Disease causing mutations in the TNF and TNFR superfamilies: Focus on molecular mechanisms driving disease

Protein Sciences, Catalyst Biosciences, 260 Littlefield Avenue, South San Francisco, CA 94080, USA.
Trends in Molecular Medicine (Impact Factor: 9.45). 07/2011; 17(9):494-505. DOI: 10.1016/j.molmed.2011.05.006
Source: PubMed


The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies comprise multidomain proteins with diverse roles in cell activation, proliferation and cell death. These proteins play pivotal roles in the initiation, maintenance and termination of immune responses and have vital roles outside the immune system. The discovery and analysis of diseases associated with mutations in these families has revealed crucial mechanistic details of their normal functions. This review focuses on mutations causing four different diseases, which represent distinct pathological mechanisms that can exist within these superfamilies: autoimmune lymphoproliferative syndrome (ALPS; FAS mutations), common variable immunodeficiency (CVID; TACI mutations), tumor necrosis factor receptor associated periodic syndrome (TRAPS; TNFR1 mutations) and hypohidrotic ectodermal dysplasia (HED; EDA1/EDAR mutations). In particular, we highlight how mutations have revealed information about normal receptor-ligand function and how such studies might direct new therapeutic approaches.

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    • "It has been well accepted that cervical cancer is mainly initiated by HPV infection, and tumor necrosis factor-alpha (TNF-α) is an inflammatory cytokine which may play important roles in the immune response of cervical lesions [5], [7]. TNF-α is located on chromosome 6 (region p21.3), and it is a potent proinflammatory cytokine playing an important role in the development of the immune response [5], [6]. Currently, there are several common single nucleotide polymorphisms (SNP) in the TNF-α gene which can regulate the transcription and production of TNF-α, such as TNF-α rs1800629 and TNF-α rs361525 [8], [9]. "
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    ABSTRACT: Tumor necrosis factor- alpha (TNF-α) is an inflammatory cytokine which may play important role on the immune response may control the progression of cervical lesions. There is a possible association between TNF-α rs1800629 G/A polymorphism and cervical lesions, but previous studies report conflicting results. We performed a meta-analysis to comprehensively assess the association between TNF-α rs1800629 polymorphism and cervical lesions risk. Literature searches of Pubmed, Embase, Web of Science, and Wanfang databases were performed for all publications on the association between TNF-α rs1800629 polymorphism and cervical lesions through December 15, 2012. The pooled odds ratios (ORs) with their 95% confidence interval (95%CIs) were calculated to assess the strength of the association. Twenty individual case-control studies from 19 publications with a total of 4,146 cases and 4,731 controls were finally included into the meta-analysis. Overall, TNF-α rs1800629 polymorphism was significantly associated with increased risk of cervical lesions under two main genetic comparison models (For A versus G: OR 1.22, 95%CI 1.04-1.44, P = 0.017; for AA versus GG: OR 1.32, 95%CI 1.02-1.71, P = 0.034). Subgroup analysis by ethnicity further showed that there was a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical lesions in Caucasians but not in Asians. Subgroup analysis by the types of cervical lesions showed that there was a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical cancer (For A versus G: OR 1.24, 95%CI 1.05-1.47, P = 0.011; for AA versus GG: OR 1.31, 95%CI 1.01-1.70, P = 0.043; for AA/GA versus GG: OR 1.25, 95%CI 1.01-1.54, P = 0.039). The meta-analysis suggests that TNF-α rs1800629 polymorphism is associated with increased risk of cervical lesions, especially in Caucasians.
    Preview · Article · Aug 2013 · PLoS ONE
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    • "Either BLyS or APRIL (with other appropriate cytokines) elicits TI-like class switching in cultured human B cells (Litinskiy et al., 2002). Interestingly, a range of mutations in TACI is associated with common variable immune deficiency (CVID) and IgA deficiency (Castigli et al., 2007; Lobito et al., 2011; Martinez-Gallo et al., 2013). Furthermore, there is increasing evidence in both mice and humans that TI responses to many innate-like antigens occur through pathways that integrate BLyS or APRIL signaling through TACI with Toll-like receptor (TLR) signaling (He et al., 2010; Oropallo et al., 2011). "
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    ABSTRACT: B-1 and B-2 B cell populations have different progenitors, receptor diversity, anatomic location, and functions - suggesting vastly differing requisites for homeostatic regulation. There is evidence that the B lymphocyte stimulator (BLyS) family of cytokines and receptors, key factors in the homeostatic regulation of B-2 B cell subsets, is also a major player in the B-1 compartment. Here we review the development and differentiation of these two primary B cell lineages and their immune functions. We discuss evidence that BLyS or a proliferation-inducing ligand (APRIL) availability in different anatomic sites, coupled with signature BLyS receptor expression patterns on different B cell subsets, may be important for homeostatic regulation of B-1 as well as B-2 populations. Finally, we extend our working model of B cell homeostasis to integrate B-1s.
    Full-text · Article · Feb 2013 · Frontiers in Immunology
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    • "In addition, two cases of patients with mutations in caspase-8 have been reported. However, although these patients exhibit phenotypes similar to ALPS, in contrast to other ALPS patients, these cases exhibited defects in lymphocyte and natural killer cell activation leading to immunodeficiency and hence recurrent bacterial and viral infection (reviewed in [22]). "
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    ABSTRACT: Cell death is critical to the normal functioning of multi-cellular organisms, playing a central role in development, immunity, inflammation, and cancer progression. Two cell death mechanisms, apoptosis and necroptosis, are dependent on the formation of distinct multi-protein complexes including the DISC, Apoptosome, Piddosome and Necrosome following the induction of cell death by specific stimuli. The role of several of these key multi-protein signalling platforms, namely the DISC, TNFR1 complex I/II, the Necrosome and Ripoptosome, in mediating these pathways will be discussed, as well as the open questions and potential therapeutic benefits of understanding their underlying mechanisms.
    Full-text · Article · Apr 2012 · Experimental Cell Research
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