Germline HAVCR2/TIM-3 Checkpoint Inhibitor Receptor Deficiency in Recurrent Autoinflammatory Myocarditis

• Published in: Journal of clinical immunology 2024-03, Vol.44 (3), p.81, Article 81
• Main Authors: Pernaa, Nora, Vakkuri, Anni, Arvonen, Miika, Kuismin, Outi, Santaniemi, Wenny, Glumoff, Virpi, Lappi-Blanco, Elisa, Lantto, Ulla, Okkonen, Marjo, Kaikkonen, Kari, Junttila, Juhani, Kerkelä, Risto, Åström, Pirjo, Hautala, Timo
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; CD14 antigen; CD223 antigen; CD4 antigen; CD56 antigen; CD8 antigen; Cell growth; Cell proliferation; Child, Preschool; Echocardiography; EKG; Germ Cells; Heart diseases; Hepatitis A; Hepatitis A Virus Cellular Receptor 2 - genetics; Humans; Immunology; Immunoregulation; Infectious Diseases; Inflammation; Interleukin 1 receptor antagonist; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Interleukins; Internal Medicine; Leukocytes, Mononuclear; Lymphoblasts; Lymphocytes; Lymphocytes T; Magnetic resonance imaging; Male; Medical Microbiology; Monocytes; Myocarditis; Myocarditis - diagnosis; Myocarditis - drug therapy; Myocarditis - etiology; Natural killer cells; Patients; PD-1 protein; Peripheral blood mononuclear cells; Phosphorylation
• ISSN: 0271-9142; 1573-2592; 1573-2592
• DOI: 10.1007/s10875-024-01685-x

Myocarditis can be caused by viral infection, drug reaction or general inflammatory condition. 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 A > G p.Tyr82Cys pathogenic variant in Hepatitis A Virus Cellular Receptor 2 ( HAVCR2 ) 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 + and CD8 + T lymphoblasts, CD56 + natural killer cells and CD14 + monocytes were negative for surface TIM-3 expression. In vitro, TLR4 mediated interleukin-1β (IL-1β) response was high after LPS/ATP stimulation. Clinical symptoms responded to IL-1 receptor antagonist anakinra. TIM-3 p.Tyr82Cys CD4 + and CD8 + 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 HAVCR2 c.245 A > G p.Tyr82Cys pathogenic variant in the patient described here is associated with autoinflammatory symptoms limited to early onset recurrent febrile myocarditis. Excessive IL-1β production and defective regulation of T cell proliferation may contribute to this clinical condition responsive to anakinra treatment.