Introduction Autoimmunity occurs

when the immune system recognizes and attacks its own host tissue.

Many factors are thought to contribute: Genetics Age Environment

Viruses, bacteria and parasites are the major environmental triggers of autoimmunity

The immune system has many checks and balances to prevent the destruction of host tissue.

A strong immune response to an invading pathogen could disrupt this regulation and lead to autoimmunity.

Role of infections in autoimmune disease In which ways does an infectious agent initiate or

exacerbate autoimmunity?

What evidence links the infectious agents to autoimmune disease in humans? How are they being studied?

In which ways does an infectious agent initiate or exacerbate autoimmunity? Links between infection and autoimmunity are

stronger for certain diseased than for others.

Main mechanisms:

Molecular mimicry

Epitope spreading

Bystander activation

Cryptic antigens

Molecular mimicry Pathogen carries elements similar in sequence or

structure to a self-antigen. The pathogen acts as a “self mimic”.

T cells or B cells are activated in response to pathogen, but are also cross-reactive to self, leading to direct damage and further activation of immune system.

Epitope spreading The immune response to a persisting pathogen or lysis

to self-tissue caused by pathogen results in continuous damage to self.

Antigens released from damaged tissue are taken up by APCs, initiating a self-specific immune response.

Bystander activation Indirect or nonspecific activation of autoimmunity

caused by the inflammatory environment.

Domino effect where various parts of immune system respond to the invading pathogen.

Damages self-tissue non-specifically, triggers non-specific activation of immune cells.

Cryptic antigens Subdominant cryptic antigens are normally invisible to

the immune system, unlike dominant antigenic determinants.

Inflammatory environment during infection can induce increased protease production and processing of released self-epitopes by APCs.

What evidence links the infectious agents to autoimmune disease in humans? Coxsackievirus B

Streptococcus pyogenes: group A streptococcus

Trypanosoma cruzi

Borrelia burgdorfeii

Herpes simplex virus

Uveitis

Diabetes

Guillain-Barre syndrome

Multiple sclerosis

Coxsackievirus B (CVB) & infectious myocarditis Infectious virus and viral RNA can be

isolated from patients hearts. Chronic stage of the disease is

characterized by mononuclear cell infiltration into myocardium, and production of antibodies to cardiac myosin (virus is undetectable by then).

Virus specific antibodies arise after infection, followed by antibodies to myosin, tropomyosin and actin.

Evidence of T cell role T-cells can transfer disease to naïve

recipients Athymic mice exhibit reduced disease

after infection Depletion of CD8+ T cells increases

myocarditis

Coxsackievirus B (CVB) & infectious myocarditis Evidence for epitope spreading

CVB causes myocarditis in most mice strains Including SCID mice (no B cells, no T cells), showing that virus can

directly infect and lyse cells , the damage may lead to epitope spread

Evidence for bystander activation TNF-a or IL-1 treatment of genetically resistant mice renders

them susceptible to cardiac disease

Evidence for molecular mimicry Neutralizing anti-mCVB3 mAbs are cross-reactive to myosin

and surface epitopes on cardiac fibroblasts.

Evidence for cryptic epitopes CVB3 infection increases ubiquitination of cellular proteins

leading to release of cryptic epitopes

Streptococcus pyogenes: group A streptococcus & cardiac pathology Evidence for bystander effect

Bacterial material and DNA persists in host tissue for years after infection – ongoing immunity may lead to bystander effect

Evidence for molecular mimicry (major mechanism) Myosin reactive mAbs derived from patients with acute

rheumatic fever are cross-reactive to M-protein & NAG

T cell clones from heart lesions of rheumatic heart disease patients can recognize both M protein and heart proteins

BALB/c mice immunized with human myosin developed T cells cross-reactive with M protein

T cell lines from rats immunized with M protein were cross reactive with myosin.

