The Role of Diverse Immune Cells in Sarcoidosis

Abstract

Sarcoidosis is a systemic inflammatory disorder of unknown etiology characterized by tissue infiltration with macrophages and lymphocytes and associated non-caseating granuloma formation. The disease primarily affects the lungs. Patients suffering from sarcoidosis show a wide range of clinical symptoms, natural history and disease outcomes. Originally described as a Th1-driven disease, sarcoidosis involves a complex interplay among diverse immune cells. This review highlights recent advances in the pathogenesis of sarcoidosis, with emphasis on the role of different immune cells. Accumulative evidence suggests Th17 cells, IFN-γ-producing Th17 cells or Th17.1 cells, and regulatory T (Treg) cells play a critical role. However, their specific actions, whether protective or pathogenic, remain to be clarified. Macrophages are also involved in granuloma formation, and M2 polarization may be predictive of fibrosis. Previously neglected cells including B cells, dendritic cells (DCs), natural killer (NK) cells and natural killer T (NKT) cells were studied more recently for their contribution to sarcoid granuloma formation. Despite these advances, the pathogenesis remains incompletely understood, indicating an urgent need for further research to reveal the distinct immunological events in this process, with hope to open up new therapeutic avenues and if possible, to develop preventive measures.

Keywords: B cells; Th17 cells; dendritic cells; macrophages; natural killer cells; regulatory T cells; sarcoidosis.

Figure 1

Proposed role of diverse immune cells involved in sarcoidosis. The presence of a still unknown antigen in the lungs triggers antigen recognition through innate immune receptors such as TLR2. DCs and alveolar macrophages, acting as APCs, process and present antigens through MHC II - TCR complex to CD4+ T cells, activated by the surrounding abundant cytokines like TNF-α and IFN-γ secreted by NK cells and NKT cells and by activated macrophages. Activated CD4+ T cells can differentiate into various effector T cells depending on the immune microenvironment. In a Th1 cytokine environment, they convert into Th1 cells which express T-bet mRNA, secrete IFN-γ, and interact with matched ligands through IL-2R, IL-12R, IL-18R and CXCR3. Under Th17 inducing conditions, Th17 cells are the prominent effector T cells which express RORγt mRNA in the nucleus, and IL-23R and CCR6 on the membrane, and produce IL-17. In a suppressive immune milieu, Treg cells expressing FoxP3 mRNA play an immune regulatory role by expressing CTLA4 on the membrane and secreting IL-10. There is a delicate balance of transcription factor expression, indicating T-cell plasticity. Th17 cells can co-express RORγt and T-bet mRNA, converting to the so-called Th17.1 cells, regulated by IL-1β. Th17.1 cells capable of producing simultaneously IL-17 and IFN-γ, may lose the expression of RORγt mRNA and ultimately differentiate into T-bet expressing Th1 cells through uncertain mechanisms, secreting IFN-γ alone. Treg cells can lose the expression of FoxP3 and instead express RORγt, thereby turning into Th17 cells in certain circumstances. Upon the recognition of antigens, activated macrophages secrete diverse chemokines, such as CXCL10, attracting and recruiting neutrophils, monocytes and lymphocytes from blood into the lungs, and CXCL9/11 which is recognized by CXCR3 on Th1 cells and promotes further accumulation of Th1 cells. Activated macrophages also secrete cytokines such as TNF-α, IL-1β, IL-6 and IL-13 which mediate the formation of epithelioid macrophages and multinucleated giant cells. Patients with specific TCR Vα2.3/Vβ22 are able to completely clear antigens by specific IgA and IgG through T-B-cell interaction and the granulomas resolve with the help of regulatory effects from Treg cells. In those patients without this specific TCR variant, there is a higher total Ig concentration with no antigen specificity, and through interactions of IL-13 induced polarized M2 macrophages and fibroblasts the granulomatous inflammation can become chronic and progress to permanent fibrotic lesions, regulated by TGF-β and CCL18. The straight solid arrow implies the identified differentiation of T-cell subsets or monocyte/macrophage polarization, while the dotted one indicates the possible conversion of T-cell subgroups. The flexible solid arrow describes the contribution of diverse immune cells to the formation of granuloma and lung fibrosis or granuloma resolution, and the hollow one emphasizes the two significantly different disease outcomes after granuloma formation in sarcoidosis. TLR, toll-like receptor; DCs, dendritic cells; APC, antigen-presenting cell; MHC, major histocompatibility complex; TCR, T cell receptor; TNF, tumor necrosis factor; IFN, interferon; NK: natural killer; IL-2R, interleukin-2 receptor; CXCR, chemokine (C-X-C motif) receptor; CCR, chemokine (C-C motif) receptor; CXCL, chemokine (C-X-C motif) ligand; Treg cells, regulatory T cells; CTLA4, cytotoxic T-lymphocyte antigen 4; TGF, transforming growth factor. Created with BioRender.com.