Autoimunitate si

Boli autoimune

Autoimunitate
Reactii autoimune (RAI)
Incidenta:
Caracteristici:

Boli Autoimune
Incidenta
Caracteristici:

model BAI organ specifica mediata T celular

4

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

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))

Modele Experimentale Murine

BAI Umana
AR (PR)

Model Murin
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

Organe/tesuturi afectate
Uveita Autoimuna (B1-cristalin)

Scleroza Multipla
(Ac a-P. Mielinice)

Sd Sjogrens (ANA)
Sd Goodpasture (AMBG-col.IV))
Ciroza Biliara Primitiva (ANA)
Hepatita Autoimuna (ANA)
Endometrioza (IgG anti-P.endometriale)
Artrita Reumatoida (IgG,FR)
Sclerodermia Sistemica (ACA, ANA, Scl70)

B Basedow-Graves
(Ac a-TSH. R)
Tiroidita Hashimoto
(Ac a-Tiroglobulina)

RAA
(Ac a mn card)

Diabet (Ac a-glutamat decarboxilaza)

Boala Addison
( Ac a- P citopl.
cel adrenale corticale
Boala Crohn?
Anemia Hemolitica Autoimuna
LES (ANA, a DNAds)

Clasificarea BAI
Clinica: dupa localizare

organ-specifice

sau

sistemice

10

Example de BAI Organ Specifice

Plamanii unui
bolnav cu Sd
Goodpasture

Tiroidita autoimuna
(Hashimoto)

Vitiligo

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Exemple de BAI Sistemice

Fibroza
pulmonara
Afectare
cardiaca
Afectare
renala
Afectare
articulara

Fenomen
Raynaud

Sclerodermia
Sistemica

Example de BAI Sistemice

Sd Sjogren

Cauzele Autoimunitatii

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

1. Asocieri ale HLA cu BAI

16

1. Asocieri ale HLA cu BAI

17

Asocieri ale genelor non-HLA

cu BAI
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 domaincontaining protein)

Crohns disease (25%)

Defective Microbial recognition

(microbial sensor)

CD25 (IL-2R)

MS, others

Defective development of T regs

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2. Asocieri ale genelor non-HLA

cu BAI

Recunoastere Ag: Sensor microbian-NOD2

Cai de semnalizare (fosfatazei)-PTPN22
Reglarea tolerantei periferice-CD25

(IL-2R):

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Genetica BAI:

Boli monogenice
Boala

Sindroame autoimune
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
FAS, FASL
(Autoimmune
LymphoProliferative Syndrome )

Esec al mecanismelor
apoptotice implicate in
distrugerea periferica a
LT, LB autoreactive 20

Cauzele Autoimunitatii

21

II. Mediul
a. Fatori Infectiosi:
b. Agenti non-infectiosi:
Agenti modulatori: hormoni

A. Agenti Infectiosi
Mecanisme de inducere a Autoimunitatii
1.

Infectii ale APC

2. Legarea patogenului la Ag self

3. Mimicitatii Moleculare
4. Superantigene

23

IIa. Mecanisme
Agenti infectiosi:
Mimetismul
Molecular
Exemple:

Reumatism articular acut :

LES:
Artrita Lyme:

24

II.b. Medicamente & Toxine

Medicamente:

LES indus medicamentos

Toxine

Sd Uleiului Toxic

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II.c. Hormonii

Distributia pe sexe a BAI majore

Numerele de deasupra barelor se
refera la nr total de cazuri
( x 1 ,000,000) in USA

EREs

Nature Immunology 2, 777 - 780 (2001)

26

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, Hashimotos

IPEX
RA, SLE, Crohns
ALPS

REMEMBER!

2015-6-9

Clasificarea
Imunologica BAI
=>
~ tipul de RI
~ mec imunopatogenic

31

 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 M)

BAI tip II

2015-6-9

BAI tip II
R. Citotoxice:

Ac anti moleculele de suprafata

Fara distrugerea citotoxica a celulelor

1. Boala Graves:

AAc RTHS => H tiroidian

Clinic:

2. Miastenia gravis:
Aac- Receptor Ach

Clinic:

34

BAI tip III

2015-6-9

BAI tip III

B.Complexe Imune

Artrita Reumatoida :

cauza?,
mecanism Aac -> patogeneza
Clinic

Lupus Eritematos Sistemic:

mecanism
AAc patogeneza
Clinic

LES

37

BAI tip IV

2015-6-9

BAI tip IV
Diabetul Zaharat Insulino-dependent (Tip I)

CLINIC: Complicatii severe/fatale: gangrena, afectare cardiaca, renala

si nervoasa

Clasificarea
Imunologica BAI
=>
mecanism
unic
multiplu

40

BAI T+B
Scleroza 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/tesuturilorimunofluorescenta
Ac impotriva Ag solubiliELISA

Simptome specificeTeste specifice

Ex Neurologic SM
TGOP - DZ

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%)
44

Tratament

Cheia pentru
tratarea BAI este
imunomodularea

I. Ag Specific
1.
2.
3.
4.

Ac vs. TCR autoreactive

Vacinuri TCR autoreactive
Adm Antagonist TCR
Adm de autoantigen/ cDNA

Observatie: experimental

II. Antigen Non-specific

1.
2.
3.
4.
5.
6.

Ac Mo anti LT -CD2, CD3, CD4

Ac anti CD28, CD40L
Ac anti CAM (VLA-4, ICAM-1)
Adm IV Ig (IVIG)
Neutralizarea CK proinflam (AcMo anti-TNF)
Adm de CK anti-inflamatory

Tratament Nespecific
Anti-inflamatoare
AINS, AIS

Imunosupresoare
MTX

Iradiere
Plasmafereza

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