Walsh & Hoyt: Sarcoidosis: Pathogenesis

Recent evidence supports the hypothesis that sarcoidosis is the result of an antigen-driven process leading initially to granuloma formation in susceptible tissues. The granulomas form as a part of an exaggerated delayed cellular immunologic response against an unidentified antigen that may persist in low levels at the sites of disease involvement. A cascade of events unfolds in the formation of the granulomas including: (a) accumulation of immunocompetent cells at the tissue site, (b) triggering of T-cells by antigen-presenting cells, and (c) the release of cytokines with inflammatory effects. Cytokines play a crucial role in the pathogenesis of sarcoid granulomas and are produced by two types of CD4+ T cells, termed Th1 and Th2 cells. The Th1 cells produce the cytokines interleukin (IL)-2, IL-12, interferon-gamma (IFN-gamma), and tumor necrosis factor-beta (TNF-beta), whereas Th2 cells generate IL-4, IL-5, IL-6, IL-9, and IL-10. In the early phases of the disease, Th1-type cells predominate, leading to the deposition of granulomas via IL-2 and IFN-gamma cytokine effects. In chronic disease, a switch may occur to production of Th2 cytokines, such as IL-4, a potent stimulator of fibroblasts, and subsequent organ fibrosis.