Glycomics Center Research Could Aid Autoimmune Diseases Treatment
By Beth Potier, Media Relations
May 14, 2008
Researchers at the UNH Glycomics Center have helped identify a specific carbohydrate
structure that confers anti-inflammatory activity to a glycoprotein antibody
that could lead to improved treatment of autoimmune diseases like lupus or
rheumatoid arthritis. The study, reported in a recent edition of the journal
Science, was led by immunologist Jeffrey Ravetch of Rockefeller University.
The work revolves around immunoglobulin G (IgG), the most abundant antibody
in blood plasma. Intravenous immunoglobulin (IVIG) has within it a trace amount
of a very active material that is effective in relieving the inflammatory affects
of lupus, rheumatoid arthritis, asthma, and other autoimmune disorders. But
because of the trace amounts of active material, effective doses of IVIG need
to be very high, frequently leading to unwanted side effects.
This study involved rebuilding the human IVIG into a fully active molecule
with a slight modification to a carbohydrate residue. These carbohydrate structures
are linked to the immunoglobulin and referred to as glycans, and on the tip
of this glycan is a specifically linked sialic acid. All the sialic acid on
IVIG was converted to the active linkage that confers anti-inflammatory properties.
Understanding and analyzing the exact structure of sialic acid was the contribution
of the Glycomics Center, headed by director and research professor Vernon Reinhold.
The center has developed tools and protocols using multidimensional mass spectrometry
to determine the structure and functional relationships of these carbohydrates.
Reinhold notes that while most biopolymers are linear and thus relatively easy
to sequence, bush-shaped carbohydrates have proved challenging.
“With sequential mass spectrometry, we systematically untangle this
bush,” says Reinhold. “We take it down to the trunk then try to
put it back together to determine its structure.”
Reinhold and Glycomics Center research scientist David Ashline helped Ravetch
pinpoint exactly how sialic acid was linked, which let the researchers engineer
a synthetic human antibody that mimicked the linkages in IgG, providing an
IVIG with enhanced activity for treatment of autoimmune diseases. In the Science
paper, the researchers report that when given to arthritic mice, the engineered
IgG was about 30 times more effective than IVIG.
“Now that we know what the exact structure is, we can build on it,” says
Reinhold. “Just as once you know what the motor in a car is, you can
modify and make it more effective, and in principle, if you know the antigen,
you can build the antibody.”
Beyond this work with IgG, the Glycomics Center is demystifying the carbohydrate
connections in cancer that contributes to metastatic growth and in avian flu
where sialic residues on airway surface tissues serve as doorways for viral
entry.
“Carbohydrates are the glue that pulls things together, the cell surface
matrix in which cells communicate, and they provide the connections for signal
transduction. It’s only been within the last decade that we’ve
realized that such structures are critical for all kinds of biological function,” says
Reinhold. “Now that we can define precise structures, we can begin to
understand their function. This structure-functional relationship will have
a huge impact on our health in respect to immune regulation.”
To read the abstract of the article, from the April 18 issue of Science, go
to http://www.sciencemag.org/cgi/content/abstract/sci;320/5874/373.
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