HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech...
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Transcript of HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech...
HOW THE IMMUNE SYSTEM WORKS
Václav Hořejší
Inst. of Molecular Genetics AS CR, Prague, Czech Republic
BASIC TASKS:
- PROTECTION FROM PATHOGENS
- REMOVAL OF ABNORMAL SELF CELLS
RECOGNITION
RECOGNITION OF PATHOGENS AND ABNORMAL SELF CELLS
BY MEANS OF:
- SURFACE RECEPTORS
- “SOLUBLE RECEPTORS”
INNATE (NON-ADAPTIVE)
SYSTEM
SOLUBLE AND MEMBRANE RECEPTORS OF THE INNATE SYSTEM (MAINLY ON VARIOUS
TYPES OF PHAGOCYTES) RECOGNIZE:
PATHOGEN-ASSOCIATED MOLECULAR PATTERNS (PAMPs)
The number of the innate receptors is limited,
shared structural features are recognized
MANNOSE-BINDING LECTIN, COMPLEMENT
TOLL-LIKE RECEPTORS
SURFACE LECTINS
A SPECIAL SORT OF THE CELLS OF THE INNATE (NON-ADAPTIVE) SYSTEM ARE NK (NATURAL KILLER) CELLS.
SPECIALIZE IN KILLING OF ABNORMAL SELF CELLS CONSPICUOUS BY LOW EXPRESSION OF MHC MOLECULES (e.g. many tumors).
ADAPTIVE (ANTIGEN-SPECIFIC)
SYSTEM
THE ADAPTIVE SYSTEM:
- Based on huge repertoir of B- and T-lymphocyte clones, each carrying a slightly different receptor (BCR or TCR)
- The “soluble receptors” of the adaptive system are antibodies (= soluble BCR)
- The system is “anticipating”, clonal, “wasteful”
- Clonal receptors arise mainly by gene rearrangement and somatic mutations.
B CELL DIFFERENTIATION
T LYMPHOCYTE DEVELOPMENT AND SELECTION IN THYMUS
T-CELL RECEPTORS:
MAINLY RECOGNITION OF MHC-PEPTIDE COMPLEXES ON OTHER CELL’S SURFACE
PURPOSE: DETECTION OF CELLS INFECTED BY “HIDDEN” INTRACELLULAR PARASITES (e.g. VIRUSES)
PRODUCTIVE STIMULATION OF T LYMPHOCYTES REQUIRES PROFESSIONAL APC (DC) AND COSTIMULATION
T LYMPHOCYTES: IMPORTANT FUNCTIONAL SUBSETS
Leo A., Schraven B.Curr Opin Immunol 2001 Jun;13(3):307-16
BASIC DOGMA FOR THE ADAPTIVE RESPONSES:
ANTIBODY RESPONSES (B, Th2) – EFFECTIVE FOR EXTRACELLULAR PARASITES
INFLAMMATORY RESPONSES (Th1, Tc) – EFFECTIVE FOR INTRACELLULAR PARASITES
MUTUAL INHIBITION Th1 vs. Th2 (POSITIVE FEEDBACK REGULATION)
WRONG CHOICE Th1 vs. Th2 CAN BE FATAL (LEPROSY…)
Th1 x Th2
ESSENTIAL LINK BETWEEN THE INNATE AND ADAPTIVE SYSTEMS:
DENDRITIC CELLS
DENDRITIC CELLS MUST BE PRE-STIMULATED BY
DANGER SIGNALS
TO BE ABLE TO ACTIVATE T LYMPHOCYTES
DANGER SIGNALS:
- EXOGENOUS (PAMPs)
- ENDOGENOUS (e.g. STRESS PROTEINS RELEASED FROM NECROTIC CELLS)
DISPOSAL
EFFECTOR MECHANISMS OF PATHOGEN REMOVAL (FOLLOWING RECOGNITION BY EITHER INNATE OR ADAPTIVE RECEPTORS):
- KILLING BY MIROBICIDAL PEPTIDES, REACTIVE OXYGEN SPECIES, OR OTHER “CHEMICAL WEAPONS”
- PHAGOCYTOSIS
- INFLAMMATION (BASED ON CYTOKINES, CHEMOKINES)
- KILLING (NOT CURING!!) OF INFECTED CELLS
PHAGOCYTOSIS
SELF-TOLERANCE
BIG PROBLEM:
HOW TO MAINTAIN SELF-TOLERANCE AND PREVENT
AUTOIMMUNITY?
