Adhesion Molecules

"Eschew Obfuscation"

Introduction

Adhesion molecules - one of the fastest growing and most confusing topics in cell biology today. Their clinical relevance is immense, especially concerning the body's local immune response to what it sees as an attack. This can be summarised by saying that the vascular endothelium largely determines the nature and magnitude of the local immune response! Adhesion molecules are however much more important than this. They appear to play a role in cellular interactions throughout the body, and are even more important in development of the organism.

Basic ideas

Nomenclature of cellular adhesion molecules (CAM) is varied and confusing. The following points may clear things up a bit:

homophilic interactions means that similar molecules stick to one another;
heterophilic interactions on the other hand refer to the attraction of different molecules;
a lectin is a protein that can bind to a carbohydrate;
Often CAM concepts are best understood if one understands the embryology;
Expression of a molecule on the cell surface doesn't necessarily mean that the molecule is activated and ready to bind;
Functional redundancy is common (e.g. E-selectin and P-selectin appear to have very similar roles);
One CAM often has multiple functions (e.g. VCAM-1 is important in heart development and immune function);
To further confuse things, one molecule often has multiple names. A list of these synonyms appears below.
A ligand is something which a molecule binds to, ie "that which is bound";
Things are further confused by the cryptic nomenclature used for naming binding sites on ligands: this usually relies on the incredibly non-mnemonic single-letter abbreviations for various amino acids eg. Aspartate = D, Arginine = R, etc.

CAMs are fascinating for several reasons. One is the relatively low affinity they have for their ligands. Initially one wonders why the 'glue' is so 'unsticky', until you realise that this weak binding is actually an advantage - the degree of stickiness can be regulated by the number of CAMs expressed (or the density of CAM ligands on the target), and CAMs also do not have to grab hold of the target like grim death - they can be used (for example) to slow down a moving leukocyte! Very cunning.

The four main types of cell-surface adhesion molecules

CAMs fall into two broad groups, the integrins which can bind molecules in the intercellular matrix as well as sometimes binding to other cells, and a second group that binds to other cells more-or less exclusively. There are three categories in the latter group, the cadherins, the immunoglobulin superfamily, and the selectins. The cadherins and the selectins need calcium ions to bind their targets, while the immunoglobulin superfamily don't.

integrins	cadherins	Ig-superfamily	selectins
over 20, heterodimers, alpha & beta subunits (16[+?] alpha, 8 beta)	homophilic, Ca++ required, common progenitor	No Ca++ needed	lectins
e.g. alpha1-beta1 integrin binds type IV collagen	e.g. cadherin-E acts as a universal intercellular epithelial 'glue'	e.g. NCAMs in neural tissue (homophilic) also VCAM1 (heterophilic)	e.g. P-selectin (heterophilic)

bind matrix OR cells	bind cells

The integrins

There are numerous integrins, each composed of an alpha and beta subunit. Traditionally, they have been classified according to the type of beta subunit (beta 1 to beta 8) but it has now been realised that the alpha subunit is just as important in some instances. For example, alpha-4 integrins bind VCAM-1 and fibronectin, whether they are alpha-4 beta-1 or alpha-4 beta-7. Monoclonal antibodies that block the alpha-4 subunit interfere with this binding, and have been shown to interfere with recruitment of eosinophils and T-cells in the inflamed lung. [ Lobb et al, Eur Respir J Suppl Aug 1996 22 104S-108Spp, also Foster CA, J Allergy Clin Immunol Dec 1996 98(6.2) S270-7pp]

Classifying in the traditional way (by beta subunit) we get the following families

beta-1: bind extracellular components,
e.g. collagens, laminin, fibronectin, but also VCAM-1 (alpha-4);
beta-2: ICAMs, clotting factors, and C3b (alpha_M) - expressed exclusively on leukocytes.
beta-3: bind clotting factors, and more;
beta-4: bind laminin
beta-5: bind vitronectin
beta-6: bind fibronectin
beta-7: bind fibronectin, VCAM-1
beta 8: ?

