20. autoimunitate (2015) v2
DESCRIPTION
imunologieTRANSCRIPT
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:
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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