Inmunidad Innata 2013
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Transcript of Inmunidad Innata 2013
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Mecanismos especficos de reconocimiento
en la respuesta inmune innata
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Cintica de respuesta adquirida
durante una infeccin
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La respuesta inmune La respuesta a un
contacto inicial ocurre en tres fases:
Las primeras dos requieren reconociemiento asociados a patrones de reconocimiento asociado a la lnea germinal
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Inmunidad Innata Immunidad Adptativa
rpida (minutos a horas) lenta (4-7 das)
varios receptores TCR, Ig
asociada a la lnea germinal recombinacin gentica
distribuda ampliamente distribucin limitada
MF, DC, PMN, NK Clulas B y T
no-clonal clonal
sin memoria immunolgica memoria inmunolgica
Contrastes entre la inmunidad innata y adaptativa
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Los cdigos de reconocimiento para diferenciar entre lo propio y lo no propio: carbohidratos (el cdigo de barras)
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Glicoconjugados
A: Porcin glicano
B: Porcin aglicona
A
B
Glicoprotena
A
B
Glicolpido
OH H
HN H
CH2
H
O H
H
H
H O
HO
O
H
H
H
H
H H
H
H H
H
H H H
H
H
H H H H
H
H
HO OH
OH
O
O
OH O
O
O
O O
O
O
O NH
C CH3
CH2OH CH2OH
CH2OH
CH2OH
H2C
HO
OH
OH NH
OH
C O
CH3
NH4 C OH
OH
+ -
O
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Proceso de glicosilacin en eucariotes
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Mecanismos de glicosilacin en procariotes
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O
O NH
H
N
O
NH HO
HO
O
O
HO
HO NH
O
O O
O HO
O
O
O O
O
O O
O
O
O O
O
O
O O
O
O
O
O
O
O
O
HO
HO HO
HO
HO HO
HO HO
HO HO
OH
HO HO
HO
HO
HO
OH
HO
OH OH
OH
HO
HO HO HO
HO
HO
OH
OH
OH
HO
OH OH
OH
OH
OH
O
CH
2 OH
H
H
H
H
H
NH
Ac
OH
O
N H
C
C
C
O
H2
NH H CO NH CO NH CH CH2
CH2
OH
CO
N-glicosilacin
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Esquema de la O-glicosilacin
Ser/Ser/ThrThr
Ser/Ser/ThrThr Ser/Ser/ThrThr
Ser/Ser/ThrThrSer/Ser/ThrThr
Ser/Ser/ThrThr
Ser/Ser/ThrThr Ser/Ser/ThrThr
antgeno Tn
Antgeno sialyl Tn
6
antgeno T
6
Antgeno disialyl Tn
Core 1 GalT
ST6GalNAc-I ST6GalNAc-II
(ST6GalNAc-I)
Core 2 GalNAcT
ST3Gal-I
(ST3Gal-II)
(ST3Gal-IV)
ST6GalNAc-III
ST6GalNAc-IV
(ST6GalNAc-I)
(ST6GalNAC-II)
Ser/Ser/ThrThr
(n)
Ser/Ser/ThrThr
Ser/Ser/ThrThr Ser/Ser/ThrThr
Ser/Ser/ThrThrSer/Ser/ThrThr
Ser/Ser/ThrThr
Ser/Ser/ThrThr Ser/Ser/ThrThr
antgeno Tn
Antgeno sialyl Tn
6
antgeno T
6
Antgeno disialyl Tn
Core 1 GalT
ST6GalNAc-I ST6GalNAc-II
(ST6GalNAc-I)
Core 2 GalNAcT
ST3Gal-I
(ST3Gal-II)
(ST3Gal-IV)
ST6GalNAc-III
ST6GalNAc-IV
(ST6GalNAc-I)
(ST6GalNAC-II)
Ser/Ser/ThrThr
Ser/Ser/ThrThr Ser/Ser/ThrThr
Ser/Ser/ThrThrSer/Ser/ThrThr
Ser/Ser/ThrThr
Ser/Ser/ThrThr Ser/Ser/ThrThr
Ser/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThr
Ser/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThr Ser/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThr
Ser/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThr
Ser/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThr
Ser/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThr Ser/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThr
antgeno Tn
