Granuloma formation in pulmonary sarcoidosis

Abstract

Sarcoidosis is a granulomatous disorder of unknown cause, affecting multiple organs, but mainly the lungs. The exact order of immunological events remains obscure. Reviewing current literature, combined with careful clinical observations, we propose a model for granuloma formation in pulmonary sarcoidosis. A tight collaboration between macrophages, dendritic cells, and lymphocyte subsets, initiates the first steps toward granuloma formation, orchestrated by cytokines and chemokines. In a substantial part of pulmonary sarcoidosis patients, granuloma formation becomes an on-going process, leading to debilitating disease, and sometimes death. The immunological response, determining granuloma sustainment is not well understood. An impaired immunosuppressive function of regulatory T cells has been suggested to contribute to the exaggerated response. Interestingly, therapeutical agents commonly used in sarcoidosis, such as glucocorticosteroids and anti-TNF agents, interfere with granuloma integrity and restore the immune homeostasis in autoimmune disorders. Increasing insight into their mechanisms of action may contribute to the search for new therapeutical targets in pulmonary sarcoidosis.

Keywords: T helper 1 cells; T helper 17 cells; dendritic cells; formation; granuloma; integrity; pulmonary sarcoidosis; regulatory T cells.

Figure 1

A schematic model for granuloma formation in pulmonary sarcoidosis. An unknown airborne-antigen activates (A) interstitial dendritic cells (DCs), (B) alveolar macrophages (AMs), and (C) alveolar epithelial cells type II (AEC-II) (dark green), simultaneously. This process is initiated by toll-like receptor-2 (TLR-2) ligands, possibly Mycobacterium tuberculosis-derived ESAT-6 or mKatG. (A) The interstitial DCs pick up the putative antigen and migrate toward the mediastinal lymph nodes (LNs), where they initiate differentiation and clonal expansion of T helper (Th)1 and 17 cells. (B) Simultaneously, AMs produce tumor necrosis factor-α (TNF-α), which initiates upregulation of activation (HLA-DR and CD80/86) and adhesion (ICAM-1 and LeuCAM) molecules. Macrophages produce chemokine ligands (MCP-1, CCL20, CXCL10, and CXCL16) under stimulation of both TNF-α and natural-killer (NK) cell-derived interferon-γ (INF-γ), thereby attracting Th1/17 cells, monocytes, regulatory T cells (Tregs), and B cells. (C) The lung environment is characterized by the presence of Th1 and Th17 favoring cytokines, such as IL-6, IL-12, IL-18, IL-23, and TGF-β, produced by macrophages, perilymphatic DCs, and AEC-II. Persistent stimulation, mediated by antigen presenting cells (APCs), leads to continuous cellular recruitment to the site of inflammation, which leads to granuloma formation. Tregs infiltrating the granuloma fail to diminish the exaggerated immune response, thereby contributing to granuloma persistence and integrity.