IMMUNOLOGICAL HIT (WITH EMBARRASSING HISTORY…)
REGULATORY (= SUPPRESSOR) T LYMPHOCYTES
(Treg, Ts, Th3, Tr1…)
REGULATORY T LYMPHOCYTES ARISE IN:
- THYMUS (SUPPRESS AUTOIMMUNITY) - PERIPHERY (THESE DOWN-REGULATE
EXCESSIVE IMMUNE RESPONSES
PRACTICAL CONSEQUENCES?
HOPEFULLY:
- BETTER VACCINES (WEAK ANTIGENS, TUMORS?)
- IMMUNOSUPPRESSION (AUTOIMMUNE DISEASES, TRANSPLANTATION)
21st CENTURY – THE AGE OF IMMUNOTHERAPEUTICS?
WE WILL SEE IN 20, 50, 100 YEARS…
SUMMARY:- RECOGNITION BY SOLUBLE OR MEMBRANE-ASSOCIATED RECEPTORS - INNATE SYSTEM (LIMITED NUMBER OF PAMP-RECEPTORS)
- ADAPTIVE SYSTEM (HUGE REPERTOIR OF HIGHLY SPECIFIC CLONAL RECEPTORS)
- CRUCIAL ROLE OF DENDRITIC CELLS IN LINKING OF THE INNATE AND ADAPTIVE SYSTEM
- DANGER SIGNALS (EXOGENOUS OR ENDOGENOUS) “WAKE UP” DC’s FOR STIMULATION OF T CELLS
- CRUCIAL ROLE OF THE DECISSION FOR THE ANTIBODY-BASED (Th2) vs. INFLAMMATORY (Th1, Tc) RESPONSES
- CRUCIAL ROLE OF SELF-TOLERANCE MECHANISMS (DELETION OF AUTOREACTIVE LYMPHOCYTES, REGULATORY T CELLS)
MOLECULAR MECHANISMS:
THOUSANDS OF MOLECULES, RECEPTORS, CYTOKINES,
PATHWAYS…
Leo A., Schraven B.Curr Opin Immunol 2001 Jun;13(3):307-16
LIPID RAFTS (GEMs)
Lck
TM protein
CD48CD55
CD59
GLP
Fyn
LAT
TM protein
TM protein
RAFTs - DISTRIBUTION AND HETEROGENEITY
1 1
2
3
4
M H C M H C
Z A P -7 0
G P I-d o m a in T C R co m p lex
L ck
C D 48C D 55
C D 59
G L P
F ynL AT
T C RC D 4/8
C D 3 C D 3
()2
5
GEMs IN IMMUNORECEPTOR SIGNALLING
TRANSMEMBRANE ADAPTOR PROTEINS (TRAPs) IN GENERAL
Closely associated withimmunoreceptors
Not associatedwith rafts
Associated with rafts(palmitoylated)
Signaling components of leukocyte rafts:
Src kinases:Štefanová et al, Science 254(1991)1016Cinek et al, J. Immunol. 149(1992)2269
Transmembrane adaptor LAT (critical for TCR signaling):Brdička et al, Biochem. Biophys. Res. Commun. 248(1998)356
Transmembrane adaptor PAG (activates Csk – regulation of Src-kinases): Brdička et al, J. Exp. Med. 191(2000)1591
Transmembrane adaptor NTAL (LAT-like function in BCR and FcR signaling): Brdička et al, J. Exp. Med. 196(2002)1617
Transmembrane adaptor p33 (a role in CD4, CD8 signaling?):Brdičková et al, submitted
Collaboration with Burkhart Schraven (Heidelberg, Magdeburg)