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| Scientists at Johns Hopkins have uncovered an important link between
getting specific bacterial infections and developing autoimmune diseases
such as arthritis. |
| In a study reported in this month's edition of the journal Nature
Medicine, the researchers show clearly that immune system cells which
fight bacteria can also attack normal cells carrying a specific mimic
molecule -- one that closely resembles a bacterial protein. |
| Further, they show that as long as there's been a previous bacterial
infection, immune cells can attack "innocent bystander" cells -- body
cells that bacteria have never infected. This occurs when the cells are
stressed by exposure to irradiation, environmental toxins or the body's
stress chemicals.
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| "We've found this evidence that the immune system can be fooled," says
Mark Soloski, Ph.D, who led the research team, "and it suggests subtle
changes that could underlie many autoimmune diseases." The study also
offers a starting place for scientists to investigate environmental or
genetic triggers to autoimmune diseases. |
| The team focused on infections by Salmonella, bacteria well known for
food poisoning but also long thought to trigger arthritis in some
people. "As many as 10 percent of those who get Salmonella develop a
'reactive' kind of arthritis which lasts a few weeks," says Soloski.
"But a smaller, significant number of those patients get a severe,
debilitating type of arthritis that's long-lasting." |
| To investigate bacteria/arthritis connections, the scientists observed
behavior of a typical bacteria-fighting immune cell, the cytotoxic
lymphocyte (CTL), as it approached infected body cells. Cells invaded by
bacteria normally give clear signals that they're infected. "They
display small pieces of bacterial proteins on their surface that say, in
effect, 'Hey, here's a sick cell,'" says Soloski. Attracted by this
protein "flag," CTLs dock with the infected cells and trigger their
rapid self-destruction. |
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The Hopkins scientists first identified the protein "flag" in mouse
cells infected with Salmonella as one common to certain bacteria
associated with human arthritis, including Borrelia -- the cause of Lyme
disease.
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But they also found the bacterial "flag" was almost identical to parts
of a "universal housekeeping molecule" found in humans, mice and all
living organisms. This "housekeeping molecule" helps proteins keep their
shape.
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When researchers artificially coaxed mouse body cells to display the
Salmonella "flag," the mouse CTLs would readily attack them. But CTLs
also went into attack mode if the cells displayed a piece of the mouse's
own housekeeping molecule or the identical human version. "This shows us
the immune cells readily respond to a molecular mimic," says Soloski.
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In a normal Salmonella infection in mice, Soloski says "at least half of
the CTLs are stirred up to recognize the mouse's own protein as well as
the bacterial one. That's a huge immune response." Based on the
similarity of the set-up in humans, he adds, the response is likely the
same. Now the scientists are trying to find why and how this immune
response translates into arthritis in some mice and humans.
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In a small side study, the team also found that normal, uninfected body
cells could be attacked by CTLs if the cells were stressed in some way,
such as being exposed to higher temperature or radiation or general
infection. "We don't know what's going on here," says Soloski, "but it's
a good place to study other triggers of autoimmune diseases."
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| Other researchers were lead author Wei-Feng Lo, M.D., Ph.D., Amy
DeCloux, Ph.D., Amina S. Woods, Ph.D., and Robert J. Cotter, Ph.D., of
Hopkins, as well as Eleanor S. Metcalf, Ph.D., of the Uniformed Services
University of the Health Sciences in Bethesda, Md.
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The research was funded by NIH grants and by an award from the Maryland
Chapter of The Arthritis Foundation.
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| (back to top) |
Molecular mimicry mediated by MHC class Ib molecules after infection
with Gram-negative pathogens.
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| Lo WF, Woods AS, DeCloux A, Cotter RJ, Metcalf ES, Soloski MJ
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| Division of Rheumatology, Department of Medicine and The Graduate
Program in Immunology, The Johns Hopkins University School of Medicine,
Baltimore, Maryland 21218, USA.
[Record supplied by publisher]
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| The development of many autoimmune diseases has been etiologically
linked to exposure to infectious agents. For example, a subset of
patients with a history of Salmonella infection develop reactive
arthritis. The persistence of bacterial antigen in arthritic tissue and
the isolation of Salmonella or Yersinia reactive CD8+ T cells from the
joints of patients with reactive arthritis support the etiological link
between Gram-negative bacterial infection and autoimmune disease.
Models proposed to account for the link between infection and
autoimmunity include inflammation-induced presentation of cryptic
self-epitopes, antigen persistence and molecular mimicry. Several
studies support molecular mimicry as a mechanism for the involvement of
class II epitopes in infectious disease-induced self-reactivity. Here,
we have identified an immunodominant epitope derived from the S.
typhimurium GroEL molecule. This epitope is presented by the mouse
H2-T23-encoded class Ib molecule Qa-1 and was recognized by CD8+
cytotoxic T lymphocytes induced after natural infection. S.
typhimurium-stimulated cytotoxic T lymphocytes recognizing the GroEL
epitope cross-reacted with a peptide derived from mouse heat shock
protein 60 and recognized stressed macrophages. Our results indicate
involvement of MHC class Ib molecules in infection-induced autoimmune
recognition and indicate a mechanism for the etiological link between
Gram-negative bacterial infection and autoimmunity.
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