Red Blood Cell Surface Adhesion Molecules: Their Possible Roles in Normal Human Physiology and Disease
Human erythrocytes express a relatively large number of known adhesion receptors, despite the fact that red blood cells (RBCs) are generally considered to be nonadhesive for endothelial cell surfaces. Some of these adhesion receptors are expressed by many other tissues, while others have more limited tissue distribution. Some adhesion receptors, including CD36 and VLA-4, are only expressed by immature erythroid cells, while others are present on mature erythrocytes. The structure and function of these proteins is reviewed here. LW, CD36, CD58, and CD147 have been shown in other tissues to mediate cell-cell interaction. Other receptors, such as CD44, VLA-4, and B-CAM/LU, can mediate adhesion to components of extracellular matrix. In addition, their roles in normal erythropoiesis, as well as in the pathophysiology of human disease, are summarized. The most convincing evidence for a pathophysiologic role for any of these receptors on erythrocytes comes from studies of cells from patients homozygous for hemoglobin S, as RBC adhesion is thought to contribute to vaso-occlusion. Thus, receptors such as B-CAM/LU may become targets for future therapy aimed at preventing or ameliorating this thrombotic process. Semin Hematol3 7:130-142. Copyright 0 2000 by W.B. Saunders Company.
II”
GENERAL, the major rolesof the erythrocytesuch as oxygen and carbon dioxide transporthave not been thought to require red blood cell (RBC) adhesion.Adhesion of blood cells has been hypothesized to be reserved for such fYmctions as occlusion of sitesof vascularinterruption by platelets or as a preliminary stagein the migration of leukocytes out of blood vesselsand into other tissues. Nevertheless,it hasnow becomeapparent that erythrocytes express on their surfacesmany molecules known to provide adhesionfunctions in other cells.In addition, at least one protein (band 3), a transport protein whose homologs in other tissuesare not generallythought to be involved in adhesion,hasnow been shown to play a role in adhesionunder certain circumstances.Furthermore, at least three human diseases are associated with adhesionof REKs, and in two, adhesionis likely to be integral to pathogenesis. Therefore, it is timely to review which adhesion
moleculesare expressedon the surfaceof erythrocytes, as well as to assess evidence for the role of these molecules both in normal physiology and in the pathophysiology of human disease.
From the Division ofHematology and ComprehensiveSickle Cell Center, Duke UniversityMedical Center,Durham, NC. Supported in part b Grant No. ROl HL58939 fiorn the National Heart, Lung and Blood Imtitute, NationalInstitutes of Health Address reprint requeststo Marilyn J T&n, MD, Box 2615, Duke Umiversi~Medical Center,Durbam, NC2771 0. Copyright 0 2000 b WB. Saunders Company
Molecules Whose tipression to Reticulocytes
0037-1963/00/3702-0004$10.00/O 130
Adhesion Molecules Expressed by Erythrocytes The adhesion proteins known to be expressedon immature and mature circulating erythrocytes are listed in Table 1. The functions of many of these moleculeshave been at least partially characterized through the study of nonerythroid and, in somecases, nonhematopoietic tissues.As illustrated in Fig 1, many of these moleculesare proteins with one or more immunoglobulin superfamily (IgSF) domains and thus belong to a classof ubiquitous adhesion molecules responsiblefor both cell-cell and cellextracellularmatrix interactions.
