Transcript Adhesion Proteins PCOL 582

Adhesion
Proteins
PCOL 582
Adhesion
Proteins
Integrins
IgSf
Selectins
Cadherins
L,L,NN
EC
EC
Adhesion Proteins
• White blood cells migrate through
all the tissues of the body.
• Migration:
1. attachment
2. traversing
• Response to:
1. infection
2. necrotic tissue
Adhesion Proteins
Organ
• Lung
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Disease
Adult Respiratory Distress
Syndrome
Asthma
Asbestosis
Emphysema
Idiopathic pulmonary fibrosis
Adhesion Proteins
• Organ
• Kidney
•
• Heart
Disease
Glomerulonephritis
Interstitial nephritis
Myocardial reperfusion
•
• Joint
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• Systemic
Ischaemic heart disease
Rheumatoid arthritis
Gout
Scleroderma Vasculitis
injury
Adhesion Proteins
Adhesion Proteins
These binding reactions are controlled
by a varying array of adhesion
molecules on the surface of the T
lymphocyte that recognize a
complementary array of adhesion
molecules on the surface of the cells
with which the T cell interacts.
Adhesion Proteins
The majority of adhesion molecules
fall into one of four families;
• cadherins.
• integrins,
• immunoglobulin superfamily (IgSF),
• selectins
Adhesion Proteins
The majority of adhesion molecules
fall into one of four families;
• cadherins.
• integrins,
• immunoglobulin superfamily (IgSF),
• selectins
CADHERINS
• They play a fundamental role in
maintaining the integrity of
multicellular structures and
• are important in the diapedesis of
lymphocytes and neutrophils
cadherins
CADHERINS
• There is strong evidence to suggest that
cadherins may be involved in invasion and
metastasis of tumor cells.
• Finally, cadherins may play a role in
intercellular signalling due to the
discovery of kinases regulating
cytoplasmic cadherin phosphorylation.
Adhesion Proteins
The majority of adhesion molecules
fall into one of four families;
• cadherins.
• integrins,
• immunoglobulin superfamily (IgSF),
• selectins
INTEGRINS
INTEGRINS
INTEGRINS
INTEGRINS
Important roles:
• platelet
aggregation,
• inflammation,
• immune
function,
• wound healing,
• tumor
metastasis,
• tissue migration
during
embryogenesis.
• signalling
pathways,
transmitting
signals both into
and out from
cells
Integrins
• Integrins are a large family of heterodimeric
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proteins that play key roles in extracellular
matrix formation, morphogenesis, and cell
adhesion.
There are 17 alpha subunit types and 8 beta
subunit types.
Depending on the association of alpha and
beta subunits, integrins can bind to collagen,
laminin, vitronectin, and fibronectin.
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Integrins
Integrins
• Integrins are present in a low-affinity state in
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resting T cells.
Chemokines produced by the antigenpresenting cell (APC) and signals induced by the
TCR when it recognizes antigen both act on
integrins and lead to their clustering and to
conformational changes that increase the
affinity of the integrins for their ligands.
As a result, the integrins bind with high avidity
to their ligands on APCs and thus promote T
cell activation.
Integrins
• In the immune system, the most
important integrins, those of the b1, b2,
and b7 subfamilies, participate in T-cell
migration and provide stimulatory
signals for T-cell proliferation and
effector functions.
INTEGRINS
Lymphocyte function-associated
antigen-1 (LFA-1, CD11a/CD18).
This is thought to be the most
important adhesion molecule for
lymphocyte activation as antibodies
to LFA-1 effectively inhibit the
activation of both naive and armed
effector T cells.
INTEGRINS
• Expression of the b1 integrins
increases significantly late in T-cell
activation, and they are thus often
called VLA for very late antigen and
play an important part in directing
armed effector T cells to their target
tissues.
INTEGRINS
• Leukocyte adhesion deficiency (LAD)
is a rare inherited disorder in which
key functions of leukocytes are
impaired, notably the migration of
neutrophils to sites of extravascaular
inflammation
INTEGRINS
• CD11a/CD18 (LFA-1)
L,N,M
• CD11b/CD18 (CR3, MAC-1)
N, NK, M
ICAMs
ICAMs,
iC3b
• CD11c/CD18 (CR4, p150.95) M,N,L, NK
iC3b
Adhesion Proteins
The majority of adhesion molecules
fall into one of four families;
• cadherins.
• integrins,
• immunoglobulin superfamily (IgSF),
• selectins
IMMUNOGLOBULIN SUPERFAMILY
• IgSF members are widely utilized in
two areas involving complex
interactions among a diverse array
of cell types;
• during nervous system development
and
• in the regulation of the immune
system
IMMUNOGLOBULIN SUPERFAMILY
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CD2 (LFA-2)
ICAM-1 (CD54)
ICAM-2 (CD102)
ICAM-3 (CD50)
LFA-3 (CD58)
VCAM-1 (CD106)
T-cells
LFA-3
APCs, lymphocytes LFA-1
APCs, lymphocytes LFA-1
APCs
LFA-1
APCs, lymphocytes CD2
EC (activated)
VLA-4
IMMUNOGLOBULIN SUPERFAMILY
IgSF
IMMUNOGLOBULIN SUPERFAMILY
•.
IMMUNOGLOBULIN SUPERFAMILY
• ICAM-1 is expressed by antigen
presenting cells.
• Induced or upregulated by IFNg,
IL-1b, TNFa and LPS.
• Ligands are CD11a/CD18,
CD11b/CD18, CD43 (mucin-like
vascular addressin).
• Adhesion is calcium dependent
Adhesion Proteins
The majority of adhesion molecules
fall into one of four families;
• cadherins.
• integrins,
• immunoglobulin superfamily (IgSF),
• selectins
SELECTINS
• Are earliest expressed in
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inflammatory
responses
Lead to neurtophil activation and
extravasation
L-selectin
E-selectin
P-selectin
Bind to SLex of neutrophil
SELECTINS
SELECTINS
• L-selectin down regulated by IL-1
• P-selectin up-regulated by
thrombin, histamine, peroxides,
TNF-a, IL-4, IL-1, and IFN-g
• E-selectin up-regualted IL-1b,
TNFa and LPS
SELECTINS
Role of Adhesion
Molecules in Pathology
States
Extravasation
• First of these is mediated by
selectins
• Second step depends upon LFA-1
(CD11a/CD18) and CR3
(CD11b/CD18
• Third step, the leukocyte crosses
the endothelial wall, or
extravasates
• Fourth step is the migration due to
chemoattractant molecules (IL-8)
Diseases Associated with
Adhesion Molecules
• Leukocyte adhesion deficiency (LAD)
• The involvement of integrins
• Tumor metastasis
• Colorectal
CD44
• Meleanomas
VLA-4 - selectin
• Osteosarcomas VLA-4 - selectin
• Multiple myeloma N-CAM
Adhesion Molecules and
Allograft Rejection
• E-selectin and VCAM-1
expression were associated with
markers of rejection
• Anti-CD11/CD18 mAbs prevented
early rejection
• anti-ICAM-1 could induce
allograft tolerance
Reperfusion Injury
• Neutrophil the CD11a/CD18 is
expressed subsequently to
reperfusion
• The cytokines involved in the
modulation of CD11a/CD18
expression, are PAF. C5a, IL-1, TNF,
IL-6, and IL-8.
• The ICAM-1 can be controlled by IL1, TNF, and IFNg
Figure 12-2