Antgeno sialyl Tn
6
antgeno T
6
Antgeno disialyl Tn
Core 1 GalT
ST6GalNAc-I ST6GalNAc-II
(ST6GalNAc-I)
Core 2 GalNAcT
ST3Gal-I
(ST3Gal-II)
(ST3Gal-IV)
ST6GalNAc-III
ST6GalNAc-IV
(ST6GalNAc-I)
(ST6GalNAC-II)
Ser/Ser/ThrThr
(n)
Ser/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThrSer/Ser/ThrThr
(n)(n)
GalNAc
cido Silico
Gal
GlcNAc
Fuc
GalNAc
cido Silico
Gal
GlcNAc
Fuc
-
H
N
O
NH HO
HO
O
O
HO
HO NH
O
O O
O HO
O
O
O O
O
O O
O
O
O O
O
O
O O
O
O
O
O
O
O
O
HO
HO HO
HO
HO HO
HO HO
HO HO
OH
HO HO
HO
HO
HO
OH
HO
OH OH
OH
HO
HO HO HO
HO
HO
OH
OH
OH
HO
OH OH
OH
OH
OH
O
O NH
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Estructuras de oligosacridos marcadores de identidad (Los grupos sanguneos)
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Innate immunity mechanisms Recognition (self/non-self)
Soluble
Lectins, LBP, PGBP
Membrane-associated receptors
NK cell, homing, scavenger, complement, TLRs, etc
Intracellular
NODs
Signaling
TLRs
NODs
Effector functions
Soluble
Complement, lysozyme, antimicrobial peptides
Membrane-associated
Nramp
Intracellular
Oxidative burst
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C1q
Lectins
(MBL, ficolins
lung surfactant)
Pentraxins
(CRP, SAP)
Soluble Receptors
Mammalian Innate Immune Receptors
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Selectin
C1q
Lectins
(MBL, ficolins
lung surfactant)
Pentraxins
(CRP, SAP)
Soluble Receptors
C
C
C
C
C
DC-SIGN MF-MR
C-type Lectin Membrane Receptors
PM
Mammalian Innate Immune Receptors
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Selectin
C1q
Lectins
(MBL, ficolins
lung surfactant)
Pentraxins
(CRP, SAP)
Soluble Receptors
C
C
C
C
C
DC-SIGN MF-MR
C-type Lectin Membrane Receptors
Mammalian Innate Immune Receptors
KIR2DL3 NKGA NITR
ITIM
ITIM
ITIM
ITIM
J
NK Cell Receptors
ITIM
ITIM
C2
C2 V/C2
CL V
PM
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Selectin
C1q
Lectins
(MBL, ficolins
lung surfactant)
Pentraxins
(CRP, SAP)
Soluble Receptors
C
C
C
C
C
DC-SIGN MF-MR
C-type Lectin Membrane Receptors
Mammalian Innate Immune Receptors
CD-36 CD68 SR-A
Scavenger Receptors
KIR2DL3 NKGA NITR
ITIM
ITIM
ITIM
ITIM
J
NK Cell Receptors
ITIM
ITIM
C2
C2 V/C2
CL V
PM
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Selectin
C1q
Lectins
(MBL, ficolins
lung surfactant)
Pentraxins
(CRP, SAP)
Soluble Receptors
C
C
C
C
C
DC-SIGN MF-MR
C-type Lectin Membrane Receptors
Mammalian Innate Immune Receptors
CD-36 CD68 SR-A
Scavenger Receptors
Complement Receptors
CR3 CD14 FcR
KIR2DL3 NKGA NITR
ITIM
ITIM
ITIM
ITIM
J
NK Cell Receptors
ITIM
ITIM
C2
C2 V/C2
CL V
PM
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Selectin
C1q
Lectins
(MBL, ficolins
lung surfactant)
Pentraxins
(CRP, SAP)
Soluble Receptors
LRR
NOD-2
NBS
CARD
NBS
CARD
CARD NOD-1
Intracellular Receptors
C
C
C
C
C
DC-SIGN MF-MR
C-type Lectin Membrane Receptors
TIRAP
MyD
88
TRIF
NF-kB
Immune response
genes
Mammalian Innate Immune Receptors
CD-36 CD68 SR-A
Scavenger Receptors
Complement Receptors
CR3 CD14 FcR
KIR2DL3 NKGA NITR
ITIM
ITIM
ITIM
ITIM
J
NK Cell Receptors
ITIM
ITIM
C2
C2 V/C2
CL V
PM
Toll-like Receptors
CD14
TIR
LBP
MD-2
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Specificity of Toll-Like Receptors
PM TIR TIR TIR TIR TIR TIR TIR TIR TIR TIR
1 2 3 4 5 6 7 8 9 10
LP PG
LP
dsRNA
LPS Flagellin Zym
LP
(?) (?) CpG
CpG (?)
