@article{0376167ac2ea4c86a90eadc661651be5,
title = "Myelin oligodendrocyte glycoprotein-specific antibodies from multiple sclerosis patients exacerbate disease in a humanized mouse model",
abstract = "Myelin oligodendrocyte glycoprotein (MOG) is exposed on the outer surface of the myelin sheath, and as such, represents a possible target antigen for antibodies in multiple sclerosis (MS) and other demyelinating diseases. However, despite extensive analyses, whether MOG-specific antibodies contribute to pathogenesis in human MS remains an area of uncertainty. In the current study we demonstrate that antibodies derived from adult MS patients exacerbate experimental autoimmune encephalomyelitis (EAE) in {\textquoteleft}humanized{\textquoteright} mice that transgenically express human FcγRs (hFcγRs). Importantly, this exacerbation is dependent on MOG recognition by the human-derived antibodies. The use of mice that express hFcγRs has allowed us to also investigate the contribution of these receptors to disease in the absence of confounding effects of cross-species differences. Specifically, by engineering the Fc region of MOG-specific antibodies to modulate FcγR and complement (C1q) binding, we reveal that FcγRs but not complement activation contribute to EAE pathogenesis. Importantly, selective enhancement of the affinities of these antibodies for specific FcγRs reveals that FcγRIIA is more important than FcγRIIIA in mediating disease exacerbation. These studies not only provide definitive evidence for the contribution of MOG-specific antibodies to MS, but also reveal mechanistic insight that could lead to new therapeutic targets.",
keywords = "Autoantibodies, EAE, Fc engineering, Fcγ receptors, MOG, MS",
author = "Priyanka Khare and Challa, {Dilip K.} and Devanaboyina, {Siva Charan} and Ramraj Velmurugan and Samuel Hughes and Greenberg, {Benjamin M.} and Ober, {Raimund J.} and Ward, {E. Sally}",
note = "Funding Information: We are indebted to Drs. Jeffrey V. Ravetch and Patrick Smith (The Rockefeller University, NY) for generously providing mice that transgenically express human FcγRs. We are grateful to Dr. Gurumoorthy Krishnamoorthy (Max Planck Institute for Neurobiology, Germany) and Dr. Mark Hogarth (Burnet Institute, Australia) for the kind gifts of EL4 cells expressing mouse MOG and the X63-21/7.2 hybridoma, respectively. We thank Drs. Anne Cross and Jerry Lyons (Washington University, St. Louis, MO) for kindly providing baculoviral stocks to express recombinant hMOG. We thank Joseph Heimann and Kyle Current for assistance with protein production and mice breeding, respectively. We also thank Dr. Stephen Anthony for developing a computational algorithm for mouse grouping. This work was supported in part by a grant from the National Multiple Sclerosis Society ( RG 4308 ; E. Sally Ward) and UTSW CONQUER Project (Benjamin M. Greenberg). Funding Information: We are indebted to Drs. Jeffrey V. Ravetch and Patrick Smith (The Rockefeller University, NY) for generously providing mice that transgenically express human Fc?Rs. We are grateful to Dr. Gurumoorthy Krishnamoorthy (Max Planck Institute for Neurobiology, Germany) and Dr. Mark Hogarth (Burnet Institute, Australia) for the kind gifts of EL4 cells expressing mouse MOG and the X63-21/7.2 hybridoma, respectively. We thank Drs. Anne Cross and Jerry Lyons (Washington University, St. Louis, MO) for kindly providing baculoviral stocks to express recombinant hMOG. We thank Joseph Heimann and Kyle Current for assistance with protein production and mice breeding, respectively. We also thank Dr. Stephen Anthony for developing a computational algorithm for mouse grouping. This work was supported in part by a grant from the National Multiple Sclerosis Society (RG 4308; E. Sally Ward) and UTSW CONQUER Project (Benjamin M. Greenberg). Publisher Copyright: {\textcopyright} 2017 The Authors",
year = "2018",
month = jan,
doi = "10.1016/j.jaut.2017.09.002",
language = "English (US)",
volume = "86",
pages = "104--115",
journal = "Journal of Autoimmunity",
issn = "0896-8411",
publisher = "Academic Press Inc.",
}