Card9/neutrophil signalling axis promotes IL-17A-mediated ankylosing spondylitis

Area of Science:

• Immunology
• Rheumatology
• Molecular Biology

Background:

• Polymorphisms in CARD9 are linked to ankylosing spondylitis (AS).
• Understanding the cellular mechanisms of CARD9 in AS pathogenesis is crucial.

Purpose of the Study:

• To investigate how CARD9 controls pathogenic Th17 responses.
• To elucidate the role of CARD9 in AS onset in murine models and human patients.

Main Methods:

• Experiments in SKG mice (wild-type, Card9 knockout, neutrophil-depleted) and in vitro co-cultures of murine neutrophils and CD4+ T cells.
• Analysis of neutrophil-to-T cell ratios and the Bath Ankylosing Spondylitis Functional Index in AS patients.
• In vitro studies using autologous neutrophil: T cell co-cultures to assess CARD9 variants and IL-17A production.

Main Results:

• Card9 is essential for Th17 cell induction, arthritis, and spondylitis in SKG mice, functioning downstream of Dectin-1.
• Card9 expression in T cells is dispensable for arthritis; neutrophils are key drivers of Th17 expansion and disease.
• Neutrophils expressing CARD9 potentiate IL-17A production by CD4+ T cells.
• A similar mechanism was observed in AS patients, where neutrophils from HLA-B27+ patients expanded Th17 cells, and the CARD9 S12N variant increased IL-17A.

Conclusions:

• CARD9 has a novel neutrophil-intrinsic function in promoting arthritogenic Th17 responses.
• This finding provides insights into CARD9-specific mechanisms in spondyloarthritis pathogenesis.