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Domain Structure of C-type Lectin Subunits
C RD Cys-rich Collagen-like
EGF-like
Domain
(var. number)
C RD Complement- binding
Domain
(var. number)
Trans-
membrane
Domain
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MBL
Roles of C-Type Lectins in Innate Immunity
Direct interaction with microbes
opsonins
macrophage
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Roles of C-Type Lectins in Innate Immunity
Direct interaction with microbes
opsonins
macrophage
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Roles of C-Type Lectins in Innate Immunity
Direct interaction with microbes
opsonins
macrophage
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Roles of C-Type Lectins in Innate Immunity
Direct interaction with microbes
opsonins
cell surface receptors
macrophage
FMR
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Roles of C-Type Lectins in Innate Immunity
Direct interaction with microbes
opsonins
cell surface receptors
macrophage
FMR
bacterium
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Figure 2-5 part 1 of 2
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Figure 2-5 part 2 of 2
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Complement Pathways
C3
Classical Pathway Alternative Pathway
Ab-antigen
C1qrs
C2
C4
C3-H2O
Factor D
Factor B
C3 convertase
Phagocytosis Lytic pathway
Roles of Lectins in Innate Immunity
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Complement Pathways
C3
Classical Pathway Lectin Pathway Alternative Pathway
MASP
C2
C4
Ab-antigen
C1qrs
C2
C4
C3-H2O
Factor D
Factor B
C3 convertase
Phagocytosis Lytic pathway
Roles of Lectins in Innate Immunity
MBL
-
Interfase entre la inmunidad Innata
y Adaptativa
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C3b, C5b
Interfase entre la inmunidad Innata y Adaptativa
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C3b, C5b
PMN
Interfase entre la inmunidad Innata
y Adaptativa
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C3b, C5b
Macrophage
PMN
TLRs
MF-MR
Interfase entre la inmunidad Innata
y Adaptativa
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C3b, C5b
Macrophage
PMN
+ + x
NK
Target cell
TLRs
MHC
CD94 NCR-L
NCR
Ly49H
MF-MR
Interfase entre la inmunidad Innata
y Adaptativa
-
C3b, C5b
Macrophage
PMN
+ + x
NK
Target cell
TLRs
MHC
CD94 NCR-L
NCR
Ly49H
MF-MR
Pathogen destruction
Effector function
Pathogen destruction
Effector function
Interfase entre la inmunidad Innata
y Adaptativa
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Interfase entre la inmunidad Innata
y Adaptativa
C3a, C5a
Pathogen destruction
Effector function Macrophage
PMN
IFN- IFN-
+ IFN-g
+
Dendritic
Cell +
+ + x
NK
Target cell
TLRs
TLRs
MHC
CD94 NCR-L
NCR
Ly49H
Pathogen destruction
Effector function
MF-MR
-
C3b, C5b
Pathogen destruction
Effector function Macrophage
PMN
IFN- IFN-
+ IFN-g
+
Dendritic
Cell +
+ + x
NK
Target cell
TLRs
TLRs
MHC
CD94 NCR-L
NCR
Ly49H
Pathogen destruction
Effector function
MF-MR
Interfase entre la inmunidad Innata
y Adaptativa
-
C3b, C5b
Pathogen destruction
Effector function Macrophage
PMN
IFN- IFN-
+ IFN-g
+
Dendritic
Cell +
+ + x
NK
Target cell
TLRs
TLRs
MHC
CD80
CD86
CD40
MHC
CD94 NCR-L
NCR
Ly49H
Pathogen destruction
Effector function
MF-MR
Interfase entre la inmunidad
Innata y Adaptativa
-
C3a, C5a
Pathogen destruction
Effector function Macrophage
PMN
IFN- IFN-
+ IFN-g
+
Dendritic
Cell +
+ + x
NK
Target cell
TLRs
TLRs
MHC
CD80
CD86
CD40
MHC
CD94 NCR-L
NCR
Ly49H
Pathogen destruction
Effector function
MF-MR
Interfase entre la inmunidad
Innata y Adaptativa
-
C3b, C5b
Destruccin patgeno
Funcin efectora Macrophage
PMN
IFN- IFN-
+ IFN-g
+
B Cell
T Cell
Dendritic
Cell +
+ + x
NK
Target cell
TLRs
TLRs
MHC
CD80
CD86
CD40
MHC
CD40
TCR
CD28
CD40L
CD40L
CD94 NCR-L
NCR
Ly49H
Destruccin patgeno
Funcin efectora
