Re: NIH Intramural Study

a_weisman_at_yahoo.com
Date: 01/13/05 

Date: 13 Jan 2005 06:38:55 -0800

Molecular Mimicry: FOR

Molecular Mimicry
http://www.direct-ms.org/molecular_mimicry.html
Molecular Mimicry
The concept that molecular mimicry is an important factor in autoimmune
disease was first published in 1985 and since that time substantial
evidence has accumulated such that it has become the favoured mechanism
for causing many autoimmune diseases including MS.

The concept is deceiving simple but entails a lot of understanding of
the workings of the immune system. Basically molecular mimicry means
that part of a molecule of a given protein closely resembles a part of
another totally different protein. Proteins are made up of strings of
amino acids and in molecular mimicry one series amino acids(eg~10) in
one protein is very similar to a string of ten amino acids in another
protein. Given that there are 20 different amino acids it is a rather
rare occurrence to find such mimicking arrangements but many examples
have been demonstrated.

The main types of proteins which came into play in autoimmune disease
are:

self proteins which are part of the human body.An example of this would
be myelin basic protein which is the most common protein in myelin;
proteins of infectious agents such as viruses and bacteria;
food proteins.For example over 400 different proteins occur in cow's
milk and most have over 150 amino acids.
To understand how molecular mimicry works in the induction of
autoimmunity one must understand the basic mechanisms of an immune
response to a foreign invader in the body. The immune system recognizes
a part of the protein portion of the invader. It does this with T cells
which have receptors which bind to short segments(~10 amino acids) of a
foreign protein. It is helped in this task by so called antigen
presenting cells such as macrophages. A macrophage will engulf a
foreign invader(eg a bacteria or food particle) and break it down into
fragments. A special molecule in the macrophage then carries a protein
fragment(peptide) to the surface of the cell and "presents" it to the
millions of circulating T cells. A T cell which has a matching receptor
locks onto the presented protein fragment. The T cell then becomes
activated and stimulates other portions of the immune system to begin
an immune response against all proteins which contain a similar looking
amino acid string. The details of what constitutes a similar looking
string are beyond this summary but suffice to say it has been found
that a variety of similar, yet somewhat different strings, can be
recognized by the same T cell.

Thus, it is easy to understand how molecular mimicry can trigger an
autoimmune reaction. If the protein fragment from a foreign invader
which is presented to the T cell closely resembles part of a self
protein then the activated immune system will not only attack all
foreign invaders which have the same string of amino acids but will
also attack a very similar string in a self protein. It has been shown
that parts of proteins in various foods and infectious agents resemble
parts of various self proteins. Sometimes a three way mimicry occurs
with a protein fragment from a food closely resembling that of an
infectious agent which in turn closely resembles part of a self
protein. In Celiac disease part of the gliadin molecule (found in
various grains such as wheat and rye), part of adenovirus 12 and part
of a gut protein all closely resemble each other and the result of such
mimicry is an immune attack on the gut when food containing gliadin
protein is eaten. A similar three way mimicry occurs between a cell
wall protein in grains and legumes, part of the Epstein Barr virus and
part of the collagen in joints. This leads to rheumatoid arthritis in
genetically susceptible people. For type 1 diabetes parts of milk
proteins and viral proteins mimic proteins in the insulin-producing
beta cells of the pancreas.

For MS it has been established that numerous viruses and bacteria have
amino acid strings which mimic parts of proteins in the myelin proteins
of the central nervous system. Undoubtedly food proteins also contain
such mimicking protein fragments and thus two and three way mimicry is
a ready explanation for why the immune system attacks myelin and causes
MS.

An important part of molecular mimicry is what exact string of amino
acids is presented to the immune system because that will determine if
part of a self protein is also mimicked or not. That is why MS and
other autoimmune diseases are strongly dependent on genetic makeup and
why only a small percentage of the population contracts these diseases.
Most people do not have genes which result in mimicking peptides being
presented to their immune system. A person's genes will also determine
which self protein is mimicked and thus what specific autoimmune
disease that person gets. People, who have genes such that a myelin
protein is mimicked by a presented foreign protein fragment, will
experience an immune attack on their myelin which eventually leads to
clinical symptoms and a diagnosis of MS. Those who present
collagen-mimicking fragments get rheumatoid arthritis.

Currently most researchers are concentrating on infectious agents as
the main drivers of molecular mimicry despite the strong evidence that
food proteins also supply appropriate mimics. In fact it is likely that
food proteins are the main mimics in some cases because the
geographical distribution of diseases such as MS and type 1 diabetes
closely follows differences in dietary habits rather than differences
in infectious agents. Of course it has been established that food
proteins are the driver of Celiac disease, one of the few autoimmune
diseases for which the cause is known.

In summary, molecular mimicry is currently the best explanation for
why the immune system attacks self tissue in some people. When all is
said and done it just comes down to a case of mistaken identity in
which the immune system in genetically susceptible people mistakes part
of the body for a foreign invader. Below are some medline abstracts on
the concept of molecular mimicry.

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Medline Abstracts
Molecular mimicry and immune-mediated diseases.
FASEB J 1998 Oct;12(13):1255-65

Oldstone MB

Viral Immunobiology Laboratory, Division of Virology, The Scripps
Research Institute, Department of Neuropharmacology, La
Jolla, California 92037, USA. mbaobo@scripps.edu

Molecular mimicry has been proposed as a pathogenetic mechanism for
autoimmune disease, as well as a probe useful in uncovering its
etiologic agents. The hypothesis is based in part on the abundant
epidemiological, clinical, and experimental evidence of an association
of infectious agents with autoimmune disease and observed
cross-reactivity of immune reagents with host 'self' antigens and
microbial determinants. For our purpose, molecular mimicry is defined
as similar structures shared by molecules from dissimilar genes or by
their protein products. Either the molecules' linear amino acid
sequences or their conformational fits may be shared, even though their
origins are as separate as, for example, a virus and a normal host self
determinant. An immune response against the determinant shared by the
host and virus can evoke a tissue-specific immune response that is
presumably capable of eliciting cell and tissue destruction. The
probable mechanism is generation of cytotoxic cross-reactive effector
lymphocytes or antibodies that recognize specific determinants on
target cells. The induction of cross-reactivity does not require a
replicating agent, and immune-mediated injury can occur after the
immunogen has been removed a hit-and-run event. Hence, the viral or
microbial infection that initiates the autoimmune phenomenon may not be
present by the time overt disease develops. By a complementary
mechanism, the microbe can induce cellular injury and release self
antigens, which generate immune responses that cross-react with
additional but genetically distinct self antigens. In both scenarios,
analysis of the T cells or antibodies specifically engaged in the
autoimmune response and disease provides a fingerprint for uncovering
the initiating infectious agent.

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Evidence for monoclonal expansion of synovial T cells bearing V alpha
2.1/V beta 5.5 gene segments and recognizing a synthetic peptide that
shares homology with a number of putative autoantigens.
Immunology 1995 Oct;86(2):168-75

Ostenstad B, Dybwad A, Lea T, Forre O, Vinje O, Sioud M

Institute of Immunology and Rheumatology, University of Oslo, Norway.

A peptide of 15 amino acids derived from the cereal glycine-rich cell
wall protein (GRP), sharing a significant homology with Epstein-Barr
virus nuclear antigen-1 (EBNA-1), fibrillar and procollagen, stimulated
synovial fluid (SF) T cells from juvenile (JRA) and adult (RA)
rheumatoid arthritis patients. An over expression of the V alpha 2 gene
family was found in the SF from patients who responded significantly to
the peptide. To investigate in more detail the SF T-cell responses to
the GRP peptide, we established peptide-specific T-cell lines and
clones from a DR8+ positive JRA patient with pauciarticular form. The
T-cell clones were phenotyped as T-cell receptor (TCR)alpha beta+/CD4+
and their clonality was investigated by polymerase chain reaction (PCR)
and flow cytometric analysis. TCR sequences from different clones
demonstrated that the clones were identical and used the V alpha 2. 1/J
alpha 6 combined with V beta 5. 5/J beta 2. 7 gene segments.
Interestingly, direct sequencing of the V alpha 2 family PCR product
obtained from cDNA prepared from freshly isolated SF mononuclear cells
identified the same TCR sequence as that used by the clones, suggesting
the monoclonality of SF CD4+ T cells bearing V alpha 2. 1/J alpha 6
gene products. The present data suggest a recruitment and expansion of
a SF T-cell subpopulation, and also support the hypothesis that
autoimmune diseases can be triggered by protein epitopes with crucial
amino acids homologous to self-proteins.

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Molecular mimicry in T cell-mediated autoimmunity: viral peptides
activate human T cell clones specific for myelin basic protein.
Cell 1995 Mar 10;80(5):695-705

Wucherpfennig KW, Strominger JL

Department of Molecular and Cellular Biology, Harvard University,
Cambridge, Massachusetts 02138.

Structural similarity between viral T cell epitopes and self-peptides
could lead to the induction of an autoaggressive T cell response. Based
on the structural requirements for both MHC class II binding and TCR
recognition of an immunodominant myelin basic protein (MBP) peptide,
criteria for a data base search were developed in which the degeneracy
of amino acid side chains required for MHC class II binding and the
conservation of those required for T cell activation were considered. A
panel of 129 peptides that matched the molecular mimicry motif was
tested on seven MBP-specific T cell clones from multiple sclerosis
patients. Seven viral and one bacterial peptide efficiently activated
three of these clones. Only one peptide could have been identified as a
molecular mimic by sequence alignment. The observation that a single T
cell receptor can recognize quite distinct but structurally related
peptides from multiple pathogens has important implications for
understanding the pathogenesis of autoimmunity.

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T-cell epitopes in type 1 diabetes autoantigen tyrosine phosphatase
IA-2: potential for mimicry with rotavirus and other environmental
agents.
Mol Med 1998 Apr;4(4):231-9

Honeyman MC, Stone NL, Harrison LC

Autoimmunity and Transplantation Division, Walter and Eliza Hall
Institute of Medical Research, Parkville, Australia.
honeyman@wehi.edu.au

The tyrosine phosphatase IA-2 is a molecular target of pancreatic islet
autoimmunity in type 1 diabetes. T-cell epitope peptides in
autoantigens have potential diagnostic and therapeutic applications,
and they may hold clues to environmental agents with similar sequences
that could trigger or exacerbate autoimmune disease. We identified 13
epitope peptides in IA-2 by measuring peripheral blood T-cell
proliferation to 68 overlapping, synthetic peptides encompassing the
intracytoplasmic domain of IA-2 in six at-risk type 1 diabetes
relatives selected for HLA susceptibility haplotypes. The dominant
epitope, VIVMLTPLVEDGVKQC (aa 805-820), which elicited the highest
T-cell responses in all at-risk relatives, has 56% identity and 100%
similarity over 9 amino acids (aa) with a sequence in VP7, a major
immunogenic protein of human rotavirus. Both peptides bind to
HLA-DR4(*0401) and are deduced to present identical aa to the T-cell
receptor. The contiguous sequence of VP7 has 75% identity and 92%
similarity over 12 aa with a known T-cell epitope in glutamic acid
decarboxylase (GAD), another autoantigen in type 1 diabetes. This
dominant IA-2 epitope peptide also has 75-45% identity and 88-64%
similarity over 8-14 aa to sequences in Dengue, cytomegalovirus,
measles, hepatitis C, and canine distemper viruses, and the bacterium
Haemophilus influenzae. Three other IA-2 epitope peptides are 71-100%
similar over 7-12 aa to herpes, rhino-, hanta- and flaviviruses. Two
others are 80-82% similar over 10-11 aa to sequences in milk, wheat,
and bean proteins. Further studies should now be carried out to
directly test the hypothesis that T-cell activation by rotavirus and
possibly other viruses, and dietary proteins, could trigger or
exacerbate beta-cell autoimmunity through molecular mimicry with IA-2
and (for rotavirus) GAD.

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J Clin Invest, April 2001, Volume 107, Number 8, 943-944
Copyright ©2001 by the American Society for Clinical Investigation

Commentary
Infection, mimics, and autoimmune disease

Noel R. Rose

Department of Pathology and The W. Harry Feinstone Department of
Molecular Microbiology and Immunology, The Johns Hopkins Medical
Institutions, 720 Rutland Avenue, Ross 659, Baltimore, Maryland 21205,
USA.

Phone: (410) 955-0330; Fax: (410) 614-3548; E-mail: nrr...@jhsph.edu.
The observation that infection can precipitate an autoimmune disease
dates
back more than a century. The first human autoimmune disease described,

paroxysmal cold hemoglobulinuria, was thought of as a late consequence
of
syphilis, and rheumatic fever is still associated with preceding
streptococcal infection.

In modern times, these associations have been attributed to molecular
mimicry. In its simplest form, the concept of molecular mimicry states
that antigenic determinants of infectious microorganisms resemble
structures in the tissues
of the host but differ enough to be recognized as foreign by the host’s
immune system. It is now clear that mimicry on the molecular level is
a common phenomenon; that is, many sequential and structural
determinants of infectious
agents simulate epitopes of host tissues (1). But, as Mackay and I
remarked recently, "There are, as yet, no firm instances of molecular
mimicry by microorganisms serving as initiating agents of human
autoimmune disease..."
(2).

Molecular mimicry in Chagas’ disease

There is probably no better candidate for investigating mimicry than
the cardiomyopathy of chronic Chagas’ disease. It afflicts about 30%
of the 20 million individuals infected with the protozoan Trypanosoma
cruzi in the Americas. The presence of a cardiac inflammatory
infiltrate in apparent absence of parasites suggests that the
trypanosome initiates an autoimmune response.
Indeed, a number of cross-reactive human antigens have been implicated
by their reaction with sera of Chagas patients. They include, for
example, a 23 kDa ribosomal protein (3), a functional epitope on the ß1
adrenergic receptor (4), a 48 kDa
protein found in neuronal axons (5), and a heptapeptide of cardiac
myosin heavy chain (6). In this issue of the JCI, Girončs and
colleagues have identified another cross-reactive antigen (Cha), a
novel peptide from human cells (7).

This peptide, which reacts with the sera of patients with chronic
Chagas’ disease and of mice infected with T. cruzi, was found in
abundance in human and mouse hearts. Cross-reaction between the
mammalian and trypanosomal peptides was documented for both T and B
cells. The finding that this peptide bears both B-
and T-cell epitopes makes it a leading candidate for the induction of
the cardiomegaly of Chagas’ disease through molecular mimicry, since it
would facilitate T/B-cell cooperation (8).
This work leaves critical questions unanswered. Some patients with
Chagas’ disease develop megacolon and megaesophagus due to destruction
of parasympathetic ganglia, but Cha is not found in nervous tissue. No
functional changes were associated with Cha-specific antibodies. On the
other hand, mice immunized
with a 13 amino acid ribosomal peptide of T. cruzi produced antibodies
that caused functional changes in the heart without evidence of
mononuclear infiltration (9). Finally, living trypanosomes induce
Chagas-like lesions in the hearts of
mice, but recombinant Cha does not. Thus, the question of whether
molecular mimicry using a single, defined antigen of the parasite in
the absence of infection actually mirrors clinical autoimmune disease
remains unaddressed.

Molecular mimicry abounds

Recent insights into T-cell recognition have greatly broadened the
original concept of molecular mimicry. A number of studies have shown
that there is a fair measure of flexibility in the amino acid sequence
acceptable for both MHC class II binding and for recognition by the
T-cell receptor (10, 11). Clearly, microbial peptides with relatively
limited sequence homology to myelin basic
protein (MBP) can activate autoreactive T cells. Using an extensive
combinatorial peptide library, Hemmer et al. (12) described differing
recognition profiles of individual autoreactive T-cell clones from
patients with multiple sclerosis. Li et al. (13) showed that, because
of topological differences in their peptide finding sites, different
MHC class II molecules can create different alignments of the same
bound MBP peptide, thereby creating distinct T-cell epitopes from the
same peptide. Thus, T-cell recognition is even more
degenerate than previously anticipated, and primary amino acid sequence
similarities provide little clue to a molecular mimic.
Further expansion of the autoimmune response probably occurs due to
epitope spreading. Vanderlugt and colleagues (14) developed a murine
model of relapsing encephalomyelitis, using an immunodominant epitope
of the myelin antigen, proteolipid protein (PLP). In the course of the
disease, T-cell clones recognizing epitopes of MBP are detected that
are not present on PLP,
suggesting that the release of endogenous antigen during the initial
response can stimulate self-reactive T cells and play a critical role
in disease progression. These data further suggest that an unrelated
infection could mobilize a self-peptide and
potentiate but not initiate an attack of autoimmune disease in a
subclinically primed individual (15). All of these findings demonstrate
why it may be difficult to identify a single organism as the
etiological agent of an autoimmune disease.

