Genetic polymorphisms of cell adhesion molecules in Behcet’s disease in a Chinese Han population

Abstract

Cell adhesion molecules (CAMs) are involved in various immune-mediated diseases. This study was conducted to investigate the association of single nucleotide polymorphisms (SNPs) of CAMs with Behçet’s disease (BD) in a Chinese Han population. A two-stage association study was carried out in 1149 BD patients and 2107 normal controls. Genotyping of 43 SNPs was performed using MassARRAY System (Sequenom), polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and TaqMan SNP assays. The expression of CD6 and CD11c was examined by real-time PCR and cytokine production was measured by ELISA. A significantly higher frequency of the CT genotype, and a lower frequency of the CC genotype and C allele of CD6 rs11230563 were observed in BD as compared with controls. Analysis of CD11c rs2929 showed that patients with BD had a significantly higher frequency of the GG genotype and G allele, and a lower frequency of the AG genotype as compared with controls. Functional experiments showed an increased CD11c expression and increased production of TNF-α and IL-1beta by LPS stimulated PBMCs in GG carriers of CD11c rs2929 compared to AA/AG carriers. Our study provides evidence that CD6 and CD11c are involved in the susceptibility to BD in a Chinese Han population.

Targeting CD6 for the treatment of experimental autoimmune uveitis

“…Optic neuritis is often the first manifestation of MS, and a proportion of MS patients have an associated uveitis [28, 29]. Furthermore, in another genetic study directly related to this report, certain CD6 gene polymorphisms associated with MS have also been associated with Behçet’s disease [17], a condition in which patients develop autoimmune uveitis, thus suggesting that CD6 plays an important role in the pathogenesis of autoimmune uveitis.…”

“…Although certain CD6 polymorphisms have been associated with Behçet’s disease [17], the potential role of CD6 in the pathogenesis of autoimmune uveitis, positive or negative, remains unknown. To address this issue, we compared the induction of EAU in age- and sex-matched CD6 KO (n=18) and WT mice (n=17) on a DBA/1 background following immunization with peptide IRBP 161-180 in CFA and pertussis toxin according to a published protocol [5].…”

“…When combined with methotrexate, itolizumab was also found to reduce T cell numbers and pro-inflammatory cytokine levels in patients with rheumatoid arthritis (RA) [12]. In addition, certain polymorphisms of the CD6 gene have been associated with increased risks of multiple sclerosis (MS) [13-16] and Behçet’s disease [17], in which patients develop autoimmune uveitis.…”

The role of CD6 in autoimmune diseases

“…In 2009, CD6 was identified as a susceptibility locus in multiple sclerosis 2 , and more recently, CD6 was identified as a susceptibility locus in Behcet's disease. 3 Epigenetic regulation of CD6 expression is implied by its progressive upregulation during thymocyte maturation. Hypomethylation of CD6 in an autoimmune disease has been shown in the vasculitic lesions of giant cell arteritis, together with hypomethylation of various other genes related to T cell activation and effector T cell differentiation.…”

Modulation of CD4 T cell function via CD6-targeting

“…In humans, CD6 was also implicated in the pathogenesis of several autoimmune diseases, including rheumatoid arthritis (RA), Sjögren's syndrome and psoriasis [[22], [23], [24], [25]]. Furthermore, genome wide association studies (GWAS) and gene-specific candidate-driven studies also identified CD6 as a major susceptibility locus for multiple sclerosis (MS), psoriasis and Behcet's disease [[26], [27], [28], [29]].…”