TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis
Eric Gracey, … , Wenyan Miao, Robert D. Inman
Eric Gracey, … , Wenyan Miao, Robert D. Inman
Published March 9, 2020
Citation Information: J Clin Invest. 2020;130(4):1863-1878. https://doi.org/10.1172/JCI126567.
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Research Article Autoimmunity

TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis

Abstract

Spondyloarthritis (SpA) represents a family of inflammatory diseases of the spine and peripheral joints. Ankylosing spondylitis (AS) is the prototypic form of SpA in which progressive disease can lead to fusion of the spine. Therapeutically, knowledge of type 3 immunity has translated into the development of IL-23– and IL-17A–blocking antibodies for the treatment of SpA. Despite being able to provide symptomatic control, the current biologics do not prevent the fusion of joints in AS patients. Thus, there is an unmet need for disease-modifying drugs. Genetic studies have linked the Janus kinase TYK2 to AS. TYK2 is a mediator of type 3 immunity through intracellular signaling of IL-23. Here, we describe and characterize a potentially novel small-molecule inhibitor of TYK2 that blocked IL-23 signaling in vitro and inhibited disease progression in animal models of SpA. The effect of the inhibitor appears to be TYK2 specific, using TYK2-inactive mice, which further revealed a duality in the induction of IL-17A and IL-22 by IL-23. Specifically, IL-22 production was TYK2/JAK2/STAT3 dependent, while IL-17A was mostly JAK2 dependent. Finally, we examined the effects of AS-associated TYK2 SNPs on TYK2 expression and function and correlated them with AS disease progression. This work provides evidence that TYK2 inhibitors have great potential as an orally delivered therapeutic for SpA.

Authors

Eric Gracey, Dominika Hromadová, Melissa Lim, Zoya Qaiyum, Michael Zeng, Yuchen Yao, Archita Srinath, Yuriy Baglaenko, Natalia Yeremenko, William Westlin, Craig Masse, Mathias Müller, Birgit Strobl, Wenyan Miao, Robert D. Inman

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Figure 7

AS-associated SNPs at the TYK2 locus do not alter TYK2 expression, but correlate with altered Th1 frequency and AS disease progression.

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AS-associated SNPs at the TYK2 locus do not alter TYK2 expression, but c...
qPCR was used to assess whole-blood TYK2 expression in a cohort of 47 healthy controls (HC), 76 ankylosing spondylitis patients (AS), and 21 rheumatoid arthritis patients (RA) by patient type (A) and rs35164067 (B) and rs12720356 (C) genotypes. (D) TYK2 expression in peripheral joint synovial biopsies measured by qPCR. PrimeFlow was used to detect TYK2 mRNA by flow cytometry. (E) Representative histograms showing TYK2 mRNA expression in selected cell populations. White histograms represent FMO controls, gray histograms represent TYK2-stained cells. Values under cell populations are the respective MFIs of TYK2. (F) TYK2 MFI in CD4+ T cells by patient group. (G) AS/RA/HC subjects were pooled to assess TYK2 expression by rs12720356 genotype. (H) PBMCs from the same cohort were stimulated with PMA/ionomycin for IL-17A and IFN-γ detection by flow cytometry. AS, RA, and HC pooled and data stratified by rs12720356. (I) Frequency chart of rs12720356 genotype assessed in a separate cohort of AS patients with progressing (n = 84) or nonprogressing (n = 79) disease based on mSASSS scores. qPCR analysis in A–C was normalized to HPRT expression and to GAPDH in D. A and B, 1-way ANOVA with Tukey post hoc test; C, D, and H, Mann-Whitney test; I, Fisher’s exact test. *P < 0.05, **P < 0.01.