{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTumor necrosis factor receptor superfamily member 1B (TNFRSF1B), whose protein product is commonly referred to as TNFR2, plays a critical role in mediating selective TNF‐α signals that are distinct from those elicited by TNFR1. Genetic studies have revealed that polymorphisms and mutations in the TNFRSF1B gene are associated with several chronic inflammatory and autoimmune disorders. For example, in rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, and even endocrine disturbances such as polycystic ovary syndrome, specific TNFRSF1B (or TNFR2) allelic variants—including the M196R change—alter downstream NF‑κB activation and apoptotic sensitivity, thereby affecting disease susceptibility and even patients’ responses to therapies such as infliximab. Moreover, candidate gene studies in ANCA‐associated vasculitis and sepsis have probed TNFRSF1B polymorphisms for their impact on disease outcome and inflammatory profiles."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to modulating cell survival and apoptotic pathways, TNFRSF1B is central to immune regulation. In several studies the activation of TNFR2 on T lymphocytes has been shown to preferentially stimulate the canonical NF‑κB cascade in regulatory T cells (Tregs), thereby upregulating costimulatory receptors and anti‐apoptotic genes that bolster their suppressive capacity. Such effects have been documented in contexts ranging from autoimmune inflammation to the tumor microenvironment, where TNFR2‐expressing Tregs are enriched and contribute to immune escape. Furthermore, altered TNFR2 signaling in resident stromal cells, for example in the kidney, can influence inflammatory and repair responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging therapeutic strategies now aim to exploit the unique functions of TNFRSF1B. In cancer, for example, the presence of activating mutations or genomic gains in TNFRSF1B—as reported in cutaneous T cell lymphomas—coupled with its role in sustaining immunosuppressive myeloid and T cell populations, render it a promising target for selective antagonism. In other settings, such as hepatic fibrogenesis and neurodegeneration, selective modulation of TNFR2 signaling (either via antagonistic antibodies or agonistic TNF‐derivatives) can shift the balance from pro‑inflammatory outcomes toward protection and regeneration. Preclinical models have demonstrated that targeting TNFRSF1B can impede tumor cell proliferation and metastasis while also conferring neuroprotection by activating PI3K–Akt pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "A Barton, S John, W E Ollier, et al. 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