1. Infection and Autoimmune Diseases
Eung Soo Hwang, M.D.,Ph.D.
Department of Microbiology and Immunology
Seoul National University College of Medicine 1

2. [Learning Objectives]
List autoimmune diseases caused by microbial agents
List microbial agents associated with autoimmune diseases
List mechanisms of autoimmunity caused by microbial agents

3. 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

4. (1) Molecular mimicry
Activation of autoreactive T cells by microbial peptides that have sufficient structural similarity to self-peptides 3

5. 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(각막염) (HSK):
T cell clones cross-react with a peptide from HSV-1 UL6
Chlamydia: myocarditis(심근염)
30 a.a. from cardiac myosin heavy chain 4

6. (Science 283:1335, 1999) 5

7. Control M7Ab M7Aa ChTR1 ChPN Expression Vector (ChT) Adoptive Transfer6
(Science 283:1335, 1999)

8. (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

9. (3) Enhanced processing and presentation of autoantigens
Enhanced presentation of autoantigens by antigen-presenting cells recruited to an inflammatory site, followed by priming of autoreactive lymphocytes
epitope spreading 9

10. 10

11. PLP: proteolipid protein
Figure 2 | Hierarchical pattern of intramolecular and intermolecular epitope spreading in PLP induced relapsing EAE and Theiler's virus-induced demyelinating disease (TMEV-IDD).
PLP: proteolipid protein 11

12. (4) Bystander activation
Expansion of previously activated T cells at an inflammatory site
limiting dilution methods : pathogen- specific T cell clone 12

13. 13

14. (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

15. Importance of genetic susceptibility
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

16. Human inflammatory diseases induced by defined infectious agents
Diseases Major target organs Pathogens MHC Associations
Postinfectious syndromes
Guillain-Barré Peripheral nerve Campylobacter jejuni
syndrome Epstein-Barr virus
Cytomegalovirus
Rheumatic fever Heart muscle & valves Group A streptococci
Kidney, CNS
Acute and chronic inflammatory diseases
Lyme arthritis Large joints Borrelia burgdorferi HLA-DR4, HLA-DR1
Reactive arthritis Axial skeleton Yersinia HLA-B27
Shigella
Salmonella
Chlamydia trachomatis
Immune complex–mediated disease
Mixed cryoglobulinemia Blood vessels Hepatitis C virus
Kidney, lung 16

17. 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

18. 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

19. 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

20. 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

21. Fig. 1. Initiation of diabetogenesis
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 up-regulation of Class I and Class II MHC molecules. 21

22. Fig. 2. Damage to islet β cells by primed T-cells
Fig. 2. Damage to islet β 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 Vβ7/Vβ13 Th1 cells by cross-linkage of TCR and HLA-DQ by ERV superantigen. 22

23. (Nature Review Immunology 2:85, 2002)23
(Nature Review Immunology 2:85, 2002)