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Future directions and personalized medicine
Published in M. Alan Menter, Caitriona Ryan, Psoriasis, 2017
One study investigated the potential influence of both TNF-α and accompanying TNF receptor (TNFRSF1A and TNFRSF1B) polymorphisms on infliximab, etanercept, and adalimumab.44 Numerous SNPs in TNF (−238G>A, −308G>A, −857C>T), TNFRSF1A (36A>G), and TNFRSF1B (676T>G) were sequenced by PCR restriction fragment length polymorphism assays in 80 patients who were treated for 6 months. Sixty-three (78.8%) of the patients were classified as responders to one of the three biologics, based on achieving a PASI 75 response. There was a significant association between response to etanercept and carriage of the TNF-857C or TNFRSF1B 676T alleles (p = 0.002 and p = 0.001, respectively). No other allele was associated with treatment response to any of the agents. In another study of 90 patients receiving TNF inhibitors for psoriasis, next generation sequencing (NGS) was used to identify nucleotide variants in TNFRSF1A and TNFRSF1B and TNF-α.45 Carriers of allele G (p.196R) carriers were more likely to be in the nonresponder group (56%) (p = 0.05).
Genetics of Psoriasis and Psoriatic Arthritis
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
Of the biologic drugs, TNFi are the most extensively researched. A study of both psoriasis and PsA patients from Toronto and Michigan demonstrated an association of the TNFAIP3 rs610604*G allele and the haplotype TNFAIP3 rs610604*G-rs2230926*T with response to TNFi, including etanercept, infliximab, and adalimumab, in Michigan patients, but not in Toronto patients [191]. Another study in a Greek population of psoriasis patients showed an association between variants in TNFA (rs1799724*CC) and TNFRSF1B (rs1061622*TT) and a positive response to etanercept, defined as a >75% reduction in the Psoriasis Area and Severity Index (PASI) score after 6 months, but not infliximab or adalimumab. This may be explained by slight differences in their modes of action, as etanercept binds the soluble form of TNFα, while adalimumab and infliximab bind transmembrane TNFα. TNFA-TNFRSF1B haplotypes (rs1799724-rs1061622 CT, CG, and TG) are also associated with response to TNFi [192]. In studies of PsA patients, the TNFA –308GG genotype was associated with better TNFi response than the AA or AG genotypes [193], and the TNFRSF10A rs20575*CC genotype was associated with a response to infliximab at 6 months, while TNFR1A rs767455*AA was associated with a response at 3 months [194]. Interestingly, epistatic interactions between HLA-C*06 and LCE and PDE3A and SLCO1C1 genotypes have also been associated with clinical improvement in psoriasis patients treated with TNFi [193]. Recently, GWASs have also yielded hits associated with clinical response to TNFi in TNFAIP3 [191]. Lastly, in addition to response to TNFi, response to the IL12/23 inhibitor ustekinumab has been investigated. Ustekinumab is a monoclonal antibody that targets the shared p40 subunit of IL12/23. A more rapid and increased response to ustekinumab has been found in a single study of psoriasis patients who are HLA-C*06 positive [195].
New frontiers in personalized medicine in psoriasis
Published in Expert Opinion on Biological Therapy, 2022
Elisa Camela, Luca Potestio, Gabriella Fabbrocini, Angelo Ruggiero, Matteo Megna
Response to anti-TNF was evaluated through the assessment of several genes among which the HLA:Cw6, the TNF cytokine, and its receptor were prominent [3–5]. The presence of the HLA:C:06:02 was traditionally associated with favorable outcome, although more recent studies questioned the association [1,3]. Probably, the great heterogeneity of genetic analyses as well as the differences in allele frequencies in ethnic subgroups may explain these discrepancies [3]. Similarly, polymorphisms (single nucleotide polymorphisms [SNPs]) in the TNF gene such as rs1800629, rs1799964, rs1799724, rs361520 were investigated with contrasting results [1]. As regards TNF receptor, the role of the TNF receptor superfamily member 1B (TNFRSF1B) was investigated in several studies in relation to different anti-TNF agents [3]. In detail, the TNFRSF1B rs1061622-TT was associated with a better response to all anti-TNF and statistically significantly with etanercept [3]. By contrast, the rs1061622-G polymorphism was associated with a worst outcome [3].
