20. autoimunitate (2015) v2

Autoimunitate si Boli autoimune

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Reactii autoimune (RAI)

• Incidenta↑: • Caracteristici:

Autoimunitate

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Caracteristici:

Boli AutoimuneIncidenta

model →BAI organ specifica mediata T celular

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Observatii• Incidenta BAI • Mecanism autoimun in patologie • RAI= N (nivel ↓) :

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Modele Experimentale Animale categorii:

1. BAI cu debut sponatan :ex: Lupus Sistemic la soarecele Noua Zeelanda ([NZBxNZW]F1)

2. BAI induse prin interventii exogene: (immunizari):ex. experimental allergic encephalomyelitis – EAE

3. BAI induse prin manipulari genetice: animale knockout (IL-2, Fas)/ transgenic (Bcl-2, HLA-B27) (SLE, RA, SA))

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Modele Experimentale MurineBAI Umana Model MurinAR (PR) Collagen Induced Arthritis

(CIA)SM Experimental Autoimmune

Encephalitis (EAE)Colita Ulcerativa (UC) Dextran Sodium Sulfate

induced Colitis (DSS)Diabet Non Obese Diabetic (NOD)

Lupus MRLlpr (Lpr = lupus prone)

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Bolile Autoimune: Definitie

Definitia “Imunologica ”

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Organe/tesuturi afectate

Tiroidita Hashimoto (Ac a-Tiroglobulina)

Scleroza Multipla (Ac a-P. Mielinice)

Sd Sjogren’s (ANA)

RAA (Ac a mn card)

Hepatita Autoimuna (ANA)

Boala Crohn?

Sd Goodpasture (AMBG-col.IV))

Diabet (Ac a-glutamat decarboxilaza)

Uveita Autoimuna (βB1-cristalin)

Anemia Hemolitica Autoimuna

Boala Addison ( Ac a- P citopl. cel adrenale corticale

Artrita Reumatoida (IgG,FR)

Endometrioza (IgG anti-P.endometriale)

Sclerodermia Sistemica (ACA, ANA, Scl70) LES (ANA, a DNAds)

Ciroza Biliara Primitiva (ANA)

B Basedow-Graves (Ac a-TSH. R)

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Clasificarea BAIClinica: dupa localizare

organ-specifice sau sistemice

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Example de BAI Organ Specifice

Plamanii unui bolnav cu Sd Goodpasture

VitiligoTiroidita autoimuna (Hashimoto)

Exemple de BAI Sistemice

Sclerodermia Sistemica

Afectare renala

Fibroza pulmonara

Afectare cardiaca

Afectare articulara

Fenomen Raynaud

Example de BAI SistemiceSd Sjogren

Cauzele Autoimunitatii

I. Genetica BAI• Identificarea genelor:• Mutatiile punctiforme (SNP) → • BAI = boli complexe (genetic)

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1. Asocieri ale HLA cu BAI

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1. Asocieri ale HLA cu BAI

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Genes Disease association mechanism

Complement proteins (C2, C4)

Lupus –like disease Defective clearence of IC ?Defects in B Ly tolerance (?)

Fas/FasL Autoimmune lymphoproliferative Sy

Defective elimination of self reactive T &B Ly by AICD

PTPN22 (Protein Tyr phosphatase, non-receptor type 22 )

RA, SLE, others Defective phosphatase signalization pathway

NOD2 (Nucleotide-binding oligomerization domain-containing protein)

Crohn’s disease (25%) Defective Microbial recognition (“microbial sensor”)

CD25 (IL-2R) MS, others Defective development of T regs

Asocieri ale genelor non-HLA cu BAI

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• Recunoastere Ag: “Sensor microbian”-NOD2 • Cai de semnalizare (fosfatazei)-PTPN22• Reglarea tolerantei periferice-CD25 (IL-2Rɑ):

2. Asocieri ale genelor non-HLA cu BAI

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Boala Gena Mecanism

APS-1(Autoimmune Polyglandular Syndrome type 1)

AIRE ↓ expr Ag self (timus) → selectie negativa defectuoasa

IPEX(Immunodysregulation, polyendocrinopathy, enteropathy,X-linked)

FOXP3 ↓ productia de Tregs

ALPS(Autoimmune LymphoProliferative Syndrome )

