20. autoimunitate (2015) v2
DESCRIPTION
imunologieTRANSCRIPT
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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)
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Exemple de BAI Sistemice
Sclerodermia Sistemica
Afectare renala
Fibroza pulmonara
Afectare cardiaca
Afectare articulara
Fenomen Raynaud
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Example de BAI SistemiceSd Sjogren
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Cauzele Autoimunitatii
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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
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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
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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
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Cauzele Autoimunitatii
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III. Reglarea Imuna
• .Un defect pe ORICARE dintre ramurile SI poate => autoimunitate
Complement
T cells B cells
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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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2015-6-9
REMEMBER!
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Clasificarea Imunologica BAI
=>~ tipul de RI ~ mec imunopatogenic
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• 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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2015-6-9
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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2015-6-9
BAI tip III
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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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2015-6-9
BAI tip IV
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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
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BAI T+BScleroza Multipla
Pacientii cu MS pot avea atat Aac anti MBP cat si LTC autoreactive
→demielinizare
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Simptomele BAI• Generale:
• Specifice
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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%)
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Tratament
Cheia pentru tratarea BAI este imunomodularea
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I. Ag Specific1. Ac vs. TCR autoreactive2. Vacinuri → TCR autoreactive3. Adm Antagonist TCR4. Adm de autoantigen/ cDNAObservatie: → experimental
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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