HLAVN

1
(No Transcript)
2
HOW THE IMMUNE SYSTEM WORKSVáclav
HorejšíInst. of Molecular Genetics AS CR,
Prague, Czech Republic
3
BASIC TASKS- PROTECTION FROM PATHOGENS-
REMOVAL OF ABNORMAL SELF CELLS
4
RECOGNITION
5
RECOGNITION OF PATHOGENS AND ABNORMAL SELF CELLS
BY MEANS OF- SURFACE RECEPTORS -
SOLUBLE RECEPTORS
6
INNATE (NON-ADAPTIVE) SYSTEM
7
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
8
MANNOSE-BINDING LECTIN, COMPLEMENT
9
TOLL-LIKE RECEPTORS
10
SURFACE LECTINS
11
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).
12
ADAPTIVE (ANTIGEN-SPECIFIC) SYSTEM
13
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.
14
B CELL DIFFERENTIATION
15
T LYMPHOCYTE DEVELOPMENT AND SELECTION IN THYMUS
16
T-CELL RECEPTORSMAINLY RECOGNITION OF
MHC-PEPTIDE COMPLEXES ON OTHER CELLS
SURFACEPURPOSE DETECTION OF CELLS INFECTED BY
HIDDEN INTRACELLULAR PARASITES (e.g. VIRUSES)
17
(No Transcript)
18

19
PRODUCTIVE STIMULATION OF T LYMPHOCYTES REQUIRES
PROFESSIONAL APC (DC) AND COSTIMULATION
20
T LYMPHOCYTES IMPORTANT FUNCTIONAL SUBSETS
21
(No Transcript)
22
(No Transcript)
23

24
BASIC DOGMA FOR THE ADAPTIVE RESPONSES
ANTIBODY RESPONSES (B, Th2) EFFECTIVE FOR
EXTRACELLULAR PARASITESINFLAMMATORY RESPONSES
(Th1, Tc) EFFECTIVE FOR INTRACELLULAR
PARASITESMUTUAL INHIBITION Th1 vs. Th2
(POSITIVE FEEDBACK REGULATION)WRONG CHOICE Th1
vs. Th2 CAN BE FATAL (LEPROSY)
25
Th1 x Th2
26
ESSENTIAL LINK BETWEEN THE INNATE AND ADAPTIVE
SYSTEMSDENDRITIC CELLS
27

28
DENDRITIC CELLS MUST BE PRE-STIMULATED BY
DANGER SIGNALS TO BE ABLE TO ACTIVATE T
LYMPHOCYTES
29
DANGER SIGNALS- EXOGENOUS (PAMPs) -
ENDOGENOUS (e.g. STRESS PROTEINS RELEASED
FROM NECROTIC CELLS)
30

31

32
DISPOSAL
33
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
34
PHAGOCYTOSIS
35
SELF-TOLERANCE
36
BIG PROBLEM HOW TO MAINTAIN SELF-TOLERANCE AND
PREVENT AUTOIMMUNITY?
37

38
IMMUNOLOGICAL HIT (WITH EMBARRASSING
HISTORY)REGULATORY ( SUPPRESSOR) T
LYMPHOCYTES (Treg, Ts, Th3, Tr1)
39

40
REGULATORY T LYMPHOCYTES ARISE IN- THYMUS
(SUPPRESS AUTOIMMUNITY) - PERIPHERY (THESE
DOWN-REGULATE EXCESSIVE IMMUNE RESPONSES
41
PRACTICAL CONSEQUENCES?
42
HOPEFULLY- BETTER VACCINES (WEAK ANTIGENS,
TUMORS?)- IMMUNOSUPPRESSION (AUTOIMMUNE
DISEASES, TRANSPLANTATION)
43

44

45
21st CENTURY THE AGE OF IMMUNOTHERAPEUTICS?WE
WILL SEE IN 20, 50, 100 YEARS
46
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 DCs 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)
47
MOLECULAR MECHANISMSTHOUSANDS OF MOLECULES,
RECEPTORS, CYTOKINES, PATHWAYS
48
(No Transcript)
49
LIPID RAFTS (GEMs)
50

RAFTs - DISTRIBUTION AND HETEROGENEITY
51
GEMs IN IMMUNORECEPTOR SIGNALLING
52
TRANSMEMBRANE ADAPTOR PROTEINS (TRAPs) IN GENERAL
Closely associated with immunoreceptors
Not associated with rafts
Associated with rafts (palmitoylated)
53
Signaling components of leukocyte raftsSrc
kinasesŠtefanová et al, Science
254(1991)1016Cinek et al, J. Immunol.
149(1992)2269Transmembrane adaptor LAT
(critical for TCR signaling)Brdicka et al,
Biochem. Biophys. Res. Commun. 248(1998)356Trans
membrane adaptor PAG (activates Csk regulation
of Src-kinases) Brdicka et al, J. Exp. Med.
191(2000)1591Transmembrane adaptor NTAL
(LAT-like function in BCR and FcR signaling)
Brdicka et al, J. Exp. Med.
196(2002)1617 Transmembrane adaptor p33 (a
role in CD4, CD8 signaling?)Brdicková et al,
submittedCollaboration with Burkhart Schraven
(Heidelberg, Magdeburg)
54
(No Transcript)