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Structural Insight into the Function of Myelin Basic Protein as a Ligand for Integrin _Mβ₂¹

Romualdas Stapulionis^*,, Cristiano Luis Pinto Oliveira^,¶, Mikkel Carstensen Gjelstrup^*,, Jan Skov Pedersen^,¶, Marianne Elisabet Hokland, Søren Vrønning Hoffmann, Knud Poulsen, Christian Jacobsen^|| and Thomas Vorup-Jensen^2,*,,

^* Biophysical Immunology Laboratory, Institute for Medical Microbiology and Immunology, Institute for Storage Ring Facilities Aarhus, Interdisciplinary Nanoscience Center, ^¶ Department of Chemistry, and ^|| Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark

Multiple sclerosis (MS) is an inflammatory disease where phagocytic cells infiltrate the nerve tissue and act as terminal agents in destruction of the myelin sheath. However, the mechanism that triggers the ability of these cells to recognize myelin remains obscure. We show that myelin basic protein (MBP), a major autoantigen in MS, is a potent and specific ligand for the integrin _Mβ₂ (Mac-1, CD11b/CD18) expressed mainly on phagocytic cells. MBP undergoes a dramatic conformational change when liberated from the lipid-rich environment of the myelin sheath. The MS drug glatiramer acetate mimics the conformationally labile regions of MBP, interacts in the unfolded state strongly with _Mβ₂, and inhibits the MBP binding to _Mβ₂. Our study reveals a link between MBP, glatiramer acetate, and the _Mβ₂ integrin, and suggests a new model for MS pathogenesis based on the recognition of unfolded MBP by the _Mβ₂ integrin.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by The Naomi Bramson Trust with salary to R.S., by Anna og Dagny Hjerrilds Foundation, The LEO Pharma Foundation, and The Danish Sclerosis Society.

² Address correspondence and reprint requests to Dr. Thomas Vorup-Jensen, Institute for Medical Microbiology and Immunology, University of Aarhus, DK-8000 Aarhus C, Denmark. E-mail address: vorup-jensen{at}microbiology.au.dk

³ Abbreviations used in this paper: MBP, myelin basic protein; SAXS, small angle x-ray scattering; CD, circular dichroism; MS, multiple sclerosis; EAE, experimental autoimmune encephalitis; GA, glatiramer acetate; MNC, mononuclear cell; SRCD, synchrotron radiation circular dichroism; TFE, trifluoroethanol; HSA, human serum albumin; SPR, surface plasmon resonance.

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