Integrins on cell surfaces often need to be activated before they will bind their ligand. The alpha_IIbbeta₃ integrin on platelets, for example, is only able to bind fibrinogen, Von Willebrand factor and other blood components when the platelet itself is activated.

What do integrins bind to? Initially it was thought that a particular sequence of amino acids is present in the ligand that binds the integrin. The first one identified was Arg-Gly-Asp, abbreviated to "RGD". Later, a similar sequence called LDV was discovered, and recently it has been established that all of the immunoglobulin superfamily that bind integrins use LDV-like sequences. For the record these are:

VCAM1 == IDSP
MAdCAM-1 == LDTS
ICAMs == IETP or LETS
fibrinogen == QAGDV
type I collagen == DGEA [?] ... {have you had enough yet?}

Integrins do not only bind the cell to their ligands, but serve to transduce the passage of information between the cell and its environment in both directions. Integrin binding probably alters the mechanical structure of the cytoskeleton. Cross-linking and/or clustering of integrins on the cell membrane is also apparently vital for a full biological response to integrin binding! Integrins are probably also vital in permitting the cell to sense its shape, linking the cytoskeleton to the exterior of the cell!

Cadherins

Cadherins are vital for tissue differentiation. E-, P- and N-cadherins are most widely expressed, although there are over thirty, with a wide variety being expressed in the brain in particular. Cadherins are generally homophilic. All cadherins appear to have evolved from the same predecessor. E-cadherin is the intercellular glue that holds together most epithelia. It is also known as uvomorulin. During embryonic development, there is a complex sequence of expression and loss of various cadherins, as cells migrate to their rightful places. N-cadherins are found not only in nervous tissue, but also in the lungs, the heart and the eye lens, and P-cadherins are found in trophoblast.

The Immunoglobulin superfamily

This comprises a vast array of molecules, including:

NCAMs: nerve cell adhesion molecules, homophilic proteins that bind nerve cells but are also expressed in differentiating muscle and glial cells, adhesion being modified by the amount of sialic acid attached to the NCAM.
ICAM1 and ICAM2
VCAM1
PECAM-1
and so on..

The role of some of these molecules is discussed below in the section on leukocyte migration.

Selectins

These are also intimately involved in leukocyte margination and movement into the tissues. P-selectin is particularly important here. It too is discussed below. The ligand for P-selectin is a specific oligosaccharide sequence prevalent on leukocytes, called the sialyl Lewis-x anigen. P-selectin is found on platelets and endothelium, L-selectin on lymphocytes, and E-selectin on endothelium.

A practical example: Leukocyte movement into tissues

Leukocyte extravasation is intimately associated with adhesion molecule interactions. This movement occurs in several phases:

Expression of P-selectin. Within seconds of an "inflammatory signal" being set off in the endothelial cells, P-selectin is released from vesicles within these cells and expressed on the cell surface.
"Rolling" : leukocytes bind to P-selectin, and are slowed down.
Tight adhesion of the leukocyte to the endothelial cell: this is mediated by integrins. The integrins (e.g. alpha_Lbeta₂ integrin) must first be activated, for example by platelet-activating factor! The integrin then binds endothelial ICAM-1 and ICAM-2. The alpha_L containing integrins are normally found on Lymphocytes, while alpha_M integrins are found on Macrophages, and so on.
Yet other adhesion molecules are involved in migration of the leukocyte through the epithelium. PECAM-1 appears important here.

