| Popis: |
Pediatric patients with constitutively active gain-of-function (GOF) mutations in the cytosolic double-stranded-DNA sensing adaptor STING develop an autoinflammatory syndrome known as STING associated vasculopathy with onset in infancy (SAVI). Despite persistent circulating lymphopenia, SAVI patients suffer from interstitial lung disease (ILD) with lymphocyte predominant bronchus associated lymphoid tissue (BALT). Mice expressing SAVI mutations (STING V154M [VM]) recapitulate lymphopenia concomitant with ILD. We find that although lymphopenia results from central developmental defects attributable to immune intrinsic STING GOF, lymphocytes accumulate in lung tissue and are critical for lung pathology and mortality. However, lethally irradiated VM recipients fully reconstituted with wild type (WT) immune cells still develop ILD, indicating that STING GOF in hematopoietic cells is not required for lung disease. Additionally, WT B cells that develop in a VM host produce auto-antibodies against lung and show a repertoire dependent activation in lung tissue. This indicates that STING GOF in radioresistant stromal cells initiates lung autoimmunity. We identified lung endothelial cells as radioresistant cells that express STING. Transcriptional analysis of VM endothelial cells revealed significant up-regulation of chemokine, cytokine, and antigen presentation genes. Conditional expression of the STING GOF mutation in endothelial cells was sufficient to initiate recruitment of lymphocytes to lung tissue. Together, our data show that VM-expressing radioresistant cells, particularly endothelial cells, initiate lymphocyte driven interstitial lung disease in VM mice and provide insights for treatment of SAVI patients, with implications for ILD associated with other connective-tissue-disorders. |
