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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