A List of Synonyms

CAM	Binds to..
alpha4beta1 integrin = VLA-4 = CD49d/CD29	VCAM, FN=CS-1, PP-HEV
alpha5beta1 integrin = VLA-5 = CD49e/CD29	FN(RGD)
alpha6beta1 integrin = VLA-6 = CD49f/CD29	LM
alphaLbeta2 integrin = LFA-1 = CD11a/CD18	ICAM-1, ICAM-2
alphaMbeta2 integrin = MAC-1 = CR3 = CD11b/CD18)	ICAM-1, C3bi, FN, FX
alphaXbeta2 integrin = p150,95 = CR14receptor	FN, ?C3bi
alpha4beta7 integrin = LPAM-1 = CD49d/CD-	MadCAM-1, VCAM

LFA-2 = CD2	LFA-3
LFA-3 = CD58	LFA-2
VCAM = CD106	VLA-4 / alpha₄beta₁
ICAM-1 = CD54	CD_II,CD18 / alpha_Lbeta₂, alpha_Mbeta₂
ICAM-2 = CD102	alpha_Lbeta₂
PE-CAM-1 = CD31
CD36 = "leukocyte differentiation antigen"	oxidised LDL, long chain fatty acids,..
MAdCAM-1

E-selectin = CD62E = ELAM-1	sialyated mucinlike molecules
P-selectin = CD62P = GMP-140 = PADGEM	P-selectin glycoprotein ligand1=PSGL-1
L-selectin = CD62L = LAM-1 = Mel-14	Glycosylated mucinlike molecules: Glycam-1,CD34,MadCAM-1

Cadherin E = uvomorulin	homophilic
Cadherin P	homophilic
Cadherin N	homophilic

A Recent Peek at the Literature

This section contains just a very few ideas from the recent literature. It is not meant to be comprehensive, it is just a taste!

Specific adhesion molecules

Selectins:

Selectin binds to glycoconjugate ligands. Activated endothelial cells express E and P selectin; platelets P selectin, and peripheral leukocytes L-selectin. Leukocytes don't stick to and migrate through epitelia well without selectin binding. A ligand for all is P-selectin glycoprotein ligand-1 (PSGL-1 = CD162), a mucin-like leukocyte glycoprotein. It mediates interaction between leukocytes and endothelia/platelets. [Moore KL, Leuk Lymphoma 1998 Mar;29(1-2):1-15] tPA or urokinase-induced fibrinolysis may up regulate local P-selectin expression, and predispose to monocyte infiltration. This may be central to the pathogenesis of atheroma. [Holvoet P & Collen D, Curr Opin Lipidol 1997 Oct;8(5):320-328 ] P-selectin is important not only in adhesion but also for intercellular communication. Binding to monocytes for example causes expression of tissue factor & cytokines. [Furie B & Furie BC, Thromb Haemost 1997 Jul;78(1) pp306-309 ] Expression of L-selectin on CD34 positive cells is deficient in chronic myeloid leukaemia. [Kimura A et al, Leuk Lymphoma 1998 Jan;28(3-4):399-404 ]

