infections and autoimmunity
TRANSCRIPT
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INFECTIONS AND AUTOIMMUNITYThe diverse interactions between
infections and autoimmunity revealthe posibility of a protective or
pathogenic relationship.
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AUTOIMMUNITY
Breakdown of self-tolerance -> the organism does not
recognize its own components as self => IR against it own
cells on various organs and tissues =Autoimmune Disease
(AD).
Factors:
-genetic
-inmmunologic-hormonal the mosaic of autoimmunity
-envioronmental
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INFECTIONS
Important role in the mosaic of autoimmunity.
Infectious agents involved in ADs:
-Viruses
-Bacteria
-Parasites
-Fungi
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THEINTERPLAY BETWEEN
AUTOIMMUNITYANDINFECTIONS
A. I nfectious agents can induce autoimmunity:
- Almost every AD investigated is linked to one or more specific
infectious agents
- Anti-phospholipid syndrome (APS) -> 2 glicoprotena 1 (GPI)
epitopes and Haemophilus influenzae, Neisseria
gonorrhoeae, tetanus toxoid and CMV.
Rheumatic fever (RF)
with Streptococcus
pyogenes.
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B. Infectious agents can determinate disease-specific auto-
antibodies and their clinical manifestations:
- Neuropsychiatric lupus -> Rubella (Ig M) = psychosis ordepression
-> Epstein-Barr virus (Acs) = skin and joint manifestations of
lupus.
C. Infections can trigger an underlying immune dysregulation
to express an overtAD:
- Rotavirus -> insulitis + exacerbate diabetes in NOD mice.
D. The bidirectional paradigm of autoimmunity and
infections:
- EBV-> is associated with many ADs:SLE => susceptibility to EBV
infection owing to their inabiliy to control latent infection.
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DIFFERENT PATHOGENSAGENTSCAN
INDUCEAUTOIMMUNITY
Viruses:
HCV-> cryoglobulonemia / also different ADs -> autoimmunethyroiditis, Crohns disease, Pemphigus vulgaris (PV), APS and
vasculitides.
EBV -> SLE, RA, Pemphigus vulgaris (PV) , giant cell arthritis, MS,
Sjgrens syndrome and polymyositis. Bacteria:
Helicobacter pylori-> autoimmune gastritis / atherosclerosis /
other ADs:Henoch-Schonlein purpura, Sjgrens syndrome,
autoimmune thyroiditis andR
aynauds syndrome.
An infectious agent can trigger diverse ADs/ several
agents can cause a single AD.
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Parasites:
They are host immune system manipulators.
Fungi:
Aspergillus fumigatus -> Allergic bronchopulmonary aspergillosis
in patiens with chronic lung diseases.
Trypanosoma cruzi-> ChagasChagas diseasedisease (CHD):(CHD):
-30% severe autoimmune cardiomyopathy -> sudden death
-Pathegenesi :
Parasite -> mecanic lessionHost nflammatory response (TNF-)
Autoimmunity -> molecular mimicry of antigens (B13, cruzipain
and Cha).
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MECHANISMS BYWHICHINFECTIOUS
AGENTS PRODUCEAUTOIMMUNITY
1. Molecular mimicry:
- The most likely mechanism.
- Crossreactivity between epitopes shared by the pathogen and
the host.
- Criteria:
The pathogen must be associated with the oneset of the AD
The pathogen must produce an IR that crossreacts with host
antigens
The shared epitope (auto-antigen) can induce the disease in an
animal model (active immunization).
Autoreactive cells or autoantibodies can induce the disease in
animals models (passive immunization).
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Example -> RF:
The streptococcalepitope M-protein mimics cardiac myosin in
the valve.Crossreactive peptides -> myocarditis in mice.Passive transfer of purified antibodies from rats immunizated
with cardiac myosin -> IgG deposition and apoptosis =
cardiomyopathy.
2. Epitope spreading:
- Variety of epitope specifity from a dominant epitope to a
subdominant (cryptic) epitope -> molecular mimicry to the
dominant epitope + protein processing and antigen
presentation = autoimmune response directed at a neo-epitope.
- Role in viral-induced ADs:TMEV-> life-long infection ofAPCs in
the CNS => chronic T-cell-mediated demyelinating disease in
mice.
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3. Bystander activation:
- Virallyinduced tissue damage causes the release of
sequestered antigen-> activates autoreactive lympocytes- Also virally infected APCs activate macrophages and specific T-
cell -> inflammatory microenvironment => bystander killing of
closed cells and bystander activation of an autoimmune
response.
- Diabetes and experimental autoimmune encephalomyelitis.
4.Persistent infection and polyclonal activation:
- Prolonged infectivity with viruses, viral proteins or viral genome
-> constant activation ofIR => monospecific proliferation +
circulating immune complexes and damage to self-tissues.
Example:Mixed Cryoglobulinemia + HCV
- IR -> monoclonal + polyclonal autoantibodies = AD.
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THE BURDENOFINFECTIONSFROM
CHILDHOODTOAUTOIMMUNITY
Pathogen count can begin early and manifest asautoimmunity years later-> infections during the first year of
life are associates with RA (sero-negative and juvenile) / a big
study correlated the presence ofantiocardiolipin antibodies
with diarrhoeal diseases during the first year of life.
Autoimmunity can be developed by a cumulative process due
to the burden of infections during life.
Repeted infections from childhood canreach a breakthrough point of immune
system -> Atherosclerosis:Chlamydia
pneumoniae, H.pylori and CMV.
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THE PROTECTIVEDIALOGUE BETWEEN
INFECTIONSANDAUTOIMMUNITY
Infections can protect individuals from autoimmune and
allergic diseases -> Hygiene Hypothesis (Strachan, 1989):
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Most Ads, all over T1D, MS and IBD.
The problem: the protective pathogen is usually unidentified,healthy individuals are not routinely evaluated and the same
infectious agent can induceinduce one AD andprotectprotect from another
AD -> HBVinduces APS and protects from SLE.
The evidence is based on retrospective epidemiologic andexperimental studies:African people have a low prevalence of
SLE correlated with the presence ofPlasmodium berghei.
The protective role of infections focus is centrated on early
childhood infections.
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THEGENETICS-AUTOIMMUNITY-
INFECTIONSTRIAD
Genetics: susceptibility to undergo autoimmunity andinfluence the response of an individual to infections -> this isevidenced in clustering in families and twin studies: they havea high concordance rate respect to ADs.
Coxsackievirus -> autoimmune myocarditis in mice.
The MHC and non-MHC genes are associated with AD:
- HLA-DRB1*07 is linked to post-Streptococcus RF / HLA-DR7seems to protect HCV-infected patiens from MC.
- The non-MHC autoimmune susceptible alleles are difficult toidentify: immune regulatory genes CTLA4 y PTPN22 are linkedto T1D, autoimmune thyroid disease, SLE and RA / tissuespecific genes-> ADAM33 is closed to asthma and NOD2, toCrohns disease.
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CONCLUSIONS
Pathogen agents can triggerautoimmunity
and also they canprotectfrom specific ADs
through differents mechanisms. Discovering the actually interactions between
infections and autoimmunity and their genetic
codes might lead to reduce the burden ofinfections and ofADs.
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THANK YOUfor your attention!
Magdalena Gmez-Mateos Prez