2. 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.

3. 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?

4. 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

5. 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.

7. 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.

9. 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.

11. 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.

13. 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

14. 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

15. 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

16. 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.

17. 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

18. 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

19. 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

20. 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.

21. 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

22. 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.

23. 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

24. 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)

25. 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.

26. 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.

27. 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.

28. 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.

29. 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

30. 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

31. 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.

32. 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

33. 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.

34. 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

35. The other side of the coin

36. 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.

37. 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.

38. Questions?