| Autor: |
Sati S; Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA., Huang J; Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA., Kersh AE; Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA., Jones P; Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA., Ahart O; Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA., Murphy C; Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA., Prouty SM; Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA., Hedberg ML; Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA., Jain V; Duke Molecular Physiology Institute, Durham, North Carolina, USA., Gregory SG; Duke Molecular Physiology Institute, Durham, North Carolina, USA., Leung DH; Singapore Management University, Singapore., Seykora JT; Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA., Rosenbach M; Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA., Leung TH; Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.; Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA. |
| Abstrakt: |
Sarcoidosis is a multiorgan granulomatous disease that lacks diagnostic biomarkers and targeted treatments. Using blood and skin from patients with sarcoid and non-sarcoid skin granulomas, we discovered that skin granulomas from different diseases exhibit unique immune cell recruitment and molecular signatures. Sarcoid skin granulomas were specifically enriched for type 1 innate lymphoid cells (ILC1s) and B cells and exhibited molecular programs associated with formation of mature tertiary lymphoid structures (TLSs), including increased CXCL12/CXCR4 signaling. Lung sarcoidosis granulomas also displayed similar immune cell recruitment. Thus, granuloma formation was not a generic molecular response. In addition to tissue-specific effects, patients with sarcoidosis exhibited an 8-fold increase in circulating ILC1s, which correlated with treatment status. Multiple immune cell types induced CXCL12/CXCR4 signaling in sarcoidosis, including Th1 T cells, macrophages, and ILCs. Mechanistically, CXCR4 inhibition reduced sarcoidosis-activated immune cell migration, and targeting CXCR4 or total ILCs attenuated granuloma formation in a noninfectious mouse model. Taken together, our results show that ILC1s are a tissue and circulating biomarker that distinguishes sarcoidosis from other skin granulomatous diseases. Repurposing existing CXCR4 inhibitors may offer a new targeted treatment for this devastating disease. |
