{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTNFSF8, which encodes the CD30 ligand (also known as CD153), is a key immunomodulatory molecule that helps regulate the balance between pro‐ and anti‐inflammatory responses. In several studies investigating autoimmune and inflammatory conditions, increased expression of CD30L has been linked with a skewing toward Th2 cytokine profiles and elevated IL‑6 production. For example, expression of CD30L in acute myeloid leukemia (PMID"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "and in thyroid nodules and autoimmune thyroid diseases (PMID"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "; PMID"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "; PMID"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "has been associated with IL‑6/IL‑6R co-expression and disease aggressiveness, while CD30 engagement on mast cells promotes chemokine secretion in chronic skin inflammation (PMID."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n \n \nIn tumor and inflammatory settings, the TNFSF8/CD30L axis exerts additional functions that can influence disease outcome. Co-expression of CD30 variants together with CD30L in leukemias (PMID"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "is linked to aggressive disease features, while in rheumatoid arthritis a soluble form of CD30L is detected in serum and synovial fluid and can bind CD30 on T cells to induce apoptosis, thereby modulating the inflammatory cell network (PMID."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Moreover, genetic polymorphisms in the TNFSF8 locus have been correlated with bone lesions in myeloma (PMID"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "and with altered extrinsic apoptosis signaling in lung cancer (PMID"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", while fine‐mapping studies in spondylarthritis (PMID"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "and associations with innate immune cell counts (PMID"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "further underscore its involvement in disease biology. In addition, engagement of CD30L on dendritic cells has been shown to trigger MAPK/ERK-dependent cytokine secretion and promote maturation during cross-talk with natural killer cells (PMID"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", and elevated levels of soluble CD30L in rheumatoid arthritis are implicated in modulating T-cell proliferation (PMID."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n \n \nEmerging evidence also highlights roles for TNFSF8 in host defense and immunometabolic regulation. During pulmonary Mycobacterium tuberculosis infection, CD153 expressed by CD4 T cells is critical for limiting bacterial growth through mechanisms beyond classical IFN‑γ responses (PMID"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "; PMID"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ", while in Hodgkin lymphoma, extracellular vesicles bearing CD30 carry functional CD30 that indirectly contacts CD30L-positive cells (PMID."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " In tandem, reconstitution studies and large-scale genetic screens have associated CD153 with protective immunity against tuberculosis (PMID"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "and identified variants in the CD30L-encoding region as contributors to susceptibility in autoimmune conditions such as systemic sclerosis (PMID."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " Collectively, these findings demonstrate that TNFSF8/CD30L is a pleiotropic mediator bridging innate and adaptive immunity, with its expression and function shaping immune cell activation, cytokine production, cellular apoptosis, and ultimately, clinical outcomes in infections, cancer, and autoimmune diseases.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "F M Rossi, M Degan, L Mazzocut-Zecchin, et al. 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