Dysregulated tissue immunity in human fatal asthma

Asthma is an immune-mediated lung disease causing airway constriction that is fatal in rare cases, though the immune mechanisms underlying asthma severity are poorly understood. Here, we present a comprehensive immunological profiling of lymphoid organs, lungs, and intestines from human organ donors who died of fatal asthma (FA) compared to donors who died of unrelated causes with or without a history of asthma. Compared to control donors, FA donors exhibit elevated plasma IgE along with enhanced and aberrant immune responses in mucosal-associated lymph nodes (LN) and lungs, respectively. In particular, FA donors show increased memory T and B cells and decreased Treg cells with age in the gut- and lung-associated LN, increased Th2 and Th1 resident memory cells in the lungs, and increased associations between gut and lung immune responses compared to control donors. Our findings reveal mucosal immune dysregulation underlying asthma exacerbation through site-specific and inter-tissue disruption of immune homeostasis. Immune mechanisms driving severe asthma and fatal outcomes remain elusive. Through cross-tissue immune profiling of organ donors who died of fatal asthma versus other causes, the authors here reveal mucosal immune dysregulation marked by enhanced T- and B-cell memory, reduced Tregs, and increased lung Th2 and Th1 effectors linked to priming in gut-associated lymph nodes.