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COLLEGE STATION, TX - Humans have been raising cows for their
meat, hides and milk for millennia. Now it appears that the cow
immune system also has something to offer. A study of an
extraordinary family of cow antibodies, led by researchers at The Scripps Research
Institute (TSRI) and coauthored by three investigators from
Texas A&M College of Veterinary Medicine & Biomedical
Sciences (CVM), points to new ways to make human medicines.
The CVM's faculty members' expertise in immunology and
infectious disease, as well as their easy access to a herd of
cattle, made them a natural fit as collaborators.
"These antibodies' structure and their mechanism for creating
diversity haven't been seen before in other animals' antibodies,"
said Vaughn V. Smider, assistant professor of Cell
and Molecular Biology at TSRI and principal investigator for the
study, which appears in the June 6, 2013 issue of the journal
Antibodies, large proteins in the immune system, resemble
lobsters with a tail and two identical arms for grabbing specific
targets, called "antigens," often parts of pathogens like bacteria
or viruses. At the end of each arm is a small set of protein loops
called complementarity-determining regions (CDRs), which actually
do the grabbing. By rearranging and mutating the genes that code
for CDRs, an animal's immune system can generate a vast and diverse
population of antibodies-which, collectively, can bind to just
about any foreign invader.
In humans and in many other mammals, most of an antibody's
specificity for a target is governed by the largest CDR region, CDR
H3. Researchers have been finding hints that an unusually long
version of this domain can sometimes be the key to a successful
defense against a dangerous infection, such as HIV.
Assistant Professor in the Texas A&M College of Veterinary
Medicine and Biomedical Sciences (CVM) and an author on the Cell
paper, suggests thinking of these long CDRs as a probe on a thin
extended scaffold that can fit narrow crevices to reach and bind
unique hidden pathogen determinants that ordinary antibodies
As Smider's area of research includes finding new ways to
generate therapeutic antibody proteins, reports of long CDR H3 use
caught his interest. "We started thinking about how we could make
these long CDR3s that are so rare in humans, and we knew from the
literature that cows make even longer ones all the time," he
Although the structure of the long CDR H3 protein in previous
studies of the human anti-HIV antibody had seemed unusual, the
corresponding structure in the cow antibodies turned out to be
unique in the known world of animal antibodies: a long "stalk"
element topped by an antigen-binding "knob." Sequencing of the DNA
that codes for the knob region revealed an unusual abundance of
cysteine-a sulfur-containing amino acid that is apt to bond to a
nearby cysteine on the same protein chain, thus forming a loop.
Analyses of these DNA sequences, some of which were conducted at
Texas A&M, also indicated that, in the cow B-cells where these
antibodies are made, the knob-coding gene segments are
extraordinarily likely to develop point mutations that either add
or subtract cysteines. The effect of these tiny mutations is to
create or remove-often radically-antigen-grabbing loops on the
In the cows, binding of these antibodies to viruses is almost
entirely done by the knob on the long CDR H3, which shows that
these antibodies do have an important function in the immune
system. "For the very first time we have an ultra-long CDR3
antibody binding to an actual pathogen," said Mwangi, an expert in
immunology who completed the initial assays that determined the
binding target for these antibodies.
One question that remains is why the cow immune system evolved
to make such antibodies. Smider suspects that it has to do with
cows' unusual, four-chambered, grass-fermenting stomach, with its
extensive collection of bacteria and other microorganisms. "If some
of these escape from the stomach and get into the bloodstream or
other tissues, there could be some pretty serious infections; so
that's our starting hypothesis for why cows have this unusual
immune defense," he said.
The stalk-and-knob structure of the CDR H3 loops on these
antibodies, which resemble structures found in some insect poisons
and other proteins, also suggest that they evolved to grab a
particular type of target. "What comes to mind are ion channel or
pore structures in the walls of cells," Smider said. "In any case,
we're hoping to find out whether any of the structures targeted by
these knobs exist on microorganisms that cause human disease."
"Potentially, the outcome of this research is going to be huge,"
Mwangi said, "not only for cattle but also for human health."
Criscitiello, Assistant Professor at the CVM and one of the
study's authors, said this was a wonderful chance to contribute to
such a groundbreaking study, as researchers at the CVM had
experience with-and access to-cows. The entire project was made
possible through collaborations of various people and labs each
contributing their expertise to add pieces to the puzzle.
"Such collaborations bring together specialists in diverse
fields and certainly facilitate future research," said Terje
Raudsepp, Associate Professor at the CVM and another of the study's
authors. "This is expected to lead to new collaborative projects in
The study was supported by the American Cancer Society, National Institutes of Health, Skaggs Institute for
Chemical Biology, Scripps
Translational Science Institute, Texas A&M College of
Veterinary Medicine & Biomedical Sciences, and United States Department of
For more information about the Texas A&M College of
Veterinary Medicine & Biomedical Sciences, please visit our
website at vetmed.tamu.edu or join us on Facebook.
Angela G. Clendenin
Director, Communications & Public Relations
Ofc - (979) 862-2675
Cell - (979) 739-5718
Texas A&M University, College Station, Texas 77843
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