Is Limited
Two adhesion molecules, CD36 and VL,A-4, are limited to reticulocytes among RBCs. Except during stressreticulocytosis, these molecules are relatively weakly expressedby immature circulating RBCs and are lost ascellsprogressbeyond the reticulocyte stage. CD36, also known as glycoprotein IV when
Seminars in Hematology, Vo137, No 2 (April), 2000:~~ 130-142
131
RBC Suvjiie Adhesion Molecules
Table 1. Adhesion Molecules Erythrocytes Adhesion Molecule
CD36 VLA-4 CD44 CD47 CD58
CD99 CDwl08 CD147 ICAMB-CAM/LU CDw75 Band 3
Expressed
by Circulating
Blood Alternate
Name
Platelet glycoprotein 0~~8~ integrin Hyaluronan receptor Integrin-associated protein Lymphocyte-associated antigen-3 MIC2 gene product
IV
receptor
Anion exchanger
Naka (platelets) Indian
(Ina/lnb)
JMH Oka LW Lutheran
Neurothelin Laminin
Group Antigens (where known)
(AE-1)
Diego,
Wright
expressedby platelets,isa protein of 471 amino acids. It hasat leastone transmembranedomain composed of amino acid residues439 to 465; its 438%amino acid N-terminal region may be entirely extracellular or may contain a secondtransmembraneregion. Its short C-terminal domain (residues 466 to 471) residesin the cytoplasm. Glycoprotein IV is a major membraneglycoprotein of plateletsand is alsohighly expressedby mature monocytes and macrophages, microvascularendothelial cells,mammary endothelial B-CAM/l-U LFA3
1. Erythrocyte adhesion molecules belonging to the immunoglobulin superfamily (IgSF). Mature erythrocytes bear a number of surface proteins containing 1 or more IgSF domains. LFA-3 (lymphocyte function-associated antigen-3, CD58) is attached to the membrane by a glycosylphosphatidylinositol anchor, while LW, Oka (neurothelin), and BCAM/LU are type I membrane proteins with external amino termini and a single transmembrane domain. However CD47, also known as integrin-associated protein, is predicted to have 5 transmembrane domains. Not pictured is the VLA-4 (very late antigen-4) heterodimer, which is only expressed by immature RBCs (reticulocytes).
Figure
cells, and some macrophage-deriveddendritic cells. Glycoprotein IV hasbeenshown to be a receptor for thrombospondin and may alsobe capableof acting as a receptor for collagentypes I, IV and V46 CD36 also binds oxidized low-density lipoprotein, long-chain fatty acids, and anionic phospholipids.35,70 In addition to its important role in platelet adhesion and aggregation,CD36 may act in the recognition and phagocytosisof apoptotic cells,9oaswell asin plateletmonocyte and platelet-tumor cell interactions. Its activity is at leastpartially regulatedby phosphorylation, and the protein is physically associatedwith SK family kinasesin the platelet membrane.5,54 VIA-4, the other adhesion protein limited to reticulocytes, is a heterodimer comprising integrin chains CD49d (~4) and CD29a @J. VIA-4 expressedby lymphocytes and in other tissuesis known to be involved in both cell-cell and cell-extracellular matrix interactions. VIA-4 promotes leukocyteendothelial cell static adhesion through interaction with RAM-I, especiallyas expressedby activated endothelial cells,88~‘31 and this associationinduces a variety of events in the targeted endothelial cells. VIA-4 also binds the propolypeptide of von Willebrand factor.57Lie many other adhesionmolecules, VIA-4 can undergo activation, possibly through a pathway requiring phospholipaseC, Ca2+ mobilization, and/or the Kit receptor.x7,96~‘32 At least some evidence suggeststhat VIA-4 activation may be complex, as a variety of epitopes appear to mediate adhesionto different ligands.7xThe cytoplasmic domain of VIA-4 may be associatedwith cytoskeletal proteins. Adhesion or ligand binding through VIA-4 appearsto have various effectson different tissues;for example,VIA-4 hasbeenpostulatedto play a role in activation of memory B lymphocytes98and to prevent apoptosisof CD34+ stem cells.6,55J’23 Some of the rolesthought to be important for VIA-4 alsoappear to involve its interaction with another membrane protein, CD44. 25~100~121 The CD44 protein is expressedduring erythropoiesis, as well as by mature RBCS,“~ and will be discussedbelow.