Streptococcus pyogenes: group A streptococcus & cardiac pathology Infection by S. pyogenes has been associated with

movement/behavioral disorders: Sydenham chorea, Tourette’s, OCD.

Molecular mimicry between basal ganglia and S. pyogenes proteins

Trypanosoma cruzi & Chagas disease 10-30% infected individuals develop the disease, which has

2 clinical phases- acute and chronic

Acute – parasitaemia in heart muscle cells, inflammation

Asymptomatic phase (up to 30 years)

Chronic – irreversible cardiomyopathy – some GI dysfunction

Trypanosoma cruzi & Chagas disease T. cruzi antigens and DNA can be detected in

asymptomatic infected individuals

Tissue destruction in this phase may be due to autoimmunity

Trypanosoma cruzi & Chagas disease Evidence for bystander effect

Chagas disease cardiomyopathy is characterized by CD8+ and CD4+ cell infiltrates, with upregulation of IFN-g inducible chemokines and their receptors in heart tissue.

Evidence for molecular mimicry

T. cruzi protein B13 elicits cross-reactive responses to cardian myosin. Cross-reactivity found in all Chagas disease cardiomyopathy patients.

Trypanosoma cruzi & Chagas disease Animal models

Various mice strains (C3H/Hej, BALB/c, CBA)

Somewhat mirror histopathology in humans

T cell and B cell mimicry between murine and T. cruzi proteins

Borrelia burgdorfeii, Lyme disease & arthritis Lyme disease is caused by tick-borne spirochete B.

burgdorfeii. 60% of untreated patients develop arthritis in large joints &

knee. These patients have Bb specific antibodies and Bb DNA in joint fluid.

Evidence for bystander effect Treatment with antibiotics ameliorates arthritis

But a subset of patients will progress from acute to chronic arthritis despite antibiotics - an antibiotic resistant Lyme arthritis that is associated with certain HLA alleles. There might be mimicry between an HLA adhesion molecule

homologous to the Bb outer surface protein OspA. Other peptides may be more important though.

Borrelia burgdorfeii, Lyme disease & arthritis Rodent models

Arthritis has been induced upon infection with Bb, in various mice strains

Transferring Bb-specific T cells in the absence of B cells will accelerate onset of arthritis in some strains.

Macrophage derived anti-inflammatory cytokines might protect mice from severe joint inflammation

Herpes simplex virus & herpetic stromal keratitis (HSK) HSK is caused by corneal infection by HSV, may lead

to blindness

Cannot be stopped by antiviral drugs, but can be alleviated with immunosuppresive drugs (i.e. corticosteroids)

Herpes simplex virus & herpetic stromal keratitis (HSK) Studied in mice infected with HSV-1. Inflammatory cytokines IL-1 and IL-6 are produced,

neutrophils flow into corneal stroma, as well as macrophages and NK cells, contributing to disease pathology.

10 days after infection a second wave or neutrophils and CD4+ cells flow in- these CD4+ cells are necessary for development of HSK.

Possible molecular mimicry of cornea-specific T-cell clones cross reacting with epitope in immunoglobulin locus.

In humans, disease may be mostly due to bystander destriction since T cell lines isolated from cornea of patients do not show reactivity to corneal antigens.

Uveitis Group of intra-ocular inflammatory diseases that may

cause blindness.

Subgroups of disease may be autoimmune-mediated, due to humoral and cellular responses to retinal antigens interphotoreceptor retinoid binding protein and S- antigen

CD4+ T cell epitope in human S-antigen identified, has similarities to viruses (i.e. rotavirus) and E. coli-derived peptides – and cross-reactive responses.

No pathogen officially associated with uveitis.

Type I diabetes Autoimmune destruction of pancreatic cells by

autoreactive T cells and/or inflammatory cytokines.

Definite genetic component, but pathogens may play a role in development.

Presence of rubella virus, mumps virus, cytomegalovirus and antibodies to pancreatic islet cells.

May be due to molecular mimicry; T-cells isolated isolated from patients are cross-reactive.

