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Transcript
Infection and Autoimmune Diseases
Eung Soo Hwang, M.D.,Ph.D.
Department of Microbiology and Immunology
Seoul National University College of Medicine
1
[Learning Objectives]
1.List autoimmune diseases caused by
microbial agents
2.List microbial agents associated with
autoimmune diseases
3.List mechanisms of autoimmunity caused
by microbial agents
I. Mechanisms for activation of autoreactive
T and B cells by infectious agents
(1) Molecular mimicry
(2) Viral and bacterial superantigens
(3) Enhanced processing and presentation of
autoantigens
(4) Bystander activation
(5) Activation of lymphocytes by lymphotropic
viruses
2
(1) Molecular mimicry
Activation of
autoreactive T cells
by microbial peptides
that have sufficient
structural similarity to
self-peptides
3
Expansion of Autoreactive T cells:
TCR activation by MHC-bound peptide
or CD1-bound lipid/glycosides
• HBV polymerase peptide:
six aa (Tyr-Gly-Ser-Leu-Pro-Gln ) identical to
encephalitogenic myelin basic protein (MBP)
-> experimental autoimmune encephalomyelitis (EAE)
• herpes simplex keratitis (HSK):
T cell clones cross-react with a peptide from HSV-1 UL6
• Chlamydia: myocarditis
30 a.a. from cardiac myosin heavy chain
4
(Science 283:1335, 1999)
5
6
(Science 283:1335, 1999)
7
(2) Viral and bacterial superantigens
Activation of autoreactive T cells that express particular Vβ segments
• induces relapses and exacerbations of T cell-mediated
autoimmune process
(SEB (staphylococcal enterotoxin B) -> cannot induce EAE, but
relapse and exacerbate EAE)
• reactivation of bacterial cell wall or collagen-induced arthritis
(Mycoplasma arthritidis superantigen (MAM))
• Crohn disease: bacterial transcription factor (I2)
8
(3) Enhanced processing and presentation of
autoantigens
Enhanced presentation of autoantigens by antigenpresenting cells recruited to an inflammatory site, followed
by priming of autoreactive lymphocytes
• epitope spreading
9
10
Figure 2 | Hierarchical pattern of intramolecular and intermolecular epitope
spreading in PLP139-151-induced relapsing EAE and Theiler's virus-induced
demyelinating disease (TMEV-IDD).
PLP: proteolipid protein
11
(4) Bystander activation
Expansion of previously activated T cells at an inflammatory site
• limiting dilution methods : pathogen- specific T cell clone
12
13
(5) Activation of lymphocytes by lymphotropic
viruses
Viral infection of lymphocytes, such as infection of B cells
with hepatitis C virus, resulting in enhanced antibody
production and formation of circulating immune complexes
14
II. Role of infectious agents in human inflammatory diseases
• Importance of genetic susceptibility
• Criteria for establishing a role of infectious agents
• Autoimmune diseases triggered by acute infections
• Triggering of rheumatic fever by group A streptococci
• CD4+ T cells in Lyme arthritis
• CD8+ T cells in reactive arthritis
• HCV and mixed cryoglobulinemia
15
Human inflammatory diseases induced by defined infectious agents
Diseases
Major target organs
Pathogens
MHC Associations
Postinfectious syndromes
Guillain-Barré
syndrome
Rheumatic fever
Peripheral nerve
Heart muscle & valves
Kidney, CNS
Campylobacter jejuni
Epstein-Barr virus
Cytomegalovirus
Group A streptococci
Acute and chronic inflammatory diseases
Lyme arthritis
Reactive arthritis
Large joints
Axial skeleton
Borrelia burgdorferi HLA-DR4, HLA-DR1
Yersinia
HLA-B27
Shigella
Salmonella
Chlamydia trachomatis
Immune complex–mediated disease
Mixed cryoglobulinemia
Blood vessels
Kidney, lung
Hepatitis C virus
16
Importance of Genetic Susceptibility
• alleles of MHC class II gene :
strong association in majority of autoimmune diseases
• MHC class I (HLA-B27):
ankylosing spodylitis, reactive arthritis
17
Criteria for establishing the role of infectious agents in
autoimmune diseases
Identification of pathogen(s) in patients with autoimmune disease
• Isolation of pathogen, which requires diagnosis of autoimmune process
at the time of infection
• Analysis of appropriate control groups
(household and community controls)
• Analysis of IgM antibodies specific for pathogen
Determination of the autoimmunity mechanisms by pathogens
• Analysis of T cell– and B cell–mediated immune responses
to pathogen and potential self-antigens
• Development of an animal model that recapitulates essential features
of the disease process
18
Autoimmune diseases triggered by acute infections
• Guillain-Barre syndrome :
Campylobacter jejuni, Epstein-Barr virus
cytomegalovirus, Mycoplasma pneumoniae
Campylobacter jejuni
induce Ab reactive with peripheral nerve Ag.
crossreact with gangliosides from peripheral nerve
prominent motor symptom (GM1 ganglioside)
Cytomegalovirus
pronounced sensory involvement (GM2 ganglioside)
19
• Triggering of rheumatic fever by group A streptococci
streptococcal M proteins
• CD4+ T cells in Lyme arthritis
Borrelia burgdorferi, HLA-DR4 HLA-DR1
• CD8+ T cells in reactive arthritis
HLA-B27
Chlamydia, Salmonella, Shigella, Yersinia
• HCV and mixed cryoglobulinemia
HCV-hepatocyte, B cells (E2 : CD81)
immune complex - vascular deposit
20
Fig. 1. Initiation of diabetogenesis. Enteroviral infection of pancreatic cell
results in production of Type 1 IFN, which simultaneously arms dendritic cells
(DC) and, in adjacent cells, activates quiescent Virus X or endogenous
retrovirus (ERV). DC, responding to `danger' signals through Toll like receptors
(TLR), migrate to draining lymph nodes (LN). Inflammatory process leads to upregulation of Class I and Class II MHC molecules.
21
Fig. 2. Damage to islet  cells by primed T-cells. Th1 helper T-cells recognize viral
peptides presented by up-regulated MHC Class II molecules and produce many different
cytokines, some of which may have antiviral effects on target cells and others, which
affect adjacent lymphocyte activity. Alternatively, CD4 T-cells may require presentation of
viral antigens via Class II MHC molecules on tissue resident antigen presenting cells.
Killer T-cells, dependent upon IL-2 from helper T-cells, recognize processed peptides from
Virus X presented by MHC Class I molecules via specific TCRs. Cell death could result
from a number of pathways including apoptosis. Note activation of V7/V13 Th1 cells by
22
cross-linkage of TCR and HLA-DQ by ERV superantigen.
23
(Nature Review Immunology 2:85, 2002)