Molecules
Expressed by Mature
Erythrocytes
Surprisingly, a number of adhesionproteins remain abundantly expressedin the membranesof mature erythrocytes. One of the first such proteins to be identified on RBCs was CD44, originally described on erythrocytes as In@)-related ~80. CD44 of erythrocytes is an 80-kd type I transmembranepro-
tein42,103 whose expression on erythrocytes is suppressed by the autosomal-dominant In (Lu) gene.l15,1I6 The CD44 protein is a receptor for hyaluronan, as well as for fibronectin.2J59,121 CD44 may serve to anchor epithelial cells to hyaluronan in the basement membrane and to maintain polar orientation. CD44 is involved in leukocyte attachment to and rolling on endothelial cells and in lymphocyte homing to peripheral lymphoid organs and migration to sites of inflarnmation.29,33 It also appears to be important in leukocyte aggregation, which may involve homologous association of CD44. The function of CD44 varies with cell activation: exposure of cells expressing recombinant CD44 to phorbol esters increased CD44 ability to bind hyaluronan, and the pattern of glycosylation of CD44 also regulates its ability to bind its ligands. In some cells, growth factors have been shown to change such glycosylation patterns.11,13,32,h5,73 CD44 activation may also involve G proteins. 2oSignaling throug h CD44 when it binds its ligands can induce cytokine release by leukocytes, as well as provoke T-cell activation. In addition, accumulating evidence strongly supports a role for CD44 in the metastatic potential of a wide variety of cancer cells.lo7 CD47, also called integrin-associated protein, is a transmembrane glycoprotein with five membranespanning domains and a single extracellular V-type IgSF domain.75 In the RBC membrane, CD47 appears to be associated with the Rh macromolecular complex; Rh,d cells express reduced amounts of CD47.75 CD47 forms a signaling complex with l31 and p3 integrins and functionally couples to heterotrimerit Gi proteins. 39CD47 has also been shown to be a receptor for thrombospondin in some tiss~es~~ and facilitates leukocyte spreading and chemotaxis,80~s1 as well as platelet aggregation.28 CD47 knockout mice exhibit a severe defect in leukocyte-mediated defenses against bacterial infection.74 CD%, also called lymphocyte function-associated antigen-3 (LFA-3), is a glycosylphosphatidylinositol (GE?)-anchored protein on erythrocytes, although its mRNA undergoes alternate splicing, giving rise to both GPI-anchored and transmembrane forms on other cells.94,122The extracellular domain of LFA-3 contains one V-type and one CZtype IgSF domain. LFA-3 is widely expressed by both hematopoietic and nonhematopoietic tissues. Among nonhematopoietic tissues expressing LFA-3 are endothelial cells, epithelial cells, and fibroblasts. LFA-3 effects cell-cell adhe-
sion through binding to its ligand, CD2.3,4,84 LFA-3 mediates a number of diierent cell-cell interactions, including interactions between killer and target cells, between antigen-presenting cells and T cells, and between thymocytes and thymic epithelial cells. Ligand binding to LFA-3 provides a costimulatory signal in the immune response. On lymphocytes, its activity is at least partially regulated by CD44.49 The CD99 glycoprotein, also’ called the MICZ gene product, is remarkable for containing five glyX-Y repeats such as those found in collagen and collagen-like proteins. lo CD99 is encoded by a gene in the pseudoautosomal region of the X chromosome, and this gene escapes X-inactivation.43 On thymocytes and T cells, CD99 is involved in rosette formation, as anti-CD99 antibodies block spontaneous T-cell rosettes.16 In RBCs, CD99 is only detectable at the surface of cells that express the X-linked gene encoding xg”; Xg(a-) RBCs have detectable CD99 in the cells, but not at the surface.41 Monoclonal antibodies to CD99 also induce surface exposure of phosphatidylserine in human lymphocytes.’ CDwlO8 is also a GPI-anchored protein and has been shown to carry the JMH blood group antigen. 18,77Although long postulated to serve an adhesion function, little in detail has been known about the function of CDwlO8, due to the fact that its cDNA sequence has only become available recently.130 However, studies in lymphocytes have shown that CDwIO8 is associated with protein tyrosine kinases in the membrane.’ CDwl08 is preferentially expressed on activated lymphocytes, as well as on REKs.~‘~ It is now known to have a single R-G-D (arg-gly-asp) sequence, a common motif for adhesion function. 130 CD147, also called neurothelin, is a transmembrane glycoprotein whose extracellular N-terminal domain contains two C2-type IgSF domains.63 Its 2 l-amino acid transmembrane domain is unusual in that it contains a leucine zipper and charged residues that are highly conserved among species, including rat, chicken, and humans; both of these characteristics offer potential sites of protein-protein interaction. CD147 is expressed by many types of hematopoietic cells, as well as by epithelium and some endothelium.‘06 However, one epitope of CD147 is not presented by RBCs or resting lymphocytes. In contrast, expression of this epitope is markedly increased in granulocytes from patients with rheumatoid arthritis.38 The assignment of an adhesive function to
