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Research
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UW
professor of medicine Seymour Klebanoff was the first to discover
a key biochemical mechanism used by the immune system to destroy
invading microorganisms.
The
body fights off invaders like bacteria by unleashing types of
white blood cells called "phagocytes." The phagocytes engulf the
bacterial cells and sequester them in an intracellular compartment
called the phagosome. During that process, phagocytes consume
oxygen at a sharply increased rate in what is called a "respiratory
burst." The burst generates hydrogen peroxide along with
highly reactive chemicals called free radicals (an atom or group
of atoms with an unpaired electron). Meanwhile, granules inside
the phagocyte release an arsenal of enzymes and toxic agents,
including a bright green enzyme found in pus called yeloperoxidase,
into the phagosome.
Myeloperoxidase
in turn reacts with the hydrogen peroxide and an ion such as chloride
(a component of table salt, ubiquitous in the body), generating
a powerful weapon against bacteria: hypochlorous acid--the active
ingredient in household bleach. Klebanoff first described this "myeloperoxidase-mediated
antimicrobial system" in a paper published in 1967 in The Journal
of Experimental Medicine.
"It's
as if the phagocytes attract bacteria into an intracellular swimming
pool and then turn on a spigot of Clorox to kill them," says Klebanoff.
Infants born with a genetic defect that impairs the respiratory
burst of their white blood cells face a lower life expectancy.
Klebanoff and others have had some success in treating these patients
with gamma interferon to kick-start their inactive phagocytes.
This
vital weaponry that protects us against microorganisms can also
damage other kinds of cells and organs. Klebanoff and colleagues
showed the system can cause damage to the kidney, sperm cells,
red and white blood cells, platelets, and tumor cells.
Recently,
Klebanoff demonstrated that hydrogen peroxide formed by bacteria
called lactobacilli can kill the HIV virus. Those bacteria are
the predominant bacterial species found in the vagina of normal
women. But hydrogen peroxide can also activate the part of the
AIDS virus that functions as an on-off switch for viral replication.
Klebanoff says that at this point it's not clear which, if either,
of the two diametrically opposed roles these bacteria play: killing
the virus or activating viral replication. But he emphasizes that
these bacteria are of considerable interest not
only with respect to heterosexual AIDS transmission, but in other
sexually transmitted diseases and vaginal infections as well.
Authored
by Javed Sheikh, MD, Instructor, Department of Medicine,
Division
of Allergy and Inflammation, Harvard Medical School
Top
of Page
eMedicine
Journal, October 24, 2001, Volume 2, Number 10
INTRODUCTION
Section 2 of 10
Background:
Myeloperoxidase (MPO) is a human enzyme in the azurophilic granules
of neutrophils and in the lysosomes of monocytes. Its major
role is to aid in microbial killing. Although MPO received little
clinical attention until 1966, the enzyme was first isolated
in 1941, and deficiency of MPO was first described in 1954.
Some patients with MPO deficiency have impaired microbial killing,
but most are asymptomatic, and the condition usually goes undiagnosed.
Since most cases go undiagnosed, the condition initially was
believed to be very rare; only 15 cases were reported before
the 1970s. Modern laboratory techniques have allowed us to discover
that MPO deficiency actually is not so rare.
Pathophysiology:
Normal
function of myeloperoxidase MPO, an iron-containing protein,
is found in the azurophilic granules of neutrophilic polymorphonuclear
leukocytes (PMNs) and in the lysosomes of monocytes in humans.
MPO is most abundant in the granules of neutrophils.
Monocytes contain only about a third of the MPO present in
neutrophils. When neutrophils become activated, which can
happen in conjunction with phagocytosis, they undergo a process
referred to as a respiratory burst.
This respiratory burst causes production of superoxide, hydrogen
peroxide, and other reactive
oxygen derivatives, which are all toxic to microbes. During
respiratory bursts, granule contents are released into the
phagolysosomes and outside the cell, allowing released contents
to come into contact with any microbes present. MPO catalyzes
the conversion of hydrogen peroxide and chloride ions (Cl)
into hypochlorous acid. Hypochlorous acid is 50 times more
potent in killing than hydrogen peroxide.
MPO
also chlorinates phagocytosed bacteria directly, so the MPO-hydrogen
peroxide-Cl system seems to have an important role in microbial
killing. While the exact mechanism by which microbial killing
occurs is controversial, it is fairly certain that the MPO system
is important for the process to occur optimally. In addition
to
killing bacteria, the products of the MPO-hydrogen peroxide-Cl
system are thought to play a role in killing fungi, parasites,
protozoa, viruses, tumor cells, natural killer (NK) cells, red
cells, and platelets.
by
Stephen D. Herman, M.D., D.A.B.R.
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