Mecanismos especficos de reconocimiento

en la respuesta inmune innata

Cintica de respuesta adquirida

durante una infeccin

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

Contrastes entre la inmunidad innata y adaptativa

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

Los cdigos de reconocimiento para diferenciar entre lo propio y

lo no propio: carbohidratos (el cdigo de barras)

Glicoconjugados

B
Glicoprotena

OH CH OH
2

HO
H

OH

Glicolpido

CH2OH O
H H

O
O
H
HN
NH H
H
CH2OH
OH H
H
H
O
C CH3 H
HO
O CH2
H H
H
O
O
H OH
O
O
O
NH4
OH
C
CH2OH
H
H
H
+ - O
H
O
H
H
H
H
HO
OH
H2C H OH
NH H
OH
C CH3
O

O
H H
OH

A
A: Porcin glicano
B: Porcin aglicona

Proceso de glicosilacin en eucariotes

Mecanismos de glicosilacin en procariotes

HO
HO
HO

HO O

N-glicosilacin
HO
HO
HO

OO

OH

HO O

HO
HO

HO

HO O
O

O
O

O
HO

HO

HO

OH

O
O

HO

HO
OH
HO
HO

NH

HO
O
HO

O
NH

H
N
O

O
O

HO

HO

O
O
O
HO

HO
O
HO

NH

OH
OH

O
O

OH
OH
OH

HO

CH2OH

OH
OH

H H

OH

NHAc

OH

OH
HO

H H

OH

NH

C O

OH

CH2

CH2

NH CH CO NH CH2 CO NH CH CO

Esquema de la O-glicosilacin

ST6GalNAc-III
ST6GalNAc-IV
(ST6GalNAc-I)
(ST6GalNAC-II)

Ser/Thr

Ser/Thr

Antgeno disialyl Tn

ST3Gal-I
(ST3Gal-II)
(ST3Gal-IV)

Core 1 GalT

Core 2 GalNAcT

GalNAc

cido Silico

(n)

Gal

Ser/Thr
antgeno Tn

Ser/Thr
antgeno T

ST6GalNAc-I

Ser/Thr

Antgeno sialyl Tn

ST6GalNAc-II
(ST6GalNAc-I)

Ser/Thr

Ser/Thr

GlcNAc
Fuc

Ser/Thr

HO
HO
HO

HO O

HO
HO
HO

OO

OH

HO O

HO
HO

HO

HO O

O
O

HO
HO

HO

OH

O
O

HO

HO
OH
HO
HO

NH

HO
O
HO

O
NH

H
N
O

O
O

HO

HO

O
O
O
HO

HO
O
HO

OH
OH

O
OH
O
OH
HO

O
OH

O
O

OH
OH

HO
O

OH
OH
OH

NH

Estructuras de oligosacridos marcadores de identidad (Los

grupos sanguneos)

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

Soluble
Receptors

Lectins
(MBL, ficolins
lung surfactant)

C1q

Pentraxins
(CRP, SAP)

Mammalian Innate Immune

Receptors

Mammalian Innate Immune

Receptors

Soluble
Receptors

C-type Lectin
Membrane Receptors
Lectins
(MBL, ficolins
lung surfactant)

C1q

PM

Pentraxins
(CRP, SAP)

DC-SIGN

C
C
C
C
C

Selectin

MF-MR

Mammalian Innate Immune

Receptors

Soluble
Receptors

C-type Lectin
Membrane Receptors
Lectins
(MBL, ficolins
lung surfactant)

C1q

PM

Pentraxins
(CRP, SAP)

DC-SIGN

C
C
C
C
C

MF-MR

NK Cell
Receptors

Selectin
CL

C2

J
C2

V/C2

ITIM

ITIM

ITIM

ITIM

ITIM

ITIM

NKGA KIR2DL3 NITR

Mammalian Innate Immune

Receptors

Soluble
Receptors

C-type Lectin
Membrane Receptors
Lectins
(MBL, ficolins
lung surfactant)

C1q

PM

Pentraxins
(CRP, SAP)

DC-SIGN

C
C
C
C
C

MF-MR

NK Cell
Receptors

Selectin
CL

C2

Scavenger
Receptors

J
C2

V/C2

ITIM

ITIM

ITIM

ITIM

ITIM

ITIM

NKGA KIR2DL3 NITR

CD68 CD-36

SR-A

Mammalian Innate Immune

Receptors

Soluble
Receptors

C-type Lectin
Membrane Receptors
Lectins
(MBL, ficolins
lung surfactant)

