Characterization of Pathogenic Human Monoclonal Autoantibodies Against GM-CSF

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2013 Apr 27

PMID 23620516

Citations 21

Authors

Yanni Wang

Christy A Thomson

Lenka L Allan

Linda M Jackson

Melanie Olson

Timothy R Hercus

Tracy L Nero

Amanda Turner

Michael W Parker

Angel L Lopez

Thomas K Waddell

Gary P Anderson

John A Hamilton

John W Schrader

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Neutralizing GM-CSF autoantibodies in pulmonary alveolar proteinosis, cryptococcal meningitis and severe nocardiosis.

Salvator H, Cheng A, Rosen L, Williamson P, Bennett J, Kashyap A Respir Res. 2022; 23(1):280.

PMID: 36221098 PMC: 9552154. DOI: 10.1186/s12931-022-02103-9.

Determination of a distinguished interferon gamma epitope recognized by monoclonal antibody relating to autoantibody associated immunodeficiency.

Yasamut U, Wisitponchai T, Lee V, Yamabhai M, Rangnoi K, Thongkum W Sci Rep. 2022; 12(1):7608.

PMID: 35534543 PMC: 9085737. DOI: 10.1038/s41598-022-11774-9.

Autoimmune Pulmonary Alveolar Proteinosis.

McCarthy C, Carey B, Trapnell B Am J Respir Crit Care Med. 2022; 205(9):1016-1035.

PMID: 35227171 PMC: 9851473. DOI: 10.1164/rccm.202112-2742SO.

Pulmonary alveolar proteinosis: from classification to therapy.

Salvaterra E, Campo I Breathe (Sheff). 2020; 16(2):200018.

PMID: 32684997 PMC: 7341616. DOI: 10.1183/20734735.0018-2020.

Proteogenomic analysis of granulocyte macrophage colony- stimulating factor autoantibodies in the blood of a patient with autoimmune pulmonary alveolar proteinosis.

Hashimoto A, Takeuchi S, Kajita R, Yamagata A, Kakui R, Tanaka T Sci Rep. 2020; 10(1):4923.

PMID: 32188922 PMC: 7080758. DOI: 10.1038/s41598-020-61934-y.

References

Wrammert J, Smith K, Miller J, Langley W, Kokko K, Larsen C . Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature. 2008; 453(7195):667-71. PMC: 2515609. DOI: 10.1038/nature06890. View

Hercus T, Cambareri B, Dottore M, Woodcock J, Bagley C, Vadas M . Identification of residues in the first and fourth helices of human granulocyte-macrophage colony-stimulating factor involved in biologic activity and in binding to the alpha- and beta-chains of its receptor. Blood. 1994; 83(12):3500-8. View

Puel A, Doffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, Picard C . Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med. 2010; 207(2):291-7. PMC: 2822614. DOI: 10.1084/jem.20091983. View

Schweizerhof M, Stosser S, Kurejova M, Njoo C, Gangadharan V, Agarwal N . Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain. Nat Med. 2009; 15(7):802-7. DOI: 10.1038/nm.1976. View

Uchida K, Beck D, Yamamoto T, Berclaz P, Abe S, Staudt M . GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis. N Engl J Med. 2007; 356(6):567-79. DOI: 10.1056/NEJMoa062505. View

Toyka K, Drachman D, Griffin D, Pestronk A, Winkelstein J, Fishbeck K . Myasthenia gravis. Study of humoral immune mechanisms by passive transfer to mice. N Engl J Med. 1977; 296(3):125-31. DOI: 10.1056/NEJM197701202960301. View

Lingwood D, McTamney P, Yassine H, Whittle J, Guo X, Boyington J . Structural and genetic basis for development of broadly neutralizing influenza antibodies. Nature. 2012; 489(7417):566-70. PMC: 7095019. DOI: 10.1038/nature11371. View

Watson C, Breden F . The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease. Genes Immun. 2012; 13(5):363-73. DOI: 10.1038/gene.2012.12. View

Akkaraju S, Canaan K, Goodnow C . Self-reactive B cells are not eliminated or inactivated by autoantigen expressed on thyroid epithelial cells. J Exp Med. 1998; 186(12):2005-12. PMC: 2199176. DOI: 10.1084/jem.186.12.2005. View

10.

Hamilton J . Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol. 2008; 8(7):533-44. DOI: 10.1038/nri2356. View

11.

Handman E, Burgess A . Stimulation by granulocyte-macrophage colony-stimulating factor of Leishmania tropica killing by macrophages. J Immunol. 1979; 122(3):1134-7. View

12.

Schmidt A, Xu H, Khan A, ODonnell T, Khurana S, King L . Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody. Proc Natl Acad Sci U S A. 2012; 110(1):264-9. PMC: 3538208. DOI: 10.1073/pnas.1218256109. View

13.

Zenewicz L, Abraham C, Flavell R, Cho J . Unraveling the genetics of autoimmunity. Cell. 2010; 140(6):791-7. PMC: 3491807. DOI: 10.1016/j.cell.2010.03.003. View

14.

Patino E, Kotzsch A, Saremba S, Nickel J, Schmitz W, Sebald W . Structure analysis of the IL-5 ligand-receptor complex reveals a wrench-like architecture for IL-5Rα. Structure. 2011; 19(12):1864-75. DOI: 10.1016/j.str.2011.08.015. View

15.

Laver W, Air G, Webster R . Epitopes on protein antigens: misconceptions and realities. Cell. 1990; 61(4):553-6. DOI: 10.1016/0092-8674(90)90464-p. View

16.

Hamilton J, Stanley E, Burgess A, Shadduck R . Stimulation of macrophage plasminogen activator activity by colony-stimulating factors. J Cell Physiol. 1980; 103(3):435-45. DOI: 10.1002/jcp.1041030309. View

17.

Dal Porto J, Haberman A, Kelsoe G, Shlomchik M . Very low affinity B cells form germinal centers, become memory B cells, and participate in secondary immune responses when higher affinity competition is reduced. J Exp Med. 2002; 195(9):1215-21. PMC: 2193705. DOI: 10.1084/jem.20011550. View

18.

Anhalt G, Labib R, Voorhees J, Beals T, Diaz L . Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease. N Engl J Med. 1982; 306(20):1189-96. DOI: 10.1056/NEJM198205203062001. View

19.

Rowley D, JENKIN C . Antigenic cross-reaction between host and parasite as a possible cause of pathogenicity. Nature. 1962; 193:151-4. DOI: 10.1038/193151a0. View

20.

Cook A, Pobjoy J, Sarros S, Steidl S, Durr M, Lacey D . Granulocyte-macrophage colony-stimulating factor is a key mediator in inflammatory and arthritic pain. Ann Rheum Dis. 2012; 72(2):265-70. DOI: 10.1136/annrheumdis-2012-201703. View