Immunoglobulin Superfamily

ICAM-1 :
Expression is a hallmark of the allergic inflammatory process [Canonica GW et al, Allergy 1997;52(34 Suppl):25-30 ] In focal ischemia("stroke"), expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) may cause polymorphs to produce reactive oxygen species, with all the consequences of reperfusion injury. [Kuroda S & Siesjo BK, Clin Neurosci 1997;4(4):199-212 ] "Apart from its role in adhesion of inflammatory cells to vascular endothelium, the extracellular matrix and epithelium, ICAM-1 mediates T-cell/T-cell, T-cell/target cell and T-cell/B-cell interactions. ICAM-1 on the surface of T-cells is thought to participate in signal transduction and may thus modulate several functions including activation, proliferation, cytotoxicity and cytokine production. Because ICAM-1 is the receptor for the major group of rhinoviruses, the most important cause of acute asthma attacks, binding of rhinovirus (RV) to ICAM-1 on T-cells may, at least theoretically, modulate their function." [Stanciu LA & Djukanovic R, Eur Respir J 1998 Apr;11(4):949-957 ]
VCAM1:
VCAM-1 is bound by alpha-4 integrins. Expression is increased by inflammatory cytokines such as interleukin 4. All leukocytes except neutrophils express alpha-4 beta-1 integrins. There is much speculation on the possible use of agents that block this interaction to prevent a variety of inflammatory and autoimmune disorders. [Foster CA, J Allergy Clin Immunol 1996 Dec;98(6 Pt 2):S270-S277; Lobb RR et al, Ann N Y Acad Sci 1996 Oct 31;796:113-123 ] Blocking of alpha-4 integrin based pathways can experimentally decrease "insulitis" in models of type I diabetes mellitus! [Michie S, Curr Top Microbiol Immunol 1998;231:65-83 ] Peritubular capillary VCAM-1 is a good indicator of chronic rejection in renal allografts. [Solez K et al, Kidney Int 1997 May;51(5):1476-1480 ] VCAM-1 may be important in rheumatoid arthritis, expression in synovial lining and stroma being increased. [Veale DJ & Maple C, Drugs Aging 1996 Aug;9(2):87-92 ] When VLA-4 on T cells binds VCAM-1, matrix metalloproteinase is induced in these cells - this may facilitate T cell migration into tissues. [Madri JA et al, Biochem Cell Biol 1996;74(6):749-757 ] Haemopoietic progenitor cells bind bone marrow stroma mainly via VCAM-1. VCAM-1 may also be important in some tumour metastases, for example renal cell carcinoma. [Tomita Y & Saito K, Nippon Rinsho 1995 Jul;53(7):1666-1671 ]
CD22 :
A member of the Ig superfamily, important in development of B cells. [Tedder TF et al, Annu Rev Immunol 1997;15:481-504 ] B-cell responses to antigen receptor aggregation can be modulated by co-aggregation of receptors for immunoglobulin G (Fc gamma RIIB1), complement components (CR2), and alpha 2, 6-sialoglycoproteins (CD22). [Buhl AM & Cambier JC, Immunol Rev 1997 Dec;160:127-138 ] CD22 and other sialoadhesins (myelin associated glycoprotein and CD33) mediate sialic acid binding. [Crocker PR, Glycoconj J 1997 Aug;14(5):601-609 ] CD22 regulates the threshold of antigen-receptor binding, and restricts B cell responses to T-cell zones of secondary lymphoid organs. [O'Rourke L et al, Curr Opin Immunol 1997 Jun;9(3):324-329; Doody GM et al, Curr Opin Immunol 1996 Jun;8(3):378-382 ]
CD36 :
