Impaired inhibitory Fcγ receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy

doi:10.1073/pnas.0807319106

Impaired inhibitory Fcγ receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy

^aDepartment of Neurology, Clinical Neuroimmunology Group, Philipps-University, 35039 Marburg, Germany;
^bInstitute for Neuroimmunology and Clinical Multiple Sclerosis Research Center for Molecular Neurobiology Hamburg, University Medical Center Eppendorf, 20251 Hamburg, Germany;
^cLaboratory of Experimental Immunology and Immunotherapy, Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen-Nuremberg, 91054 Erlangen, Germany; and
^dLaboratory of Viral Immunobiology, Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10065

Edited by Jeffrey Ravetch, The Rockfeller University, New York, NY, and approved January 14, 2009
↵¹B.T., I.J., and A.B. contributed equally to this work.
↵²F.N. and J.D.L. contributed equally to this work. (received for review July 30, 2008)

Abstract

The inhibitory Fc-γ receptor FcγRIIB, expressed on myeloid and B cells, has a critical role in the balance of tolerance and autoimmunity, and is required for the antiinflammatory activity of intravenous Ig (IVIG) in various murine disease models. However, the function of FcγRIIB and its regulation by IVIG in human autoimmune diseases are less well understood. Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common treatable acquired chronic polyneuropathy, and IVIG is widely used as a first-line initial and maintenance treatment. We found that untreated patients with CIDP, compared with demographically matched healthy controls, showed consistently lower FcγRIIB expression levels on naive B cells, and failed to up-regulate or to maintain up-regulation of FcγRIIB as B cells progressed from the naive to the memory compartment. Concomitantly, the rare −386C/−120A FcγRIIB promoter polymorphism resulting in reduced promoter activity previously associated with autoimmune phenotypes was overrepresented in CIDP. Also, FcγRIIB protein expression was up-regulated on monocytes and B cells after clinically effective IVIG therapy. Thus, our results suggest that the inhibitory FcγRIIB is impaired at a critical B cell differentiation checkpoint in CIDP, and that modulating FcγRIIB expression might be a promising approach to efficiently limit antibody-mediated immunopathology in CIDP.

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Footnotes

³To whom correspondence may be addressed. E-mail: fnimmerj{at}molmed.uni-erlangen.de or jlunemann{at}rockefeller.edu
Author contributions: F.N. and J.D.L. designed research; B.T., I.J., A.B., F.N., and J.D.L. performed research; B.T., W.H.O., and N.S. contributed clinical data; W.H.O., N.S., and F.N. contributed new reagents/analytic tools; B.T., I.J., A.B., F.N., and J.D.L. analyzed data; and B.T., I.J., A.B., F.N., and J.D.L. wrote the paper.
↵⁴Present address: Institute of Experimental Immunology, Viral Immunobiology, University Hospital of Zürich, Zürich, Switzerland.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.