Infection and Autoimmune Diseases Eung Soo Hwang M

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 CD 1 -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 UL 6 • Chlamydia: myocarditis(심근염) 30 a. a. from cardiac myosin heavy chain 4

(Science 283: 1335, 1999) 5

M 7 Aa Control M 7 Ab Ch. TR 1 Ch. PN Adoptive Transfer (Ch. TR 1) Expression Vector (Ch. T) 6 (Science 283: 1335, 1999)

(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 (I 2) 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

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Figure 2 | Hierarchical pattern of intramolecular and intermolecular epitope spreading in PLP 139 -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

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(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 • CD 4+ T cells in Lyme arthritis • CD 8+ 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-DR 4, HLA-DR 1 Yersinia HLA-B 27 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-B 27): 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 Ig. M 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 (GM 1 ganglioside) Cytomegalovirus pronounced sensory involvement (GM 2 ganglioside) 19

• Triggering of rheumatic fever by group A streptococci streptococcal M proteins • CD 4+ T cells in Lyme arthritis Borrelia burgdorferi, HLA-DR 4 HLA-DR 1 • CD 8+ T cells in reactive arthritis HLA-B 27 Chlamydia, Salmonella, Shigella, Yersinia • HCV and mixed cryoglobulinemia HCV-hepatocyte, B cells (E 2 : CD 81) 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 β cells by primed T-cells. Th 1 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, CD 4 T-cells may require presentation of viral antigens via Class II MHC molecules on tissue resident antigen presenting cells. Killer Tcells, 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 Vβ 7/Vβ 13 Th 1 cells by cross 22 linkage of TCR and HLA-DQ by ERV superantigen.

23 (Nature Review Immunology 2: 85, 2002)