Assessment of clinical, cellular and molecular determinants in sarcoidosis

Abstract

Sarcoidosis is a complex, multisystem inflammatory disease with highly varied presentations, organ involvement and natural history. Its aetiology has remained enigmatic and previous attempts at investigating the cellular and genetic mechanisms that give rise to this disease have yielded conflicting and inconsistent results, largely due to the heterogeneous composition of patient cohorts studied. This project set out to address the problem of phenotypic heterogeneity in sarcoidosis in order to facilitate a more productive investigation into cellular and molecular determinants associated with this disease. We hypothesised that extreme or homogeneous presentations of sarcoidosis would be associated with distinct cellular and molecular characteristics. Through the establishment of a quaternary referral sarcoidosis clinic, patients with diverse presentations of sarcoidosis underwent clinical phenotyping to identify subgroups with consistent clinical characteristics and disease outcomes. Our phenotypic model identified 3 subgroups (neurosarcoidosis, sarcoid uveitis and hepatosplenic sarcoidosis) that were significantly associated with organ limited disease or associated with a distinct presentation that correlated with organ involvement. Patients with a newly described presentation of isolated tattoo and ocular inflammation were also studied as a distinct subgroup. Genetic analysis which focussed on NOD2 variants, demonstrated a significant association between the carriage of P268S and the development of sarcoid uveitis and multisystem disease. Patients with the extreme clinical phenotype of neurosarcoidosis were found to possess a baseline peripheral cellular signature consisting of reduced effector T regulatory cells and increased T effector memory, Th1 and Th2 cells, that was distinct from other clinical phenotypes of sarcoidosis. Finally, we identified global downregulation of chemokine receptor CXCR5 on lymphocyte populations in patients with active tattoo uveitis which normalised upon remission. This finding of chemokine receptor dysregulation is likely to be significant in a disease process that is characterised by organ restricted inflammation. Our results have demonstrated the utility of clinical phenotyping in heterogeneous disease processes. Further investigation will be required to clarify the mechanistic implications of the genetic and cellular associations identified. Show more