how the immune system works václav hořejší inst. of molecular genetics as cr, prague, czech...

54

Upload: gilbert-phelps

Post on 12-Jan-2016

220 views

Category:

Documents


2 download

TRANSCRIPT

Page 1: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic
Page 2: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

HOW THE IMMUNE SYSTEM WORKS

Václav Hořejší

Inst. of Molecular Genetics AS CR, Prague, Czech Republic

Page 3: 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

Page 4: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

RECOGNITION

Page 5: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

RECOGNITION OF PATHOGENS AND ABNORMAL SELF CELLS

BY MEANS OF:

- SURFACE RECEPTORS

- “SOLUBLE RECEPTORS”

Page 6: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

INNATE (NON-ADAPTIVE)

SYSTEM

Page 7: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

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

Page 8: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

MANNOSE-BINDING LECTIN, COMPLEMENT

Page 9: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

TOLL-LIKE RECEPTORS

Page 10: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

SURFACE LECTINS

Page 11: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

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).

Page 12: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

ADAPTIVE (ANTIGEN-SPECIFIC)

SYSTEM

Page 13: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

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.

Page 14: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

B CELL DIFFERENTIATION

Page 15: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

T LYMPHOCYTE DEVELOPMENT AND SELECTION IN THYMUS

Page 16: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

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)

Page 17: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic
Page 18: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic
Page 19: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

PRODUCTIVE STIMULATION OF T LYMPHOCYTES REQUIRES PROFESSIONAL APC (DC) AND COSTIMULATION

Page 20: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

T LYMPHOCYTES: IMPORTANT FUNCTIONAL SUBSETS

Page 21: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic
Page 22: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

Leo A., Schraven B.Curr Opin Immunol 2001 Jun;13(3):307-16

Page 23: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic
Page 24: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

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…)

Page 25: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

Th1 x Th2

Page 26: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

ESSENTIAL LINK BETWEEN THE INNATE AND ADAPTIVE SYSTEMS:

DENDRITIC CELLS

Page 27: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic
Page 28: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

DENDRITIC CELLS MUST BE PRE-STIMULATED BY

DANGER SIGNALS

TO BE ABLE TO ACTIVATE T LYMPHOCYTES

Page 29: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

DANGER SIGNALS:

- EXOGENOUS (PAMPs)

- ENDOGENOUS (e.g. STRESS PROTEINS RELEASED FROM NECROTIC CELLS)

Page 30: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic
Page 31: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic
Page 32: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

DISPOSAL

Page 33: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

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

Page 34: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

PHAGOCYTOSIS

Page 35: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

SELF-TOLERANCE

Page 36: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

BIG PROBLEM:

HOW TO MAINTAIN SELF-TOLERANCE AND PREVENT

AUTOIMMUNITY?

Page 37: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic
Page 38: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

IMMUNOLOGICAL HIT (WITH EMBARRASSING HISTORY…)

REGULATORY (= SUPPRESSOR) T LYMPHOCYTES

(Treg, Ts, Th3, Tr1…)

Page 39: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic
Page 40: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

REGULATORY T LYMPHOCYTES ARISE IN:

- THYMUS (SUPPRESS AUTOIMMUNITY) - PERIPHERY (THESE DOWN-REGULATE

EXCESSIVE IMMUNE RESPONSES

Page 41: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

PRACTICAL CONSEQUENCES?

Page 42: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

HOPEFULLY:

- BETTER VACCINES (WEAK ANTIGENS, TUMORS?)

- IMMUNOSUPPRESSION (AUTOIMMUNE DISEASES, TRANSPLANTATION)

Page 43: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic
Page 44: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic
Page 45: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

21st CENTURY – THE AGE OF IMMUNOTHERAPEUTICS?

WE WILL SEE IN 20, 50, 100 YEARS…

Page 46: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

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)

Page 47: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

MOLECULAR MECHANISMS:

THOUSANDS OF MOLECULES, RECEPTORS, CYTOKINES,

PATHWAYS…

Page 48: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

Leo A., Schraven B.Curr Opin Immunol 2001 Jun;13(3):307-16

Page 49: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

LIPID RAFTS (GEMs)

Lck

TM protein

CD48CD55

CD59

GLP

Fyn

LAT

TM protein

TM protein

Page 50: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

RAFTs - DISTRIBUTION AND HETEROGENEITY

Page 51: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

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

Page 52: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

TRANSMEMBRANE ADAPTOR PROTEINS (TRAPs) IN GENERAL

Closely associated withimmunoreceptors

Not associatedwith rafts

Associated with rafts(palmitoylated)

Page 53: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic

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)

Page 54: HOW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. of Molecular Genetics AS CR, Prague, Czech Republic