IGG4-galactosylation as a pathogenic post-translational modification in IGG4-mediated autoimmunity

The National Institute of Allergy and Infectious Diseases awarded The General Hospital Corporation (Massachusetts General Hospital) $834,190 on July 15, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate IgG4 galactosylation as a pathogenic post-translational modification in IgG4-mediated autoimmunity.

The award funds research dissecting the role of IgG4 galactosylation (IgG4-GAL) and Fc gamma receptors in IgG4-related diseases and muscle-specific kinase myasthenia gravis. The research combines biophysics, biochemistry, and cell-based approaches across three specific aims: determining the stability of IgG4-GAL across the treatment course of IgG4-related disease; defining how IgG4-GAL and Fc gamma receptor alleles interact to promote inflammation; and assessing autoantigen-specific IgG glycosylation in muscle-specific kinase myasthenia gravis and pemphigus vulgaris. The investigator will analyze IgG from patient serum and cells, evaluate glycoengineered IgG4 in receptor binding and effector assays, and test the central hypothesis that IgG4-GAL contributes to more severe IgG4-mediated pathology in individuals carrying specific Fc gamma receptor alleles.

Performance takes place in Boston, Massachusetts. The period of performance runs from July 15, 2026, through June 30, 2031. The assistance type is a Project Grant.

Abstract

Approximately 5% of the population of the united states is affected by autoimmune diseases. Many of these diseases associated with autoantibodies, directed against self. However, the role of these autoantibodies in the pathology of autoimmune disease is not always know. IGG4-related diseases (IGG4-RDS) is a chronic, immune- mediated fibrotic disorder characterized by tumor-like lesions composed of CD4+ T cells, IGG4+ plasma cells, and markedly elevated oligoclonal IGG4. However, whether IGG4 antibodies contribute to IGG4-RD pathology remains unclear. We identified a post-translational modification on IGG4 in IGG4-RD that render this IGG subclass inflammatory, and propose to extend these finding to defined disease statuses in IGG4-RD, and to other autoimmune indications that are also associated with IGG4 autoantibodies, including muscle-specific kinase myasthenia gravis (musk+ MG) and pemphigus vulgaris (PV). Our long-term goals are to understand the role and regulation of glycosylation to antibody biology, to ultimately modulate antibody effector functions in vitro and in vivo. The overall objective of this application is to dissect the role of IGG4-GAL and FC Γ receptors (FCΓRS) in IGG4-RD and musk+ MG. Our central hypothesis is that IGG4-GAL contributes to more severe IGG4-mediated pathology in FCΓRIIAR131 homozygous individuals. To test this, our approach will analyze IGG from patient serum and cells and evaluate glycoengineered IGG4 in receptor binding and effector assays. We propose the following three specific aims: 1. Determine the stability of IGG4-GAL across the treatment course of IGG4-RD. 2. Define how IGG4-GAL and FC Γ receptor alleles interact to promote inflammation. 3. Assess autoantigen-specific IGG glycosylation in musk+ MG and pemphigus vulgaris (PV). Using an integrated approach that combines biophysics, biochemistry, cellular and molecular functional immunology, and glycobiology, we will characterize the autoantigen-specific IGG response from three autoimmune diseases associated IGG4 autoantibodies. These studies will identify biomarkers predictive of autoimmune disease status, and provide mechanistic insights in the autoimmune pathology, enabling development of novel and precise therapeutics.