A recent study published in Annals of Rheumatic Diseases has revealed pivotal role of the caspase recruitment domain-containing protein 9 (CARD9) /neutrophil signaling axis in promoting IL-17A-mediated ankylosing spondylitis (AS). Researchers found that polymorphisms in CARD9 are associated with an increased risk of AS, and that CARD9 plays a critical role in the activation of pathogenic Th17 cells, a subset of T cells implicated in the disease.
The study highlights CARD9, a critical antifungal signaling molecule, as a central regulator in the expansion of pathogenic Th17 cells. Using a combination of experimental murine models and clinical samples from AS patients, researchers demonstrated that CARD9 operates downstream of Dectin-1 and is essential for triggering Th17 responses and disease onset. Importantly, the study revealed that neutrophils, rather than T cells, are the primary mediators of these effects. In genetically susceptible SKG mice, CARD9 expression within neutrophils was necessary and sufficient to induce IL-17A production, driving AS-like symptoms.
Clinical data corroborated these findings, showing that neutrophils from HLA-B27-positive AS patients enhanced autologous Th17 responses, particularly in individuals with a recently diagnosed disease (<5 years). Moreover, a specific AS-associated CARD9 variant (S12N) was linked to elevated plasma IL-17A levels, further emphasizing the neutrophil-centric mechanism in AS pathogenesis.
The research offers a novel perspective on the pathogenesis of AS, emphasizing the role of neutrophils in driving Th17-mediated inflammation. The study suggests that targeting the CARD9 pathway, particularly its neutrophil-intrinsic function, could provide a promising therapeutic approach for treating AS and other spondyloarthropathies.
A similar study by Seufert et al. found that both genetic and clinical research highlight the significant role of environmental factors in triggering axial spodyloarthritis, particularly the involvement of microbes and the innate immune response. For instance, mutations in genes related to innate immunity, such as the anti-fungal signaling molecule CARD9, have been associated with an increased susceptibility to axSpA.
CARD9 is traditionally considered an important signaling molecule in antifungal immunity, and the recent study shows that its role extends far beyond infection control. CARD9 is crucial for neutrophil activation and for amplifying Th17 responses in AS. This opens new avenues for targeted therapies aimed at modulating this pathway to treat AS and potentially other autoimmune diseases.
These findings represent a significant step forward in understanding the immunological mechanisms driving AS. By uncovering a key neutrophil-dependent role for CARD9 in Th17 expansion and disease progression, the study highlights the potential for future research into CARD9-specific interventions as novel treatments for spondyloarthritis.
References
- Rosenzweig HL, Vance EE, Asare-Konadu K, Koney KV, Lee EJ, Deodhar AA, et al. Card9/neutrophil signalling axis promotes IL-17A-mediated ankylosing spondylitis. Ann Rheum Dis. 2024 Jan 11;83(2):214–22.
- Zhong X, Chen B, Yang L, Yang Z. Molecular and physiological roles of the adaptor protein CARD9 in immunity. Cell Death Dis. 2018 Jan 19;9(2):1–11.
- Seufert AL, Struthers H, Caplan L, Napier RJ. CARD9 in the pathogenesis of axial spondyloarthritis. Best Pract Res Clin Rheumatol. 2024 May;38(2):101964.