CARD9 in the pathogenesis of axial spondyloarthritis

Abstract

Axial spondyloarthritis (axSpA) has been long classified as an autoimmune disease caused by a breakdown in the ability of the immune system to delineate self from foreign, resulting in self-reactive T cells. The strong genetic association of HLA-B27 supports this role for T cells. More recently, genetic and clinical studies indicate a prominent role of the environment in triggering axSpA, including an important role for microbes and the innate immune response. As an example, mutations in genes associated with innate immunity, including the anti-fungal signaling molecule Caspase recruitment domain-containing protein 9 (CARD9), have been linked to axSpA susceptibility. Thus, current thought classifies axSpA as a "mixed pattern condition" caused by both autoimmune and autoinflammatory mechanisms. The goal of this review is to convey.

Keywords: Ankylosing spondylitis; Axial spondyloarthritis; CARD9 protein; Neutrophils; Spondyloarthritis.

Fig. 1.. Overview of the pathogenesis of axSpA.

Genetic and clinical studies indicate a role for both the environment and genetic factors in axSpA pathogenesis. This interaction leads to the development of pathogenic T cells that recognize self-antigens (i.e., self-reactive T cells), pro-inflammatory cytokines, and hyper-innate immune responses that cumulatively contribute to inflammation and damage of the spine and other associated tissues.

Fig. 2.. Neutrophil-intrinsic CARD9 in fungal infection and sterile inflammation.

Diagram summarizing the known effects of external environmental factors on the function of CARD9-sufficient and CARD9-deficient neutrophils. Immune functions downstream neutrophil-mediated immune responses are detailed following exposure to fungal pathogens (i.e., fungal infection [top panel]) or antibodies bound to antigen (i.e., immune complexes [middle panel]). The bottom panel shows how currently unknown environmental triggers may control neutrophils expressing the CARD9 S12N SNP to promote: disease and IL-17 production in axSpA, IBD, and experimental allergy.

Fig. 3.. Hypothetical role for CARD9^S12N SNP in axSpA pathogenesis.

We hypothesize that fungal exposure of patients with underlying genetic predisposition to axSpA (e.g., co-expression of HLA-B27 and CARD9^S12N SNP) may lead to the generation of pathogenic immune responses including self-reactive T cells and CARD9-activated inflammatory neutrophils. Downstream of these affects we further propose that an interaction between the self-reactive T cells and CARD9-activated neutrophils would result in development of pathogenic Th17 cells that produce IL-17A and target the enthesis and spine to promote disease in axSpA.