Interstitial Lung Disease and Pulmonary Fibrosis in Hermansky-Pudlak Syndrome Type 2, an Adaptor Protein-3 Complex Disease

Abstract

Pulmonary fibrosis develops in Hermansky-Pudlak syndrome (HPS) types 1 and 4. Limited information is available about lung disease in HPS type 2 (HPS-2), which is characterized by abnormal function of the adaptor protein-3 (AP-3) complex. To define lung disease in HPS-2, one child and two adults with HPS-2 were evaluated at the National Institutes of Health on at least two visits, and another child was evaluated at the University of Texas Health Science Center San Antonio. All four subjects with HPS-2 had findings of interstitial lung disease (ILD) on a high-resolution computed tomography scan of the chest. The predominant feature was ground glass opacification. Subject 1, a 14-year-old male, and subject 4, a 4-year-old male, had severe ILD, pulmonary fibrosis, secondary pulmonary hypertension and recurrent lung infections. Lung biopsy performed at 20 months of age in subject 1 revealed interstitial fibrosis and prominent type II pneumocyte hyperplasia without lamellar body enlargement. Subject 2, a 27-year-old male smoker, had mild ILD. Subject 3, a 22-year-old male nonsmoker and brother of subject 2, had minimal ILD. Severe impairment of gas exchange was found in subjects 1 and 4 and not in subjects 2 or 3. Plasma concentrations of transforming growth factor-β1 and interleukin-17A correlated with severity of HPS-2 ILD. These data show that children and young adults with HPS-2 and functional defects of the AP-3 complex are at risk for ILD and pulmonary fibrosis.

Genetic susceptibility and pulmonary fibrosis

“…For instance, abnormalities in surfactant proteins in particular are strongly implicated in familial pulmonary fibrosis [11-13]. In addition, pleiotropic genetic disorders such as dyskeratosis congenita [14] and Hermansky-Pudlak syndrome [15] are associated with pulmonary fibrosis. However, these mutations account for a small proportion of the population risk of disease making further research into genetic predisposition necessary.…”

The role of Endoplasmic Reticulum (ER) stress in pulmonary fibrosis

“…We could show that hyperplastic AECII of patients with HPS1 indicate pro-apoptotic ER stress, as shown by immunohistochemistry for the ER stress markers ATF4 and CHOP and the apoptosis-marker cleaved caspase-3 [64]. In contrast, ultrastructural findings in lung tissue of HPS2-patients with ILD demonstrated prominent AECII cell hyperplasia, but no lamellar body enlargement, thus underscoring the significant difference between HPS1 and HPS2 (or AP3B1) gene mutations [171]. However, the expression of ER stress markers has not yet been addressed in lungs of HPS2-patients with concomitant ILD.…”

“…More importantly, the development of pulmonary fibrosis in some HPS patients (HPS-IP) has been linked to the dysfunction of lamellar bodies. Adults with HPS1 or HPS4, whose genetic defects lead to a loss of function of the ″biogenesis of lysosomerelated organelle complex 3″ (BLOC3) develop lung fibrosis which reveals exactly the usual interstitial pneumonia (UIP) histology found in IPF [166][167][168][169][170], whereas children and young adults with the rare HPS2, who have a defect in the β3a subunit of the adaptor protein 3 (AP3) complex, seem to develop predominantly other histopathological patterns of pulmonary fibrosis [171,172]. The AP3 complex regulates the biogenesis of lysosome-related organelles and is crucially implicated in intracellular trafficking of proteins to late endosomes, lysosomes and lysosomerelated organelles [173].…”

Genetic Diseases Predisposing to HLH

“…Pulmonary fibrosis and interstitial lung disease is also a frequent feature of HPS2. Some of these patients have facial dysmorphisms, conductive hearing loss, and developmental delay 63,64,144 (Table 20.3). Defective cytotoxic activity or impaired degranulation of patients' NK cells and CTLs characterizes HPS2, but development of HLH is not a constant feature of this condition.…”