RBC Su$ae Adhesion Moleada
CD147 comes from several types of observations. Soluble recombinant CD147 binds to various cell types, including endothelial cells and fibroblasts. In addition, some anti-CD 147 monoclonal antibodies inhibit aggregation of the breast cancer cell line MCF-7 and/or inhibit adhesionof MCF-7 cells to type IV collagen, laminin, and fibronectin.” However, more specific information regarding target ligandsfor CD 147 isnot available. LW which has also been called ICAM-4, is a glycoprotein bearing the LW blood group antigens and is homologous to intercellular adhesion molecules (ICAMs 1-3).8 Among hematopoietic cells, expressionof LW appearsrestricted to erythrocytes. LW is a type I transmembrane protein with two extracellularC2 IgSF domains.In RBCs, LW appears to be expressedas part of the macromolecular Rh protein complex, along with the Rh peptides,the Rh glycoprotein (I&50), CD47, and glycophorin B.26 LW antigensare relatively poorly expressedwhen the RhD polypeptide is absent, as in the RhD-negative blood group phenotype.72Recombinant LW protein has been shown capable of binding CD1 l/CD 18 leukocyte integrins.’ B-CAM/LU comprises a pair of spliceoforms encoded by the Lutheran blood group gene.24t82,85 B-CAM (basal cell adhesion molecule) was first describedasa protein expressedat the basalsurfaceof epithelial cells and was thus hypothesized to be an adhesionmolecule that might play a role in attachment of the basal surface of epithelial cells to the basement membrane.24The cDNA for B-CAM encodesa 58%amino acid type I transmembrane glycoprotein containing five IgSF domains: two Vtype and three C2-type domains.The cDNA encoding Lutheran, describedshortly thereafter,encodedan identical protein except for the cytoplasmic domain, which contained an additional 40 amino acids in which a proline-rich motif similar to other sequences known to bind SH3 domainswas found.82The two cDNAs were then shown to arise by alternative splicing of a single pre-mRNA.s5 B-CAM/LU has ratherwide tissuedistribution and isespeciallystrongly expressedby the basalcell layer of epithelium and by endothelial cells.In at leastsometissues,such asliver, expression of B-CAM/LU is also developmentally regulated.82B-CAM/LU hasnow beenshown to be a receptor for laminin. 120Although relatively inactive on normal RBCs, both its expressionand its activity are increasedon RBCs from patients with sickle cell
133
disease.120 B-CAM/LU expressionis also high on a number of malignant epithelial tumors, which also losethe polarity of B-CAM/LU expressionof normal tissues.24 Both spliceoformsbear identical Lutheran blood group antigens,as their extracellular domains are identical. B-CAM/LU is similar in structure to two other known human membraneproteins:CD 166 (ALCAM; activated leukocyte cell adhesion molecule)21and CD 146 (MUC 18, basigin).56,63,93 While neither of theseother proteins is expressedby RBCs, they are also both adhesionmoleculesand mediate cell-celland cell-extracellularmatrix interactions. CDw75 is a sialoglycan with a core epitope comprising NeuAc-(or2,6)gal-(p 1,4)GlcNAc; its expression is thus dependent on the function of an a2,6-sialyltransferase. 12,67CDw75 is weakly expressed by normal RBCs but is increasedin RBCs of the In&) Lu(a-b-) phenotype4’ and perhapsalso in certain diseases(Telen, unpublished observations). CDw75 is expressedby mature circulating surface immunoglobulin-positive B cells,aswell asby B cells of lymphoid secondaryfollicles. A small subpopulation of T cells also expressesCDw75. CDw75 mediatesB cell-B cell interactions through adhesion to its ligand, CD22.36,104 Erythrocyte band 3, alsocalledanion exchanger1 &El), ispart of a fam;ly of anion transport channels and is one of the major membrane proteins of RBCS~~J~*-~~~; about one million copiesof band 3 are present in the membrane of each RBC. Band 3 mediatesCl-/HC03- exchangeasan integral part of respiration. Band 3 is also important to membrane stability and providesa link from the lipid membrane to the cytoskeletonvia its interaction with ankyrin. l l l Band 3 spansthe membrane multiple times, as do most membrane transport proteins, and it bearsa singlelarge oligosaccharideon its fourth extracellular domain.‘12 Severallines of evidence suggestthat at leastone extracellular protein domain plays a role in adhesionaswell.
