Re: NIH Intramural Study

a_weisman_at_yahoo.com
Date: 01/13/05 

Date: 13 Jan 2005 06:16:35 -0800

Another one of great interest discussing the dubious nature of the
circumstantial evidence for "autoimmunity" via molecular mimicry:

Mechanisms of Disease: Molecular Mimicry and Autoimmunity

Lori J. Albert, Robert D. Inman

Autoimmune disease is the consequence of an immune response against
self-antigens that results in the damage and eventual dysfunction of
target organs. Although the triggering event in most autoimmune
diseases is unknown, an infectious cause has long been postulated to
explain the development of autoimmunity. Molecular mimicry is one
mechanism by which infectious agents (or other exogenous substances)
may trigger an immune response against autoantigens.

...

In some patients infected with the spirochete Borrelia burgdorferi,
Lyme arthritis develops as a late sequela. In about 10 percent of these
patients, the arthritis is resistant to antibiotic therapy and becomes
chronic. There is usually no detectable spirochetal DNA in the affected
joints. Human leukocyte-function-associated antigen 1 (LFA-1,
CD11a/CD18, or integrin (alpha)L(beta)2) has been proposed as an
autoantigen in these patients because it contains a peptide sequence
that is homologous to one in the outer-surface protein A (OspA) of B.
burgdorferi. (47) Synovial-fluid T cells from some patients with
chronic Lyme arthritis, but not from patients with other forms of
arthritis, react in vitro with the peptide, as well as with the intact
LFA-1 and OspA proteins. In patients with the appropriate genetic
background associated with Lyme arthritis, priming by B. burgdorferi
infection is apparently still required for the development of an
autoimmune response to LFA-1. The mechanistic link between this
autoreac
tivity against LFA-1 and the synovitis of B. burgdorferi infection
awaits further definition.

...
Conclusions

The experimental and clinical models discussed above fall short of
resolving the key issues in the demonstration of molecular mimicry as a
pathogenic mechanism in autoimmune disease. For researchers in this
area, challenges remain. Infection is common; autoimmunity is not. The
frequency of shared peptide sequences and the flexibility inherent in
immune recognition suggest that mimicry may be ubiquitous in biologic
systems. Defining the default pathways that normally protect the host
from the dangers of an autoreactive response during or after infection
remains an important area of research.

>>From the clinical perspective, work in this area has not led to any
treatments with proven efficacy. Antibiotic treatment has not been
proved to alter the course of rheumatic fever or postdysenteric
reactive arthritis. (50,51) On the other hand, in a recent trial
comparing immunosuppressive therapy (glucocorticoids plus either
azathioprine or cyclosporine) with conventional therapy (diuretics and
vasodilators) in patients with viral myocarditis, there was no
difference in outcome
between the treatment groups. (52) The patients with markers of immune
activation, either humoral or cellular, had a better outcome,
regardless of the treatment they received. Thus, in some disorders, the
immune response, instead of having the deleterious role suggested by
the concept of mimicry, may actually contribute to a successful host
defense and to healing.

If molecular mimicry is a biologically important phenomenon, it has
important implications for vaccination. It is possible that vaccination
against infectious diseases activates pathways of molecular mimicry in
genetically susceptible hosts, and this may be the basis of adverse
reactions to vaccines. The data discussed above suggest an important
caveat in the performance of large-scale trials of vaccination, such as
those involving vaccination against Lyme disease. (53,54) By the same
token, the concept of molecular mimicry suggests that nonresponsiveness
to vaccines could be a function of tolerance.

Molecular mimicry has remained an attractive explanation for autoimmune
diseases for three decades, mainly on the
basis of circumstantial evidence. No data convincingly demonstrate that
mimicry is an important mechanism in the development of autoimmune
disease in humans. Nonetheless, molecular mimicry retains an intrinsic
appeal, because it links current concepts of the role of the immune
system in the host defense with concepts of autoimmunity.

Source Information

>>From the Division of Rheumatology, Department of Medicine,
Toronto Western Hospital,
University Health Network (L.J.A., R.D.I.); and the
Immunology (R.D.I.), University of Toronto -- both in
Toronto. Address reprint requests to Dr.
Inman at the Arthritis Center of Excellence, Toronto
Western Hospital, FP 1-221, 399 Bathurst St.,
Toronto, ON M5T 2S8, Canada, or at
rin...@torhosp.toronto.on.ca.

Copyright © 1999 by the Massachusetts Medical Society. All rights
reserved.

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