Introduction
 Autoimmunity occurs

when the immune system
recognizes and attacks its
own host tissue.
 Many factors are ...
Role of infections in autoimmune
disease
 In which ways does an infectious agent initiate or

exacerbate autoimmunity?
 ...
In which ways does an infectious agent
initiate or exacerbate autoimmunity?
 Links between infection and autoimmunity are...
Molecular mimicry
 Pathogen carries elements similar in sequence or

structure to a self-antigen. The pathogen acts as a ...
Epitope spreading
 The immune response to a persisting pathogen or lysis

to self-tissue caused by pathogen results in co...
Bystander activation
 Indirect or nonspecific activation of autoimmunity

caused by the inflammatory environment.
 Domin...
Cryptic antigens
 Subdominant cryptic antigens are normally invisible to

the immune system, unlike dominant antigenic
de...
What evidence links the infectious agents to
autoimmune disease in humans?
 Coxsackievirus B
 Streptococcus pyogenes: gr...
Coxsackievirus B (CVB) & infectious
myocarditis
 Infectious virus and viral RNA can be

isolated from patients hearts.
 ...
Coxsackievirus B (CVB) & infectious
myocarditis
 Evidence for epitope spreading
 CVB causes myocarditis in most mice str...
Streptococcus pyogenes: group A
streptococcus & cardiac pathology
 Evidence for bystander effect
 Bacterial material and...
Streptococcus pyogenes: group A
streptococcus & cardiac pathology
 Infection by S. pyogenes has been associated with

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

2 clinical phases- acute ...
Trypanosoma cruzi & Chagas disease
 T. cruzi antigens and DNA can be detected in

asymptomatic infected individuals
 Tis...
Trypanosoma cruzi & Chagas disease
 Evidence for bystander effect
 Chagas disease cardiomyopathy is characterized by
CD8...
Trypanosoma cruzi & Chagas disease
 Animal models
 Various mice strains (C3H/Hej, BALB/c, CBA)
 Somewhat mirror histopa...
Borrelia burgdorfeii, Lyme disease &
arthritis
 Lyme disease is caused by tick-borne spirochete B.

burgdorfeii.
 60% of...
Borrelia burgdorfeii, Lyme disease &
arthritis
 Rodent models
 Arthritis has been induced upon
infection with Bb, in var...
Herpes simplex virus & herpetic stromal
keratitis (HSK)
 HSK is caused by corneal infection by HSV, may lead

to blindnes...
Herpes simplex virus & herpetic stromal
keratitis (HSK)
 Studied in mice infected with HSV-1.
 Inflammatory cytokines IL...
Uveitis
 Group of intra-ocular inflammatory diseases that may

cause blindness.
 Subgroups of disease may be autoimmune-...
Type I diabetes
 Autoimmune destruction of pancreatic cells by

autoreactive T cells and/or inflammatory cytokines.
 Def...
Type I diabetes
 NOD (non-obese diabetic) mice models used to study

T1D.
 Some studies support mimicry hypothesis (cros...
Guillain-Barre syndrome
 Paralytic illness affecting myelin and axons of

peripheral nervous system, has different clinic...
Guillain-Barre syndrome
 Various pathogens associated with syndrome, mainly

Campylobacter jejuni.
 LPS may mimic host g...
Multiple sclerosis (MS)
 Loss of myelin sheath surround axons in central nervous system.
 Demyelination is associated wi...
Multiple sclerosis (MS)
 Rodent models of demyelination are

not identical to the human disease.
 Use Theiler’s murine
e...
Multiple sclerosis (MS)
 Demyelination may have different causes.
 Evidence for epitope spreading from viral determinant...
Animal models
 Direct evidence for roles of particular pathogens in

autoimmune disease is weak – we need to have animal
...
The other side of the coin
Conclusion
 A strong immune response to a pathogen disrupts immune

system regulation and can lead to autoimmunity.
 The...
References
 Ercolini AM, Miller SD.(2009) The role of infections in autoimmune

disease.Clin Exp Immunol. 155(1):1-15.
 ...
Questions?
The role of infections in autoimmune disease
The role of infections in autoimmune disease
The role of infections in autoimmune disease
The role of infections in autoimmune disease
The role of infections in autoimmune disease
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The role of infections in autoimmune disease

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The role of infections in autoimmune disease

  1. 1. 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.
  2. 2. 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?
  3. 3. 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
  4. 4. 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.
  5. 5. 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.
  6. 6. 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 nonspecific activation of immune cells.
  7. 7. 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.
  8. 8. 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
  9. 9. 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
  10. 10. 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
  11. 11. 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.
  12. 12. 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
  13. 13. 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
  14. 14. 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
  15. 15. 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.
  16. 16. 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
  17. 17. 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.
  18. 18. 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
  19. 19. 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)
  20. 20. 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.
  21. 21. 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. coliderived peptides – and cross-reactive responses.  No pathogen officially associated with uveitis.
  22. 22. 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.
  23. 23. 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.
  24. 24. 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
  25. 25. 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 crossreactive with ganglioside
  26. 26. 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.
  27. 27. 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
  28. 28. 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.
  29. 29. 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
  30. 30. The other side of the coin
  31. 31. 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.
  32. 32. 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.
  33. 33. Questions?

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