FAS, FASL Esec al mecanismelor apoptotice implicate in distrugerea periferica a LT, LB autoreactive

Sindroame autoimune

Genetica BAI: “Boli monogenice”

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Cauzele Autoimunitatii

II. Mediula. Fatori Infectiosi: b. Agenti non-infectiosi:

Agenti modulatori: hormoni

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A. Agenti Infectiosi   Mecanisme de inducere a Autoimunitatii

1. Infectii ale APC2. Legarea patogenului la Ag self3. Mimicitatii Moleculare 4. Superantigene

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IIa. Mecanisme Agenti infectiosi: Mimetismul Molecular

Exemple:Reumatism articular acut : LES: Artrita Lyme:

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II.b. Medicamente & Toxine

• Medicamente:– LES indus medicamentos

• Toxine– Sd Uleiului Toxic

26Nature Immunology  2, 777 - 780 (2001)

II.c. Hormonii

Distributia pe sexe a BAI majoreNumerele de deasupra barelor se refera la nr total de cazuri ( x 1 ,000,000) in USA

EREs

Cauzele Autoimunitatii

III. Reglarea Imuna

• .Un defect pe ORICARE dintre ramurile SI poate => autoimunitate

Complement

T cells B cells

Mecanisme de pierderea tolerantei si BAI

Disease Example

APS-1

MS, Uveitis, Male infetility

IDDM, Hashimoto’s

IPEX

ALPS

RA, SLE, Crohn’s

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REMEMBER!

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Clasificarea Imunologica BAI

=>~ tipul de RI ~ mec imunopatogenic

• BAI prin Aac autoreactivi (RIU aN– Hipersensibilitate tip II (citotoxica)– Hipersensibilitate tip III (mediata prin CI)

• BAI mediate celular (RIC aN) – Hipersensibilitate tip IV (CTL sau Mф)

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BAI tip II

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R. Citotoxice:─ Ac anti moleculele de suprafata─ Fara distrugerea citotoxica a celulelor

BAI tip II

2. Miastenia gravis: • Aac- Receptor Ach Clinic:

1. Boala Graves: AAc – RTHS => ↑H tiroidian Clinic:

2015-6-9

BAI tip III

B.Complexe Imune•Artrita Reumatoida :

• cauza?, • mecanism -• Aac -> patogeneza • Clinic

•Lupus Eritematos Sistemic: • mecanism • AAc → patogeneza • Clinic

BAI tip III

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LES

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BAI tip IV

Diabetul Zaharat Insulino-dependent (Tip I)– CLINIC: Complicatii severe/fatale: gangrena, afectare cardiaca, renala

si nervoasa

BAI tip IV

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Clasificarea Imunologica BAI

=>mecanism• unic• multiplu

BAI T+BScleroza Multipla

Pacientii cu MS pot avea atat Aac anti MBP cat si LTC autoreactive

→demielinizare

Simptomele BAI• Generale:

• Specifice

Diagnostic

• Teste biologice si biochimice • PCR• FR

– Detectarea Aac: • Ac impotriva Ag asociati

celulelor/tesuturilor→imunofluorescenta• Ac impotriva Ag solubili→ELISA

• Simptome specifice→Teste specifice– Ex Neurologic – SM– TGOP - DZ

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Diagnostic pentru LES• Valorile Ig (↑ >90%)• Valorile componentelor Complementului

(↓60%)• Ac Anti-nucleari (ANA)(1:80< 95%)• Ac Anti-ds DNA (90-95%)• Factor Reumatoid (30%)• CI depozitate in piele 60%)• „ „ in rinichi (90%)

Tratament

Cheia pentru tratarea BAI este imunomodularea

I. Ag Specific1. Ac vs. TCR autoreactive2. Vacinuri → TCR autoreactive3. Adm Antagonist TCR4. Adm de autoantigen/ cDNAObservatie: → experimental

II. Antigen Non-specific

1. Ac Mo anti LT -CD2, CD3, CD42. Ac anti CD28, CD40L 3. Ac anti CAM (VLA-4, ICAM-1)4. Adm IV Ig (IVIG)5. Neutralizarea CK proinflam (AcMo anti-TNF)6. Adm de CK anti-inflamatory

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Tratament Nespecific• Anti-inflamatoare

• AINS, AIS

• Imunosupresoare • MTX

• Iradiere • Plasmafereza