Possible Roles of Adhesion Molecules in Normal Erythrocyte Biology The adhesion molecules expressedby erythrocytes and discussedabove suggestthat RBCs have at least the potential capability of adhering to a number of ligands,including thrombospondin, fibronectin, laminin, hyaluronan, endothelial cells, and leukocytes. Since adhesionmoleculesare expressedby both early
and mature erythrocytes, it is natural to ask whether these molecules serve an important physiologic fimction during erythropoiesis or, perhaps, during cell senescence. Moreover, if adhesion molecules are only important during erythropoiesis, why are they not lost completely from the membrane of the mature erythrocyte, as is, for example, the transferrin receptor? At this time, we have many more questions than answers. What we have learned thus far is the nature of the targets of these receptors, as outlined above, as well as some of the adhesion characteristics RBCs exhibit during specific stages of development.
Adhesion
Molecules
During
Erythropoiesis
Both pluripotent stem cells and erythroid progenitor cells are believed to “home” to the bone marrow microenvironment, a fact that makes stem cell transplantation possible. Fetal liver and umbilical cord stem cells appear to display different adhesion molecules and diierent adhesion characteristics compared with adult bone marrow progenitor cells.89 However, relatively little is known about the molecules that mediate stem cell adhesion and homing,99 or about the factors or processes that trigger and effect release of more mature cells from the bone marrow into the circulation. Early erythroid progenitors adhere to fibronectin, an extracellular matrix component relatively abundant in bone marrow. Adhesion of erythroid progenitors to fibronectin appears to require the ~$1 integrin (VLA-4), as well as CD44.i21 CD44 is also thought to play a role in adhesion of clonogenic progenitor cells to bone marrow stromal cells; such adhesion can be modulated by antibodies to CD44, concomitantly affecting clonal proliferation. Conversely, downregulation of expression of CD49d (the 014protein of VIA-4) may be important in stem cell release from the bone marrow, such as during granulocyte colony-stimulating factor administration prior to peripheral blood stem cell harvesting by apheresis. lo5 However, other evidence suggests that adhesion and release may be affected by activation or inactivation of adhesion molecules, rather than regulation of expression.45 Additional evidence that other adhesion molecules may be critical for erythroid development is scant. One study implicated GPI-linked molecules in the process of progenitor cell adhesion to bone marrow stroma, but these molecules remain unidentified. In addition, a study of a family in which two siblings had an unusual form of congenital dyserythropoietic
anemia showed that the two affected siblings, but not the unaffected siblings or the parents, had a deficiency of Owl08 from their RBCS.~*~‘~J’~ Thus far, no further relationship has been shown between the CDw 108 deficiency and the congenital anemia. Study of a special class of reticulocytes has offered further insight into the role of adhesion molecules during erythropoiesis. Stress reticulocytes are made during periods of increased marrow activity, as with hyperproductive erythropoiesis due to blood loss or accelerated BBCs destruction; congenital anemias such as thalassemia and sickle cell anemia are also associated with stress reticulocytosis. Stress reticulocytes can be distinguished from normal reticulocytes: they demonstrate increased “2 and decreased “I” antigen expression, increased expression of CL,& integrin, and increased CD36.“i They may also contain higher concentrations of fetal hemoglobin. what is not known is whether the characteristics of these cells are simply the result of premature release from the bone marrow, possibly due to having undergone one less cell division than normal, or whether there is a different level of expression of certain genes due to specific signaling pathways active during heightened hematopoietic activity. A further question is whether any of these differences are functionally useful during increased RBC turnover. While increased expression of adhesion molecules should hamper exit of young RBCs from the bone marrow, it appears that expression of these molecules is increased just when release of more and perhaps younger RBCs is required! However, several lines of evidence suggest that stress reticulocytes may be shorter-lived than normal reticulocytes, due either to the quality of the cells or to host physiology.
