TY - JOUR
T1 - Intracellular virus sensor MDA5 mutation develops autoimmune myocarditis and nephritis
AU - Ohto, Taisuke
AU - Tayeh, Ahmed Abu
AU - Nishikomori, Ryuta
AU - Abe, Hiroto
AU - Hashimoto, Kyota
AU - Baba, Shiro
AU - Arias-Loza, Anahi Paula
AU - Soda, Nobumasa
AU - Satoh, Saya
AU - Matsuda, Masashi
AU - Iizuka, Yusuke
AU - Kondo, Takashi
AU - Koseki, Haruhiko
AU - Yan, Nan
AU - Higuchi, Takahiro
AU - Fujita, Takashi
AU - Kato, Hiroki
N1 - Funding Information:
This study was supported by independent grants from the Japan Science and Technology Agency , from the Ministry of Education, Culture, Sports, Science and Technology of Japan (innovative areas, infection competency, 24115004), Japan Agency for Medical Research and Development under grants JP17ek0109100h0003 and JP18ek0109387h0001, The Kato Memorial Trust for Nambyo Research, and the Japan Society for the Promotion of Science Core to Core Program.
Funding Information:
It was also funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany's Excellence Strategy – EXC2151 – 390873048 and TRR237 , and also by the Deutsche Forschungsgemeinschaft (German Research Foundation) Grant No. 369799452 – Project number 404459591.
Publisher Copyright:
© 2022
PY - 2022/2
Y1 - 2022/2
N2 - Mutations in IFIH1 gene encoding viral RNA sensor MDA5 have been reported responsible for many interferonopathies, including Aicardi-Goutières syndrome (AGS) and monogenic lupus, however, the pathological link between IFIH1 mutations and various autoimmune symptoms remains unclear. Here, we generated transgenic mice expressing human MDA5 R779H mutant (R779H Tg), reported in AGS and monogenic lupus patient. Mice spontaneously developed myocarditis and nephritis with upregulation of type I IFNs in the major organs. R779H Tg Mavs−/− and R779H Tg Ifnar−/− showed no phenotypes, indicating direct MDA5-signaling pathway involvement. Rag-2 deficiency and bone marrow cells transfer from wild type to adult mice did not prevent myocarditis development, while mice with cardiomyocyte-specific expression of hMDA5 R779H showed cardiomegaly and high expression of inflammatory cytokines. Taken together, our study clarifies that type I IFNs production and chemokines from cardiomyocytes starts in neonatal period and is critical for the development of myocarditis. Activated lymphocytes and auto-antibodies exacerbate the pathogenesis but are dispensable for the onset.
AB - Mutations in IFIH1 gene encoding viral RNA sensor MDA5 have been reported responsible for many interferonopathies, including Aicardi-Goutières syndrome (AGS) and monogenic lupus, however, the pathological link between IFIH1 mutations and various autoimmune symptoms remains unclear. Here, we generated transgenic mice expressing human MDA5 R779H mutant (R779H Tg), reported in AGS and monogenic lupus patient. Mice spontaneously developed myocarditis and nephritis with upregulation of type I IFNs in the major organs. R779H Tg Mavs−/− and R779H Tg Ifnar−/− showed no phenotypes, indicating direct MDA5-signaling pathway involvement. Rag-2 deficiency and bone marrow cells transfer from wild type to adult mice did not prevent myocarditis development, while mice with cardiomyocyte-specific expression of hMDA5 R779H showed cardiomegaly and high expression of inflammatory cytokines. Taken together, our study clarifies that type I IFNs production and chemokines from cardiomyocytes starts in neonatal period and is critical for the development of myocarditis. Activated lymphocytes and auto-antibodies exacerbate the pathogenesis but are dispensable for the onset.
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U2 - 10.1016/j.jaut.2022.102794
DO - 10.1016/j.jaut.2022.102794
M3 - Article
C2 - 35168003
AN - SCOPUS:85124495394
SN - 0896-8411
VL - 127
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
M1 - 102794
ER -