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


METHODS
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.


RESULTS
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.


CONCLUSIONS
The ancestral Ala471 CD5 allele confers lymphocyte hyper-responsiveness to TCR/CD3 cross-linking and is associated with nephritis in SLE patients.
Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain.
Maria Carmen
MC
Cenit
ImmunNovative Developments, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Mario
M
Martínez-Florensa
Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Marta
M
Consuegra
Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Lizette
L
Bonet
Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Departament de Ciències Experimentals i de la Salut, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain.
Elena
E
Carnero-Montoro
Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Noelia
N
Armiger
Department of Immunology, Hospital Clínic de Barcelona; Barcelona, Spain.
Miguel
M
Caballero-Baños
Department of Immunology, Hospital Clínic de Barcelona; Barcelona, Spain.
Maria Teresa
MT
Arias
Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Daniel
D
Benitez
Department of Internal Medicine, Hospital Clínico San Cecilio, Granada, Spain.
Norberto
N
Ortego-Centeno
Department of Internal Medicine, Hospital Carlos Haya, Málaga, Spain.
Enrique
E
de Ramón
Department of Internal Medicine, Hospital Virgen de las Nieves, Granada, Spain.
José Mario
JM
Sabio
Department of Internal Medicine, Hospital Virgen del Rocío, Seville, Spain.
Francisco J
FJ
García-Hernández
Department of Internal Medicine, Hospital Parc Taulí, Sabadell, Spain.
Carles
C
Tolosa
Department of Functional Biology, Immunology Area, Faculty of Medicine, University of Oviedo, Oviedo, Spain.
Ana
A
Suárez
Department of Rheumatology, Hospital Marques de Valdecilla, IFIMAV, Santander, Spain.
Miguel A
MA
González-Gay
Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Departament de Ciències Experimentals i de la Salut, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain.
Elena
E
Bosch
Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain.
Javier
J
Martín
Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Department of Immunology, Hospital Clínic de Barcelona; Barcelona, Spain; Departament de Biologia Cel·lular, Immunologia i Neurociencies, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
Francisco
F
Lozano
D000483:Alleles; D015551:Autoimmunity / Q000276:immunology; D018956:CD5 Antigens / Q000235:genetics*; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000235:genetics* / Q000276:immunology; D008181:Lupus Nephritis / Q000175:diagnosis / Q000209:etiology*; D008213:Lymphocyte Activation / Q000276:immunology*; D011110:Polymorphism, Genetic / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology*
D018956:CD5 Antigens