Session Title: Rheumatoid Arthritis - Animal Models II
Session Type: Abstract Submissions (ACR)
Autoimmune valvular carditis occurs in patients with systemic lupus erythematosus, rheumatoid arthritis and rheumatic fever, but the pathogenic mechanisms remain incompletely defined. Spontaneous autoimmune valvular carditis develops in the K/BxN T cell receptor transgenic mouse model of autoantibody-dependent inflammatory arthritis. CD4 T helper (Th) cells and macrophages cooperate to promote carditis in this model. We investigated which effector Th cell population was the predominant driver of cardiovascular pathology in K/BxN mice.
We first used RT-PCR to measure key cytokine transcript levels in cardiac valves of arthritic K/BxN mice and controls. We then used anti-cytokine blocking antibodies and gene knockout mice to determine which Th effector cells and cytokines were most critical for valve inflammation.
We found increased expression of the genes encoding the Th17 differentiation factor IL-6 and IL-17A itself in K/BxN mitral valves relative to controls; IL-4 and IFNγ transcript levels were not different. Antibody blockade of IL-6 or IL-17A reduced the severity of valve inflammation, whereas blocking IL-4 had no effect. Genetic deficiency of IFNγ did not affect carditis severity. K/BxN mice lacking the key Th17 transcription factor RORγt had delayed onset of arthritis and were protected from valvular carditis.
Th17 cells are key drivers of autoimmune valvular carditis in K/BxN mice. We suggest a model in which autoantibodies engage Fc receptors on macrophages, leading to IL-6 production, which in turn promotes the differentiation of valve-infiltrating Th17 effector cells. Our results provide new insight into the mechanisms of valvular carditis in systemic autoantibody-mediated rheumatic diseases. More broadly, these findings may help guide the selection of therapies to reduce cardiovascular morbidity and mortality among patients with rheumatoid arthritis and systemic lupus erythematosus.
J. L. Auger,
B. J. Engelson,
E. J. Peterson,
B. A. Binstadt,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-il-6th17-axis-promotes-autoantibody-associated-autoimmune-valvular-carditis-in-mice/