Key Players and Biomarkers of the Adaptive Immune System in the Pathogenesis of Sarcoidosis

Emily-Rose Zhou, Sergio Arce, Emily-Rose Zhou, Sergio Arce

Abstract

Sarcoidosis is a systemic inflammatory disease characterized by development of granulomas in the affected organs. Sarcoidosis is often a diagnosis of exclusion, and traditionally used tests for sarcoidosis demonstrate low sensitivity and specificity. We propose that accuracy of diagnosis can be improved if biomarkers of altered lymphocyte populations and levels of signaling molecules involved in disease pathogenesis are measured for patterns suggestive of sarcoidosis. These distinctive biomarkers can also be used to determine disease progression, predict prognosis, and make treatment decisions. Many subsets of T lymphocytes, including CD8+ T-cells and regulatory T-cells, have been shown to be dysfunctional in sarcoidosis, and the predominant CD4+ T helper cell subset in granulomas appears to be a strong indicator of disease phenotype and outcome. Studies of altered B cell populations, B cell signaling molecules, and immune complexes in sarcoidosis patients reveal promising biomarkers as well as possible explanations of disease etiology. Furthermore, examined biomarkers raise questions about new treatment methods and sarcoidosis antigens.

Keywords: B cells; T-cells; chemokines; cytokines; fibrosis; granuloma; macrophages; plasma cells; sarcoidosis.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
An overview of the serum and bronchoalveolar lavage (BAL) fluid biomarkers produced by cells of the innate and adaptive immune system during granuloma development in sarcoidosis. Granulomas are tightly packaged clusters of cells comprising a central core of macrophages, epithelioid histiocytes, multinucleated giant cells and unknown sarcoid antigens surrounded by a lymphocyte collar. The lymphocyte collar contains, mainly, CD4+ T-cells, but CD8+ T-cells, Treg cells, B cells, plasma cells and fibroblasts can also be found. During granuloma development, a number of biomarkers are produced and released by these cells. CD4+ T lymphocytes are key players in granuloma formation. They differentiate into specific TH cell subtypes (i.e., TH1, TH2, T follicular helper (Tfh), TH17, TH17.1 and Treg) depending mainly on the cytokine microenvironment. The TH1, TH17 and TH17.1 subtypes produce inflammatory markers (i.e., Interferon (IFN)-γ, IL-17A, and IFN-γ/IL-17A, respectively). Through IL-2 production the TH1 subtype helps CD8+ T-cells differentiate into cytotoxic effectors which produce biomarkers of inflammation (i.e., perforin and granzyme), while the TH17 subtype attracts neutrophils via IL-17A and C-X-C motif ligand 8 (CXCL8), further contributing to inflammatory marker production. The TH2 and TH17 subtypes can secrete IL-4 (Interleukin-4)/IL-13 and Transforming Growth Factor β1 (TGF-β1), respectively, which are biomarkers of fibrosis. JAK-STAT signaling is strongly implicated in sarcoidosis pathogenesis with Signal Transducer and Activator of Transcription 3 (STAT3) and STAT1/STAT4 playing important roles in TH17 and TH1 cell differentiation, respectively. Altered mammalian target of rapamycin (mTOR) signaling negatively affects TH17 differentiation and production of TH17-associated inflammatory biomarkers. Through expression of CD40 Ligand (CD40L) and Inducible Co-stimulator (ICOS), the Tfh subtype helps B cells differentiate into plasma cells which secrete antibodies to sarcoid antigens. Sarcoid antigens and their specific antibodies form immune complexes that can potentially be used as specific biomarkers of sarcoidosis. The Treg subtype negatively controls production of inflammatory markers by the above-mentioned TH cell subsets. Natural killer T (NKT) cells (not shown) also modulate the CD4+ T-cell immune response. Macrophages are also important for granuloma formation and produce different biomarkers depending on their polarization state. M1 macrophages release inflammatory biomarkers (i.e., Serum Amyloid A (SAA), Chitotriosidase (CTO), IL-12, CXCL9, CXCL10, and CXCL11), while M2 macrophages produce biomarkers of fibrosis (i.e., C-C motif ligand 18 (CCL18) and Transforming Growth Factor β1 (TGF-β1)). Image created using BioRender.

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