Fig. 1

Legend of the figure. A schematic model for granuloma formation. a Dendritic cells pick up the initiating antigen (likely an environmental airborne antigen or a microbe) and migrate toward lymph nodes, where they interact with appropriate T cells, promoting the differentiation and clonal expansion of T helper (Th)1 and 17 cells. Activated Th1 and Th17 cells promote an inflammatory response via the release of cytokines such as interferon γ (INF-γ), interleukin 2 (IL-2) and IL-17 contributing to granuloma formation. b Microbes, such as mycobacteria or C. acnes, may directly infect monocytes or macrophages, which fail to properly eliminate the infection and in turn differentiate into giant cells or epithelioid cells. Simultaneously, giant cells or epithelioid cells produce tumor necrosis factor-α (TNF-α), which promotes the formation and maintenance of sarcoid granulomas. In addition, by secreting MCP-1 and CXCL10 chemokines, macrophages attract Th1/17 cells, monocytes, regulatory T cells (Tregs). These Tregs fail to control the inflammatory response and secrete transforming grow factor β (TGF- β) that may contribute to fibrosis and granuloma organization (c) An altered composition of the microbiota (dysbiosis) of the gut or lungs may act as a source of microbes that secrete pathogen-associated molecular patterns (PAMPs), which may activate immune cells of the innate system, such as monocytes or eosinophils, by interacting with pathogen recognition receptors (PRRs) like toll-like receptors (TLRs) and in the presence of sustained activation, it may further promote the generation of giant cells and epithelioid cells from macrophages and thereby contribute to granuloma formation via the secretion of cytokines such as IL-6, IL-12, IL-18, and TNF-α