Type I diabetes NOD (non-obese diabetic) mice models used to study

T1D.

Some studies support mimicry hypothesis (cross-reactions), others don’t induce cross-reactivity.

Bystander activation is more likely in the NOD model.

In BDC2-5 mice, the release of cryptic antigens following viral infection might be the mechanism of diabetes induction.

Guillain-Barre syndrome Paralytic illness affecting myelin and axons of

peripheral nervous system, has different clinical variants

Anti-glycolipid (gangliosides, cerebrosides) antibodies present in serum of some patients.

Clinical variants correlate with specific type of glycolipid targeted by antibodies

Guillain-Barre syndrome Various pathogens associated with syndrome, mainly

Campylobacter jejuni.

LPS may mimic host gangliosides – similar structurally. Shown in rabbits and mice.

Other pathogens:

Patients infected with Mycoplasma pneumoniae often have antibodies to galactocerebroside

Patients infected with Haemophilus influenzae can develop antibodies to bacterial LPS that are cross-reactive with ganglioside

Multiple sclerosis (MS) Loss of myelin sheath surround axons in central nervous system.

Demyelination is associated with high levels of CD4+ T cells specific for major myelin proteins.

Trigger is unknown, but relapses or flares are associated with upper respiratory infections- more than 24 viral agents have been linked to MS Herpes virus 6

Herpes simplex virus 1

Chlamydia pneumoniae

Adenovirus

Human papillomavirus

A cumulative exposure to certain microorganisms may influence disease development.

Multiple sclerosis (MS) Rodent models of demyelination are

not identical to the human disease.

Use Theiler’s murine encephalomyelitis virus, murine hepatitis virus and Semiliki Forest virus to show potential ways pathogens may induce MS.

Initial acute gray matter disease followed by chronic demyelination in white matter of spinal cord, or single major episodes

Multiple sclerosis (MS) Demyelination may have different causes. Evidence for epitope spreading from viral determinants to

self-myelin determinants. Immune response is initiated by persistent viral antigens, but reactivity to myelin appears after the onset of clinical symptoms.

There may also be bystander myelin destruction by the immune response initially recruited to the CNS

Macrophages recruited by T cells may be responsible primarily for myelin destruction in MHV model.

Demyelination due to cytolytic damage of virus-infected oligodendrocytes.

Molecular mimicry: antibodies cross-reactive to myelin oligodendrocyte protein and SFV surface protein.

Animal models Direct evidence for roles of particular pathogens in

autoimmune disease is weak – we need to have animal models where infectious agent causes similar disease in humans and animals Heart disease in mice infected with T. cruzi and

Coxsackievirus B

Arthritis in mice infected with Bb

In other models, disease can be shown by priming with a pathogen-derived antigen Heart disease in rats primed with Streptococcal M

protein

The other side of the coin

Conclusion A strong immune response to a pathogen disrupts immune

system regulation and can lead to autoimmunity. There is significant evidence that pathogens trigger or

propagate self-reactive immune responses. Evidence linking infection and autoimmunity is still

questionable- possibly because of the heterogeneity of human population.

There are 4 main models for how this occurs: molecular mimicry, epitope spreading, bystander effect, and cryptic antigens.

Defining the genetic markers that predispose individuals to autoimmune disease with a suspected infectious trigger would help define the disease pathogenesis.

References Ercolini AM, Miller SD.(2009) The role of infections in autoimmune

disease.Clin Exp Immunol. 155(1):1-15.

Samarkos M, Vaiopoulos G. (2005) The role of infections in the pathogenesis of autoimmune diseases. Curr Drug Targets Inflamm Allergy. 4(1):99-103.

Robert Fujinami, Matthias von Herrath, Urs Christen, and J Lindsay Watson (2006) Molecular Mimicry, Bystander Activation, or Viral Persistence: Infections and Autoimmune Disease, Clinical Microbiology Reviews 19: 80-94.

Questions?