IgG antibodies display paradoxical properties: they can initiate inflammation by forming immune complexes that crosslink Fc receptors and activate cells, and conversely when given intravenously at high doses (1-2 g/kg intravenous immunoglobulin) actively suppress inflammation. Studies from our laboratory have indicated that IgG antibodies with Fc glycans terminating in a2,6 sialic acid linkages are responsible for this anti-inflammatory. Sialylated IgG Fc can attenuate inflammation in rheumatoid arthritic and nephrotoxic nephritis inflammatory models. The sialylated IgG antibodies bind lectin receptors SIGN-R1 (in mice) or DC-SIGN (in humans), triggering the release of an anti-inflammatory mediator that promotes upregulation of the inhibitory Fc receptor, Fc?RIIb on inflammatory macrophages, thereby attenuating immune complex induced inflammation. The studies proposed herein will examine the regulation and production of sialylation of IgG antibodies, and will characterize the molecular signaling events of the anti-inflammatory response promoted by sialylated IgG antibodies. Specifically, aim 1 will examine B cells in homeostatic and inflammatory states to determine the conditions and B cell populations that produce anti-inflammatory sialylated IgG antibodies. Next, B cells will be engineered to express increased levels of sialylated IgGs, and transferred to autoimmune disease prone mice, and the onset and progress of disease monitored in the recipient mice. Manipulation of IgG antibody glycosylation in vivo might prove to be a means to treat inflammatory diseases. The tools required for these experiments will be developed in the mentoring laboratory, but the in vivo experiments will be conducted in the independent laboratory.
Aim 2 proposes to dissect the anti-inflammatory cascade triggered upon ligation of SIGN receptors with sialylated IgG. These findings will provide a mechanistic understanding of IVIG that is already used routinely in the clinic. Furthermore, understanding these pathways will aid in the development of more effective anti-inflammatory therapies that target SIGN receptors to increase expression of Fc?RIIb. The experiments proposed in this aim will be carried out in the established mentoring laboratory, using its resources and the resources at the mentoring institution. IgG antibodies are a crucial component of the immune system, and significantly contribute to host protection against cancer and infectious diseases. Additionally, therapeutic IgG antibodies have been developed for treatment of cancer and inflammatory diseases. The studies proposed herein will elucidate one important aspect of how IgG antibodies act as anti-inflammatory agents, and may lead to the design of more effective IgG based therapies for the treatment of inflammatory diseases or cancer.
IgG antibodies are a crucial component of the immune system, and significantly contribute to host protection against cancer and infectious diseases. Additionally, therapeutic IgG antibodies have been developed for treatment of cancer and inflammatory diseases. The studies proposed herein will elucidate one important aspect of how IgG antibodies act as anti-inflammatory agents, and may lead to the design of more effective IgG based therapies for the treatment of inflammatory diseases or cancer.
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|Wermeling, Fredrik; Anthony, Robert M; Brombacher, Frank et al. (2013) Acute inflammation primes myeloid effector cells for anti-inflammatory STAT6 signaling. Proc Natl Acad Sci U S A 110:13487-91|
|Anthony, Robert M; Kobayashi, Toshihiko; Wermeling, Fredrik et al. (2011) Intravenous gammaglobulin suppresses inflammation through a novel T(H)2 pathway. Nature 475:110-3|