Gene Variation at Immunomodulatory and Cell Adhesion Molecules Loci Impacts Primary Sjögren's Syndrome

Sergi Casadó-Llombart; Hoda Gheitasi; Silvia Ariño; Marta Consuegra-Fernández; Noelia Armiger-Borràs; Belchin Kostov; Manuel Ramos-Casals; Pilar Brito-Zerón; Francisco Lozano

doi:10.3389/fmed.2022.822290

Gene Variation at Immunomodulatory and Cell Adhesion Molecules Loci Impacts Primary Sjögren's Syndrome

Front Med (Lausanne). 2022 Mar 18:9:822290. doi: 10.3389/fmed.2022.822290. eCollection 2022.

Authors

Affiliations

¹ Immunoreceptors del Sistema Innat i Adaptatiu, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
² Department of Autoimmune Diseases, ICMiD, Hospital Clínic, University of Barcelona, Barcelona, Spain.
³ Primary Care Centre Les Corts, Consorci d'Atenció Primària de Salut Barcelona Esquerra (CAPSBE), Barcelona, Spain.
⁴ Primary Healthcare Transversal Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
⁵ Department of Statistics and Operations Research, Universitat Politècnica de Catalunya (UPC), Barcelona, Spain.
⁶ Research and Innovation Group in Autoimmune Diseases, RGAD-Sanitas Digital Hospital, Barcelona, Spain.
⁷ Systemic Autoimmune Diseases Unit, Internal Medicine, Millenium Clinic, Sanitas, Barcelona, Spain.
⁸ Servei d'Immunologia, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Barcelona, Spain.
⁹ Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.

Abstract

Primary Sjögren's syndrome (pSS) is an autoimmune disease triggered by a combination of environmental and host genetic factors, which results in the focal lymphocytic infiltration of exocrine glands causing eye and mouth dryness. Glandular infiltrates include T and B cell subsets positive for CD5 and/or CD6, two surface scavenger receptors involved in the fine-tuning of intracellular signals mediated by the antigen-specific receptor complex of T (TCR) and B (BCR) cells. Moreover, the epithelial cells of inflamed glands overexpress CD166/ALCAM, a CD6 ligand involved in homo and heterotypic cell adhesion interactions. All this, together with the reported association of functionally relevant single nucleotide polymorphisms (SNPs) of CD5, CD6, and CD166/ALCAM with the risk or prognosis of some immune-mediated inflammatory disorders, led us to investigate similar associations in a local cohort of patients with pSS. The logistic regression analyses of individual SNPs showed the association of CD5 rs2241002^T with anti-Ro/La positivity, CD6 rs17824933^C with neutropenia, and CD6 rs11230563^T with increased leukopenia and neutropenia but decreased peripheral nervous system EULAR Sjögren's syndrome disease activity index (ESSDAI). Further analyses showed the association of haplotypes from CD5 (rs2241002^T-rs2229177^C) with anemia and thrombocytopenia, CD6 (rs17824933^G-rs11230563^C-rs12360861^G) with cutaneous ESSDAI, and CD166/ALCAM (rs6437585^C-rs579565^A-rs1044243^C and rs6437585^C-rs579565^G-rs1044243^T) with disease susceptibility and several analytical parameters (anti-nuclear antibodies, neurological ESSDAI, and hematologic cytopenias). These results support the relevance of gene variation at loci coding for cell surface receptors involved in the modulation of T and B lymphocyte activation (CD5, CD6) and epithelial-immune cell adhesion (CD166/ALCAM) in modulating the clinical and analytical outcomes in patients with pSS.

Keywords: CD166/ALCAM; CD5; CD6; SNP; Sjögren's syndrome; polymorphism.