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Synopsis on cellular adhesion molecules from Middleton's Allergy: Principles and Practice, 7th edition …

Synopsis on cellular adhesion molecules from Middleton's Allergy: Principles and Practice, 7th edition

Presented by Sawad Boonpiyathad, MD.

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  • 1. Cellular Adhesion Molecule
  • 2.  Cell adhesion molecules (CAMs) - important molecules to selective recruitment of circulating leukocytes to sites of inflammation by promoting cell–cell and cell–matrix interactions Middleton 7th edition
  • 3. CAMs subdivided 3 main families 1. Selectins 2. Integrins 3. Immunoglobulin gene super family (IgSF) members 4. Other; gelectin, cadherin and CD44 Middleton 7th edition
  • 4. Selectin  Selectins are a family of CAMs which bind to specific sugar determinants on the surface of adjacent cells  Selectin family  leukocyte-expressed L-selectin (CD62L)  endothelial-expressed E-selectin (CD62E)  P-selectin (CD62P) which is expressed by both platelets and endothelial cells Middleton 7th edition
  • 5. Klaus Ley and Kansas GS. Nat Rev Immunol 2004 (4):1-11
  • 6. critical 120-amino acid N-terminal Ca2+- dependent (C-type) lectin 2-9 consensus repeats similar to those found in complement regulatory proteins, a transmembrane region 17–35 amino acid cytoplasmic tail epidermal growth factor-like region Middleton 7th edition
  • 7. L-selectin  L-selectin was originally identified as a peripheral lymph node homing receptor responsible for lymphocyte adhesion to high endothelial venules in lymph nodes  Expressed on the tips of the microvilli of most leukocytes, neutrophils, eosinophils, monocytes, naïve T and B cells as well as on the surface of some activated T cells and memory T cells Middleton 7th edition
  • 8. L-selectin  L-selectin mediates leukocyte margination and tethering to endothelium under conditions of shear stress associated with blood flow  L-selectin is irreversibly and rapidly shed from the leukocyte cell surface by endogenous membrane-bound proteases Middleton 7th edition
  • 9. E-selectin  E-selectin is not expressed on the surface of unstimulated endothelium but is induced within several hours following exposure to either IL-1, TNF-α, or bacterial endotoxin  Surface expression of E-selectin in vitro is relatively transient, with endothelial expression levels peaking at 4– 6h and approaching baseline levels by 24 h Middleton 7th edition
  • 10. P-selectin  P-selectin functions as a vascular ligand for most myeloid and lymphoid cells  Expressed by activated platelets  P-selectin is stored in intracellular granules (Weibel- Palade bodies and in α granules of platelets)and can be rapidly translocated to the cell surface when endothelial cells are stimulated with agents such as C5a, histamine, thrombin, phorbol esters or leukotriene C4 Middleton 7th edition
  • 11.  Leukocyte interaction with endothelial P-selectin has been shown to alter leukocyte cellular functions, including superoxide production, integrin-mediated phagocytosis, and production of cytokines and chemokines Middleton 7th edition
  • 12. Selectin ligands  All 3 selectins can recognize glycoproteins and/or glycolipids containing the tetrasaccharide sialyl-LewisX (sialyl-CD15, sLeX) and in some cases its isomer sialyl- Lewis Middleton 7th edition
  • 13. Selectin Ligands Distribution E-selectin Sialylated Lewis X and Endothelium related glycans activated by (eg. CLA1) cytokines (IL1, TNF) P-selectin Sialylated Lewis X and Storage granules & related glycans on PSGL-1 surface of (P-selectin glycoprotein endothelium and ligand-1) platelets L-selectin GlyCAM-1(HEV) Lymphocytes (high MadCAM-1(GALT) expression on Naive CD 34 T cell)
  • 14. Integrin  Structurally related non-covalently linked α and β heterodimeric cell adhesion receptors  α and β subunits are type I transmembrane proteins containing large extracellular domains (700–1100 amino acids) and relatively small cytoplasmic domains (30–50 amino acids)  In vertebrates there are 18 α subunits and 8 β subunits combining to form 24 integrins Middleton 7th edition
  • 15.  4 of the β subunits are expressed on leukocytes (ie, β1, β2, β3, and β7)  β2 and β7 expression limited to leukocytes, and β1 expression occurring on most of the body’s cell types. Middleton 7th edition
  • 16.  Globular heads contain divalent cation-binding domains  Divalent cation: integrin receptor function, interact with integrin ligands  Stalks: Extend from globular heads to plasma membrane  transmembrane segment and cytoplasmic tails  Extracellular domains bind: extracellular matrix glycoproteins, activated complement component and proteins on surface of other cells  Cytoplasmic domains bind cytoskeletal component (vinculin, talin, actin Middleton 7th edition
  • 17. Structure of β2 integrin. Schematic representation of the structure of the β2 integrin heterodimer. The I domain and divalent cation-binding domains on the α subunit that contribute to adhesive function are shown, as is the cysteine-rich repeat region of the β2 subunit that is conserved among integrin β subunits.
