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Fc?RIIb inhibits immune complex-induced VEGF-A production and intranodal lymphangiogenesis.


ABSTRACT: IgG immune complexes (ICs) are generated during immune responses to infection and self-antigen and have been implicated in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Their role, and that of the fragment crystallizable (Fc) receptors that bind them, in driving local inflammation is not fully understood. Low affinity-activating Fc? receptors (Fc?Rs) that bind immune complexes are controlled by a single inhibitory receptor, Fc?RIIb (CD32b). We investigated whether Fc?R cross-linking by IC might induce VEGF-A and lymph node lymphangiogenesis. Murine macrophages and dendritic cells (DCs) stimulated with ICs produced VEGF-A, and this was inhibited by coligation of Fc?RIIb. Similarly, IC-induced VEGF-A production by B cells was inhibited by Fc?RIIb. In vivo, IC generation resulted in VEGF-A-dependent intranodal lymphangiogenesis and increased DC number. We sought to determine the relevance of these findings to autoimmunity because elevated serum VEGF-A has been observed in patients with SLE; we found that lymphangiogenesis and VEGF-A were increased in the lymph nodes of mice with collagen-induced arthritis and SLE. In humans, a SLE-associated polymorphism (rs1050501) results in a dysfunctional Fc?RIIB(T232) receptor. Monocyte-derived macrophages from subjects with the Fc?RIIB(T/T232) genotype showed increased Fc?R-mediated VEGF-A production, demonstrating a similar process is likely to occur in humans. Thus, ICs contribute to inflammation through VEGF-A-driven lymph node lymphangiogenesis, which is controlled by Fc?RIIb. These findings have implications for the pathogenesis, and perhaps future treatment, of autoimmune diseases.

SUBMITTER: Clatworthy MR 

PROVIDER: S-EPMC4273345 | BioStudies | 2014-01-01

REPOSITORIES: biostudies

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