Genetic Variation on TNF/LTA and TNFRSF1A Genes is Associated with Outcomes of Hepatitis C Virus Infection
Published in Immunological Investigations, 2021
Ming Yue, Peng Huang, Chunhui Wang, Haozhi Fan, Ting Tian, Jingjing Wu, Fan Luo, Zuqiang Fu, Xueshan Xia, Ping Zhu, Jun Li, Yaping Han, Yun Zhang, Wei Hou
As a relatively significant member of the TNFSF, tumor necrosis factor (TNF) as well as lymphotoxin alpha (LTA) are important cytokines produced by activation of macrophages and T cells after injury to tissue (Dostert et al. 2019). TNF and LTA share the same membrane receptors, including TNFRSF member 1A (TNFRSF1A) and TNFRSF member 1B (TNFRSF1B). These membrane receptors each exert different regulatory effects by activating different inflammatory responses, and differentially affect proliferation, and differentiation of immune cells (Baud and Karin 2001; Vielhauer and Mayadas 2007). Recent research has indicated that TNF and LTA can enhance HCV entry by inducing the activation of nuclear factor κ-light-chain-enhancer in activated B cells and enhances entry by way of inducing activation of myosin light chain kinase signaling pathways thereby reducing tight junction integrity of hepatocytes (Miao et al. 2017). Moreover, binding of the HCV core protein to the cytoplasmic domain of TNFRSF1A, particularly to the “death domain”, may act to either hinder or promote cell death during HCV infection (Getachew et al. 2004). Additional research has indicated that the levels of serum TNF and soluble TNFRSF1A were elevated in patients with chronic hepatitis C and indicated that high levels of TNF were associated with poor prognosis and low responses to interferon based treatment (Grebely et al. 2015; Larrea et al. 1996; Tilg et al. 1992).
Pleural Macrophages can Promote or Inhibit Apoptosis of Malignant Cells via Humoral Mediators Depending on Intracellular Signaling Pathways
Published in Cancer Investigation, 2018
Mariusz Kaczmarek, Blazej Rubis, Magdalena Frydrychowicz, Agata Nowicka, Beata Brajer-Luftmann, Magdalena Kozlowska, Malgorzata Lagiedo, Halina Batura-Gabryel, Jan Sikora
The effectiveness of the transmission of signals between the cells by cytokines is dependent upon the presence on the surface of target cells of functional receptors. Activation of a receptor by cytokine triggers intracellular signaling that links the activity of cytokines present in the microenvironment with the expression of the proteins regulating apoptosis. To evaluate possible sensitivity of studied cell lines on the presence of selected cytokines in environment, we analyzed the constitutive expression of mRNA encoding for seven genes for cytokine receptor subunits, namely IL2RA, IL2RB, IL2RG, IL6R, IL6ST, TNFRSF1A, and TNFRSF1B. All cell lines showed constitutive expression of the tested genes. However, the A549 and HT29 lines were characterized by a very low expression of the TNFRSF1B, IL2RB, and IL2RG genes. The weak constitutive expression of the TNFRSF1B, IL2RB, and IL2RG genes in the A549 and HT29 cells, which was observed during the study, is most likely related to the fact that the unstimulated cells frequently show very low levels or lack of expression of genes coding cytokines and cytokine receptors. The increase in the expression of genes encoding cytokine receptors is often due to appropriate stimulation. The mRNA expression alone does not guarantee the existence of entirely functional receptor on a cell surface, however, makes it highly feasible.