  • 18. β1 Integrin  VLA molecules (very late activation)  a1b1 and a2b1: express on T cell 2-4 wks after repetitive stimulation  CD49a-fCD29  Most express on leukocytes  VLA4 (a4b1): constitutively express on some T cell or rapidly induced  homing lymphocytes to endothelium at peripheral site of inflammation  binds to VCAM-1 Middleton 7th edition
  • 19. Subunit (CD, name) Ligands Lymph Mon Neutr Eosino Baso Mast o o o α1β1 (49a/29,VLA-1) Laminin, collagen + − − − − − α2β1 (49b/29,VLA-2) Collagen, laminin + + − − − − α3β1 (49c/29,VLA-3) Collagen, laminin, fibronectin + − − − − + α4β1 (49d/29, VLA-4) VCAM-1, fibronectin CS-1 + + − + + + domain α5β1 (49e/29,VLA-5) Fibronectin + + + − + + α6β1 (49f/29,VLA-6) Laminin + + + + − − αLβ2 (11a/18, LFA-1) ICAM-1,-2,-3,-4, and -5 + + + + + − αMβ2 (11b/18, Mac-1) ICAM-1 and -2, C3bi, − + + + + − fibrinogen, heparin αXβ2 (11c/18, p150,95) C3bi, fibrinogen + + + + + + αdβ2 (αd/18) ICAM-3,VCAM-1 + + + + + − αvβ3 (51/61) Vitronectin, PECAM-1, other − + − − − + RGD peptides α4β7 (49d/β7, ACT-1) MAdCAM-1,VCAM-1, + + − + + − fibronectin CS-1 domain αEβ7 (103/β7, HML-1) E-cadherin + − − − − −
  • 20. β2 Integrin  CD11a-cCD18  Expression restricted to leukocytes  CD11aCD18 = LFA-1(leukocyte function-associated antigen-1) Important role in adhesion of lymphocytes with other cell ex. APCs, vascular endothelium Middleton 7th edition
  • 21.  Mac-1 (CR3) & CR4 mediate leukocyte attachment to endothelial cell & subsequent extravasation  For all leukocytes : processes dependent on β2 integrins  Firm adhesion  Locomotion  Transendothelial migration Middleton 7th edition
  • 22. Integrin signaling  Inside-out signaling  activation of the cytoplasmic tail of the integrin sends a signal to the extracellular domain of the integrin to change its conformation  important in a key step of the adhesion of leukocytes to endothelium  Outside-in signaling  transduce the extracellular signal from the cell surface to the interior of the cell  influence cell proliferation, differentiation, migration, gene transcription, and apoptosis Middleton 7th edition
  • 23. Inside-out signaling
  • 24. Chemokine and Integrin  Activation by chemokines can enhance or inhibit integrin avidity  CCR3: enhance LFA-1 function but inhibiting VLA-4 function  Chemokines, such as eotaxin and IL-8, are potential in situ regulators of integrin activity on leukocytes (i.e. eosinophils and neutrophils, respectively) interacting with vessel walls or migrating across the extracellular matrix Middleton 7th edition
  • 25. IMMUNOGLOBULIN GENE SUPERFAMILY  consists of more than 25 molecules  Have a series of globular Ig-like domains, formed by disulfide bonds
  • 26. leukocyte endothelial cell adhesion, as well as in endothelial cell- endothelial cell, and leukocyte- leukocyte adhesion Structure of immunoglobulin gene superfamily. Schematic representation of several immunoglobulin gene superfamily molecules expressed on endothelial cells and leukocytes. The counterligands, most of which are integrins, are also shown.
