Download IDPs (PIDs)

IMMUNOPATHOLOGIE
1
Plan du cours
•
•
•
•
•
•
1. Immunodeficiences primaires
2. Immunodeficiences secondaires
3. Autoimmunite
4. Atopie et inflammation
5. Transplantation et immunosuppreseurs
6. Cancer
2
Autoimmunite
•
=> Immune Response: protection
•
•
=> host damage
Response immune dirigee contre des
antigens du soi (auto-antigenes)
3
Autoimmunite
•
=> Horror autotoxicus (1903) Paul Ehrich
•
•
•
•
1902:Portier et Richet: anaphylaxis
1903: Maurice Arthus
1904: Donath et Landsteiner: first described autoimmune disease (paroxxysmal
cold hemoglobinuria)
1905: vonPirquet et Schick: serum sickness
1906: aTreponema pallidum : crossreactivity cardiolipin
1930s: RA patients: rheumatoid factor (IgM anti Fc of IgG-coated sheep RBSs)
1940s: Peter Medawar: skin rejection
1950s: William J Harrington: platelet depletion by serum transfer from patients
with idiopathic thrombocytopenic purpura (‘autoantibodies’)
1950s: peter Miescher&Henry kinkel: SLE patient serum: anti-nuclear (DNA,
RNA, nucleoproteins) antibodies
1956: Noel Rose: immunization of healthy rabbits with thyroid extracts ->
thyroiditis
1960s: NZB mice models (Marianne & Feliz Bielschowsky) - autoimmune
hemolytic anemia; anti-kidney antibodies
1970s: GF Bottazzo; WJ Irvine: anti-pancreatic beta-islet cell Abs in IDM
•
ORGAN SPECIFIC / SYSTEMIC AUTOIMMUNE DISEASES
•
•
•
•
•
•
•
•
4
Autoimmunite
•
=> WE Paul, 6th ed
5
Autoimmunite
•
=> WE Paul, 6th ed
6
Autoimmunite
•
=>
•
Hypersensitivity mechanism vers le self
•
Beakdown of immune tolerance
•
Presence of an autoimmune reaction
•
That reaction is of primary importance (not colateral)
•
absence of other causes
•
therapeutic effect
7
Antigenes
•
A) Antigenes cryptiques
–
–
•
B)Reactions croisee avec tissus de l’hote apres respose immune
–
•
cristallin: ophtamie sympathique
testicule: vasectomie
S. beta-hemolytique: Abs anti-tissu cardiaque; RAA
C) Modification antigeniques des antigenes de l’hote
–
–
(physico-induites: UV)
(chimio-induites)
8
Acteurs cellulaires
•
A) Cellules B
–
–
–
•
B) Cellules T
–
–
•
Cellules T autoreactives
Treg; NKT, Th17, Th9
C) Extensions sur des cellules auxiliares
–
•
Autoanticorps naturesl: faible affinite; taus faibles, ^ des sujets ages
B1 cells
HMS
DCs; Mast cells; Macrophages
D) Celules cible
–
–
–
–
Cellules cible du soi normalles
Cellules cible du soi alteree
Cellules microbiennes
Allogeneic cells (fetal)
9
Acteurs molleculaires
•
A) Antigenes
•
•
•
•
•
•
genetiques
B) MHCs
C) Cytokines
D) Corecepteurs
E) Molecules de transmission du signal
F) Facteurs transcriptionelles: FoxP3, T-bet, GATA-3, IFR4,
•
•
•
microbiens
E) interferant (cytokine homologues)
D) epitopes mimetiques
10
Autoimmunite
•
=> Types de reactions
d’hypersensibilite
•
Burmester & Pezzuto, Atlas de poche
d’immunologie
11
Autoimmunite
•
=> Kuby 5th Immunology
12
Autoimmunite
•
=> Defects in tolerance induction (central
tolerance)
•
=>Defects in tolerance maintenance
(peripheral tolerance)
•
=>Defects in isolating priviledged site self
antigens
•
=>Immune deviation
13
Autoimmunite
•
=> Facteurs :
•
Inflammation:
–
–
–
–
•
cytokines proinflammatoires (IL-1b, TNF, LT, IL-6); IFN antivirale: NKT; Th17; pDCs, DCs
DC: tolerance / activatoire
eliberation du molecules d’allarme du soi (ADN, calreticulins, HMGB1, HSPs, ATP)
activation du recepteurs de l’immunitee innee: TLRs
Mimetisme antigenique:
14
Autoimmunite
•
=>
15
Autoimmunite
•
=> Anomalies en Treg: IPEX (immune
dysregulation, polyendochrinopathy,
enteropathy X-linked ): FoxP3
Scurfy mice
16
Autoimmunite
•
=>
17
Autoimmunite
•
=>Anomalies en CPAs:
–
modele animal avec reduction en MHC II/B7 sur DCs/macrofages:
•
•
–
–
–
induction deficitaire ed Treg
infections
modele animal avec reduction en cellules B
anomalies en complement
modele animal avec production exageree en cytokines
•
•
•
hu: MS, RA: IL-6, TGFb, IL-23: Th17; mAbs peut bloquer
hu: glomerulonephrite, SLE, IL-15, IL-27
=>Epitope spreading
•
•
PG: desmoglein 3 (mucouse) -> desmoglein 1 (peau)
GAD: glutamic acid decaboxylase
18
Autoimmunite
•
=>SLE (fievre, malaise, fatigue, douleur
musculaire, polyarthrite, ERYTHEME
facial en aille de papillon/masque de loup;
atteinte glomerulaire proliferative focale
ou diffuse, SNC, pericardite, myocardite)
•
Ag: nucleosomes / spliceosomes /
cumplexe ribonucleoproteiques
cytoplasmique
•
IL10: stimulation du B (proliferation +
differentiation)
19
Autoimmunite
•
=>R. A. (arthrite rheumatoide)
•
•
Th17: IL17/TNF
RF: collection de anti-IgG
20
Autoimmunite
•
=>
21
Autoimmunite
•
=>
22
Autoimmunite
•
=>
23
Autoimmunite
•
=>
24
Autoimmunite
•
=>
25
Autoimmunite
•
=>
26
Autoimmunite
•
=>
27