FcγRIIb 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 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.

• Authors: Menna R Clatworthy, Sarah K Harford, Rebeccah J Mathews, Kenneth G C Smith
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 50 Pg. 17971-6 (Dec 16 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25475856 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigen-Antibody Complex
• Cross-Linking Reagents
• Fcgr2b protein, mouse
• Receptors, IgG
• Vascular Endothelial Growth Factor A

Topics

• Animals
• Antigen-Antibody Complex (metabolism)
• Arthritis, Experimental (immunology)
• Autoimmune Diseases (immunology)
• Cross-Linking Reagents (metabolism)
• Dendritic Cells (metabolism)
• Humans
• Immunohistochemistry
• Lymph Nodes (blood supply, immunology)
• Lymphangiogenesis (immunology)
• Macrophages (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Polymorphism, Single Nucleotide (genetics)
• Receptors, IgG (metabolism)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, biosynthesis)