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Sarcoidosis is triggered by environmental agents, primarily mycobacterial infections. Genetic, epigenetic and environmental factors interact with environmental triggers to result in the following: innate immune activation of macrophages and dendritic cells, which have upregulated major histocompatibility complex (MHC) expression and express cytokines that direct the phenotype of the adaptive immune response (step 1); upregulation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway leading to differentiation of epithelioid cells (activated macrophages that resemble epithelial cells) and changes in metabolic and immune pathways (step 2); upregulation of serum amyloid A (SAA) and heat shock proteins (HSPs) as part of an acute phase response (step 3), followed by SAA aggregation in granulomas, which promotes enhanced effector T cell responses, in part through innate immune receptors, such as Toll-like receptor 2 (TLR2); an enhanced T cell response to pathogenic tissue antigens, which in the presence of IL-12, IL-18, IL-6 and transforming growth factor-β (TGFβ) promotes polarization of T helper 1 (TH1), TH17 and TH17.1 responses in affected sites (step 4); and an impaired regulatory T (Treg) cell response (dashed arrow; step 5) allows enhanced local effector T cell responses to tissue antigens to persist, resulting in chronic sarcoidosis. | APC, antigen-presenting cell; TNF, tumour necrosis factor. | Grunewald, J., Grutters, J. C., Arkema, E. V, Saketkoo, L. A., Moller, D. R., & Müller-Quernheim, J. (2019). Sarcoidosis. Nature Reviews Disease Primers, 5(1), 45. https://doi.org/10.1038/s41572-019-0096-x

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