CD36 has been implicated in hemostasis, thrombosis, malaria, inflammation, lipid metabolism and atherogenesis. [Daviet L & McGregor JL, Thromb Haemost 1997 Jul;78(1) pp65-69 ] It is a class B scavenger protein, binding a wide variety of negatively charged macromolecules. Of interest is the way thrombospondin interacts with this receptor: thrombospondin binds on the one hand to CD36 and on the other to alpha V beta 3 integrin. This bridging is one of the mechanisms by which deformed erythrocytes in sickle cell anaemia may damage vessels. [Wick TM & Eckman JR, Curr Opin Hematol 1996 Mar;3(2):118-124 ] Cells may be marked for apoptosis using a mechanism involving CD36 [Savill J, Br Med Bull 1997;53(3):491-508 ]. Platelet-cell interactions may also involve CD36 [Mannel DN & Grau GE, Mol Pathol 1997 Aug;50(4):175-185 ]. A large malarial protein called PfEMP1 binds CD36 and may mediate adhesion to endothelium. [Pasloske BL & Howard RJ, Annu Rev Med 1994;45:283-295 ]
CD44 :
There are many isoforms of this cell-surface glycoprotein, created by alternative splicing of exons v1-10. Isoforms have been well reviewed by Naot et al [Adv Cancer Res 1997;71:241-319] The main ligand is hyaluronic acid. Monocytes and lymphocytes express CD44H, but binding to hyaluronic acid depends on cellular activation. Conversely, leukocyte activation may be influenced by CD44 binding! [Lesley J et al, Glycoconj J 1997 Aug;14(5):611-622 ] CD44 is also important in embryonic development (mediating communication between epithelia and mesenchyme, e.g. on the apical ectodermal ridge. CD44 may present cellular growth factors, and this could be important in tumour metastasis. [Ponta H et al, Int J Biochem Cell Biol 1998 Mar;30(3):299-305 ] CD44 has independent prognostic importance in colon carcinoma. [Mulder JW et al, Histochem J 1997 Jun;29(6) pp439-452 ] CD-44 may also interact with the conserved ezrin protein family (ezrin, radixin, moesin and merlin). This may also be important in tumorigenesis, as merlin for example is a tumour suppressor. [Vaheri A et al, Curr Opin Cell Biol 1997 Oct;9(5):659-666 ] CD44 is also important in haemopoiesis [Wilson JG, Acta Haematol 1997;97(1-2):6-12 ]
L1 :
Important in neuronal adhesion (homophilic), but also binds matrix receptors, alpha V beta 3. [Kadmon G & Altevogt P, Differentiation 1997 Feb;61(3):143-150 ] L1, NCAM and N-cadherin are all important in nerve growth, possibly by activating fibroblast growth factor receptor. [Green PJ et al, Rev Neurol (Paris) 1997 Sep;153(8-9):509-514 ] L1 may interact with the "eph" family of receptors which mediate cell repulsion! [Zisch AH & Pasquale EB, Cell Tissue Res 1997 Nov;290(2):217-226 ] Mutations are associated with a variety of neurological abnormalities, including X-linked hydrocephalus, the MASA syndrome, x-linked complicated spastic paraplegia type 1, and X-linked callosal agenesis. These have all been unified into the CRASH syndrome ( Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus) [Fransen E et al, Hum Mol Genet 1997;6(10):1625-1632 ]
CD23 :
Formerly thought to only be a low-affinity IgE receptor (Fc epsilon RII), " the finding that CD23 displays significant homology with Ca(2+)-dependent (C-type) animal lectins, suggested the existence of natural ligands other than IgE. The recent finding that CD23 interacts with CD21, CD11b and CD11c indicates that CD23 should be viewed not only as a low affinity IgE receptor but also as an adhesion molecule involved in cell-cell interaction." [Bonnefoy JY et al, Int Rev Immunol 1997;16(1-2):113-128 ]
B7 = (CD80/CD86)
T cells are activated on recognition of peptide/MHC complexes by the T cell receptor, but this isn't enough for a full response. One costimulatory stimulus is binding of B7 to CD28, but there are many others. [Croft M & Dubey C, Crit Rev Immunol 1997;17(1):89-118 ] Antigen-presenting cells in systemic lupus erythematosus fail to up-regulate B7 expression when exposed to gamma interferon. [Tsokos GC, Curr Opin Rheumatol 1996 Sep;8(5):395-402 ]

