Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects.
High levels of granulocyte/macrophage-colony-stimulating factor (GM-CSF) autoantibodies are thought to cause pulmonary alveolar proteinosis (PAP), a rare syndrome characterized by myeloid dysfunction resulting in pulmonary surfactant accumulation and respiratory failure. Paradoxically, GM-CSF autoantibodies have been reported to occur rarely in healthy people and routinely in pharmaceutical intravenous immunoglobulin (IVIG) purified from serum pooled from healthy subjects. These findings suggest that either GM-CSF autoantibodies are normally present in healthy people at low levels that are difficult to detect or that serum pooled for IVIG purification may include asymptomatic persons with high levels of GM-CSF autoantibodies. Using several experimental approaches, GM-CSF autoantibodies were detected in all healthy subjects evaluated (n = 72) at low levels sufficient to rheostatically regulate multiple myeloid functions. Serum GM-CSF was more abundant than previously reported, but more than 99% was bound and neutralized by GM-CSF autoantibody. The critical threshold of GM-CSF autoantibodies associated with the development of PAP was determined. Results demonstrate that free serum GM-CSF is tightly maintained at low levels, identify a novel potential mechanism of innate immune regulation, help define the therapeutic window for potential clinical use of GM-CSF autoantibodies to treat inflammatory and autoimmune diseases, and have implications for the pathogenesis of PAP.
Uchida
Kanji
K
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
Nakata
Koh
K
Suzuki
Takuji
T
Luisetti
Maurizio
M
Watanabe
Masato
M
Koch
Diana E
DE
Stevens
Carrie A
CA
Beck
David C
DC
Denson
Lee A
LA
Carey
Brenna C
BC
Keicho
Naoto
N
Krischer
Jeffrey P
JP
Yamada
Yoshitsugu
Y
Trapnell
Bruce C
BC
D000328:Adult; D000936:Antigen-Antibody Complex / Q000097:blood / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood* / Q000378:metabolism; D001327:Autoimmune Diseases / Q000097:blood / Q000276:immunology / Q000378:metabolism; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology* / Q000378:metabolism; D006262:Health; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D008297:Male; D008954:Models, Biological; D022423:Myeloid Cells / Q000276:immunology* / Q000502:physiology*; D011649:Pulmonary Alveolar Proteinosis / Q000097:blood / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D055815:Young Adult
D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D016178:Granulocyte-Macrophage Colony-Stimulating Factor