Background/Purpose: Autoimmunity is a diverse group of complex conditions that can include certain congenital genetic defects leading to loss of self-tolerance with subsequent imbalances of immune homeostasis and pro-inflammatory bias. Recently we reported a monogenic disorder of interstitial lung disease, renal disease, and arthritis with accompanying autoantibodies.  This syndrome was found to be mediated by mutations in the coatomer subunit alpha (COPA) gene, which belongs to the coatomer-1 (COPI) complex involved primarily in the retrograde transport of proteins from the golgi apparatus to the endoplasmic reticulum (ER). These mutations result in an increase in ER stress, an increase in basal levels of autophagy, and an over activation of mTOR ultimately resulting in a pro-inflammatory environment, particularly increased levels of IL-1β.  

Methods: In an effort to provide more rational treatment for COPA syndrome patients we hypothesize that modulation of the autophagy axis will result in a decrease in the pro-inflammatory environment. 

Results: Here we show that treatment of COPA mutant expressing cells with autophagy modifying drugs, including rapamycin and chloroquine, result in normalization of autophagosome size, retention of IL-1β and a decrease in caspase-1 activity.

Conclusion: Taken together these data suggest that repairing the underlying cellular defect in ER stress, autophagy, and excessive mTOR activity will alleviate the pro-inflammatory environment, particularly increased IL-1β levels, and lead to a more balanced immune phenotype in COPA syndrome patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/rescue-of-copa-syndrome-cellular-phenotype-by-autophagy-modifying-drugs/