FcRn is a CD32a coreceptor that determines susceptibility to IgG immune complex-driven autoimmunity
Hubbard JJ, Pyzik M, Rath T, Kozicky LK, Sand KMK, Gandhi AK, Grevys A, Foss S, Menzies SC, Glickman JN, Fiebiger E, Roopenian DC, Sandlie I, Andersen JT, Sly LM, Baker K, Blumberg RS (2020)
Publication Type: Journal article
Publication year: 2020
Journal
Book Volume: 217
Journal Issue: 10
DOI: 10.1084/jem.20200359
Abstract
IgG immune complexes (ICs) promote autoimmunity through binding fragment crystallizable (Fc) gamma-receptors (FcyRs). Of these, the highly prevalent FcyRIIa (CD32a(H)) histidine (H)-131 variant (CD32(H)) is strongly linked to human autoimmune diseases through unclear mechanisms. We show that, relative to the CD32a arginine (R)-131 (CD32a(R)) variant, CD32a(H) more avidly bound human (h) IgG' IC and formed a ternary complex with the neonatal Fc receptor (FcRn) under acidic conditions. In primary human and mouse cells, both CD32a variants required FcRn to induce innate and adaptive immune responses to hIgG1 ICs, which were augmented in the setting of CD32a(H). Conversely, FcRn induced responses to IgG IC independently of classical FcyR, but optimal responses required FcRn and FcyR. Finally, FcRn blockade decreased inflammation in a rheumatoid arthritis model without reducing circulating autoantibody levels, providing support for FcRn's direct role in IgG IC-associated inflammation. Thus, CD32a and FcRn coregulate IgG IC-mediated immunity in a manner favoring the CD32a(H) variant, providing a novel mechanism for its disease association.
Authors with CRIS profile
Involved external institutions
Harvard University
United States (USA) (US)
Howard Hughes Medical Institute
United States (USA) (US)
University of British Columbia
Canada (CA)
University of Oslo
Norway (NO)
United States (USA) (US)
Howard Hughes Medical Institute
United States (USA) (US)
University of British Columbia
Canada (CA)
University of Oslo
Norway (NO)
How to cite
APA:
Hubbard, J.J., Pyzik, M., Rath, T., Kozicky, L.K., Sand, K.M.K., Gandhi, A.K.,... Blumberg, R.S. (2020). FcRn is a CD32a coreceptor that determines susceptibility to IgG immune complex-driven autoimmunity. Journal of Experimental Medicine, 217(10). https://dx.doi.org/10.1084/jem.20200359
MLA:
Hubbard, Jonathan J., et al. "FcRn is a CD32a coreceptor that determines susceptibility to IgG immune complex-driven autoimmunity." Journal of Experimental Medicine 217.10 (2020).
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