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] List autoimmune diseases caused by microbial agents List microbial agents associated with autoimmune diseases 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(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

(Science 283:1335, 1999) 5

Control M7Ab M7Aa ChTR1 ChPN Expression Vector (ChT) Adoptive Transfer 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 (I2) 8

(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

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PLP: proteolipid protein 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

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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

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

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

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 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

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

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