Adhesion Proteins PCOL 582

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Adhesion ProteinsPCOL 582
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Adhesion ProteinsIntegrinsIgSfSelectinsCadheri
ns
L, N
L, N
EC
EC
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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

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Adhesion Proteins

• Organ Disease
• Lung Adult Respiratory Distress Syndrome
• Asthma
• Asbestosis
• Emphysema
• Idiopathic pulmonary fibrosis

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Adhesion Proteins

• Organ Disease
• Kidney Glomerulonephritis
• Interstitial nephritis
• Heart Myocardial reperfusion injury
• Ischaemic heart disease
• Joint Rheumatoid arthritis
• Gout
• Systemic Scleroderma Vasculitis

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Adhesion Proteins
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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.

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Adhesion Proteins

• The majority of adhesion molecules fall into one
  of four families
• cadherins.
• integrins,
• immunoglobulin superfamily (IgSF),
• selectins

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Adhesion Proteins

• The majority of adhesion molecules fall into one
  of four families
• cadherins.
• integrins,
• immunoglobulin superfamily (IgSF),
• selectins

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CADHERINS

• They play a fundamental role in maintaining the
  integrity of multicellular structures and
• are important in the diapedesis of lymphocytes
  and neutrophils

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cadherins
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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.

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Adhesion Proteins

• The majority of adhesion molecules fall into one
  of four families
• cadherins.
• integrins,
• immunoglobulin superfamily (IgSF),
• selectins

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INTEGRINS
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INTEGRINS
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INTEGRINS
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INTEGRINS

• tumor metastasis,
• tissue migration during embryogenesis.
• signalling pathways, transmitting signals both
  into and out from cells

• Important roles
• platelet aggregation,
• inflammation,
• immune function,
• wound healing,

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Integrins

• Integrins are a large family of heterodimeric
  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
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Integrins

• Integrins are present in a low-affinity state in
  resting T cells.
• Chemokines produced by the antigen-presenting
  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.

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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.

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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.

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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.

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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

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INTEGRINS

• CD11a/CD18 (LFA-1) L,N,M ICAMs
• CD11b/CD18 (CR3, MAC-1) N, NK, M ICAMs,
  iC3b
• CD11c/CD18 (CR4, p150.95) M,N,L, NK iC3b

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Adhesion Proteins

• The majority of adhesion molecules fall into one
  of four families
• cadherins.
• integrins,
• immunoglobulin superfamily (IgSF),
• selectins

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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

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IMMUNOGLOBULIN SUPERFAMILY

• CD2 (LFA-2) T-cells LFA-3
• ICAM-1 (CD54) APCs, lymphocytes LFA-1
• ICAM-2 (CD102) APCs, lymphocytes LFA-1
• ICAM-3 (CD50) APCs LFA-1
• LFA-3 (CD58) APCs, lymphocytes CD2
• VCAM-1 (CD106) EC (activated) VLA-4

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IMMUNOGLOBULIN SUPERFAMILY
IgSF
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IMMUNOGLOBULIN SUPERFAMILY

• .

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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

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Adhesion Proteins

• The majority of adhesion molecules fall into one
  of four families
• cadherins.
• integrins,
• immunoglobulin superfamily (IgSF),
• selectins

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SELECTINS

• Are earliest expressed in inflammatory
  responses
• Lead to neurtophil activation and
  extravasation
• L-selectin
• E-selectin
• P-selectin
• Bind to SLex of neutrophil

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SELECTINS
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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

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SELECTINS
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Role of Adhesion Molecules in Pathology States
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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)

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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

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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

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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 IL-1, TNF, and
  IFNg

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Figure 12-2