Integrins

Beta-1 integrins :
Probably important in binding of bone marrow stem cells to stroma / matrix, especially VLA-4 and VLA-5 (associated with CD34 expression). [Cacciola RR et al, Acta Haematol 1997;97(1-2):63-66 ]
leukocyte-specific integrins :
"Leukocyte adhesion is of pivotal functional importance. Without adequate adhesion, T lymphocytes and natural killer cells are not cytotoxic, B cells cannot develop into antibody secreting plasma cells, leukocytes do not home into inflamed tissues and myeloid cells are not able to phagocytize or exhibit chemotactic responses. During evolution several leukocyte adhesion molecules have developed belonging to a few molecular families. Among these, the leukocyte-specific integrins (beta 2 integrins, CD11/CD18 molecules) are among the most important." [Gahmberg CG et al, Cell Mol Life Sci 1998 Jun;54(6):549-555 ]

Specific Disease States

As mentioned, adhesion molecules play a pathogenic role in many disease states. We here mention just a few:

Immune complex Glomerulonephritis :
Alpha M beta 2, alpha IIb beta 3, and ICAM-1 are important in polymorph migration and activation; monocyte migration is mediated by alpha L beta 2, alpha 4 beta 1, ICAM-1, VCAM-1, and possibly P-selectin. [Lefkowith JB , Kidney Int 1997 May;51(5):1469-1475]
Acute renal failure:
Blockade of CD11/CD18 integrins and ICAM-1 attenuates experimental renal failure! [Rabb H et al, Kidney Int 1997 May;51(5) pp1463-1468 ]
Acute Rejection:
"Immunohistochemically, strong expression of ICAM-1, vascular cellular adhesion molecule-1 and MHC class II antigens on tubular and endothelial cells along with interleukin-2-receptor bearing infiltrates of T-lymphocytes and significant presence of macrophages were highly correlated with acute rejection. Contrarily, the phenotype of T-lymphocytes including the ratio of CD4+/CD8(+)-lymphocytes, the presence of B-cells or deposits of immunoglobulins and complement factors showed no significant correlation in patients with acute rejection." [Andersen CB, APMIS Suppl 1997;67:1-35 ]
Renal ischaemic injury:
"1. Renal ischaemic-reperfusion injury (IRI) is an important cause of acute renal failure in native kidneys and in allografts. 2. Leucocyte adhesion molecules CD11/CD18, intercellular adhesion molecule-1 and selectins mediate cardiac, skin and muscle IRI in experimental models and recent studies have begun to evaluate their role in renal IRI. 3. The CD11/CD18 has been shown to mediate renal IRI in rat models. 4. Intercellular adhesion molecule-1 has a more prominent role in mediating renal IRI than CD11/CD18 in both rat and mouse models. Blockade of both pathways together appears to provide synergistic protection. 5. Unlike in heart and muscle, L-selectin does not appear to mediate leucocyte recruitment to postischaemic kidney or tubular damage. 6. Leucocyte adhesion molecules may mediate renal IRI by mechanisms other than simply leucocyte migration, such as signal transduction and cell transport." [Rabb H & Postler G, Clin Exp Pharmacol Physiol 1998 Mar;25(3-4):286-291 ]
Cardiopulmonary bypass-induced inflammation
"The systemic endotoxemia that occurs with the institution of cardiopulmonary bypass (CPB) is a potent stimulus for the release of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and IL-6. Raised IL-6 levels have been reported to correlate with post-CPB left ventricular wall-motion abnormalities and myocardial ischemic episodes. Neutrophil-endothelial adhesion is strongly implicated in the inflammation and reperfusion injury that may follow a period of CPB, and organ injury is thought to be, in part, neutrophil mediated. The CD11b neutrophil integrin primarily responsible for endothelial binding is rapidly, permanently, and preferentially expressed on exposure to cytokines. The endothelial ligand intercellular adhesion molecule-1 is also upregulated by cytokine exposure. Nitric oxide (NO) synthesized by the vascular endothelium can inhibit neutrophil-endothelial adhesion by downregulating CD11b/CD18 receptor expression and inhibit platelet activation. The cytokines TNF-alpha, IL-1, and endotoxin can cause the induction of NO synthase and the release of large amounts of NO that may cause tissue injury. Various treatment strategies to reduce CPB-induced inflammation provide evidence to support the causal relationship between CPB-activated cytokine