# Examining IgG4 sialylation as a gain of function post-translation modification in IgG4-related diseases

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $839,968

## Abstract

Project Summary/Abstract.
IgG4-related diseases (IgG4-RDs) are a family of related autoinflammatory diseases characterized by fibrotic
lesions comprised of CD4+ T cells and IgG4+ plasma cells, and markedly elevated oligoclonal IgG4. However,
whether IgG4 antibodies contribute to IgG4-RD pathology remains unclear. Despite the tremendous clinical
success of immunotheraputics, little is known regarding IgG4 biology relative to IgG1. 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 comprehensively dissect cytotoxic
activity of sialylated IgG4. Our central hypothesis is autoantigen-specific IgG4 in IgG4-RD is sialylated, and
contributes to the pathology Of IgG4-RD. Our approach combines characterizing IgG from the sera of IgG4-RD
and healthy patients, while examining precisely glycoengineered IgG4 in receptor binding and effector function
assays.
Our hypothesis is informed by preliminary data shown here in the Approach subsection of the Research Strategy
section. The rationale that underlies the proposed research is understanding how IgG4 mediate cytotoxic effector
function will enable new insights into IgG biology, and may lead to development of innovative antibody-based
therapies. We will test our central hypothesis and, thereby, attain the objective of this application by pursuing the
following three specific aims using a combination of biophysical experiments, and in vitro and in vivo functional
assays.
1) Define the glycosylation and FcγRs-binding profiles of total and autoantigen-specific IgG in IgG4-RD.
Hypothesis: Sialylation enables FcγR binding by IgG4.
2) Examine the effector functions of sialylated IgG4 in vitro. Hypothesis: Sialylated IgG4 mediates effector
cell-specific pro-inflammatory effector functions.
3) Determine the in vivo effector functions of sialylated IgG4. Hypothesis: Sialylated IgG4 exerts pro-
inflammatory effector functions in vivo.
This proposal is expected to have broad clinical implications, ranging from diseases where elevated IgG4 titers
are associated in the pathology or resolution, as well as to design of immunotherapeutics, and represents a
substantive departure from the status quo by underscoring the cytotoxic capacity of IgG4.

## Key facts

- **NIH application ID:** 10032974
- **Project number:** 1R01AI153441-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Robert McCullough Anthony
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $839,968
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10032974

## Citation

> US National Institutes of Health, RePORTER application 10032974, Examining IgG4 sialylation as a gain of function post-translation modification in IgG4-related diseases (1R01AI153441-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10032974. Licensed CC0.

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