AUTHOR=Casadó-Llombart Sergi , Velasco-de Andrés María , Català Cristina , Leyton-Pereira Alejandra , Gutiérrez-Cózar Rebeca , Suárez Belén , Armiger Noelia , Carreras Esther , Esteller Miriam , Ricart Elena , Ordás Ingrid , Gisbert Javier P. , Chaparro María , Esteve María , Márquez Lucía , Busquets David , Iglesias Eva , García-Planella Esther , Martín-Arranz María Dolores , Lohmann Juliane , Ayata C. Korcan , Niess Jan Hendrik , Engel Pablo , Panés Julián , Salas Azucena , Domènech Eugeni , Lozano Francisco ,  ENEIDA Project of GETECCU , Lucendo Alfredo J. , Guardiola Jordi , Calvet Xavier , Olivá́n Lorenzo , Piqueras Marta 

TITLE=Experimental and genetic evidence for the impact of CD5 and CD6 expression and variation in inflammatory bowel disease

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.966184

DOI=10.3389/fimmu.2022.966184

ISSN=1664-3224

ABSTRACT=<p>Crohn’s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) resulting from the interaction of multiple environmental, genetic and immunological factors. <italic>CD5</italic> and <italic>CD6</italic> are paralogs encoding lymphocyte co-receptors involved in fine-tuning intracellular signals delivered upon antigen-specific recognition, microbial pattern recognition and cell adhesion. While <italic>CD5</italic> and <italic>CD6</italic> expression and variation is known to influence some immune-mediated inflammatory disorders, their role in IBD remains unclear. To this end, <italic>Cd5</italic>- and <italic>Cd6</italic>-deficient mice were subjected to dextran sulfate sodium (DSS)-induced colitis, the most widely used experimental animal model of IBD. The two mouse lines showed opposite results regarding body weight loss and disease activity index (DAI) changes following DSS-induced colitis, thus supporting <italic>Cd5</italic> and <italic>Cd6</italic> expression involvement in the pathophysiology of this experimental IBD model. Furthermore, DNA samples from IBD patients of the ENEIDA registry were used to test association of <italic>CD5</italic> (rs2241002 and rs2229177) and <italic>CD6</italic> (rs17824933, rs11230563, and rs12360861) single nucleotide polymorphisms with susceptibility and clinical parameters of CD (n=1352) and UC (n=1013). Generalized linear regression analyses showed association of <italic>CD5</italic> variation with CD ileal location (rs2241002<sup>CC</sup>) and requirement of biological therapies (rs2241002<sup>C</sup>-rs2229177<sup>T</sup> haplotype), and with poor UC prognosis (rs2241002<sup>T</sup>-rs2229177<sup>T</sup> haplotype). Regarding <italic>CD6</italic>, association was observed with CD ileal location (rs17824933<sup>G</sup>) and poor prognosis (rs12360861<sup>G</sup>), and with left-sided or extensive UC, and absence of ankylosing spondylitis in IBD (rs17824933<sup>G</sup>). The present experimental and genetic evidence support a role for <italic>CD5</italic> and <italic>CD6</italic> expression and variation in IBD’s clinical manifestations and therapeutic requirements, providing insight into its pathophysiology and broadening the relevance of both immunomodulatory receptors in immune-mediated disorders.</p>