Molecular mapping of interstitial lung disease reveals a phenotypically distinct senescent basal epithelial cell population.

Compromised regenerative capacity of lung epithelial cells can lead to cellular senescence, which may precipitate fibrosis. While increased markers of senescence have been reported in idiopathic pulmonary fibrosis (IPF), the origin and identity of these senescent cells remain unclear, and tools to characterize context-specific cellular senescence in human lung are lacking. We observed that the senescent marker p16 is predominantly localized to bronchiolized epithelial structures in scarred regions of IPF and systemic sclerosis-associated interstitial lung disease (SSc-ILD) lung tissue, overlapping with the basal epithelial markers Keratin 5 and Keratin 17. Using in vitro models, we derived transcriptional signatures of senescence programming specific to different types of lung epithelial cells and interrogated these signatures in a single-cell RNA-Seq data set derived from control, IPF, and SSc-ILD lung tissue. We identified a population of basal epithelial cells defined by, and enriched for, markers of cellular senescence and identified candidate markers specific to senescent basal epithelial cells in ILD that can enable future functional studies. Notably, gene expression of these cells significantly overlaps with terminally differentiating cells in stratified epithelia, where it is driven by p53 activation as part of the senescence program.

Mechanisms underlying B cell immune dysregulation and autoantibody production in MuSK myasthenia gravis.

Pathogenic autoantibodies to muscle-specific tyrosine kinase (MuSK) can be found in patients with myasthenia gravis (MG) who do not have detectable antibodies to the acetylcholine receptor. Although the autoantibody-mediated pathology is well understood, much remains to be learned about the cellular immunology that contributes to autoantibody production. To that end, our laboratory has investigated particular components associated with the cellular immunopathology of MuSK MG. First, we found that B cell tolerance defects contribute to the abnormal development of the naive repertoire, which indicates that dysregulation occurs before the production of autoantibodies. Second, both the naive and antigen-experienced memory B cell repertoire, which we examined through the application of high-throughput adaptive immune receptor repertoire sequencing, include abnormalities not found in healthy controls. This highlights a broad immune dysregulation. Third, using complementary approaches, including production of human monoclonal antibodies, we determined that circulating plasmablasts directly contribute to the production of MuSK-specific autoantibodies in patients experiencing relapse following B cell depletion therapy. These collective findings contribute to defining a mechanistic model that describes MuSK MG immunopathogenesis.