The IL-6/Th17 Axis Promotes Autoantibody-Associated Autoimmune Valvular Carditis in Mice

Jennifer L. Auger¹, Brianna J. Engelson², Yaya Wang³, Erik J. Peterson⁴ and Bryce A. Binstadt⁵, ¹Center for Immunology and Department of Pediatrics, University of Minnesota, Minneapolis, MN, ²Pediatrics, University of Minnesota, Minneapolis, MN, ³Medicine, University of Minnesota, Minneapolis, MN, ⁴University of Minnesota, Minneapolis, MN, ⁵Pediatric Rheumatology, University of Minnesota, Minneapolis, MN

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Animal models, Heart disease, IL-6, macrophages and rheumatoid arthritis, T cells

Session Information

Title: Rheumatoid Arthritis - Animal Models II

Session Type: Abstract Submissions (ACR)

Background/Purpose:

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.

Methods:

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.

Results:

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.

Conclusion:

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.

Disclosure:

J. L. Auger,
None;

B. J. Engelson,
None;

Y. Wang,
None;

E. J. Peterson,
None;

B. A. Binstadt,
None.

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