FcRn is a CD32a coreceptor that determines susceptibility to IgG immune complex-driven autoimmunity.
Document Type
Article
Publication Date
10-5-2020
Keywords
JMG
JAX Source
J Exp Med 2020 Oct 5; 217(10):e20200359
Volume
217
Issue
10
ISSN
1540-9538
PMID
32658257
DOI
https://doi.org/10.1084/jem.20200359
Abstract
IgG immune complexes (ICs) promote autoimmunity through binding fragment crystallizable (Fc) γ-receptors (FcγRs). Of these, the highly prevalent FcγRIIa (CD32a) histidine (H)-131 variant (CD32aH) is strongly linked to human autoimmune diseases through unclear mechanisms. We show that, relative to the CD32a arginine (R)-131 (CD32aR) variant, CD32aH more avidly bound human (h) IgG1 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 CD32aH. Conversely, FcRn induced responses to IgG IC independently of classical FcγR, but optimal responses required FcRn and FcγR. 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 CD32aH variant, providing a novel mechanism for its disease association.
Recommended Citation
Hubbard J,
Pyzik M,
Rath T,
Kozicky L,
Sand K,
Gandhi A,
Grevys A,
Foss S,
Menzies S,
Glickman J,
Fiebiger E,
Roopenian DC,
Sandlie I,
Andersen J,
Sly L,
Baker K,
Blumberg R.
FcRn is a CD32a coreceptor that determines susceptibility to IgG immune complex-driven autoimmunity. J Exp Med 2020 Oct 5; 217(10):e20200359