Autoantibody-Mediated Pulmonary Alveolar Proteinosis in Rasgrp1-Deficient Mice.
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.
Department of Microbiology & Immunology, University of South Alabama, Mobile, AL 36688; Center for Lung Biology, University of South Alabama, Mobile, AL 36688; and.
Andrew
0000-0002-5426-5536
A
Ferretti
Department of Microbiology & Immunology, University of South Alabama, Mobile, AL 36688; Center for Lung Biology, University of South Alabama, Mobile, AL 36688; and.
Jarrod R
JR
Fortwendel
Center for Lung Biology, University of South Alabama, Mobile, AL 36688; and Department of Physiology & Cell Biology, University of South Alabama, Mobile, AL 36688.
Sarah A
SA
Gebb
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.
Robert A
0000-0001-5713-5369
RA
Barrington
D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency* / Q000276:immunology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011649:Pulmonary Alveolar Proteinosis / Q000235:genetics / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction
D001323:Autoantibodies; D001324:Autoantigens; D020662:Guanine Nucleotide Exchange Factors; C112278:Rasgrp1 protein, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor