Molecular Mimicry: Cross-Reactivity Between Microbes and Host Proteins as a Cause of Autoimmunity

140 Pages·1989·5.07 MB·English

by  M. B. A. Oldstone (auth.), Michael B. A. Oldstone M.D. (eds.)

Current Topics in
Microbiology
145 and Immunology
Editors
R. W. Compans, Birmingham/Alabama . M. Cooper,
Birmingham/Alabama . H. Koprowski, Philadelphia
1. McConnell, Edinburgh . F. Melchers, Basel
V. Nussenzweig, NewY ork . M. Oldstone,
La Jolla/California . S. Olsnes, Oslo . H. Saedler,
Cologne . P. K Vogt, Los Angeles . H. Wagner, Ulm
1. Wilson, La Jolla/California
Molecular Mimicry
Cross-Reactivity Between Microbes and
Host Proteins as a Cause of Autoimmunity
Edited by M. B. A. Oldstone
With 28 Figures
Springer-Verlag
Berlin Heidelberg NewY ork
London Paris Tokyo Hong Kong
MICHAEL B. A. OLDSTONE, M.D.
Dept. ofImmunology, Scripps Clinic and Research Foundation
10666 N. Torrey Pines Road, La Jolla, CA 92037, USA
ISBN-13: 978-3-642-74596-6 e-ISBN-13:978-3-642-74594-2
DOl: 10.1007/978-3-642-74594-2
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Table of Contents
M. B. A. OLDSTONE: Overview: Infectious Agents as
Etiologic Triggers of Autoimmune Disease. . . .
J. FROUDE, A. GIBOFSKY, D. R. BUSKIRK, A. KHANNA
and J. B. ZABRISKIE: Cross-Reactivity Between
Streptococcus and Human Tissue: A Model of Molecular
Mimicry and Autoimmunity. . . . . . . . . . .. 5
W. VAN EDEN, E. J. M. HOGERVORST, E. J. HENSEN, R. VAN
DER ZEE, J. D. A. VAN EMBDEN, and 1. R. COHEN:
A Cartilage-Mimicking T-Cell Epitope on a 65K
Mycobacterial Heat-Shock Protein: Adjuvant Arthritis
as a Model for Human Rheumatoid Arthritis. . . . . 27
P. L. SCHWIMMBECK and M. B. A. OLDSTONE: Klebsiella
pneumoniae and HLA B27-Associated Diseases of
Reiter's Syndrome and Ankylosing Spondylitis. . . . 45
M. E. DIEPERINK and K. STEFANSSON: Molecular Mimicry
and Microorganisms: A Role in the Pathogenesis of
Myasthenia Gravis? . . . . . . . . . . . . . . . 57
M. F. KAGNOFF: Celiac Disease: Adenovirus and Alpha
Gliadin. . . . . . . . . . . . . . . . . . . . . 67
G. B. TAKLE and L. HUDSON: Autoimmunity and Chagas'
Disease. . . . . . . . . . . . . . . . . . . . . 79
R. S. FUJINAMI: Immune Responses Against Myelin Basic
Protein and/or Galactocerebroside Cross-React with
Viruses: Implications for Demyelinating Disease. . . 93
R. T. DAMIAN: Molecular Mimicry: Parasite Evasion and
Host Defense . . . . . . . . . . . . . . !OI
T. DYRBERG: Molecular Mimicry and Diabetes. . . . . 117
M. B. A. OLD STONE : Molecular Mimicry as a Mechanism
for the Cause and as a Probe Uncovering Etiologic
Agent(s) of Autoimmune Disease. 127
Subject Index . . . . . . . . . . . . . . . . . . . 137
List of Contributors
You will find the addresses at the beginning of the
respective contribution
BUSKIRK, D. R. KAGNOFF, M. F.
COHEN, I. R. KHANNA,A.
DAMIAN, R. T. OLDSTONE, M. B. A.
DIEPERINK, M. E. SCHWIMMBECK, P. L.
DYRBERG, T. STEFANSSON, K.
FROUDE,J. TAKLE, G. B.
FUJINAMI, R. S. VAN DER ZEE, R.
GIBOFSKY, A. VANEDEN,W.
HENSEN, E. J. VAN EMBDEN, J. D. A.
HUDSON, L. ZABRISKIE, J. B.
HOGERVORST, E. J. M.
Overview: Infectious Agents as Etiologic Triggers
of Autoimmune Disease
M. B. A. OLDSTONE
Infectious agents, particularly viruses, are implicated in autoimmunity on the basis
of three findings. First, autoimmune responses are made de novo or those already
present are enhanced concomitant with infection by a wide variety of human DNA
and RNA viruses. This point is strengthened by the second finding that, in experimental
animals, both acute and persistent virus infections can induce, accelerate, or enhance
autoimmune responses and cause autoimmune disease. For example, it has been
shown that with the New Zealand mouse family, a genetically defined group of
mice from which certain strains spontaneously develop autoimmunity, autoimmune
manifestations normally present in NZB mice (DNA-specific antibodies, red blood
cell-specific antibodies) or their (NZB x W) F 1 relatives (DNA-specific antibodies)
are enormously enhanced by persistent infection with either a DNA (polyoma) or
RNA (lymphocytic choriomeningitis, LCMV) virus; that is, antibodies form earlier
and reach higher titers in the infected mice than in their uninfected counterparts
(ToNIETTI et al. 1970; LAMPERT and OLDSTONE 1973). Further, NZW mice, which
normally do not develop these autoimmune responses, do so upon polyoma or
LCMV infections. Indeed, the responses in NZB, (NZB x W) F l' or NZW mice are
so marked that autoimmune diseases occur at a higher incidence with earlier time
of death (NZB, (NZB x W) Fll or appear de novo (NZW). These events were
subsequently repeated with a number of viruses, including retroviruses (reviewed
OLDSTONE 1972). Third, utilizing an investigative approach that focuses on one
potential mechanism where by microbes cause autoimmunity, molecular mimicry,
a number of etiologic agents have been defined as potential causes of autoimmune
disease (OLDSTONE 1987).
Microbial agents can induce autoimmune responses by a variety of unique mecha-
nisms, and several of these might occur during anyone infection. For example, certain
microbes have a mitogenic effect on unique lymphocyte subsets and hence can act as
polyclonal activators. Because agents like mycoplasma can activate lymphocytes,
and mycoplasma may contaminate bacterial and viral stocks, stringent evidence must
be presented that the activation is directly due to the bacteria or virus and not
mycoplasma contamination. Microbes can also direct the release of lymphokines and
monokines. These molecules are important modulators of immune responses by acting
as growth or differentiation factors or by regulating the expression of class I and
class II major histocompatibility molecules. Hence, an infectious agent could release
a lymphokine like interferon and induce the expression of class II molecules on cells
Department of Immunology, Scripps Clinic and Research Foundation, La Jolla, CA 92037, USA
Current Topics in Microbiology and Immunology, Vol. 145
© Springer-Verlag Berlin' Heidelberg 1989
2 M. B. A. Oldstone
like epithe10id cells in the thyroid or ~ cells in the islets of Langerhans of the pancreas.
Such cells, which usually express limited or negligible amounts of MHC class II
glycoproteins, may then present self-antigens (i.e., thyroglobulin, insulin receptor, etc.)
in the context of induced class II molecules. The end result is hypothesized to be
the priming of an immune response against self (BOTTAZZO et al. 1983). Additional
microbes, especially viruses, can infect and selectively replicate in unique lymphocyte
subsets (reviewed MCCHESNEY and OLDSTONE 1987). By their presence, activation,
or replication, the microbe can cause immunosuppression or immunoenhancement.
Finally, microbes can contain chemical structures that mimic normal host "self'
proteins, an event termed molecular mimicry. Thus, an effector immune response,
either B (humoral) or T (cytotoxic T cell), directed against the microbe might then
also cross-react with "self' protein and induce autoimmunity. Several of the ways
that infectious agents can trigger autoimmunity are:
• Polyclonal activator of B or T lymphocytes
• Enhanced expression of MHC class II molecules
• Enhanced expression of MHC class I molecules
• Bystander activation of immunocompetent cells through release of lymphokines
or monokines
• Alteration of lymphocyte/macrophage function
Tropism for and lysis of unique cell subset(s)
- Tropism for and alteration of differentiated function of unique cell subset(s)
(no lysis)
• Molecular mimicry
This volume focuses on the evidence for or against molecular mimicry as a cause of
autoimmunity. Major contributors in this area of research have provided chapters
analyzing the evidence available. The group of investigators at the Rockefeller
University have a long-term interest in the role of streptococcus in rheumatic heart
diease. John Zabriskie reviews the story for streptococcal M protein, its shared
homology and immunologic cross-reactivity primarily with myocardial tissue. The
second chapter by W. van Eden relates a recent study implicating myobacteria,
cartilage proteoglycans, and heat shock proteins with a cross-reactive T cell epitope
in causing arthritis. Peter Schwimmbeck's chapter reviews the evidence suggesting
that HLA B27 is an autoantigen that cross-reacts with Klebsiella pneumoniae and
other bacteria. He argues that this may be the etiology and pathogenic mechanism
for the nonrheumatoid arthritides, ankylosing spondylitis, and Reiter's syndrome.
K. Stefansson explores the role of cross-reactive bacterial and viral antigens with
the acetylcholine receptor as a possible cause of myasthenia gravis. Martin Kagnoff
details his observation of the sequence and immunologic cross-reactivity of alpha
gliadin and an adenovirus subtype as meaningful events in celiac disease. Trypanosoma
cruzi causes the American form of trypanosomiasis called Chagas' disease. Drs.
Hudson and Takle review the evidence supporting an autoimmune etiology for this
parasitic infection. The next two chapters provide data suggesting a link for
demyelinating disease and for diabetes with infectious agents and autoimmune
response. Robert Fujinami has been interested in developing experimental animal
models that help establish the principles of molecular mimicry (FUTINAMI and
OLDSTONE 1985). In his contribution, Dr. FUJINAMI explores experimental and clinical
findil)gs relating a role for molecular mimicry in demyelinating and central nervous
Overview: Infectious Agents as Etiologic Triggers of Autoimmune Disease 3
system disease. The chapter provided by Dr. DYRBERG is perhaps the most teasing.
He provides preliminary data of a cross-reactivity between the insulin receptor,
thyroid protein, and acetylcholine receptor with several infectious agents. His finding
of a clinical condition associated with antibodies to the insulin receptor and of
events in which a cross-reactivity between papillomavirus and the receptor occurred
is most interesting.
The chapter by Dr. DAMIAN provides a balance. Reviewing the evidence for
shared determinants between parasites and host cell antigens, Dr. DAMIAN argues for
molecular mimicry as a basis of avoidance of immunologic recognition and cross-
reactive immune response. Thus, in this view molecular mimicry may be beneficial
and serve as a line of host defense.
The final chapter is positioned to review the overall perspective of molecular
mimicry, how to use its principles in clinical investigation and list the conceptual
traits by which autoimmune disease can occur.
Acknowledgements: This is publication number 5624-IMM from the Department of
Immunology, Scripps Clinic and Research Foundation, La Jolla, CA 92037. This
work was supported in part by USPHS grants AI-07007. NS-12428 and AG 04342.
References
Bottazzo GF, Pijal-Borrell PR, Hanafusa T (1983) Hypothesis: role of aberrant HLA-DR expression
and antigen presentation in induction of endocrine autoimmunity. Lancet ii: 1115-1119
Fujinami, RS, and Oldstone, MBA (1985) Amino acid homology between the encephalitogenic site
of myelin basic protein and virus: Mechanism for autoimmunity
Lampert PW, Oldstone MBA (1973) Host IgG and C3 deposits in the choroid plexus during
spontaneous immune complex disease. Science 180: 408-410
McChesney MB, Oldstone MBA (1987) Viruses perturb lymphocyte functions: selected principles
characterizing virus-induced immunosuppression. Ann Rev Immunol 5: 279-304
Oldstone MBA (1972) Virus induced autoimmune disease: viruses in the production and prevention
of autoimmune disease. In: Membranes and viruses in immunopathology. Academic, New York,
pp 469-475
Oldstone MBA (1987) Molecular mimicry and autoimmune disease. Cell 50: 819-820
Tonietti G, Old stone MBA, Dixon FJ (1970) The effect of induced chronic viral infections on the
immunologic diseases of New Zealand mice. J Exp Med 132: 89-109
Cross-Reactivity Between Streptococcus and Human Tissue:
A Model of Molecular Mimicry and Autoimmunity
J. FROUDE1 , A. GIBOFSKy2, D. R. BUSKIRK1 , A. KHANNA1 , and J. B. ZABRISKIE1
Introduction 5
2 Hyaluronic Acid 7
2.1 Biochemical Homology 7
2.2 Serological Homology 7
2.3 Biological Homology 8
3 M Protein 8
3.1 Structural Homology 9
3.2 Serological Homology. 10
3.3 Biological Significance 11
4 Carbohydrate 12
4.1 Structural Homology 12
4.2 Serological Homology 12
4.3 Biological Homology 13
5 Membrane Antigens 13
5.1 Structural Homology 13
5.2 Serological Homology 14
5.2.1 Heart 14
5.2.2 Brain 14
5.2.3 Kidney 15
5.2.4 Skin 15
5.3 HistocompatihiIity Antigens 16
6 Disease ASSOCiations 17
6.1 Rheumatic Fever 17
6.2 Post-Streptococcal Glomerulonephritis 18
7 Conclusions 20
References 22
1 Introduction
Structural homology between mammalian tissues and microbes has been demonstrated
for over 50 years. Twenty years ago the term "molecular mimicry" was coined
to describe antigenic structures common to host and protozoal parasites (DAMIAN
1964). This term has since been expanded to include other microorganisms, and
1 Laboratory of Bacteriology and Immunology, Rockefeller University, New York, NY, USA
2 Multipurpose Arthritis Center, Hospital for Special Surgery, Cornell University Medical College,
NY, USA
Current Topics in Microbiology and Immunology, Vol. 145
© Springer-Verlag Berlin· Heidelberg 1989
6 J. Froude et al.
Table 1. A selection of cross-reactions between microbes and mammalian tissues
Organism Tissue Possible Ref.
Disease Association
Streptococcus pyogenes Heart, brain, Rheumatic fever ZABRISKIE 1985
kidney, etc.
Streptococcus mutans Heart ? VAN DE RUN et al. 1976
Klebsiella HLA-BW27 Ankylosing EBRINGER 1978; SEAGER et aJ.
lymphocytes spondylitis 1979; SCHWIMMBECK et al.
Reiter's syndrome 1987
Salmonella Mouse tissues Salmonella infection ROWLEY and JENKINS 1962
Pneumococci 50 % Blood group ? Susceptibility FINLAND and CURNEN 1940;
gram-negative bacteria substances to infection SPRINGER et al. 1961
Escherichia coli Colon tissue Ulcerative colitis PERLMAN et aJ. 1965
Tubercle bacillus Cartilage Rheumatoid arthritis VAN EDEN et al. 1985
proteoglycanase
Trypanosoma cruzi High density Chagas' disease PRIOLI et al. 1987
lipoprotein
Coxsackie B virus Cardiac myosin Cardiomyopathy ROSE et al. 1986
Cell wall
Protein (M, R,Tl
Group
• Valvular
Carbohydrate
tissue
Mucopeptide
Protoplast Membrane. Myocardial
sarcolemma
a Vascular Intima
.skin ____
• HLA antigens?
Fig. 1. Schematic representation of the various structures of the group A streptococcus. Note the
wide variety of cross-reactions between its antigens and mammalian tissues