Soluble IL-7Rα/sCD127 in Health, Disease, and Its Potential Role as a Therapeutic Agent

Figures & data

Figure 1 Possible mechanisms through which sCD127 influences IL-7-induced effects on CD8+ T cells. Most evidence suggest sCD127 has an agonistic effect on IL-7-induced activity on CD8+ T cells. sCD127 was shown to influence IL-7-induced effect through: (1) competition with mCD127 for binding to IL-7 molecules; (2) while engaged to IL-7, inducing lower consumption of the cytokine, thus, increasing its bioactivity, (3) inhibition of the activity of negative regulators of IL-7/CD127 pathway (eg, SOCS, CD95), and (4) amplification of IL-7-induced CD8+ T cell proliferation and viability.

Table 1 Immune-Mediated Disorders Associated with rs6897932, the Risk Alleles, Known Functional Effects, and Disease-Specific Impact

Condition	Risk Allele	Known Functional Impacts	Disease-Specific Impact	Refs
Multiple sclerosis (MS)	C (particularly in Caucasians)	Higher sCD127 expression	Greater susceptibility to disease and more rapid disease progression	[^Citation64,Citation68,Citation81^–^Citation83,Citation87,Citation88,Citation90,Citation91,Citation100,Citation104^–^Citation106]
Systemic lupus erythematosus (SLE)	C	Higher serum levels of sCD127 in SLE patients which correlate with anti-C1q antibodies levels and SLEDAI score (marker of kidney disease activity)	Increased susceptibility to disease	[^Citation118,Citation147,Citation148]
Asthma	C		Increased susceptibility to disease	[^Citation114]
Type 1 diabetes (T1D)	C	Homozygous patients for the risk allele (CC) have higher circulating sCD127 levels compared to CT or TT	TT genotype associated with protective effect in T1D patients with early age at disease onset	[^Citation65,Citation115,Citation119]
Rheumatoid arthritis (RA)	Limited data, but likely T	Higher serum sCD127 levels than in healthy controls	TT genotype was associated with risk for the disease sCD127 levels were elevated in patients who were refractory to disease-modifying anti-rheumatic drugs therapy and treated with TNFα inhibitor, and this predicted poor response to anti-TNFα therapy	[^Citation117,Citation149]
Graft versus host disease (GVHD)	T, in donors		T allele in donors associated with higher risk of acute GVHD, increased relapse of leukemia, and higher transplant-related mortality in recipients	[^Citation120^–^Citation122]
Breast cancer	T		Increased susceptibility to aggressive breast tumor subtype in patients homozygous for risk allele (TT). TT genotype also associated with lower disease stages.	[^Citation123]
HIV	C in Caucasians T in non-Caucasians	TT genotype associated with lower plasma sCD127 levels T allele associated with lower plasma sCD127 levels both in Caucasian and African cohorts	T carriers: Faster recovery of CD4+ T cells in Caucasians. Higher mortality rates in a cohort from Zimbabwe.	[^Citation127,Citation129^–^Citation132]
HCV	T		T allele: More rapid progression of liver fibrosis	[^Citation135]
HIV/HCV coinfection	C		Higher risk of developing severe liver disease and higher likelihood of severe necroinflammatory activity	[^Citation136]

Hafler DA, Compston A, Sawcer S, et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med. 2007;357(9):851–862. doi:10.1056/NEJMoa073493

 PubMed Web of Science ®Google Scholar

Gregory SG, Schmidt S, Seth P, et al. Interleukin 7 receptor α chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet. 2007;39(9):1083–1091. doi:10.1038/ng2103

 PubMed Web of Science ®Google Scholar

Lundmark F, Duvefelt K, Iacobaeus E, et al. Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis. Nat Genet. 2007;39(9):1108–1113. doi:10.1038/ng2106