MF-MR
Interfase entre la inmunidad
Innata y Adaptativa
-
Destruccin patgenos
C3a, C5a
Destruccin patgenos
Funcin efectora Macrophage
PMN
IFN- IFN-
+ IFN-g
+
B Cell
T Cell
Dendritic
Cell +
+ + x
NK
Target cell
TLRs
TLRs
MHC
CD80
CD86
CD40
MHC
CD40
TCR
CD28
CD40L
CD40L
CD94 NCR-L
NCR
Ly49H
Destruccin patgenos
Funcin efectora
Funcin Efectora
Inmunidad Memoria
MF-MR
Interfase entre la inmunidad Innata
y Adaptativa
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Los carbohidratos funcionan como seales de interaccin clula-clula
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Roles of C-Type Lectins in Innate Immunity
Recognition of endogenous ligands
Rolling adhesion
(selectin binding)
Tight adhesion
(integrin activation)
leukocytes
epithelial
cells
Extravasation
L-selectin integrin
integrin
adhesion
molecule
selectin
adhesion
molecule
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La familia del cido silico
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Sialectinas
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La familia de SIGLECS
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Relacin de estructuras O-glicosiladas y apoptosis
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Amado et al., J Biol Chem. 2004;279:36689-97.
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Y los receptores de Ashwell-Morell ?
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Lectin receptors mediating cooled platelet clearance
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Colectinas
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Colectinas que participan en la respuesta inmune innata
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TLR modulation of phagocytosis
A) TLRs may be phagocytic receptors B) TLR signaling may modulate activation of other phagocytic receptors. C) TLR signaling may regulate the rate at which phagosomes mature into phagolysosomes. D) TLR signaling may induce or inhibit production of proteins required at all stages of phagocytosis.
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Receptores de colectinas
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Fimbria de E. coli Tipo 1
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Carbohidratos como mecanismo de reconocimiento por bacterias
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Adhesin de Mannheimia haemolytica a clulas traqueales bovinas
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Gal-4 and Gal-8 are expressed by the intestinal epithelium and each have
CRDs (left). Galectins can tightly bind blood group B carbohydrates, which
some bacteria express on the side chains of surface lipopolysaccharides.
Upon binding of either of these lectins (middle), bacteria rapidly lose
viability. Surface blebs appear as the bacteria are killed. Nat Med. 16 (2010) 263-4.
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El rubulavirus porcino LPM
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Mecanismos de patogenia
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Rubulavirus en Bulbo Olfatorio
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Y ahora quien podr salvarnos.
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Alteraciones de la glicosilacin asociadas a defectos genticos. Enfermedad Alteracin en la glicosilacin Manifestacin clnica
Fibrosis qustica Expresin de a1,3 fucosil transferasa, Poliposis nasal, tos, fiebre Sulfoniltransferasas, MUC2 y pancreatitis, disfuncin MUC5AC. heptica, infecciones respiratorias recurrentes por P. aeruginosa
Sndrome de Exceso en la O-glicosilacin de CD43 Inmunodeficiencia severa Wiskott Aldrich por aumento en la expresin de otitis media, eccema, b 1, 6 N-acetil glucosaminil petequias, linfadenopata, transferasa. esplenomegalia, anemia.
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Nada es verdad.