From left, Vadim Pedchenko, Ph.D., Agnes Fogo, M.D., and Billy Hudson, Ph.D., each provided critical contributions to the study. (Photo by Brent Weedman)
Study helps untangle collagen’s limber coils
The collagen molecules that make up the body's structural tissues are strong like scaffolding, yet supple like dancers.
If they twist the wrong way, they may be attacked by “autoantibodies” called up by the body's immune system.
That's the conclusion reached by Vanderbilt University researchers and their colleagues in this week's New England Journal of Medicine: a conformational change in collagen molecules in the kidney triggers the rare but devastating autoimmune attack known as Goodpasture's disease.
“It's not a mutation,” said Agnes Fogo, M.D., the John L. Shapiro Professor of Pathology at Vanderbilt who contributed to the study. “The molecule hasn't changed at the DNA level, but it has changed in the way it's coiled.”
It's as if the molecule was a figure skater who suddenly switched from doing a triple Salchow to a double arabesque. “It's changed its pose, if you will … and that has led it to now be recognized as foreign by the immune system,” Fogo said.
“I think we are addressing a basic mechanism whereby certain autoimmune diseases get started,” added the paper's senior author, Billy Hudson, Ph.D., director of the Vanderbilt Center for Matrix Biology.
Fogo and Hudson were part of an international team of scientists who collected and analyzed serum and tissue samples from more than 70 patients with the disease.
Vadim Pedchenko, Ph.D., left, and Arkansas-based truck driver Joe Ellis hauled frozen samples for the study 2,000 miles from San Diego to Nashville.
The samples, collected for more than 40 years by Curtis Wilson, M.D., professor emeritus of Immunology at the Scripps Research Institute in La Jolla, “were really incredibly instrumental for making this (study) happen,” said Pedchenko, research associate professor of Medicine at Vanderbilt and lead author of the study.
Goodpasture's disease, named for famed Vanderbilt pathologist Ernest Goodpasture, M.D., is characterized by rapidly progressive inflammation that can destroy the glomeruli, or filtering units of the kidney, and by the presence of autoantibodies that attack the basement membrane surrounding and supporting the glomeruli.
The autoantibodies also attack the alveolar basement membrane and can cause potentially fatal bleeding in the lung.
Treatment involves plasmapheresis to remove antibodies from the bloodstream, and immunosuppressive drugs to prevent production of new antibodies.
In many cases, however, the disease causes extensive scarring, requiring life-long dialysis or kidney transplantation.
Understanding what causes Goodpasture's disease could lead to improvements in diagnosis, treatment and prevention, and “it could change your … thinking about a whole basic process” of autoimmunity, Fogo said.
The glomerular basement membrane (GBM) consists largely of type IV collagen, a connective tissue constructed from a family of proteins called alpha chains. Like the cables supporting a bridge, the alpha chains twist around each other to form triple helical “heterotrimers.”
While at the University of Kansas Medical School in the late 1980s, Hudson and his colleagues discovered two previously unknown chains, alpha 3 and alpha 4.
They also found that the NC1 domain proteins, which tie the alpha “cables” together, are the specific targets for anti-GBM antibodies.
The collagen IV molecules that make up the basement membranes in the kidneys and the lungs consist of alpha 3, alpha 4 and alpha 5 chains twisted together in a “very specific fashion,” Pedchenko said.
In the current study, the researchers found that anti-GBM antibodies attacked the NC1 domains of both the alpha 3 and alpha 5 chains. They are attacked because the collagen molecule has twisted in an unusual way, exposing parts of itself that are normally hidden, and which are now recognized by the immune system as “foreign.”
“The development of Goodpasture's disease may be considered an autoimmune 'conformeropathy,'” the researchers concluded, caused by a conformational change in the collagen IV molecule.
Scientists speculate that environmental exposures, for example, to cigarette smoke or organic solvents like benzene, coupled with genetic predisposition, may cause the molecule to “pirouette.”
The study was made possible by Wilson's carefully preserved blood and tissue samples and others collected in Sweden, and by crucial tissue samples obtained by Fogo, with the family's permission, from a patient who died of Goodpasture's disease three years ago.
Due to the rarity of the disease, tissue samples are extremely difficult to come by. “For the first time, we could investigate the antibodies that actually bind the kidney and cause renal failure,” Hudson said.
“This is, of course, not the end of the story,” added Pedchenko, who emigrated from Ukraine to work with Hudson at Kansas, and moved with him to Vanderbilt in 2002.
The researchers currently are exploring ways to improve early diagnosis of Goodpasture's disease, perhaps by developing one of auto-antibodies as a biomarker, and to shut down the attack on the kidney without suppressing the entire immune system.
Other co-authors include Olga Bondar, Ph.D., Roberto Vanacore, Ph.D., Paul Voziyan, Ph.D., Dorin-Bogdan Borza, Ph.D., and Eric Neilson, M.D., of Vanderbilt; Richard Kitching, M.D., Ph.D., of Monash University in Australia; Jörgen Wieslander, M.D., Ph.D., of Lund University Hospital in Sweden; and Clifford Kashtan, M.D., of the University of Minnesota.
The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases.