PLoS ONE (Jan 2014)

Analysis of ancestral and functionally relevant CD5 variants in systemic lupus erythematosus patients.

  • Maria Carmen Cenit,
  • Mario Martínez-Florensa,
  • Marta Consuegra,
  • Lizette Bonet,
  • Elena Carnero-Montoro,
  • Noelia Armiger,
  • Miguel Caballero-Baños,
  • Maria Teresa Arias,
  • Daniel Benitez,
  • Norberto Ortego-Centeno,
  • Enrique de Ramón,
  • José Mario Sabio,
  • Francisco J García-Hernández,
  • Carles Tolosa,
  • Ana Suárez,
  • Miguel A González-Gay,
  • Elena Bosch,
  • Javier Martín,
  • Francisco Lozano

DOI
https://doi.org/10.1371/journal.pone.0113090
Journal volume & issue
Vol. 9, no. 11
p. e113090

Abstract

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ObjectiveCD5 plays a crucial role in autoimmunity and is a well-established genetic risk factor of developing RA. Recently, evidence of positive selection has been provided for the CD5 Pro224-Val471 haplotype in East Asian populations. The aim of the present work was to further analyze the functional relevance of non-synonymous CD5 polymorphisms conforming the ancestral and the newly derived haplotypes (Pro224-Ala471 and Pro224-Val471, respectively) as well as to investigate the potential role of CD5 on the development of SLE and/or SLE nephritis.MethodsThe CD5 SNPs rs2241002 (C/T; Pro224Leu) and rs2229177 (C/T; Ala471Val) were genotyped using TaqMan allelic discrimination assays in a total of 1,324 controls and 681 SLE patients of Spanish origin. In vitro analysis of CD3-mediated T cell proliferative and cytokine response profiles of healthy volunteers homozygous for the above mentioned CD5 haplotypes were also analyzed.ResultsT-cell proliferation and cytokine release were significantly increased showing a bias towards to a Th2 profile after CD3 cross-linking of peripheral mononuclear cells from healthy individuals homozygous for the ancestral Pro224-Ala471 (CC) haplotype, compared to the more recently derived Pro224-Val471 (CT). The same allelic combination was statistically associated with Lupus nephritis.ConclusionThe ancestral Ala471 CD5 allele confers lymphocyte hyper-responsiveness to TCR/CD3 cross-linking and is associated with nephritis in SLE patients.