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

• Published in: PloS one Vol. 9; no. 11; p. e113090
• Main Authors: Cenit, Maria Carmen, Martínez-Florensa, Mario, Consuegra, Marta, Bonet, Lizette, Carnero-Montoro, Elena, Armiger, Noelia, Caballero-Baños, Miguel, Arias, Maria Teresa, Benitez, Daniel, Ortego-Centeno, Norberto, de Ramón, Enrique, Sabio, José Mario, García-Hernández, Francisco J, Tolosa, Carles, Suárez, Ana, González-Gay, Miguel A, Bosch, Elena, Martín, Javier, Lozano, Francisco
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.11.2014; Public Library of Science (PLoS)
• Subjects: Alleles; Analysis; Antigens; Autoimmune diseases; Autoimmunity; Autoimmunity - immunology; B cells; Biology and Life Sciences; Case-Control Studies; CD3 antigen; CD5 antigen; CD5 Antigens - genetics; Cell proliferation; Chronic conditions; Clonal selection; Crosslinking; Disease; Genes; Genetic Predisposition to Disease; Genotype; Haplotypes; Haplotypes - genetics; Hospitals; Humans; Immunologia; Immunology; Internal medicine; Leukocytes (mononuclear); Limfòcits; Lupus; Lupus eritematós; Lupus erythematosus; Lupus Erythematosus, Systemic - complications; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lupus nephritis; Lupus Nephritis - diagnosis; Lupus Nephritis - etiology; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Medicine; Medicine and Health Sciences; Nephritis; Patients; Polymorphism, Genetic - genetics; Positive selection; Rheumatoid arthritis; Rheumatology; Risk factors; Signal transduction; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Studies; Systemic lupus erythematosus; T cell receptors; T cells; T-cell receptor; T-Lymphocytes - immunology; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0113090

CD5 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. The 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. T-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. The ancestral Ala471 CD5 allele confers lymphocyte hyper-responsiveness to TCR/CD3 cross-linking and is associated with nephritis in SLE patients.