Dendritic cells and t cells in pulmonary hypertension: A dangerous infl ammatory symphony

Pulmonary hypertension (PH) is a debilitating disease characterized by structural remodeling of
the arterial vasculature of the lung leading to increased vascular resistance and increased pulmonary
arterial pressures, right ventricular (RV) hypertrophy, heart failure and ultimately, death. Based on the
underlying causes of PH, the WHO classification system divides PH patients into 5 groups: (1) Pulmonary
Arterial Hypertension (PAH), (2) PH due to left heart disease, (3) PH due to lung disease, (4) Chronic
Thromboembolic PH (CTEPH), and (5) PH with unclear and/or multifactorial mechanisms.
In pulmonary arterial hypertension (PAH) patients, vascular endothelial cell proliferation along with
concurrent formation of new blood vessels (neoangiogenesis), when exuberant, results in the formation of
glomeruloid structures in pulmonary arterioles known as the plexiform lesions. These plexiform lesions
are typically defined as dynamic networks of vascular channels formed by uncontrolled proliferation of
endothelial cells. Both PAH and CTEPH histology displays extensive accumulation of immune cells.
IPAH patient lungs and lung biopsy material from CTEPH patients shows compelling evidence for
activation of the innate immune system. This includes pathological involvement of macrophages, mast
cells (MCs) and neutrophils by production of inflammatory cytokines, recruitment of other immune cells
and local inflammation and damage. Lungs of IPAH patients demonstrate increased numbers of dendritic
cells (DCs) , acting as a bridge between innate and the adaptive immune system by presentation of
antigens to T cells. DCs contribute to increased production of cytokines and chemokines, attracting other
inflammatory cells to the site of inflammation. Dysregulated Th17 immunity is another phenomenon in
PAH patients, creating a pro-inflammatory auto-immune environment. Moreover, IPAH patients display
an increase of circulating autoantibodies specifically targeting endothelial cell surface antigens. Extensive
biomarker research reveals that many inflammatory and immune markers correlate with hemodynamics
and/or prognosis of PAH and CTEPH patients.
Currently, there is still much unknown about the pathological involvement of the immune system
in PAH and CTEPH etiology. Novel insights are required, to gain knowledge into novel pathways for
therapeutic targets and new treatment options for researchers and clinicians. Therefore, the aims of this
thesis were to; (I) further unravel the immunological imbalance in pulmonary arterial hypertension
(PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) pathogenesis, (II) to find novel
biomarkers and therapeutic targets