GM-CSF Autoantibodies and Neutrophil Dysfunction in Pulmonary Alveolar Proteinosis

Uchida, Kanji; Beck, David; Yamamoto, Takashi; Berclaz, Pierre-Yves; Abe, Shuichi; Staudt, Margaret K.; Carey, Brenna; Filippi, Marie–Dominique; Wert, Susan E.; Denson, Lee A.; Puchalski, Jonathan; Hauck, Diane M.; Trapnell, Bruce C.

doi:10.1056/nejmoa062505

Cited by 268 publications

(268 citation statements)

References 35 publications

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“…S2C). We also treated whole blood with GM-CSF for 30 min at 37°C to stimulate primary neutrophils to express the integrin component, CD11b, on their cell-surface (23). Using flow cytometry, we measured the levels of CD11b on the surface of human neutrophils ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We used the human erythroleukemia cell line TF-1, which depends on growth factors such as GM-CSF or interleukin-3 (IL-3) to survive and proliferate, to compare the ability of the mAbs to neutralize the bioactivity of GM-CSF and IL-3 (10,23). We found that all 19 mAbs had some capacity to neutralize the ability of GM-CSF to promote proliferation and survival of TF-1 cells (Table S1) and had no capacity to neutralize the bioactivity of IL-3 (Table S1 and Fig.…”

Section: Resultsmentioning

confidence: 99%

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Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Wang

Thomson

Allan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The origin of pathogenic autoantibodies remains unknown. Idiopathic pulmonary alveolar proteinosis is caused by autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF). We generated 19 monoclonal autoantibodies against GM-CSF from six patients with idiopathic pulmonary alveolar proteinosis. The autoantibodies used multiple V genes, excluding preferred V-gene use as an etiology, and targeted at least four nonoverlapping epitopes on GM-CSF, suggesting that GM-CSF is driving the autoantibodies and not a B-cell epitope on a pathogen cross-reacting with GM-CSF. The number of somatic mutations in the autoantibodies suggests that the memory B cells have been helped by T cells and re-entered germinal centers. All autoantibodies neutralized GM-CSF bioactivity, with general correlations to affinity and off-rate. The binding of certain autoantibodies was changed by point mutations in GM-CSF that reduced binding to the GM-CSF receptor. Those monoclonal autoantibodies that potently neutralize GM-CSF may be useful in treating inflammatory disease, such as rheumatoid arthritis and multiple sclerosis, cancer, and pain.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Wang

Thomson

Allan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…Although neutralizing antibodies to GM-CSF are present in patients with primary PAP, 14,30,31 and secondary PAP has been linked to AML, 32,33 CML 34 and MDS, 35,36 the prevalence of these antibodies among leukemia patients and their biological link to myeloid leukemia is unknown. Kitamura et al 14 showed that anti-GM-CSF IgG, but not IgM or IgA, are present in patients with PAP and may be pathogenic in this disease.…”

Section: Discussionmentioning

confidence: 99%

High titer autoantibodies to GM-CSF in patients with AML, CML and MDS are associated with active disease

et al. 2008

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“…Above a certain threshold, aAb may render the individual deficient of the given growth factor or cytokine, however, in most cases, without overt clinical manifestations (Ross et al 1997). Exceptions are: 1) granulocyte-macrophage colony-stimulating factor aAb that plays a role in pulmonary alveolar proteinosis (Uchida et al 2007), 2) interferon-g aAbs that lead to susceptibility to certain infections (Madariaga et al 1998, Hoflich et al 2004, Kampmann et al 2005, Patel et al 2005, and 3) aAb-IL6 that are being associated with recurrent staphylococcal cellulitis and subcutaneous abscesses (Puel et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 autoantibodies are involved in the pathogenesis of a subset of type 2 diabetes

Fosgerau¹,

Galle²,

Hansen³

et al. 2009

Journal of Endocrinology

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Interleukin-6 (IL6) is critically involved in inflammation and metabolism. About 1% of people produce IL6 autoantibodies (aAb-IL6) that impair IL6 signaling in vivo. We tested the hypothesis that the prevalence of such aAb-IL6 is increased in type 2 diabetic patients and that aAb-IL6 plays a direct role in causing hyperglycemia. In humans, the prevalence of circulating high-affinity neutralizing aAb-IL6 was 2 . 5% in the type 2 diabetic patients and 1% in the controls (odds ratio 2 . 5, 95% confidence interval 1 . 2-4 . 9, PZ0 . 01). To test for the role of aAb-IL6 in causing hyperglycemia, such aAb-IL6 were induced in mice by a validated vaccination procedure.Mice with plasma levels of aAb-IL6 similar to the 2 . 5% type 2 diabetic patients developed obesity and impaired glucose tolerance (area under the curve (AUC) glucose, 2056G62 vs 1793G62, PZ0 . 05) as compared with shamvaccinated mice, when challenged with a high-fat diet. Mice with very high plasma levels of aAb-IL6 developed elevated fasting plasma glucose (mM, 4 . 8G0 . 4 vs 3 . 3G0 . 1, P!0 . 001) and impaired glucose tolerance (AUC glucose, 1340G38 vs 916G25, P!0 . 001) as compared with shamcontrol mice on normal chow. In conclusion, the prevalence of plasma aAb-IL6 at levels known to impair IL6 signaling in vivo is increased 2 . 5-fold in people with type 2 diabetes.In mice, matching levels of aAb-IL6 cause obesity and hyperglycemia. These data suggest that a small subset of type 2 diabetes may in part evolve from an autoimmune attack against IL6.

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GM-CSF Autoantibodies and Neutrophil Dysfunction in Pulmonary Alveolar Proteinosis

Abstract: The antimicrobial functions of neutrophils are impaired in patients with pulmonary alveolar proteinosis, owing to the presence of GM-CSF autoantibodies. The effects of these autoantibodies show that GM-CSF is an essential regulator of neutrophil functions.

Cited by 268 publications

References 35 publications

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

High titer autoantibodies to GM-CSF in patients with AML, CML and MDS are associated with active disease

Interleukin-6 autoantibodies are involved in the pathogenesis of a subset of type 2 diabetes

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