Folie 1

Folie 1
IMMUNÜBERWACHUNG
Hans Lassmann
Institut für Hirnforschung
Medizinische Universität Wien
Folie 2
IMMUNOLOGISCHE
ABWEHR
• Unspezifische Abwehr (Innate
Immunity)
– Makrophagen, Granulozyten, NK-Zellen
– Komplement System
• Spezifische Abwehr
– T- Lymphozyten
– B- Lymphozyten, Antikörper
Folie 3
TOLL-LIKE-RECEPTORS
• Key receptors to initiate host defense
mechanisms (Innate Immunity)
• Expression: Monocytes / Macrophages /
Dendritic Cells (Epithelial & Endothelial
Cells)
• Signalling:
– TOLL Pathway – NF-kB
– IMD (immunodeficiency) Pathway
Folie 4
TOLL-LIKE-RECEPTORS
• TLR – Ligands:
–
–
–
–
–
Lipopeptides (TLR 1, 2, 4, 6)
Lipids (Glycolipids): (TLR 2)
Double stranded RNA (TLR 3)
CpG DNA (TLR 9)
Others:
• Stress proteins, Polysaccharides (TLR 2, TLR 4)
• Fibrinogen (TLR 4)
Folie 5
TOLL-LIKE-RECEPTORS
• Effects of TLR induced activation (dendritic
cells and / or macrophages)
– Induction of Th-1 cytokines (Il-12)
– Induction of Type I interferons
– Induction of anti-microbial peptides (ßdefensins)
– Induction of apoptosis in macrophages and
endothelial cells
Folie 6
Folie 7
Chemokines
Andrew D. Luster
N Engl J Med 1998
Folie 8
Folie 9
Folie 10
Chemokines
Andrew D. Luster
N Engl J Med 1998
Folie 11
Inflammatory Diseases of the Central
Nervous System
• Innate Immunity:
• Acute (bacterial) Meningitis
• Inflammatory component of neurodegeneration
• Adaptive Immunity:
• Infectious diseases
• Putative autoimmune diseases
– T-Cell mediated
– Antibody mediated
– Complex (T-cell + antibody mediated)
Folie 12
Consequences of Brain Inflammation
• Elimination of Pathogens
• Collateral Damage
• Edema / microcirculation disturbance /
herniation
• Tissue damage by toxic inflammatory mediators
– Cytokines, O / NO radicals, proteases, lipases,
excitotoxins
• Autoimmunity
• Antigen / Epitope Spreading
Folie 13
THE BRAIN AS AN
IMMUNOPRIVILEGED ORGAN
• DOGMAS UNTIL 1990
• The blood-brain-barrier restricts the entry of
hematogenic cells into the CNS
• The brain does not express MHC molecules
• There is no lymphatic drainage of the brain
– Brain antigen does not reach the lymphatic
organs (Immunological ignorance)
Folie 14
BASIC PRINCIPLES OF BRAIN
CELL TRANSPLANTATION
accepted
rejected
unspecific immune
activation
sensitization
Folie 15
BAKTERIELLE MENINGITIS
• Einwanderung von Keimen in den
Liquorraum des zentralen
Nervensystems
• Freisetzung von immunstimulierenden
Bakterienbestandteilen
• Entzündungsreaktion im Nervensystem
• Schädigung des Nervengewebes
Folie 16
BAKTERIELLE MENINGITIS
• Keimbesiedelung des Liquorraumes:
– Direkte Infektion durch Eröffung des
Liquorraumes (ZNS Trauma; Operationen;
Fehlbildungen des Nervensystems;
Staphylokokken, Streptokokken)
– Fortgeleitete Infektion (Sinusitis, Otitis
media)
– Hämatogene Besiedelung (Sepsis;
Meningokokken, Pneumokokken, Listerien)
Folie 17
BAKTERIELLE MENINGITIS
• Induktion der Entzündungsreaktion:
– Freisetzung von immunstimulierenden
Bakterienbestandteilen (LPS, bakterielle
DNA)
– Stimulation der unspezifischen Abwehr über
Toll – like Rezeptoren (TLR)
– Synthese von Zytokinen und Chemokinen
– Rekrutierung von Leukozyten
Folie 18
BAKTERIELLE MENINGITIS
• Schädigung des Nervengewebes:
– Störung der Blut Hirn Schranke:
• Hirnödem mit Einklemmung
– Akute Vaskulitis / Thrombose:
• Perfusionsstörung / Ischaemie
– Toxische Schädigung des Nervengewebes
• Bakterielle Toxine; Toxische entzündliche
Mediatoren
• Zerstörung von Nervenzellen (Apoptose)
Folie 19
AKUTE VIRALE ENZEPHALITIS
• Herpes Viren, Enteroviren, Paramyxoviren,
Flaviviren, Retroviren, viele andere.
• Infektionswege:
– Haematogen (viraemie)
– Transport durch infizierte Leukozyten
– Neurogene Infektion (axonaler Transport)
• Abwehr: spezifische Immunreaktion
– Wettlauf: ZNS Ausbreitung / Induktion der
Immunreaktion !!