The adjuvant effect

The experiments described above remind us that the generation of an
immune response depends upon two types of signals: antigen-specific
recognition through the T-cell and B-cell receptors and a number of
non–antigen-specific, nonclonal signals. An infectious agent may
provide the specific signal by molecular mimicry or by release of
endogenous antigen. The inflammatory process itself
enhances the nonclonal costimulatory signals necessary to mount an
immune response. Lack of appropriate costimulatory signals may account
for the difference between a pathogenic and a nonpathogenic autoimmune
response following infection. Our own studies with Coxsackie B3–induced
(CB3-induced) myocarditis
exemplify such a situation. In genetically susceptible A/J mice,
infection with CB3 induces autoimmune myocarditis (16). Injection of
killed virus does not, suggesting that inflammation elicited by live
virus provides costimulatory signals that influence subsequent immune
responses. Evidence expanding this view came
from experiments using less susceptible B10.A mice. If cotreated with
bacterial LPS, as well as virus or cardiac myosin, the animals develop
typical myocarditis. LPS acts through toll-like receptor 4 (TLR-4) and
potently activates the innate immune response; particularly, it
upregulates production of inflammatory cytokines such as IL-1 and
TNF-. Administration of either of these
two cytokines converts a less susceptible to a more susceptible mouse.
Furthermore, the production of autoimmune myocarditis in the
susceptible mouse strain could be delayed or abrogated by
administration of inhibitors of either of these two cytokines.
These results point to the importance of the inflammatory response
itself in the generation of an autoimmune disease. They emphasize that
an infectious microorganism may play two roles in the induction of
disease (Figure 1). The first is to provide the requisite antigenic
signal. This may come through molecular mimicry or through the release
of excessive amounts of self-antigen from tissue cells during the
infectious process. The second role of the infectious
agent is to provide the adjuvant milieu in the form of upregulation of
costimulatory molecules and other products of inflammation. The
activation of antigen-presenting cells during microbial infection
upregulates costimulatory molecules and secretion of inflammatory
cytokines (17), thereby reducing the threshold needed for activation
of T cells by the antigenic signal. This effect, which
may promote protective immunity and thus benefit the host, may also
prove be detrimental when it increases susceptibility to damaging
autoimmune responses.

References

Oldstone, M.B.A. 1998. Molecular mimicry and immune-mediated diseases.
FASEB J. 12:1255-1265
Rose, N.R., and Mackay, I.R. 2000. Molecular mimicry: a critical look
at exemplary instances in human diseases. Cell. Mol. Life Sci.
57:542-551
Bonfa, E., Viana, V.S.T., Barreto, A.C.P., Yoshinari, N.H., and
Cossermelli, W. 1993. Autoantibodies in Chagas’ disease. J. Immunol.
150:3917-3923
Ferrari, I. et al.1995. Molecular mimicry between the immunodominant
ribosomal protein P0 of Trypanosoma cruzi and a functional epitope on
the human ß1-adrenergic receptor. J. Exp. Med. 182:59-65
Van Voorhis, W.C., Schlekewy, L., and Trong, H.L. 1991. Molecular
mimicry by Trypanosoma cruzi: the F1-160 epitope that mimics mammalian
nerve can be mapped to a 12-amino acid peptide. Proc. Natl. Acad. Sci.
USA. 88:5993-5997
Kalil, J., and Cunha-Neto, E. 1996. Autoimmunity in Chagas’ disease
cardiomyopathy: fulfilling the criteria at last? Parasitol. Today.
12:396-399.
Girončs, N. et al.2001. Dominant T- and B-cell epitopes in an
autoantigen linked to Chagas’ disease. J. Clin. Invest. 107:985-993
Liang, B., and Mamula, M.J. 2000. Molecular mimicry and the role of B
lymphocytes in the processing of autoantigens. Cell. Mol. Life Sci.
57:561-568.
Motrán, C.C., Fretes, R.E., Cerbán, F.M., Rivarola, H.W., and Vottero
de Cima, E. 2000. Immunization with the C-terminal region of
Trypanosoma cruzi ribosomal P1 and P2 proteins induces long-term
duration cross-reactive antibodies with heart functional and structural
alterations in young and aged mice. Clin. Immunol. 97:89-94.
Hausmann, S., Martin, M., Gauthier, L., and Wucherpfennig, K.W. 1999.
Structural features of autoreactive TCR that determine the degree of
degeneracy in peptide recognition. J. Immunol. 162:338-344
Barnaba, V., and Sinigaglia, F. 1999. Molecular mimicry and T
cell-mediated autoimmune disease. J. Exp. Med. 185:1529-1531
Hemmer, B. et al.1997. Identification of high potency microbial and
self ligands for a human autoreactive class II-restricted T cell clone.
J. Exp. Med.
185:1651-1659.Li, Y., Li, H., Martin, R., and Mariuzza, R.A. 2000.
Structural basis for the binding of an immunodominant peptide from
myelin basic protein in different registers by two HLA-DR2 proteins. J.
Mol. Biol. 304:177-188.
Vanderlugt, C.L. et al.2000. Pathologic role and temporal appearance of
newly emerging autoepitopes in relapsing experimental autoimmune
encephalomyelitis.
J. Immunol. 164:670-678
Rao, V.P., Kajon, A.E., Spindler, K.R., and Carayonniotis, G. 1999.
Involvement of epitope mimicry in potentiation but not initiation of
autoimmune disease. J. Immunol. 162:5888-5893.
Lane, J.R., Neumann, D.A., Lafond-Walker, A., Herskowitz, A., and Rose,
N.R. 1993. Role of IL-1 and tumor necrosis factor in coxsackie
virus-induced autoimmune myocarditis. J. Immunol. 151:1682-1690.
Manickasingham, S.P., Anderton, S.M., Burkhart, C., and Wraith, D.C.
1998. Qualitative and quantitative effects of CD28/B7-mediated
costimulation on naive T cells in vitro. J. Immunol. 161:3827-3835.

