Format

Send to

Choose Destination
J Immunol. 2016 Jul 15;197(2):470-9. doi: 10.4049/jimmunol.1502248. Epub 2016 Jun 8.

Autoantibody-Mediated Pulmonary Alveolar Proteinosis in Rasgrp1-Deficient Mice.

Author information

1
Department of Microbiology & Immunology, University of South Alabama, Mobile, AL 36688; Center for Lung Biology, University of South Alabama, Mobile, AL 36688; and.
2
Center for Lung Biology, University of South Alabama, Mobile, AL 36688; and Department of Physiology & Cell Biology, University of South Alabama, Mobile, AL 36688.
3
Department of Microbiology & Immunology, University of South Alabama, Mobile, AL 36688; Center for Lung Biology, University of South Alabama, Mobile, AL 36688; and rbarrington@southalabama.edu.

Abstract

Pulmonary alveolar proteinosis (PAP) is a rare lung syndrome caused by the accumulation of surfactants in the alveoli. The most prevalent clinical form of PAP is autoimmune PAP (aPAP) whereby IgG autoantibodies neutralize GM-CSF. GM-CSF is a pleiotropic cytokine that promotes the differentiation, survival, and activation of alveolar macrophages, the cells responsible for surfactant degradation. IgG-mediated neutralization of GM-CSF thereby inhibits alveolar macrophage homeostasis and function, leading to surfactant accumulation and innate immunodeficiency. Importantly, there are no rodent models for this disease; therefore, underlying immune mechanisms regulating GM-CSF-specific IgG in aPAP are not well understood. In this article, we identify that autoimmune-prone Rasgrp1-deficient mice develop aPAP: 1) Rasgrp1-deficient mice exhibit reduced pulmonary compliance and lung histopathology characteristic of PAP; 2) alveolar macrophages from Rasgrp1-deficient mice are enlarged and exhibit reduced surfactant degradation; 3) the concentration of GM-CSF-specific IgG is elevated in both serum and bronchoalveolar lavage fluid from Rasgrp1-deficient mice; 4) GM-CSF-specific IgG is capable of neutralizing GM-CSF bioactivity; and 5) Rasgrp1-deficient mice also lacking CD275/ICOSL, a molecule necessary for conventional T cell-dependent Ab production, have reduced GM-CSF-specific autoantibody and do not develop PAP. Collectively, these studies reveal that Rasgrp1-deficient mice, to our knowledge, represent the first rodent model for aPAP.

PMID:
27279372
PMCID:
PMC4935575
DOI:
10.4049/jimmunol.1502248
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center