C1q

PM

Pentraxins
(CRP, SAP)

DC-SIGN

C
C
C
C
C

MF-MR

NK Cell
Receptors

Selectin
CL

C2

Scavenger Complement
Receptors Receptors

J
C2

V/C2

ITIM

ITIM

ITIM

ITIM

ITIM

ITIM

NKGA KIR2DL3 NITR

CD68 CD-36

SR-A

CD14 CR3 FcR

Mammalian Innate Immune

Receptors

Soluble
Receptors

C-type Lectin
Membrane Receptors
Lectins
(MBL, ficolins
lung surfactant)

C1q

DC-SIGN

Pentraxins
(CRP, SAP)

C
C
C
C
C

MF-MR

NK Cell
Receptors

Selectin

Scavenger Complement
Receptors Receptors

Toll-like
Receptors
LBP

CD14
CL

C2

J
C2

PM
LRR

V/C2

ITIM

ITIM

ITIM

ITIM

ITIM

ITIM

CD68 CD-36

SR-A

CD14 CR3 FcR

TIR

MyD
88
NBS

NBS

CARD

CARD

NOD-1

CARD

NOD-2

TIRAP

NKGA KIR2DL3 NITR

TRIF

Intracellular
Receptors
NF-kB

MD-2

Immune response
genes

Specificity of Toll-Like Receptors

(?)

dsRNA

LP

PG
LP

TIR

TIR

TIR

(?)

CpG

Flagellin

Zym
LP

TIR

TIR

TIR

TIR

TIR

TIR

TIR

10

LPS

CpG (?)

PM

Domain Structure of C-type Lectin Subunits

Transmembrane
Domain

Cys-rich

Complementbinding
Domain
(var. number)

Collagen-like

EGF-like
Domain
(var. number)