release, neutrophil activation, and stimulation of increased NO synthesis. The significant reductions in TNF-alpha and IL-6 levels with hemofiltration during CPB in children are associated with improved hemodynamics and early postoperative oxygenation. Acadesine can inhibit the upregulation of leukocyte CD11b adhesion receptors, and treatment in patients before and during surgery can reduce early cardiac death, myocardial infarction, and combined adverse cardiovascular outcomes. Recent data suggest that administration of the serine protease inhibitor aprotinin to patients undergoing myocardial revascularization with CPB can reduce TNF-alpha blood levels and blunt neutrophil CD11b upregulation. Preliminary data suggest that aprotinin can inhibit cytokine-induced nitric oxide synthase expression and subsequent NO production by murine bronchial epithelial cells. These effects may explain some of the reported antiinflammatory effects of the serine protease inhibitors." [Hill GE, J Cardiothorac Vasc Anesth 1998 Apr;12(2 Suppl 1):21-25 ]
Adhesion Molecules in Malaria
"Intra-erythrocytic stages of malaria parasites can alter the surface of their host cells and release toxins which induce the production of cytokines, which in turn can up- or down-regulate the expression of adhesion receptors on the surface of microvascular endothelial cells. New adhesion receptors on endothelial cells provide the parasite with increased chances of survival despite an increasing level of host immunity." [Hommel M, Parasitology 1997;115 Suppl:S45-S54 ] Adherence of infected red cells to endothelium is related to ICAM1, and also to CD36, with the possible participation of P-selctin in some instances. [Ho M et al, Blood 1998 Jun 15;91(12):4803-4809 ]
Onset of Diabetes
Manipulation of adhesion molecules is a potential method for preventing type I diabetes mellitus! This seems speculative. [Martin S, Horm Metab Res 1997 Dec;29(12):639-642 ]
Diabetes: Adhesion molecules on platelets.
".. a variety of particularly important platelet features have been identified: a) promotion of liquid phase coagulation; b) regulation of the local vascular tone; c) active modulation of tissue modeling at lesion sites; d) adhesion molecule-mediated communication with a variety of corpuscular blood (and non-blood cells)." .. "In diabetes mellitus of either type, increased populations of circulating platelets have been identified expressing activation dependent adhesion molecules such as activated alpha 2 beta 3 (GPIIbIIIa), lysosomal GP53, thrombospondin or, perhaps most importantly "P-selectin" (CD62 p). This suggests that these adhesion molecules among others can also mediate platelet-leukocyte interactions potentially resulting in inflammatory tissue damaging processes.." [Tschoepe D et al, Horm Metab Res 1997 Dec;29(12):631-635]
Systemic sclerosis:
Gamma-delta T cells, particularly Vdelta1+ T cells expressing CD49d (=VLA4) are prominent in the skin of patients especially around vessels, and are uncommon in controls. [Giacomelli R et al, Arthritis Rheum 1998 Feb;41(2):327-334 ]
Carbon-tetrachloride-induced liver injury:
ICAM-1 up-regulation in the sinusoids is followed by accumulation of "leukocyte function antigen-1" positive cells and then only by necrosis. [Neubauer K et al, Lab Invest 1998 Feb;78(2):185-194 ]
Tumour metastasis
Japanese researchers have found that poly-RGD inhibits metastasis when injected with tumours in experimental models in mice by decreasing the ability of the tumour cells to "stick"; conversely, transfection of tumours with "B7-1" adhesion molecule increases the attractiveness of tumour cells to immune cells, and thus also decreases metastasis. [Saiki I, Jpn J Pharmacol 1997 Nov;75(3):215-242 ]
Cell adhesion may be important in tumour resistance to chemotherapy.
"Cell-cell interactions are known to protect cells from apoptosis, and may help to explain chemoresistance of solid tumors. Recent data implicates p27KIP1, a cyclin-dependent kinase inhibitor, as a possible mediator of adhesion-dependent drug resistance. A model is described whereby cell-cell interactions signal the upregulation of p27, which in turn causes growth arrest in the G1 phase of the cell cycle and resistance to apoptosis induced by anticancer agents that target rapidly dividing cells. We focus on E-cadherin, a homophilic cell-cell adhesion molecule capable of upregulating p27, as one potential mediator of intrinsic resistance of carcinomas." [St Croix B & Kerbel RS, Curr Opin Oncol 1997 Nov;9(6):549-556 ]