Folie 20
VIRUS INDUCED AUTOIMMUNITY
• Molecular Mimicry
• T-cells with dual T-cell Receptor
• Budding virus carries autoantigen in
envelope
• Virus induced tissue damage / antigen- or
epitope spreading
Folie 21
THE BLOOD BRAIN BARRIER
• Barrier for hydrophobic molecules
(proteins, peptides)
• Restricted CNS entry for antibodies and
inflammatory mediators
• Restricted exit of CNS molecules
• Barrier for leucocytes
• Restricted entry of immune cells (exception:
activated T-cells)
• Restricted exit of CNS derived cells into
lymphatics or circulation
Folie 22
Folie 23
Folie 24
Folie 25
Folie 26
EXPRESSION OF CHEMOKINE
RECEPTORS IN MS
Normal
Brain
CD4+, CD45Ra-, CD27+, CD69+,
CXCR 3+, CCR7+
P-selectin GPL-1+
P-selectin,
ICAM 1
Multiple
Sclerosis
Folie 27
CXCR 3
CCR7
CXCR 3
EXPRESSION OF CHEMOKINE
RECEPTORS IN MS
CCR1
CCR5
CCR5
CCR8
Folie 28
MIGRATION PATTERNS OF T-CELLS
AFTER PASSIVE TRANSFER
Flügel et al, Immunity 2001
Folie 29
THE MIGRATORY PHENOTYPE
OF EFFECTOR T-CELLS
• UPREGULATED
• MHC II
• CCR 1, CCR 2b, CCR 3, CCR 5, CCR 7,
• DOWNREGULATED
• Ox 40; Il2-R,
• UNCHANGED
• CD 4, TCR
• CCR 4, CXCR 3
Flügel et al, Immunity 2001
Folie 30
THE BRAIN AS AN
IMMUNOPRIVILEGED ORGAN
• DOGMAS UNTIL 1990
• The blood-brain-barrier restricts the entry of
hematogenic cells into the CNS
• The brain does not express MHC molecules
• There is no lymphatic drainage of the brain
– Brain antigen does not reach the lymphatic
organs (Immunological ignorance)
Folie 31
Folie 32
REGULATION OF MHC
EXPRESSION IN THE CNS
• Hippocampal tissue slices
• Electrophysiological recording and PCR
(MHC-1, ß2M, Tap-transporters etc) from
single cells
• Electrical silencing of cells with
tetrodotoxin
• Electrically silent neurons express Class I
MHC, when stimulated with g-IFN
Folie 33
ELECTRICAL ACTIVITY OF NEURONS
SUPPRESSES IMMUNE REACTION
• Immune-associated molecules (MHCantigens) are induced in CNS cells by
proinflammatory cytokines (gammaIFN)
• This induction is suppressed by
electrically active neurons
• This suppression is mediated by
neurotrophins (NGF)
Folie 34
Folie 35
Folie 36
Folie 37
Folie 38
DOWNREGULATION OF BRAIN
INFLAMMATION BY T-CELL
APOPTOSIS
• T-lymphocytes, entering the CNS are rapidly
cleared by apoptosis
• Both, antigen-specific and secondarily
recruited T-cells are destroyed
• Brain-specific mechanisms of apoptosis
induction
• Consequences:
• Prevention of autoantigen recognition
• Clonal deletion of pathogenic T-cells
Folie 39
THE BRAIN AS AN
IMMUNOPRIVILEGED ORGAN
• DOGMAS UNTIL 1990
• The blood-brain-barrier restricts the entry of
hematogenic cells into the CNS
• The brain does not express MHC molecules
• There is no lymphatic drainage of the brain
– Brain antigen does not reach the lymphatic
organs (Immunological ignorance)
Folie 40
Folie 41
LYMPHATIC DRAINAGE OF THE
CENTRAL NERVOUS SYSTEM
• The CNS parenchyma does not contain
lymphatic vessels
• The normal CNS parenchyma does not contain
professional antigen presenting „dendritic“
cells
• Foreign material, integrated into the CNS tissue is not
rejected
• Limited transport of proteins and cells from
inflamed CNS tissue into lymphatics
• Antigen spreading - autoimmunity
Folie 42
CNS Autoimmunity
• Autoreactive T-lymphocytes are a
component of the normal immune
repertoire
• Brain damage (e.g. trauma) is associated
with a T-cell mediated autoimmune
response against brain proteins
Folie 43
NEUROTROPHINS AND THE
IMMUNE SYSTEM
• Leucocytes are a potent source of
neurotrophins (BDNF, NGF, NT3, NT4)
• Immunomodulatory action of
neurotrophins (NGF: downregulation of
MHC antigens – immunosuppression)
• Protective autoimmunity
• Inflammation reduces traumatic brain damage
• Inflammation stimulates regeneration /
remyelination
Folie 44
BDNF EXPRESSION IN
LEUCOCYTES IN MS
Folie 45
FUNCTION OF LEUCOCYTE
DERIVED NEUROTROPHINS IN
INFLAMMATORY BRAIN
LESIONS
• Downregulation of the inflammatory
response
• Inhibition of bystander damage
• Stimulation of remyelination and repair
Folie 46
Neuroprotective Autoimmunity
• T-cell mediated autoimmunity improves
outcome in:
• Brain trauma
• Ischemic / excitotoxic neuronal damage
• Neuroprotective effect mediated (in part ?)
by neurotrophins, secreted by inflammatory
cells
Schwartz & Hauben (2002) Progr. Brain Res 137:401-406
Barouch & Schwartz (2002) FASEB-J 16:1304-1306
Folie 47
The Good and Bad Sides of Inflammation
• Elimination of Pathogens
• Collateral Damage of Inflamed Tissue
• Removal of Damaged Tissue
Components
• Tissue Edema / Swelling
• Vascular Damage / Ischemia
• Promotion of Regeneration and Repair
• Aberrant Regeneration
• Scar Formation