Immunity in idiopathic pulmonary arterial hypertension (IPAH), a role for activated DCs?

The presence of tertiary lymphoid organs (TLOs) in lungs of IPAH patients suggest a key role for (auto)immunity in its pathogenesis. Activated dendritic cells (DCs) play a crucial role in the induction of TLOs. DC activation leads to NF-kB activation, which is negatively regulated by the A20 enzyme. In this study, peripheral blood of PAH patients and healthy controls (HC) was examined for DC number and activation. Furthermore, mice harboring activated A20-deficient cDC1s ( Dngr1 -cre X Tnfaip3 fl/fl mice (DNGR1-A20)) were examined at 31 weeks of age. PAH development was monitored using Right Heart Catheterization (RHC), Echocardiography, RV hypertrophy, and Histology. Peripheral CD141+ DCs (cDC1) of IPAH patients showed an increased activation status by CD86 expression compared to HC. DNGR1-A20KO mice showed an significantly increased RV hypertrophy, measured both by echocardiography and Fulton index. RHC showed a trend towards increased RVSP in the DNGR1-A20 KO mice in comparison to the wildtype mice. Furthermore, lungs of DNGR1-A20KO mice exhibited increased perivascular infiltration, muscle wall thickening and collagen deposition around the pulmonary vessels compared to wildtype mice. Our IPAH patient data show a significantly increased activation of cDC1s in peripheral blood samples and our DNGR1-A20 KO mouse model shows progression towards a PAH phenotype with significantly increased RVH and a trend of increased RVSP. The pulmonary vascular infiltrates show a possible role for (auto)immunity in the development of PH. In conclusion, investigating DC activation in the development or progression of PAH will be valuable to gain more insight in the mechanisms driving the pathophysiology of IPAH.