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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 Fcγ receptors (FcγRs) that bind immune complexes are controlled by a single inhibitory receptor, FcγRIIb (CD32b). We investigated whether FcγR 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 FcγRIIb. Similarly, IC-induced VEGF-A production by B cells was inhibited by FcγRIIb. 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 FcγRIIB(T232) receptor. Monocyte-derived macrophages from subjects with the FcγRIIB(T/T232) genotype showed increased FcγR-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 FcγRIIb. These findings have implications for the pathogenesis, and perhaps future treatment, of autoimmune diseases.

Antibodies are critical for defense against a variety of microbes, but they may also be pathogenic in some autoimmune diseases. Many effector functions of antibodies are mediated by Fcγ receptors (FcγRs), which are found on most immune cells, including dendritic cells (DCs)-important antigen-presenting cells that play a central role in inducing antigen-specific tolerance or immunity. Following antigen acquisition in peripheral tissues, DCs migrate to draining lymph nodes via the lymphatics to present antigen to T cells. Here we demonstrate that FcγR engagement by IgG immune complexes (ICs) stimulates DC migration from peripheral tissues to the paracortex of draining lymph nodes. In vitro, IC-stimulated mouse and human DCs showed greater directional migration in a chemokine (C-C) ligand 19 (CCL19) gradient and increased chemokine (C-C) receptor 7 (CCR7) expression. Using intravital two-photon microscopy, we observed that local administration of IC resulted in dermal DC mobilization. We confirmed that dermal DC migration to lymph nodes depended on CCR7 and increased in the absence of the inhibitory receptor FcγRIIB. These observations have relevance to autoimmunity because autoantibody-containing serum from humans with systemic lupus erythematosus (SLE) and from a mouse model of SLE also increased dermal DC migration in vivo, suggesting that this process may occur in lupus, potentially driving the inappropriate localization of autoantigen-bearing DCs.