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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)
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