A8.25 CARD9 mediates autoantibody-induced autoimmune diseases by linking the SYK tyrosine kinase to CHEMOKINE production

Abstract

Background and Objectives CARD9 is a CARMA-like intracellular protein that is highly expressed in innate immune cells. In contrast to its well-defined role in fungal recognition pathways in dendritic cells, its function in non-infectious autoimmune inflammation has not been described yet, despite the fact that a genome-wide association screen raised a possible association between CARD9 gene polymorphisms and a human autoimmune arthritis. Here, we investigated the role of CARD9 in autoantibody-mediated diseases by a transgenic method. Materials and Methods We used the neutrophil-, macrophage-, Fc receptor and Syk-mediated K/BxN serum transfer arthritis and the anti-collagen type VII antibody-mediated epidermolysis bullosa acquisita (EBA) models in the presence or absence of CARD9. Bone marrow neutrophils (or cultured bone marrow-derived macrophages) from wild type, Syk- or CARD9-deficient mice were stimulated through their Fcγ receptors, followed by the analysis of the superoxide release (as a short-term response) and chemokine release (as a long-term response). Results In contrast to the previously published total resistance of Syk-deficient bone marrow chimeras to experimental arthritis, the absence of CARD9 resulted in a partial, but significant decrease in arthritis severity and CARD9−/− mice showed a moderate skin inflammation in the EBA model compared to the wild type animals. Neutrophil (and monocyte) accumulation at the site of inflammation was strongly affected, while CARD9-deficient neutrophils (and monocytes) had normal migratory capacities to the joints in wild type/CARD9−/− mixed bone marrow chimeras. Surprisingly, the synovial levels of the chemokines CXCL1 and CXCL2 were dramatically reduced in the absence of CARD9 upon arthritis induction. While Syk−/− neutrophils (and macrophages) failed to produce superoxide or release chemokines compared to wild type cells when stimulated through their Fcγ receptors among in vitro conditions, CARD9−/− neutrophils showed normal short-term, but strongly reduced long-term responses. Furthermore, Fcγ receptor-mediated phosphorylation of Syk was intact in CARD9−/−neutrophils. Conclusions CARD9 plays an important role in the development and progression of autoimmune arthritis and autoimmune blistering skin disease in mice, likely by linking the Syk tyrosine kinase to chemokine production in innate immune cells.

Genetic signature of differentiated thyroid carcinoma susceptibility: a machine learning approach

“…However, since the selected SNPs were associated with DTC in the combined analysis, they could be reasonably involved in the aetiology of the disease. They have been previously involved in the regulation of cell metabolism, oestrogen physiology, tumour suppression or progression and autoimmune diseases ( 61 , 62 , 63 , 64 , 65 , 66 ). These three genes are certainly interesting for future studies in connection with DTC in the future.…”