Genetic, Immunologic, and Environmental Basis of Sarcoidosis

Abstract

Sarcoidosis is a multisystem disease with tremendous heterogeneity in disease manifestations, severity, and clinical course that varies among different ethnic and racial groups. To better understand this disease and to improve the outcomes of patients, a National Heart, Lung, and Blood Institute workshop was convened to assess the current state of knowledge, gaps, and research needs across the clinical, genetic, environmental, and immunologic arenas. We also explored to what extent the interplay of the genetic, environmental, and immunologic factors could explain the different phenotypes and outcomes of patients with sarcoidosis, including the chronic phenotypes that have the greatest healthcare burden. The potential use of current genetic, epigenetic, and immunologic tools along with study approaches that integrate environmental exposures and precise clinical phenotyping were also explored. Finally, we made expert panel-based consensus recommendations for research approaches and priorities to improve our understanding of the effect of these factors on the health outcomes in sarcoidosis.

Keywords: environment; genetics; granuloma; immunology; phenotype.

Figure 1.

Schematic of the current state of the genetic, immunological, and environmental basis of sarcoidosis. Environmental triggers, mostly microbial in origin, interact with genetic, epigenetic, environmental, and immunologic host factors resulting in a hyperpolarized T-helper (Th)1 response to pathogenic tissue antigens and epithelioid granuloma formation. The local Th1 immune responses are associated with impaired regulatory T-cell function and innate immune stimulation (e.g., Toll-like receptor 2, serum amyloid A). The determinants of the different clinical phenotypes and outcomes remain uncertain. *There is a lack of consensus on whether inorganic agents can trigger multisystem sarcoidosis. MHC = major histocompatibility complex; TNF = tumor necrosis factor.