FcγRIIb inhibits immune complex-induced VEGF-A production and intranodal lymphangiogenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-12, Vol.111 (50), p.17971-17976
• Main Authors: Clatworthy, Menna R., Harford, Sarah K., Mathews, Rebeccah J., Smith, Kenneth G. C.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antigen antibody complex; Antigen-Antibody Complex - metabolism; Arthritis; Arthritis, Experimental - immunology; Autoimmune diseases; Autoimmune Diseases - immunology; B lymphocytes; Biological Sciences; Cross-Linking Reagents - metabolism; Dendritic Cells - metabolism; Humans; Immunohistochemistry; Lymph nodes; Lymph Nodes - blood supply; Lymph Nodes - immunology; Lymphangiogenesis - immunology; Macrophages; Macrophages - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Polymorphism, Single Nucleotide - genetics; Receptors; Receptors, IgG - metabolism; Systemic lupus erythematosus; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - biosynthesis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1413915111

Significance Antibody (IgG) plays an important role in defense against infection and in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Low affinity-activating fragment crystallizable gamma receptors (FcγRs) that bind IgG immune complexes (ICs) mediate many effector functions of antibody and are controlled by an inhibitory receptor, FcγRIIb. Here we show a previously unappreciated role for IC in driving an expansion of lymphatic conduits within lymph nodes. This was dependent on macrophage VEGF-A production and inhibited by FcγRIIb. Lymphangiogenesis and VEGF-A were increased in the lymph nodes of mice with arthritis and SLE and in macrophages obtained from people with a SLE-associated, defunctioning polymorphism in FCGR2B . These findings have implications for the pathogenesis and treatment of autoimmune diseases. 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