C RD

C RD

Roles of C-Type Lectins in Innate Immunity

Direct interaction with microbes
opsonins

MBL

macrophage

Roles of C-Type Lectins in Innate Immunity

Direct interaction with microbes
opsonins

macrophage

Roles of C-Type Lectins in Innate Immunity

Direct interaction with microbes
opsonins

macrophage

Roles of C-Type Lectins in Innate Immunity

Direct interaction with microbes
opsonins
cell surface receptors

FMR

macrophage

Roles of C-Type Lectins in Innate Immunity

Direct interaction with microbes
opsonins
cell surface receptors

FMR

bacterium

macrophage

Figure 2-5 part 1 of 2

Figure 2-5 part 2 of 2

Roles of Lectins in Innate Immunity

Complement Pathways
Classical Pathway

Alternative Pathway
C3-H2O

Ab-antigen

Factor D

C1qrs

Factor B

C2
C4

Lytic pathway

C3

C3 convertase

Phagocytosis

Roles of Lectins in Innate Immunity

Classical Pathway

Complement Pathways
Lectin Pathway
Alternative Pathway

Ab-antigen

MBL

MASP
C2

C1qrs

C4

C2
C4

Lytic pathway

C3

C3-H2O
Factor D
Factor B
C3 convertase

Phagocytosis

Interfase entre la inmunidad Innata

y Adaptativa

Interfase entre la inmunidad Innata

y Adaptativa

C3b, C5b

Interfase entre la inmunidad Innata

y Adaptativa

PMN

C3b, C5b

MF-MR

Interfase entre la inmunidad Innata

y Adaptativa
Macrophage

TLRs
PMN

C3b, C5b

Interfase entre la inmunidad Innata

y Adaptativa

MF-MR

Macrophage

TLRs
PMN

C3b, C5b

Target
cell
NCR-L

MHC
Ly49H
CD94

NCR

+ x
NK

Interfase entre la inmunidad Innata

y Adaptativa

MF-MR

Pathogen
destruction

Effector
function

Macrophage

TLRs
PMN

C3b, C5b

Target
cell
NCR-L

Pathogen
destruction

MHC
Ly49H
CD94

NCR

+ x

Effector
function

NK

Interfase entre la inmunidad Innata

y Adaptativa

MF-MR

Pathogen
destruction

Effector
function

Macrophage

TLRs
PMN
IFN-
IFN-

Dendritic
Cell

C3a, C5a

+
Target
cell
NCR-L

MHC
Ly49H
CD94

NCR
Pathogen
destruction

TLRs

Effector
function

+ x
NK

+
IFN-g

Interfase entre la inmunidad Innata

y Adaptativa

MF-MR

Pathogen
destruction

Effector
function

Macrophage

TLRs
PMN
IFN-
IFN-

Dendritic
Cell

C3b, C5b

+
Target
cell
NCR-L

MHC
Ly49H
CD94

NCR
Pathogen
destruction

TLRs

Effector
function

+ x
NK

+
IFN-g

Interfase entre la inmunidad

Innata y Adaptativa

MF-MR

Pathogen
destruction

Effector
function

Macrophage

TLRs
CD40

PMN
IFN-
IFN-

Dendritic
Cell

C3b, C5b

MHC

+
Target
cell
NCR-L

MHC
Ly49H
CD94

NCR
Pathogen
destruction

TLRs

Effector
function

+ x
NK

CD86

+
IFN-g

CD80

Interfase entre la inmunidad

Innata y Adaptativa

MF-MR

Pathogen
destruction

Effector
function

Macrophage

TLRs
CD40

PMN
IFN-
IFN-

Dendritic
Cell

C3a, C5a

MHC

+
Target
cell
NCR-L

MHC
Ly49H
CD94

NCR
Pathogen
destruction

TLRs

Effector
function

+ x
NK

CD86

+
IFN-g

CD80

Interfase entre la inmunidad

Innata y Adaptativa

MF-MR

Destruccin
patgeno

Funcin
efectora

Macrophage

CD40

TLRs
PMN
IFN-
IFN-

CD40L

Dendritic
Cell

C3b, C5b

CD40L
MHC

+
Target
cell
NCR-L

Funcin
efectora

+ x
NK

TCR

TLRs

T Cell

MHC
Ly49H
CD94

NCR
Destruccin
patgeno

B Cell

CD40

CD86

+
IFN-g

CD80

CD28

Interfase entre la inmunidad Innata

y Adaptativa

MF-MR

Destruccin
patgenos

Funcin
efectora

Macrophage

CD40

TLRs
PMN
IFN-
IFN-

CD40L

Dendritic
Cell

C3a, C5a

+
Target
cell
NCR-L

NCR
Funcin
efectora

+ x
NK

TCR

TLRs

T Cell

MHC
Ly49H
CD94

Funcin
Efectora

CD40L
MHC

Destruccin
patgenos

B Cell

CD40

CD86

+
IFN-g

CD80

CD28

Inmunidad
Memoria

Destruccin
patgenos

Los carbohidratos funcionan como seales de interaccin clulaclula

Roles of C-Type Lectins in Innate Immunity

Recognition of endogenous ligands
Rolling adhesion
(selectin binding)

Tight adhesion
(integrin activation)

Extravasation

leukocytes

epithelial
cells

L-selectin

selectin
adhesion
molecule

integrin
adhesion
molecule

integrin

La familia del cido silico

Sialectinas

La familia de SIGLECS

Relacin de estructuras O-glicosiladas y apoptosis

Amado et al., J Biol Chem. 2004;279:36689-97

Y los receptores de Ashwell-Morell ?

Lectin receptors mediating cooled platelet clearance

Colectinas

Colectinas que participan en la respuesta inmune innata

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.

Receptores de colectinas

Fimbria de E. coli Tipo 1

Carbohidratos como mecanismo de reconocimiento

por bacterias

Adhesin de Mannheimia haemolytica a clulas traqueales

bovinas

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.

El rubulavirus porcino LPM

Mecanismos de patogenia

Rubulavirus en Bulbo Olfatorio

Y ahora quien podr salvarnos.

Alteraciones de la glicosilacin asociadas a defectos genticos.

Enfermedad

Alteracin en la glicosilacin

Manifestacin clnica

Fibrosis qustica

Expresin de a1,3 fucosil transferasa,

Sulfoniltransferasas, MUC2 y
MUC5AC.

Poliposis nasal, tos, fiebre

pancreatitis, disfuncin
heptica, infecciones
respiratorias recurrentes
por P. aeruginosa

Sndrome de
Wiskott Aldrich

Exceso en la O-glicosilacin de CD43

por aumento en la expresin de
b 1, 6 N-acetil glucosaminil
transferasa.

Inmunodeficiencia severa
otitis media, eccema,
petequias, linfadenopata,
esplenomegalia, anemia.

Nada es verdad.