AUTHOR=Wei Chong , Zhao Danqing , Xue Song , Cai Hao , Jia Congwei , Zhou Daobin , Zhang Wei 

TITLE=Germline defects of familial hemophagocytic lymphohistiocytosis-related genes presenting as adult-onset peripheral T-cell lymphoma

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1365975

DOI=10.3389/fimmu.2024.1365975

ISSN=1664-3224

ABSTRACT=<p>Germline mutations in genes involved in perforin-granzyme-mediated cytotoxicity such as <italic>PRF1</italic>, <italic>UNC13D</italic>, <italic>STX11</italic>, and <italic>STXBP2</italic> were known to cause familial hemophagocytic lymphohistiocytosis (FHL). In this study, we reported a unique group of 3 patients with germline mutations of <italic>UNC13D</italic> and <italic>STX11</italic> genes and presented as adult-onset peripheral T-cell lymphoma (PTCL) with cytotoxic T-cell phenotype and atypical lymphoma presentations. CD107a degranulation assay and NK-cell activity analysis demonstrated impaired cytotoxic function of the NK/T-cells of the patients with FHL-related mutations. Gene expression profile study revealed that up-regulated genes of the cytotoxic T-cells were enriched in autoimmune-related pathways. It was possible that impaired cytotoxic lymphocyte-mediated immune surveillance and autoantigen stimulation may both participate in PTCL oncogenesis. Germline defects of FLH-related genes may represent a novel predisposing factor for PTCLs.</p>