  • 27. Intercellular adhesion molecule (ICAM)  ICAM-1 (CD54)  increase following stimulation by cytokines (IL-1, TNF-α, IFN-γ), or bacterial endotoxin  IFN-γ selectively induces ICAM-1 expression without affecting expression of other adhesion molecules  Ligands for the most N-terminal domain of ICAM-1 include LFA-1, fibrinogen, and most serotypes of rhinovirus, whereas the third domain is recognized by Mac-1 Middleton 7th edition
  • 28.  ICAM-2 (CD102)  2 Ig-like extracellular domains that possess 34% homology to the first two domains of ICAM-1  ligand binding site for LFA-1  ICAM-2 is constitutively expressed on mononuclear cells, basophils, mast cells, and platelets, and expression appears to be unaffected by cytokines Middleton 7th edition
  • 29.  ICAM-3 (CD50)  functions as an LFA-1 ligand , αdβ2 integrin  expressed on all leukocytes and on mast cells  ICAM-3 cross-linking results in calcium mobilization, tyrosine phosphorylation, enhanced adhesion, chemokine secretion, and modulation of basophil mediator release Middleton 7th edition
  • 30. Vascular cell adhesion molecule  VCAM-1 (CD106) is a cytokine-inducible endothelial cell adhesion molecule  Expressed on macrophage, DC, astrocytes, & BM stromal cells and respiratory epithelium cell line  Expression on umbilical vein endothelial cells induced by IL-1, TNF-α, or LPS  Expression on endothelial cells induced by IL-4, IL-13
  • 31. Platelet-endothelial cell adhesion molecule  PECAM-1 (CD31) is a cell adhesion molecule expressed on endothelial cells and circulating leukocyte  plays an important role in mediating neutrophil and monocyte transendothelial migration Middleton 7th edition
  • 32. Other adhesion molecules  Galectins  family of β-galactose-recognizing proteins that exhibit a conserved ≈130 amino acid carbohydrate-recognition domain (CRD)
  • 33.  Cadherins  transmembrane proteins that mediate intercellular adhesion in epithelial and endothelial cells  found on structural cells, including endothelium and epithelium and are potentially involved in maintaining tissue integrity, cell– cell recognition, signaling, communication, growth, and angiogenesis Middleton 7th edition
  • 34.  CD44  found in high levels on most leukocytes, endothelial cells, epithelial cells, and other cells  has been implicated in a variety of biological processes including lymphopoiesis, angiogenesis, wound healing, leukocyte extravasation at inflammatory sites, and tumor metastasis  IL3, IL5, GM-CSF  increase CD44 levels on eosinophil Middleton 7th edition
  • 35. DISEASE ASSOCIATED WITH ADHESION MOLECULE DEFICIENCY Human syndrome Adhesion molecule Clinical phenotype defect LAD-I β2 integrin structure Absent or near-absent expression of all β2 integrins; blood neutrophilia with tissue neutropenia, delayed (mutation CD18) umbilical cord separation, recurrent soft tissue infections (e.g., skin, periodontal), impaired pus formation and wound healing; reduced or absent neutrophil adhesion, transendothelial migration, and chemotactic responses; normal rolling adhesion LAD-I variants β2 integrin function β2 integrins expressed but dysfunctional; biologic consequences identical to those of LAD-I LAD-II GFTP gene Defect in fucosylation of many structures, including sialyl-Lewis-X (sLeX); developmental abnormalities (e.g., (guanosine severe mental retardation, short stature, distinctive facial diphosphate-fucose appearance). (hh) blood phenotype, impaired pus formation, pneumonia, periodontitis, and otitis; transporter gene) neutrophil studies, reduced or absent sLeX expression, and sLeX reduced rolling adhesion, normal firm adhesion LAD-III Integrin signaling LAD-III is a very rare disorder characterized by severe recurrent infections, a bleeding tendency and marked (failed inside-out leukocytosis. Leukocytes and platelets have normal signaling) expression of CD18 (defective in LAD-I), normal expression of CD15a (defective in LAD-II), but defective integrin signaling E-selectin E-selectin Case report of child with clinical presentation similar to LAD disease but whose neutrophils expressed normal levels of β1 integrins, L-selectin, and sLeX; staining of inflamed tissue revealed no E-selectin Middleton 7th edition