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Autoimmunity. 2004 Sep;37(5):387-92.
Related Articles, Links

"Molecular Mimicry to Borrelia burgdorferi: Pathway to Autoimmunity?"

Bolz DD, Weis JJ.

Lyme borreliosis is due to infection with the tick-borne spirochete
Borrelia burgdorferi, and is associated with persistent infection
unless treated with antibiotics. The persistent nature of infection by
B. burgdorferi can lead to development of chronic disease, as found in
patients infected before recognition of the effectiveness of antibiotic
therapy. Much speculation has surrounded the possibility that
autoimmune mechanisms are involved in chronic symptoms. In most cases,
involvement of autoimmunity in Lyme disease has not received
experimental support. The exception is in a small group of patients
with chronic arthritis whose abnormal joint symptoms persist after
apparent elimination of the bacteria. In this review, the evidence
supporting autoimmune mechanisms in Lyme disease will be discussed.
PMID: 15621562 [PubMed - in process]

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jid8812164 2001 May;16(3):187-92 Molecular mimicry and antigen-specific
t cell responses in multiple sclerosis and chronic cns lyme disease.

Martin R, Gran B, Zhao Y, Markovic-Plese S, Bielekova B, Marques A,
Sung
MH, Hemmer B, Simon R, McFarland HF, Pinilla C. Neuroimmunology Branch,
NINDS, NIH Building, 10 Room 5B-16, 10 Center DR MSC 1400, Bethesda,
MD,
20892-1400, USA

The concept of molecular mimicry provides and elegant
framework as to how cross-reactivity between antigens from a foreign
agent with self proteins may trigger autoimmune diseases. While it was
previously thought that sequence and structural homology between
foreign and self proteins or the sharing of T cell receptor (TCR) and
MHC- binding motifs are required for molecular mimicry to occur, we
have shown that even completely unrelated peptide sequences may lead to
cross- recognition by T cells. The use of synthetic combinatorial
peptide libraries in the positional scanning format (PS-SCL) together
with novel biometric prediction approaches has allowed us to describe
the recognition profiles of individual autoreactive T cell clones (TCC)
with unprecedented accuracy. Through studies of myelin-specific TCC as
well as clones from the nervous system of patients suffering from
chronic central nervous (CNS) Lyme disease it has become clear that at
least some T cells are more degenerate than previously anticipated.
These data will not only help us to redefine what constitutes specific
T cell recognition, but also allow us to study in more detail the
biological role of molecular mimicry. A recent clinical trial with an
altered peptide ligand (APL) of one of the candidate myelin basic
protein (MBP) epitopes in MS (amino acids 83-99) has shown that such a
modified MBP peptide may not only have therapeutic efficacy, but also
bears the potential to exacerbate disease. Thus, we provide firm
evidence that the basic principles of cross-recognition and their
pathogenetic significance are relevant in MS. Copyright 2001 Academic
Press.

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The New England Journal of Medicine -- December 30, 1999 -- Vol. 341,
No. 27

Mechanisms of Disease: Molecular Mimicry and Autoimmunity

Lori J. Albert, Robert D. Inman

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
autoreactivity against LFA-1 and the synovitis of B. burgdorferi
infection awaits further definition.