{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPerforin (PRF1) is a pivotal pore‐forming protein that enables cytotoxic T lymphocytes and natural killer cells to rapidly deliver granzymes into infected or transformed target cells, thereby triggering apoptosis. In settings such as HIV infection, studies have shown that robust immune control correlates with an enhanced capacity for rapid perforin upregulation independent of cell proliferation, ensuring immediate and effective cytolytic activity at the immune synapse."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic alterations in PRF1 underlie several immunopathologic conditions. In familial hemophagocytic lymphohistiocytosis (FHL) and related syndromes, homozygous and heterozygous mutations—including hypomorphic variants such as A91V—impair perforin function, leading to defective cytolytic activity, dysregulated immune homeostasis, and a predisposition to both hyperinflammatory syndromes and malignancies. These findings highlight a protein dosage effect whereby even partial defects can disturb immune surveillance and contribute to aberrant lymphocyte activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRegulation of perforin function is achieved at multiple levels. Epigenetic modifications—including accessible, acetylated chromatin states in memory CD8⁺ T cells—promote higher constitutive PRF1 expression, while discrete protein domains such as the C2 motif mediate calcium‐dependent membrane binding crucial for pore assembly. Cytokine signaling (for example, IL‐12–induced STAT4 activation) and microRNA modulation further fine‐tune transcription and translation of PRF1, ensuring that perforin oligomerization (often forming arc‐like structures) permits targeted granzyme delivery with minimal bystander damage."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its direct cytotoxic role, perforin participates in broader immunoregulatory and immunosurveillance functions. Its expression serves as a valuable biomarker in diverse clinical settings—from monitoring transplant rejection to characterizing immune responses in systemic autoimmune disorders and even infectious diseases such as COVID‐19. Additionally, perforin expression has been documented in non‐classical cytotoxic cells like polymorphonuclear neutrophils and is modulated by integrin signaling (e.g. via LFA‐1), all while contributing to the elimination of intracellular pathogens and regulation of vascular remodeling in atherosclerosis. These multifaceted roles underscore the importance of PRF1 in both maintaining immune homeostasis and mediating effective host defense."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "39"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Stephen A Migueles, Alisha C Laborico, W Lesley Shupert, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "The fraction of perforin-expressing HIV-specific CD8 T cells is a marker for disease progression in HIV infection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "AIDS (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/00002030-200207260-00006"}], "href": "https://doi.org/10.1097/00002030-200207260-00006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12131187"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12131187"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "George Makedonas, Pinaki P Banerjee, Rahul Pandey, et al. 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