neutrophil Responses in SKG Mice
Scheduled poster session day and time: Saturday, Nov. 7, 9 – 11 a.m. EST
What is your poster about?
Our data reveal a new role for Card9, an adaptor protein that signals downstream of C-type lectin receptors including Dectin-1, in driving pathogenic neutrophil responses that promote experimental arthritis and spondylitis in SKG mice. SKG mice have a single point mutation in Zap-70, an essential TCR-signaling molecule, that results in hyporesponsive signaling initiated by TCRx and CD3 chains. As a consequence, thymic development of T cells is compromised, resulting in the aberrant production of autoreactive T cells that cause arthritis. Whereas in SKG mice exposure to β-glucans (zymosan) results in a chronic and sustained CD4+ T cell-mediated arthritis, we found that SKG mice lacking Card9 (Card9-/-SKG) were completely resistant to disease. At eight weeks post-zymosan when arthritis in SKG mice is well-established, Card9-/-SKG mice had dramatic reductions in two particular types of immune cells: CD4+ T cells that produce the cytokine IL-17 (Th17 cells) and neutrophils. Given these data we asked whether the reduced Th17 response and lack of arthritis in Card9-/-SKG mice was due to preceding dysregulated Card9-mediated neutrophil responses. We found that as early as 4 hours post-zymosan exposure, Card9-/-SKG mice had reduced neutrophil responses in the peritoneum (the site of injection), including decreased total numbers, activation status, and exocytosis of secondary and primary granules. These data indicated that defective neutrophil responses in Card9 mice blocked progression of disease, suggesting a critical role for neutrophils in disease initiation in the SKG model. To directly test if neutrophil responses were necessary for development of autoreactive Th17 cells and arthritis in SKG mice, we performed in vivo neutrophil depletion experiments. Indeed, SKG mice lacking neutrophils mimic the lack of disease and Th17 responses seen in Card9-/-SKG mice, indicating that Card9-mediated neutrophil responses are necessary for the induction of autoreactive Th17 responses and development of arthritis. This work will open new avenues of study pertaining to how neutrophils and the Card9 pathway control autoimmune arthritis and contribute to innovative therapies for autoimmune conditions such as ankylosing spondylitis, which are currently served by very few effective pharmacologic agents.
Why did you decide to investigate this topic?
We were interested in understanding the immunological mechanism(s) by which Card9 controls spondylitis, given the known genetic association between Card9 and ankylosing spondylitis. We were additionally curious to know more about how Card9 might control disease in SKG mice given that autoimmunity is induced in SKG mice by fungal triggers and Card9 is a signaling mediator downstream of several fungal recognition receptors.
What excites you most about your work?
The most exciting part about these data is the link we have found between Card9-mediated neutrophil responses and initiation of Th17-mediated arthritis. These data provide one plausible cellular mechanism wherein an environmental trigger such as fungus might trigger disease in a genetically predisposed individual, such as Card9 variant. Evidence in the literature suggests that increased neutrophil responses in autoimmune diseases, including rheumatoid arthritis and ankylosing spondylitis, are correlated with enhanced Th17 responses and disease severity, but the mechanism is largely unknown. Our data suggest Card9 might be one molecule mediating this critical neutrophil/arthritis link. More research on this pathway may help us understand disease initiation and the general pathophysiology of some autoimmune diseases.