Abstract
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 autoan- tibodies 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.
| Original language | English |
|---|---|
| Pages (from-to) | 2547-2556 |
| Number of pages | 10 |
| Journal | Blood |
| Volume | 113 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Mar 12 2009 |
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ASJC Scopus subject areas
- Hematology
- Biochemistry
- Cell Biology
- Immunology
Cite this
Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects. / Uchida, Kanji; Nakata, Koh; Suzuki, Takuji; Luisetti, Maurizio; Watanabe, Masato; Koch, Diana E.; Stevens, Carrie A.; Beck, David C.; Denson, Lee A.; Carey, Brenna C.; Keicho, Naoto; Krischer, Jeffrey P.; Yamada, Yoshitsugu; Trapnell, Bruce C.
In: Blood, Vol. 113, No. 11, 12.03.2009, p. 2547-2556.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects
AU - Uchida, Kanji
AU - Nakata, Koh
AU - Suzuki, Takuji
AU - Luisetti, Maurizio
AU - Watanabe, Masato
AU - Koch, Diana E.
AU - Stevens, Carrie A.
AU - Beck, David C.
AU - Denson, Lee A.
AU - Carey, Brenna C.
AU - Keicho, Naoto
AU - Krischer, Jeffrey P.
AU - Yamada, Yoshitsugu
AU - Trapnell, Bruce C.
PY - 2009/3/12
Y1 - 2009/3/12
N2 - 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 autoan- tibodies 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.
AB - 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 autoan- tibodies 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.
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U2 - 10.1182/blood-2009-05-155689
DO - 10.1182/blood-2009-05-155689
M3 - Article
VL - 113
SP - 2547
EP - 2556
JO - Blood
JF - Blood
SN - 0006-4971
IS - 11
ER -