Abstract 16764: Locally Produced SAMHD1 Immune Complexes Are Associated With the Development of Idiopathic Pulmonary Arterial Hypertension
Introduction: Autoimmunity has been related to the pathophysiology of idiopathic pulmonary arterial hypertension (IPAH). We previously reported 35 IPAH-related antigens identified in immune complexes (ICs) in lungs from IPAH patients. Among these antigens, we validated increased ICs containing SAMHD1, an HIV1 restriction factor, in IPAH vs. donor control lungs.
Hypotheses: We hypothesized that 1) viruses and/or inflammatory stimuli increase SAMHD1, which is released in exosomes and induces local production of antibodies, 2) SAMHD1 ICs are observed in experimental inflammatory pulmonary hypertension (PH) induced by monocrotaline (MCT) in rats.
Methods: The viral signature of IPAH vs. control lung tissue was determined by high-throughput sequencing and validated by qPCR. Localization of SAMHD1 or SAMHD1 antibodies was determined by immunohistochemistry. Protein expression was analyzed by western blot in lung tissue and in pulmonary arterial endothelial cells (PAEC) stimulated with TNFα. Experimental PH was induced in rats by MCT injection.
Results: Viral sequencing confirmed by qPCR indicated that only human endogenous retrovirus K5 (HERVK5) was increased threefold in lung tissue from IPAH vs. controls (P<0.05, n=10 per group). The ratio of perivascular SAMHD1 positive cells to total cells was also increased more than twofold in IPAH vs. controls (P<0.05, n=4 per group), with SAMHD1 mainly localized to macrophages and PAECs, consistent with the increase in SAMHD1 by western blot (P<0.05, n=4 per group). SAMHD1 was detectable in exosomes from IPAH plasma, explaining how it might be released from cells. SAMHD1 recombinant protein was captured in tertiary lymphoid tissue in IPAH lungs, suggesting that specific SAMHD1 antibodies were produced locally. An inflammatory stimulus (TNFα) caused a twofold increase in SAMHD1 in PAECs by western blot (P<0.05, n=3 per group). A similar increase in SAMHD1 ICs was observed in lung tissues from MCT vs. control rats (P<0.05, n=7 and 6, respectively).
Conclusions: Our data suggest that human endogenous retroviruses or inflammatory stimuli (TNFα) can increase SAMHD1, inducing local ICs and chronic inflammation associated with the pathological changes causing experimental and clinical PH.
Author Disclosures: T. Saito: None. R. Tamosiuniene: None. O. Sharpe: None. W.H. Robinson: None. M. Nicolls: None. M. Rabinovitch: None.
- © 2014 by American Heart Association, Inc.