lgG4-related disease (lgG4-RD) is a fibroinflammatory disease, characterized by elevated lgG4 and IgE levels, a lymphoplasmatic infitrate, storiform fibrosis, obliterative phlebitis, and eosinophila. B cell depletion by Rituximab therapy attenuates disease symptoms and selectively reduces lgG4 levels. This observation strongly supports a role for lgG4 in the disease. However, this IgG subclass exhibits weak binding to canonical, low-affinity Fc gamma receptors, and is considered to have limited inflammatory potential. A single, N-linked glycosylation site is present on heavy chains on all IgG Fc. This glycan maintains an open heavy chain confirmation, and is an absolute requirement for pro-inflammatory interactions triggered through Fc gamma receptors. The glycan has a complex, biantenarry core structure;variable sugar additions to the core account for over 30 distinct glycans identified on IgG Fcs in healthy individuals. Importantly, the glycan composition dictates IgG effortor function, by controlling the specific receptor bound by IgG. For example, afucosylated IgGI preferentially binds activating Fc gamma RIIIA, and exhibits markedly enhanced ADCC in vivo. Conversely, terminal sialylation of the glycan converts IgG antibodies into potent anti-inflammatory mediators, by reducing affinity to canonical Fc gamma receptors, while conveying binding to dendritic cell-specific ICAM3 grabbing non-integrin (DC-SIGN). Importantly, the variable glycosylation of IgG is regulated by inflammation, and reduced levels are sialic acid are found on IgG from patients suffering from chronic autoimmune diseases. The studies proposed in the pilot project application will examine the glycans on the Fc of IgG recovered from patients suffering from lgG4-RD and healthy controls. The overarching hypothesis that will be explored is that the lgG4 recovered lgG4-RD will have a characteristic glycosylation pattern that bestows a novel and unappreciated effector function on to lgG4 antibodies. These studies will precisely define the role of the Fc glycan on IgG4, allowing for the development of improved and targeted therapies for lgG4-RD.

Public Health Relevance

IgG antibodies are important proteins, that rapidly clear infections, cancer, and can also trigger harmful inflammation. Four subclasses of IgG antibodies exist in humans, termed lgG1-4. However, little is know about the subclass lgG4. The studies proposed herein will decipher lgG4 biology in health and in the inflammatory lgG4-related disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-PA-I (J1))
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Massachusetts General Hospital
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Mattoo, Hamid; Mahajan, Vinay S; Della-Torre, Emanuel et al. (2014) De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease. J Allergy Clin Immunol 134:679-87