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Researchers probe Kidney Damage, Protection
in Lupus
Newswise — Kidney damage associated with the
autoimmune disease lupus is linked to a
malfunction of immune cells that causes them
to congregate in and attack the organs,
researchers at UT Southwestern Medical
Center have discovered in a mouse study.
In a separate study with an international
team, the researchers also found that a
certain set of genes appears to protect the
kidneys from a different sort of immune
attack in both mice and humans.
“These studies, taken together, uncover two
important molecules that underlie the
pathology of lupus, particularly kidney
disease,” said Dr. Edward Wakeland, chairman
of immunology at UT Southwestern and
co-senior author of the studies.
“In addition, they highlight a certain
molecule as a potential target for treating
this disease,” he said.
In the first study, which appears in the
April issue of The Journal of Immunology,
the researchers examined several strains of
mice that mimic human lupus.
They found that immune cells in those mice
overproduced a particular molecule called
CXCR4.
In fact, the mice had up to twice as much
CXCR4 as their normal counterparts in
several types of immune cells.
The lupus-prone mice also had more
immune-system cells in their kidneys,
indicating that the inflammatory action of
the immune cells might be causing the kidney
damage.
The CXCR4 molecule was already known to play
a role in creating various types of blood
cells and also has been shown to be active
in cancer and AIDS.
Cells with CXCR4 on their surface are
attracted to another molecule released by
cells in various organs, so they migrate
toward those organs, including the kidney.
When the researchers treated the lupus mice
with a substance that blocks CXCR4, the
symptoms of lupus significantly diminished;
many symptoms of kidney failure were
averted; and the mice lived longer. The
increased lifespan was greater when
treatment began at an early age.
“This study indicates that drugs acting
against CXCR4 might become useful
therapies,” said Dr. Chandra Mohan,
professor of internal medicine and co-senior
author of the studies.
In the second study, published in the April
issue of The Journal of Clinical
Investigation, the researchers found that
some members of a family of genes called
kallikreins offered a degree of protection
in both mice and humans against a type of
kidney damage caused by a different
mechanism.
For this mouse study, the researchers
administered antibodies that attack a part
of the kidney called the glomerular basement
membrane, the portion of the organ that
performs its main function of filtering
wastes from blood.
They then looked for genes that turned on or
off in response to the antibody assault.
Nine forms of the kallikrein, or klk, gene
became more active, resulting in a two- to
sixfold increase in the proteins encoded by
the genes in normal mouse strains, compared
with lupus-prone strains.
When some mice were given substances that
block the action of kallikrein proteins,
they showed more severe symptoms of lupus,
suggesting that kallikreins protect against
renal disease.
The researchers also studied 340 German
patients with systemic lupus, matched with
400 healthy control subjects.
The patients with lupus and kidney damage
had klk genes that were different from those
in the healthy patients.
Similar findings were noted in a larger,
more varied group of patients from Europe,
the United States and Korea.
“All humans have Klk genes, but our findings
show that some of us have a particular
version that increases our risk for systemic
lupus,” Dr. Wakeland said.
Future research will examine the mechanisms
by which CXCR4 and klk genes might be
aberrantly regulated in lupus and how they
could be therapeutically targeted in human
lupus, the researchers said.
Other UT Southwestern researchers involved
in the first study were lead author and
graduate student Andrew Wang; Dr. Anna-Marie
Fairhurst, assistant instructor of
immunology; Dr. Katalin Tus, instructor of
immunology; former graduate student Srividya
Subramanian; Dr. Yang Liu, postdoctoral
researcher in internal medicine; Dr.
Fangming Li, assistant professor of
pediatrics; Dr. Peter Igarashi, professor of
internal medicine; and Dr. Xin Zhou,
professor of pathology. Researchers from the
Université Paris-Descartes and Chemokine
Therapeutics, Canada, also participated.
The study was funded by the National
Institutes of Health.
Other UT Southwestern researchers involved
in the second study were lead co-authors Dr.
Kui Liu, instructor of internal medicine,
and Dr. Quan-Zhen Li, assistant professor of
immunology; Li Li, research associate in
internal medicine; Jinchun Zhou, research
scientist in immunology; Mei Yan, research
associate in internal medicine; Dr. Qiu Ye,
former postdoctoral fellow in immunology;
Shengxi Liu, senior research associate in
immunology; Dr. Chun Xie, former instructor
in internal medicine; and Drs. Zhou and Liu.
Researchers from Oklahoma Medical Research
Foundation; University of California, San
Franciso; Long Island Jewish Health System,
Manhasset; Medical University of South
Carolina; and University of Alabama at
Birmingham also participated, as did
researchers from institutes in Sweden,
Spain, Argentina, Germany, South Korea,
Italy and the United Kingdom.
The study was funded in part by the Alliance
for Lupus Research and the National
Institutes of Health.
Visit
http://www.utsouthwestern.org/rheumatology
to learn more about clinical services in
rheumatology at UT Southwestern. Visit
http://www.utsouthwestern.org/dermatology
to learn more about UT Southwestern’s
clinical services in dermatology, including
autoimmune diseases.
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