 PubMed Web of Science ®Google Scholar

Sombekke MH, Van Der Voort LF, Kragt JJ, et al. Relevance of IL7R genotype and mRNA expression in Dutch patients with multiple sclerosis. Mult Scler J. 2011;17(8):922–930. doi:10.1177/1352458511402411

 Web of Science ®Google Scholar

O’Doherty C, Kantarci O, Vandenbroeck K. IL7RA polymorphisms and susceptibility to multiple sclerosis. N Engl J Med. 2008;358(7):753–754. doi:10.1056/NEJMc0707553

 PubMed Web of Science ®Google Scholar

Weber F, Fontaine B, Cournu-Rebeix I, et al. IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations. Genes Immun. 2008;9(3):259–263. doi:10.1038/gene.2008.14

 PubMed Web of Science ®Google Scholar

Kim JY, Cheong HS, Kim HJ, Kim LH, Namgoong S, Shin HD. Association analysis of IL7R polymorphisms with inflammatory demyelinating diseases. Mol Med Rep. 2014;9(2):737–743. doi:10.3892/mmr.2013.1863

 Web of Science ®Google Scholar

Fang L, Isobe N, Yoshimura S, et al. Interleukin-7 receptor alpha gene polymorphism influences multiple sclerosis risk in Asians. Neurology. 2011;76(24):2125–2127. doi:10.1212/WNL.0b013e31821f466c

 Web of Science ®Google Scholar

Wu S, Liu Q, Zhu JM, Wang MR, Li J, Sun MG. Association between the IL7R T244I polymorphism and multiple sclerosis risk: a meta analysis. Neurol Sci. 2016;37(9):1467–1474. doi:10.1007/s10072-016-2608-8

 Web of Science ®Google Scholar

Kulakova OG, Bashinskaya VV, Tsareva EY, Boyko AN, Favorova OO, Gusev EI. Association analysis of cytokine receptors’ genes polymorphisms with clinical features of multiple sclerosis. Zh Nevrol Psikhiatr Im S S Korsakova. 2016;116(SpecialIssue 10):10–15. doi:10.17116/jnevro201611610210-15

 Google Scholar

Traboulsee AL, Bernales CQ, Ross JP, Lee JD, Sadovnick AD, Vilariño-Güell C. Genetic variants in IL2RA and IL7R affect multiple sclerosis disease risk and progression. Neurogenetics. 2014;15(3):165–169. doi:10.1007/s10048-014-0403-3

 Web of Science ®Google Scholar

Wang XS, Wen PF, Zhang M, et al. Interleukin-7 receptor single nucleotide polymorphism rs6897932 (C/T) and the susceptibility to systemic lupus erythematosus. Inflammation. 2014;37(2):615–620. doi:10.1007/s10753-013-9777-x

 Web of Science ®Google Scholar

Badot V, Luijten RKMAC, van Roon JA, et al. Serum soluble interleukin 7 receptor is strongly associated with lupus nephritis in patients with systemic lupus erythematosus. Ann Rheum Dis. 2013;72(3):453–456. doi:10.1136/annrheumdis-2012-202364

 Web of Science ®Google Scholar

Chi S, Xue J, Li F, et al. Correlation of serum soluble interleukin-7 receptor and anti-C1q antibody in patients with systemic lupus erythematosus. Autoimmune Dis. 2016;2016:1–11. doi:10.1155/2016/8252605

 Google Scholar

Sinha S, Singh J, Jindal SK. Association of interleukin 7 receptor (rs1494555 and rs6897932) gene polymorphisms with asthma in a north Indian population. Allergy Rhinol. 2015;6(3):168–176. doi:10.2500/ar.2015.6.0137

 PubMed Web of Science ®Google Scholar

Todd JA, Walker NM, Cooper JD, et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet. 2007;39(7):857–864. doi:10.1038/ng2068

 PubMed Web of Science ®Google Scholar

Santiago JL, Alizadeh BZ, Martínez A, et al. Study of the association between the CAPSL-IL7R locus and type 1 diabetes. Diabetologia. 2008;51(9):1653–1658. doi:10.1007/s00125-008-1070-4

