Immunogenetics of Disease-Causing Inflammation in Sarcoidosis

Abstract

Sarcoidosis is a systemic inflammatory disorder characterised by tissue infiltration by mononuclear phagocytes and lymphocytes with associated non-caseating granuloma formation. Originally described as a disorder of the skin, sarcoidosis can involve any organ with wide-ranging clinical manifestations and disease course. Recent studies have provided new insights into the mechanisms involved in disease pathobiology, and we now know that sarcoidosis has a clear genetic basis largely involving human leukocyte antigen (HLA) genes. In contrast to Mendelian-monogenic disorders--which are generally due to specific and relatively rare mutations often leading to a single amino acid change in an encoded protein--sarcoidosis results from genetic variations relatively common in the general population and involving multiple genes, each contributing an effect of varying magnitude. However, an individual may have the necessary genetic profile and yet the disease will not develop unless an environmental or infectious factor is encountered. Genetics appears also to contribute to the huge variability in clinical phenotype and disease behaviour. Moreover, it has been established that sarcoidosis granulomatous inflammation is a highly polarized T helper 1 immune response that starts with an antigenic stimulus followed by T cell activation via a classic HLA class II-mediated pathway. A complex network of lymphocytes, macrophages, and cytokines is pivotal in the orchestration and evolution of the granulomatous process. Despite these advances, the aetiology of sarcoidosis remains elusive and its pathogenesis incompletely understood. As such, there is an urgent need for a better understanding of disease pathogenesis, which hopefully will translate into the development of truly effective therapies.

Joint SNMMI–ASNC expert consensus document on the role of 18F-FDG PET/CT in cardiac sarcoid detection and therapy monitoring

“…3 A variegated disease prevalence defined by ethnicity, sex, and geographic region identifies an important interaction between genetic and environmental factors influencing the risk for developing sarcoidosis. 4 Worldwide, the lifetime risk of developing sarcoidosis has been estimated at 1%-2% in Western developed nations. [5][6][7] Once considered a rare disease, 7-9 recent estimates suggest a prevalence rate of sarcoidosis that is increasing (e.g., 141.4 per 100,000 in U.S. African Americans and 49.8 per 100,000 in U.S. Caucasians).…”

Sarcoidosis and T-Helper Cells. Th1, Th17, or Th17.1?

“…1 T-cell immune response genes in disease pathogenesis (1). The prototypical adaptive immune response in sarcoidosis is characterized by the presence of IFN-g-producing CD4…”

Joint SNMMI–ASNC Expert Consensus Document on the Role of 18F-FDG PET/CT in Cardiac Sarcoid Detection and Therapy Monitoring

“…Other data suggest a higher prevalence, at 330 cases per 100,000, in certain regions of the United States (3). A variegated disease prevalence defined by ethnicity, sex, and geographic region identifies an important interaction between genetic and environmental factors influencing the risk for developing sarcoidosis (4). Worldwide, the lifetime risk of developing sarcoidosis has been estimated at 1%-2% in Western developed nations (5)(6)(7).…”