Suppression of activin A in autoimmune lung disease associated with anti-GM-CSF.
Pulmonary alveolar proteinosis (PAP) is an autoimmune disorder characterized by neutralizing autoantibodies to granulocyte-macrophage colony stimulating factor (GM-CSF). Surfactant metabolism is severely dysregulated in PAP, resulting in a foam cell appearance of alveolar macrophages. Microarray analysis of RNA from PAP bronchoalveolar lavage (BAL) cells to explore autoimmune-related genes yielded evidence of a deficiency of activin A, a cytokine implicated in regulation of B-cell proliferation and reduction of foam cell formation. Subsequent studies confirmed a severe deficiency of activin A gene expression and protein secretion in PAP BAL cells and marked reduction of activin A protein in PAP BAL fluids compared to healthy controls. PAP cells, however, like those of healthy controls, were capable of elevated activin A production in response to GM-CSF. Treatment with activin A in vitro suppressed proliferation of PAP peripheral blood B-cells in a receptor-dependent manner and also reduced secretion of anti-GM-CSF autoantibody. These studies are the first to suggest that activin A may play a role in autoimmune disease.
Bonfield
Tracey L
TL
Department of Pulmonary, Allergy and Critical Care Medicine, Cleveland, OH, USA.
Barna
Barbara P
BP
John
Nejimol
N
Malur
Anagha
A
Culver
Daniel A
DA
Kavuru
Mani S
MS
Thomassen
Mary Jane
MJ
D028341:Activins / Q000172:deficiency* / Q000235:genetics* / Q000494:pharmacology; D000328:Adult; D001323:Autoantibodies / Q000096:biosynthesis*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics; D001402:B-Lymphocytes / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D006801:Humans; D028322:Inhibin-beta Subunits / Q000172:deficiency* / Q000235:genetics* / Q000494:pharmacology; D008297:Male; D011649:Pulmonary Alveolar Proteinosis / Q000235:genetics / Q000276:immunology*
D001323:Autoantibodies; C422405:activin A; D028341:Activins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D028322:Inhibin-beta Subunits