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To provide understanding on inflammatory myocarditis, we describe clinical, genetic, and immunological properties of a young male patient who suffered from recurrent myocarditis episodes since the age of four years. Electrocardiography, troponin I\/T, echocardiography, myocardial magnetic resonance imaging and histological findings were consistent with recurrent myocarditis episodes. Homozygous c.245\u00a0A\u2009&gt;\u2009G p.Tyr82Cys pathogenic variant in Hepatitis A Virus Cellular Receptor 2 (<jats:italic>HAVCR2<\/jats:italic>) gene encoding T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) receptor was found. Peripheral blood mononuclear cells were collected when the patient was asymptomatic; CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T lymphoblasts, CD56<jats:sup>+<\/jats:sup> natural killer cells and CD14<jats:sup>+<\/jats:sup> monocytes were negative for surface TIM-3 expression. In vitro, TLR4 mediated interleukin-1\u03b2 (IL-1\u03b2) response was high after LPS\/ATP stimulation. Clinical symptoms responded to IL-1 receptor antagonist anakinra. TIM-3 p.Tyr82Cys CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T cell proliferation in vitro was unrestrained. Findings on IL-2, interferon gamma, regulatory T cells, signal transducer and activator of transcription (STAT) 1, 3 and 4 phosphorylation, and PD-1 and LAG-3 checkpoint inhibitor receptor analyses were comparable to controls. We conclude that TIM-3 deficiency due to homozygous <jats:italic>HAVCR2<\/jats:italic> c.245\u00a0A\u2009&gt;\u2009G p.Tyr82Cys pathogenic variant in the patient described here is associated with autoinflammatory symptoms limited to early onset recurrent febrile myocarditis. Excessive IL-1\u03b2 production and defective regulation of T cell proliferation may contribute to this clinical condition responsive to anakinra treatment.<\/jats:p>","DOI":"10.1007\/s10875-024-01685-x","type":"journal-article","created":{"date-parts":[[2024,3,15]],"date-time":"2024-03-15T02:01:40Z","timestamp":1710468100000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Germline HAVCR2\/TIM-3 Checkpoint Inhibitor Receptor Deficiency in Recurrent Autoinflammatory Myocarditis"],"prefix":"10.1007","volume":"44","author":[{"given":"Nora","family":"Pernaa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anni","family":"Vakkuri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miika","family":"Arvonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Outi","family":"Kuismin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenny","family":"Santaniemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virpi","family":"Glumoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Lappi-Blanco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulla","family":"Lantto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjo","family":"Okkonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari","family":"Kaikkonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juhani","family":"Junttila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Risto","family":"Kerkel\u00e4","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pirjo","family":"\u00c5str\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"Hautala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,15]]},"reference":[{"key":"1685_CR1","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1038\/s41577-019-0224-6","volume":"20","author":"Y Wolf","year":"2020","unstructured":"Wolf Y, Anderson AC, Kuchroo VK. 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