Tnfrsf1b, also known as tumor necrosis factor receptor superfamily member 1B, encodes TNF receptor 2 (TNFR2), one of two receptors for cytokines TNF and lymphotoxin-α [4]. TNFR2 has both pro-and anti-inflammatory effects and plays protective roles on oligodendrocytes, cardiomyocytes, and keratinocytes. It is involved in the TNF-TNFR1/2 system, which has pathophysiological importance in various biological processes [4].

In ovarian cancer, a novel exhausted subpopulation of CD8+ TNFRSF1B+ T cells was identified, associated with poor survival. Blockade of TNFRSF1B inhibited tumor growth in an ovarian cancer mouse model by remodeling the immune microenvironment [1]. In cutaneous melanoma, TNFRSF1B c.587T>G and c.*922C>T variants were independent prognostic factors, with the c.*922TT genotype having higher TNFRSF1B expression [2]. In inflammatory bowel disease, LncRNA NEAT1 promoted NF-κB p65 translocation and mediated intestinal inflammation by regulating TNFRSF1B [3]. In severe COVID-19, TNFRSF1B variants influenced plasma levels of soluble TNFR1 and TNFR2, which were implicated in disease severity [5]. In multiple sclerosis, a combination of 11 cerebrospinal fluid proteins including TNFRSF1B predicted disability worsening severity [6]. In cystic fibrosis, TNFRSF1B transcript knockdown protected epithelial cells from oxidative stress, and blocking TNFR signaling increased cell viability [7]. In hepatocellular carcinoma, mucosal-associated invariant T (MAIT) cells secreted TNF to activate TNFRSF1B on regulatory T cells, promoting immunosuppression [8]. In osteoclast differentiation, miR-125a-5p promoted osteoclastogenesis by targeting TNFRSF1B [9]. In Alzheimer's disease, the interaction between TNFRSF1B variant rs976881 and cerebrospinal fluid sTNFR2 levels modulated multiple AD-associated severity markers and cognitive domains [10].

In conclusion, Tnfrsf1b plays crucial roles in multiple disease conditions, including cancer, inflammatory diseases, neurodegenerative diseases, and viral infections. Its functions in these diseases are often related to immune regulation, cell survival, and inflammation. Studies using various models, though not all explicitly gene-knockout models, have enhanced our understanding of how Tnfrsf1b contributes to disease mechanisms, potentially paving the way for new therapeutic strategies.

References:

1. Gao, Yan, Shi, Hui, Zhao, Hongyu, Liao, Xuebin, Yue, Wentao. . Single-cell transcriptomics identify TNFRSF1B as a novel T-cell exhaustion marker for ovarian cancer. In Clinical and translational medicine, 13, e1416. doi:10.1002/ctm2.1416. https://pubmed.ncbi.nlm.nih.gov/37712139/

2. Carvalho, Bruna Fernandes, Gomez, Gabriela Vilas Bôas, Carron, Juliana, Lourenço, Gustavo Jacob, Lima, Carmen Silvia Passos. 2024. TNFRSF1B Gene Variants in Clinicopathological Aspects and Prognosis of Patients with Cutaneous Melanoma. In International journal of molecular sciences, 25, . doi:10.3390/ijms25052868. https://pubmed.ncbi.nlm.nih.gov/38474115/

3. Pan, Shiyu, Liu, Rui, Wu, Xing, Wang, Xiaoyan, Deng, Minzi. . LncRNA NEAT1 mediates intestinal inflammation by regulating TNFRSF1B. In Annals of translational medicine, 9, 773. doi:10.21037/atm-21-34. https://pubmed.ncbi.nlm.nih.gov/34268386/

4. Medler, Juliane, Wajant, Harald. 2019. Tumor necrosis factor receptor-2 (TNFR2): an overview of an emerging drug target. In Expert opinion on therapeutic targets, 23, 295-307. doi:10.1080/14728222.2019.1586886. https://pubmed.ncbi.nlm.nih.gov/30856027/

5. Fricke-Galindo, Ingrid, Buendía-Roldán, Ivette, Ruiz, Andy, Chávez-Galán, Leslie, Falfán-Valencia, Ramcés. . TNFRSF1B and TNF Variants Are Associated With Differences in Levels of Soluble Tumor Necrosis Factor Receptors in Patients With Severe COVID-19. In The Journal of infectious diseases, 226, 778-787. doi:10.1093/infdis/jiac101. https://pubmed.ncbi.nlm.nih.gov/35294530/

6. Åkesson, Julia, Hojjati, Sara, Hellberg, Sandra, Ernerudh, Jan, Gustafsson, Mika. 2023. Proteomics reveal biomarkers for diagnosis, disease activity and long-term disability outcomes in multiple sclerosis. In Nature communications, 14, 6903. doi:10.1038/s41467-023-42682-9. https://pubmed.ncbi.nlm.nih.gov/37903821/

7. Checa, Javier, Fiol, Pau, Guevara, Marta, Aran, Josep M. 2024. TNFRSF1B Signaling Blockade Protects Airway Epithelial Cells from Oxidative Stress. In Antioxidants (Basel, Switzerland), 13, . doi:10.3390/antiox13030368. https://pubmed.ncbi.nlm.nih.gov/38539900/

8. Zhou, Cheng, Sun, Bao-Ye, Zhou, Pei-Yun, Ren, Ning, Qiu, Shuang-Jian. 2023. MAIT cells confer resistance to Lenvatinib plus anti-PD1 antibodies in hepatocellular carcinoma through TNF-TNFRSF1B pathway. In Clinical immunology (Orlando, Fla.), 256, 109770. doi:10.1016/j.clim.2023.109770. https://pubmed.ncbi.nlm.nih.gov/37717672/

9. Sun, Liang, Lian, Jun Xiang, Meng, Shu. 2019. MiR-125a-5p promotes osteoclastogenesis by targeting TNFRSF1B. In Cellular & molecular biology letters, 24, 23. doi:10.1186/s11658-019-0146-0. https://pubmed.ncbi.nlm.nih.gov/30976285/

10. Pillai, Jagan A, Bebek, Gurkan, Khrestian, Maria, Leverenz, James B, Bekris, Lynn M. 2021. TNFRSF1B Gene Variants and Related Soluble TNFR2 Levels Impact Resilience in Alzheimer's Disease. In Frontiers in aging neuroscience, 13, 638922. doi:10.3389/fnagi.2021.638922. https://pubmed.ncbi.nlm.nih.gov/33716716/