Impaired inhibitory Fcgamma receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy.
The inhibitory Fc-gamma receptor FcgammaRIIB, 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 FcgammaRIIB 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 FcgammaRIIB expression levels on naive B cells, and failed to up-regulate or to maintain up-regulation of FcgammaRIIB as B cells progressed from the naive to the memory compartment. Concomitantly, the rare -386C/-120A FcgammaRIIB promoter polymorphism resulting in reduced promoter activity previously associated with autoimmune phenotypes was overrepresented in CIDP. Also, FcgammaRIIB protein expression was up-regulated on monocytes and B cells after clinically effective IVIG therapy. Thus, our results suggest that the inhibitory FcgammaRIIB is impaired at a critical B cell differentiation checkpoint in CIDP, and that modulating FcgammaRIIB expression might be a promising approach to efficiently limit antibody-mediated immunopathology in CIDP.
Tackenberg
Björn
B
Department of Neurology, Clinical Neuroimmunology Group, Philipps-University, 35039 Marburg, Germany.
Jelcic
Ilijas
I
Baerenwaldt
Anne
A
Oertel
Wolfgang H
WH
Sommer
Norbert
N
Nimmerjahn
Falk
F
Lünemann
Jan D
JD
D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D003710:Demography; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007156:Immunologic Memory; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020277:Polyradiculoneuropathy, Chronic Inflammatory Demyelinating / Q000276:immunology* / Q000628:therapy; D011401:Promoter Regions, Genetic / Q000235:genetics; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
C499173:FCGR2B protein, human; D016756:Immunoglobulins, Intravenous; D017452:Receptors, IgG