ATC 2012 Report – Fc receptor crucial in the activity of antibodies

by Thomas R. Collins – Antibodies play diverse roles in the human body — they can be anti-inflammatory, they can modulate the immune system, and they can be protective against disease.

And like a puppeteer behind the scenes, the Fc receptor, in its various forms, mediates these diverse activities of antibodies, Jeffrey Ravetch, MD, PhD, said here at the 2012 American Transplant Congress. Ravetch is head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology at New York-based Rockefeller University, which was the first institution in the U.S. devoted exclusively to biomedical research.

Fc receptors are membrane receptors for antigen-antibody complexes or aggregated immunoglobulins. They bind a site in the Fc portion of the immunoglobulin molecule and might demonstrate a specificity for particular classes of immunoglobulins. They are found on B cells, K cells, macrophages, neutrophils and other kinds of cells.

How these Fc receptors function within the immune system can provide useful insight to transplantation specialists trying to keep immunity at bay after an organ is transplanted.

Dr Ravetch’s laboratory examines the autoimmunity at work in mouse models with certain diseases by looking at how the antigen-antibody complexes develop and then how they follow through in the course of the disease.

It’s a complex process, but his lab has attempted to simplify it by focusing on how the immune complexes interact with Fc receptors — they are particularly powerful because they are expressed as pairs of both activation and inhibitory molecules, giving them a way to trigger and terminate a cellular response during an immune system activity.

“The key to distinguishing between various biological responses is to identify which receptors engage the Fc region,” Dr Ravetch said. “Diverse interactions occur at the Fc region.”

Fc receptors are involved in activities as varied as tumour cytotoxicity, the use of high-dose intravenous immunoglobulin, the neutralization of toxins and viruses, and the survival of B cells, he said.

These subclasses of activities is a result of the remarkable specificity of Fc receptors — a specificity that comes about through interactions with amino acids and glycans, Dr Ravetch said.

His work has also shown that different classes of anti-tumour antibodies require distinct Fc recptors.

The anti-inflammatory properties of intravenous immunoglobulin involves the function of Fc fragments, which have been shown to be clinically active. A dose of 1 to 2g/kg is approved for treatment of idiopathic thrombocytopenic purpura (ITP), Kawasaki disease, Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy. Off-label uses can include systemic lupus, rheumatoid arthritis, multiple sclerosis and scleroderma.

Dr Ravetch’s lab is now investigating the exact cellular pathways that are engaged by Fc activation receptors by orchestrating interruptions of the receptors’ activity.

Having found that a sugar attached to intravenous immunoglobulin G antibodies is responsible for their protective effects, the lab is now trying to make a synthetic therapy based on these antibodies that are sugar-linked.

“We can now understand the diversity of activity,” Dr Ravetch said. “The direction we want to go now is to try to understand how to reverse these processes.”