Brain ischaemia
Ischaemic brain damage following stroke may be mediated by inflammation and controlled by adhesion molecules: "Evidence is emerging in support of the possibility that the acute inflammatory reaction to brain ischemia may be causally related to brain damage. This evidence includes: 1) the capacity of cytokines to exacerbate brain damage; 2) the capacity of specific cytokine antagonists such as IL-1ra to reduce ischemic brain damage; 3) that depletion of circulating neutrophils reduces ischemic brain injury; 4) and that antagonists of the endothelial-leukocyte adhesion interactions (e.g., anti-ICAM-1) reduce ischemic brain injury. However, it should be kept in mind that cytokines were also argued to provide beneficial effects in brain injury as inferred from studies with TNF-receptor knock-out mice (p55 and p75 knock-out), which display increased sensitivity to brain ischemia, and the capacity of IL-1 to elicit the state of ischemic tolerance upon repeated administration." [Feuerstein GZ et al, Ann N Y Acad Sci 1997 Oct 15;825:179-193 ]
Neutrophil MIGRATION across epithelia.
".. transepithelial migration is dependent on the neutrophil beta 2 integrin CD11b/CD18, and does not appear to involve adhesive interactions with the selectins or intercellular adhesion molecule-1. Recent studies have implicated another transmembrane glycoprotein, CD47, as a crucial component of the transepithelial migration response." [Parkos CA, Bioessays 1997 Oct;19(10):865-873 ]
The same author has written a similar article on movement of PMN across intestinal epithelia: "Adhesive interactions between PMN and intestinal epithelial cells have been shown to be distinct from interactions of PMN with endothelia. In particular, PMN transepithelial migration is modulated by a distinct array of cytokines including interferon-gamma and interleukin-4 and requires the PMN beta2-integrin CD11b/CD18 but is independent of CD11a/CD18, selectins, and intercellular adhesion molecule 1. Additionally, an integral membrane protein termed CD47 has recently been shown to play an important role in PMN transepithelial migration at point(s) subsequent to initial adhesive interactions." [Parkos CA, Am J Physiol 1997 Oct;273(4 Pt 1):G763-G768]
Myocardial Ischaemia.
Leukocyte involvement in myocardial reperfusion injury appears to be heavily dependent on expression of adhesion molecules. [Gumina RJ et al, Basic Res Cardiol 1997 Aug;92(4):201-213 ]
Experimental colitis:
MAdCAM1 interaction with alpha-4 beta-7 integrin is involved with movement of lymphocytes between blood and GIT, and may be important in experimental colitis. [Fong S et al, Immunol Res 1997;16(3):299-311 ]
Liver disease:
"Increased understanding of .. basic mechanisms of communication between resident liver cells and infiltrating leukocytes (neutrophils, lymphocytes, macrophages) not only advances our insight into the pathophysiology of hepatic inflammation but also identifies promising new targets for therapeutic interventions and expands the spectrum of diagnosis and treatment of liver diseases, including alcoholic hepatitis and cirrhosis, viral hepatitis, ischemia-reperfusion injury (transplantation, tumor resection, shock), sepsis- or endotoxin-induced liver injury, acute and chronic rejection, primary biliary cirrhosis, and primary sclerosing cholangitis." [Jaeschke H, Am J Physiol 1997 Sep;273(3 Pt 1):G602-G611 ]

We are still busy adding to this page.

If you have any information or html cross references concerning adhesion molecules, please mail us!

References

The molecular biological and medical literature is replete with references. Some are mentioned above in the text. Many we have not yet seen {mail us}. We liked:

The book "Molecular Cell Biology" (Lodish H et al) 3rd edition 1995 pp 1145-1155 has a fair bit on CAMs.
There is a complex (but good) article on adhesion molecules in autoimmune disease in: Semin Arthritis Rheumatism Feb 1996 25(4) 215-33pp.
McMurray R.
A good article on integrin signalling and binding is:
Acta Anat 1995 154 34-45.
Garrat A, Humphries M.
Specific information on VCAM-1/alpha4-integrin is to be found in:
J Allergy Clin Immunol 1996 98(6.2) S270-7.
Foster C.

Web page author: jo@anaesthetist.com