WIMPY ANTIBODY PROTECTS AGAINST KIDNEY DISEASE IN MICE
An antibody abundant
in mice and previously thought to offer poor assistance in fighting against
infection may actually play a key role in keeping immune responses in check and
preventing more serious self-inflicted forms of kidney disease, researchers say
Led by researchers
at the University of Cincinnati (UC) and Cincinnati Children's Hospital Medical
Center and published online Nov. 2, 2014, in the journal Nature,
the study finds that the mouse antibody IgG1, which is made in large quantities
and resembles a human antibody known as IgG4, may actually be protective.
"Antibodies
protect against pathogens, in large part, by clumping them together and by
activating other defenses, including a set of serum proteins, known as
complement, and cells that have antibody-binding molecules on their surface
called Fc receptors," says Fred Finkelman, MD, Walter A. and George
McDonald Foundation Chair of Medicine and professor of medicine and pediatrics
at UC.
Finkelman is also an
immunobiology researcher at Cincinnati Children's Hospital Medical Center.
Richard Strait, MD, an assistant professor of pediatrics at UC and an attending
physician at Cincinnati Children's, is the first author of the research
published in Nature.
"Surprisingly,
most of the antibody made by mice is IgG1, which is relatively defective in its
ability to clump pathogens, activate complement, and activate cells by binding
to their Fc receptors," says Finkelman, also a physician at the Cincinnati
Department of Veterans Affairs (VA) Medical Center. "Humans have a similar
type of antibody, called IgG4, which is also relatively defective in these
abilities.
"Why should you
have such a wimpy antibody? It's the antibody made in the largest amount. Our
thought was that in biology, you don't get anything for free," says
Finkelman. "If an antibody can kill bacteria and viruses very well, it
might also cause inflammation that can harm the animal that makes it. So maybe
you need some of these wimpy antibodies to protect against that type of
self-inflicted damage."
Researchers tested
their hypothesis by studying what happens when genetically bred mice that
cannot make IgG1 are injected with a foreign protein that would spur a normal
mouse's immune system to produce IgG1. The genetically bred mouse instead
produced another antibody known as IgG3, which affected capillaries in the
kidneys and ultimately led to renal failure.
"The mouse's
kidneys turned yellow because they essentially shut off blood flow and within a
few days there was total destruction of the filtering part of the kidney called
the glomerulus," explains Finkelman.
However, injecting
IgG1 into mice that could not make the antibody prevented them from developing kidney
disease, says Finkelman.
"These findings
support our hypothesis about the reason for making antibodies such as mouse
IgG1 and human IgG4," says Finkelman. "They also demonstrate a new
type of kidney disease that can be caused by certain types of antibody, such as
mouse IgG3, even without complement or Fc receptors. In addition, our findings
suggest that antibodies such as human IgG4 might be useful for treating people
who have diseases caused by other types of antibody."
These diseases
include myasthenia gravis and blistering skin diseases, says Finkelman.
Myasthenia gravis is
a chronic autoimmune neuromuscular disease characterized by varying degrees of
weakness of the skeletal (voluntary) muscles of the body. Individuals with the
ailment lose the ability to contract their muscles because their body produces
an antibody that destroys acetylcholine receptors in muscle.
"The nerves in
their muscles continue to fire and they release the chemical acetylcholine, but
there is not much for the acetylcholine to bind to," says Finkelman.
"These people become very weak and can actually die because they can no
longer swallow well or breathe well."
Individuals with
blistering skin diseases make antibodies against the molecules that hold skin
cells together, says Finkelman. As a result, the skin cells separate from each
other, forming blisters.
"People can
lose a lot of fluid and can get infected very easily," says Finkelman.
"These are very serious diseases and the treatment is not very good."
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