Havcr2, also known as T cell immunoglobulin and mucin domain 3 (TIM-3), is an activation-induced inhibitory molecule. It acts as a negative regulator, binding to ligands like galectin-9 to mediate Th1 cell apoptosis [1]. TIM-3 is expressed on various immune cells such as macrophages, dendritic cells, and monocytes, and its ligands also include Psdter, High Mobility Group Box 1 (HMGB1) and Carcinoembryonic antigen associated cell adhesion molecules (Ceacam-1), playing important roles in autoimmune diseases, chronic viral infections and tumors [1].

Germline HAVCR2 mutations are frequently detected in subcutaneous panniculitis-like T-cell lymphoma (SPTCL) patients with or without hemophagocytic lymphohistiocytosis (HLH). Male sex and younger age are associated with HLH in patients with HAVCR2 mutations. Homozygous HAVCR2Y82C mutation is more common in the presence of HLH [3]. A patient with homozygous c.245 A > G p.Tyr82Cys pathogenic variant in HAVCR2 gene had recurrent myocarditis episodes, and in vitro, TLR4-mediated interleukin-1β (IL-1β) response was high after LPS/ATP stimulation [2]. In six patients with germline homozygous mutation of HAVCR2 (p.Y82C), initially received corticosteroids, immunosuppressants or chemotherapy with unfavourable responses, but responded well to ruxolitinib targeting inflammatory cytokines [4].

In conclusion, Havcr2 plays a crucial role in immune regulation, especially in autoimmune diseases, chronic viral infections and tumors. Mutations in Havcr2 are associated with SPTCL and HLH, as well as recurrent myocarditis. The study of Havcr2 in these disease conditions helps to understand the underlying mechanisms and provides potential therapeutic directions [1,2,3,4].

References:

1. Zhao, Lizhen, Cheng, Shaoyun, Fan, Lin, Zhang, Bei, Xu, Shengwei. 2021. TIM-3: An update on immunotherapy. In International immunopharmacology, 99, 107933. doi:10.1016/j.intimp.2021.107933. https://pubmed.ncbi.nlm.nih.gov/34224993/

2. Pernaa, Nora, Vakkuri, Anni, Arvonen, Miika, Åström, Pirjo, Hautala, Timo. 2024. Germline HAVCR2/TIM-3 Checkpoint Inhibitor Receptor Deficiency in Recurrent Autoinflammatory Myocarditis. In Journal of clinical immunology, 44, 81. doi:10.1007/s10875-024-01685-x. https://pubmed.ncbi.nlm.nih.gov/38485795/

3. Moonla, Chatphatai, Polprasert, Chantana, Komvilaisak, Patcharee, Sosothikul, Darintr, Rojnuckarin, Ponlapat. 2023. Germline HAVCR2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis. In Haematologica, 108, 2743-2752. doi:10.3324/haematol.2022.282419. https://pubmed.ncbi.nlm.nih.gov/37051767/

4. Zhang, Qing, Zhou, Chun-Ju, Li, Dan-Hong, Duan, Yan-Long, Zhang, Rui. 2023. Efficacy of ruxolitinib for HAVCR2 mutation-associated hemophagocytic lymphohistiocytosis and panniculitis manifestations in children. In British journal of haematology, 202, 135-146. doi:10.1111/bjh.18817. https://pubmed.ncbi.nlm.nih.gov/37062931/