Intravenous immunoglobulin (IVIG) is a complex mixture of IgG antibodies made from human plasma that contains the pooled antibodies from thousands of people, and is only FDA-approved to treat a few assorted conditions; nonetheless, practitioners have used it off-label with varied success in patients with lupus, arthritis and asthma, among other autoimmune disorders. In the body, the antibodies in plasma act as part of the immune response to identify and deactivate foreign invaders. When they begin attacking the body's own cells, the same protective immunoglobulins (known as IgG antibodies) can cause autoimmune disorders like lupus, arthritis and asthma. And yet, when IVIG is infused into people with those exact autoimmune conditions, it calms inflammation rather than causes it.
Jeffery Ravetch, Theresa and Eugene M. Lang Professor and head of Rockefeller's Leonard Wagner Laboratory of Molecular Genetics and Immunology, was struck by this inconsistency. "If IgG triggers autoimmune disease, how could it be pathogenic and therapeutic?" he asked. "We call it the IgG paradox." Six years ago he started an investigation into exactly how IVIG worked, and what he's discovered could one day lead to a whole new class of therapeutics. In a paper published in the August 4 issue of the journal Science, Ravetch and his colleagues, Falk Nimmerjahn and Yoshi Kaneko, explain what makes IVIG effective: A small fraction of the IgG antibodies in the IVIG solution carry a sugar called sialic acid that is required for its protective ability.
IgG antibodies bind to and activate specific immune cells, with different forms or "subclasses" binding to specific receptors (called Fc receptors) on the immune cell's surface. Antibody subclasses have different abilities to induce inflammation in the body by virtue of their selective ability to engage either activating or inhibitory Fc receptors. Earlier work had shown that IVIG infusion changed this ratio of activating and inhibitory receptors on the cells that trigger inflammation, rendering the pro-inflammatory autoantibodies in autoimmune diseases, like lupus and arthritis, less inflammatory. The next logical step then, Ravetch says, was determining how the IgG molecules in IVIG preparation could have an anti-inflammatory effect.
Because a therapeutic, anti-inflammatory response to IVIG requires a concentration of IgG antibodies that's hundreds of times greater than is normally used for antibody therapy for cancer or infection, for example, Ravetch and his colleagues began to look for something that was only present in IVIG in small amounts. That's how they discovered that just the very terminal sialic acid on the Fc portions of the IgG molecule were the root of the anti-inflammatory activity. When the researchers removed the sialic acid, the molecule retained its structure and its half-life, but it lost its protective abilities. "This is a very interesting condition that's set up," Ravetch says. "IgG can shift from a state that is quite inflammatory to a state that is actively anti-inflammatory by just changing a sugar." This switch occurs during a normal immune response to a foreign substance, shifting the IgG antibodies from an anti-inflammatory state to one that is pro-inflammatory and able to efficiently dispose of the foreign challenge.
To test the theory, Ravetch and his colleagues tried enriching IVIG for the IgG molecules that contained sialic acid. They found that just enriching for this IgG species increased IVIG activity by a factor of ten, while removing it wiped out the therapeutic activity altogether. This discovery, Ravetch says, has potentially huge implications, and his lab is now working to generate a recombinant form of IgG that, by virtue of a sialic acid molecule attached in the right place, will be anti-inflammatory and could act as a novel treatment for autoimmune disorders. "We have the opportunity to make a much better form of IVIG that will work 100 times better and be a pure molecule -- to build a much better class of therapeutics based on a property that already exists in nature."