 Web of Science ®Google Scholar

Monti P, Brigatti C, Krasmann M, Ziegler AG, Bonifacio E. Concentration and activity of the soluble form of the interleukin-7 receptor α in type 1 diabetes identifies an interplay between hyperglycemia and immune function. Diabetes. 2013;62(7):2500–2508. doi:10.2337/db12-1726

 Web of Science ®Google Scholar

O’Doherty C, Alloza I, Rooney M, Vandenbroeck K. IL7RA polymorphisms and chronic inflammatory arthropathies. Tissue Antigens. 2009;74(5):429–431. doi:10.1111/j.1399-0039.2009.01342.x

 PubMedGoogle Scholar

Badot V, Durez P, Van den Eynde BJ, Nzeusseu-Toukap A, Houssiau FA, Lauwerys BR. Rheumatoid arthritis synovial fibroblasts produce a soluble form of the interleukin-7 receptor in response to pro-inflammatory cytokines. J Cell Mol Med. 2011;15(11):2335–2342. doi:10.1111/j.1582-4934.2010.01228.x

 Web of Science ®Google Scholar

Socié G, Ritz J. Current issues in chronic graft-versus-host disease. Blood. 2014;124(3):374–384. doi:10.1182/blood-2014-01-514752

 PubMed Web of Science ®Google Scholar

Shamim Z, Spellman S, Haagenson M, et al. Polymorphism in the interleukin-7 receptor-alpha and outcome after allogeneic hematopoietic cell transplantation with matched unrelated donor. Scand J Immunol. 2013;78(2):214–220. doi:10.1111/sji.12077

 PubMed Web of Science ®Google Scholar

Vitiello GAF, Losi Guembarovski R, Amarante MK, Ceribelli JR, Carmelo ECB, Watanabe MAE. Interleukin 7 receptor alpha Thr244Ile genetic polymorphism is associated with susceptibility and prognostic markers in breast cancer subgroups. Cytokine. 2018;103:121–126. doi:10.1016/j.cyto.2017.09.019

 PubMed Web of Science ®Google Scholar

Resino S, Navarrete-Muñoz MA, Blanco J, et al. IL7RA rs6897932 polymorphism is associated with better CD4+ T-cell recovery in HIV infected patients starting combination antiretroviral therapy. Biomolecules. 2019;9(6):233. doi:10.3390/biom9060233

 Web of Science ®Google Scholar

Rajasuriar R, Booth D, Solomon A, et al. Biological determinants of immune reconstitution in HIV-infected patients receiving antiretroviral therapy: the role of interleukin 7 and interleukin 7 receptor α and microbial translocation. J Infect Dis. 2010;202(8):1254–1264. doi:10.1086/656369

 Web of Science ®Google Scholar

Hartling HJ, Thørner LW, Erikstrup C, et al. Polymorphisms in the interleukin-7 receptor α gene and mortality in untreated HIV-infected individuals. AIDS. 2013;27(10):1615–1620. doi:10.1097/QAD.0b013e3283606c2d

 Web of Science ®Google Scholar

Jiménez-Sousa MÁ, Gómez-Moreno AZ, Pineda-Tenor D, et al. The IL7RA rs6897932 polymorphism is associated with progression of liver fibrosis in patients with chronic hepatitis C: repeated measurements design. PLoS One. 2018;13(5):e0197115. doi:10.1371/journal.pone.0197115

 Web of Science ®Google Scholar

Guzmán-Fulgencio M, Berenguer J, Jiménez-Sousa MA, et al. Association between IL7R polymorphisms and severe liver disease in HIV/HCV coinfected patients: a cross-sectional study. J Transl Med. 2015;13:206. doi:10.1186/s12967-015-0577-y

 Web of Science ®Google Scholar