Adhesion Molecules Cell Clearance
and Physiologic
Circulating erythroid cells are removed when they become senescent; that is, RBCs do not leave the circulation randomly. Bather, there is a mechanism for the detection of RBCs that are no longer functionally viable, and these cells are specifically cleared from the circulation while normal RBCs are not. Senescent, old, RBCs are characterized by their content of increased amounts of denatured globin,l19 as well as decreased protein kinase activity”“,67 The surface of such cells bears increased amounts of adsorbed QZ2’ Senescent BBC band 3 has reduced associations with the cytoskeleton and undergoes clustering.86 Alter-
135
RBC Su$aceAdhesion Molecules
ation of the large band kssociated polysaccharides also occurs during REX2 aging.14,15Aged RBCs bear an epitope that has been termed the “senescent cell antigen,” which is thought to be a neoepitope of band 3. However, senescent Rl3Cs adhere to vascular endothelial cells no more avidly than do normal RBCs, suggesting that clearance of senescent cells may not be dependent on adhesion to splenic and other reticuloendothelial system endothelial cells. On the other hand, their clearance may depend on macrophages, either through immunoglobulin bound to the RBC surface or by other adhesion mechanisms.22
Possible Roles of Adhesion Molecules in Human Disease Altered RBC adhesion has been found to be characteristic of three human diseases: malaria, diabetes mellitus, and sickle cell disease. Thus far, the mechanism for increased adhesion in each condition appears distinctive; adhesion of RBCs may contribute in a unique way to the overall pathophysiology of each disease.
RBC Adhesion
in Malaria
Malaria is one of the most prevalent infectious diseases in the world. Four species of Phnzodium parasites are known to cause human disease: P falcz$amn, P viva, P ovaik and P mahrzhe. Au of these parasites are transmitted through mosquito bites to humans as sporozoites and then travel to the liver, where they mature in hepatocytes, ultimately giving rise to numerous merozoites, which then invade circulating REV2 Transmission of malaria from one human to another through the mosquito vector, as well as much of the morbidity and mortality of malarial disease, relate in large measure to the cytoadherence of infected RBCs to endothelium. The development and survival of intraerythrocyte gametocytes is thought to depend critically on the ability of infected cells to sequester in the microvasculature of various organs, including spleen and bone marrow. In addition, manifestations such as cerebral malaria are thought to be due to adhesion and sequestration of infected RBCs in the microvasculature. Although several REV2 membrane proteins have long been thought to act as receptors for various Pkzvnodium species, the evidence that erythrocyte membrane proteins act as mediators of adhesion by infected RBCs to endothelial cells is more recent.
Synthetic peptides based on motifs of extracellular loops 3 and 7 of band 3 have been shown to inhibit this adhesion.30 Furthermore, production of murine monoclonal antibodies to infected human RBCs has resulted in antibodies that reacted with exofacial band 3 peptides31 This picture is complicated, however, by another finding: Phmodium parasites produce a protein termed RESA, part of which is homologous to the sequence of human band 3 implicated in adhesion. It appears uncertain, therefore, whether the adhesion of parasitized RBCs is primarily dependent on alterations of band 3 at the surface of parasitized cells or results from presentation of the parasite protein at the RBC surface.97
RE3C Adhesion
in Diabetes Mellitus
Although diabetes mellitus is primarily a disorder of absolute or relative insulin deficiency leading to abnormal glucose utilization, much of the morbidity and mortality of the disease comes from the associated accelerated atherosclerosis. Individuals with diabetes, who comprise about 14 million United States residents and 120 million people worldwide, have twoto fourfold more coronary and cerebral vascular disease than the population overall. This increased incidence of vascular disease is believed to result from the widespread metabolic disturbances observed in diabetes, including abnormal metabolism of carbohydrates, fats, and proteins. During the early development of atherosclerotic lesions, monocytes and macrophages containing large amounts of cholesterol accumulate in the subendothelial space. Eventually, the overlying endothelial monolayer is sufhciently disturbed that both subendothelial extracellular matrix proteins and macrophages are exposed to circulating blood cells. Platelets are among the adherent cells, and the ensuing cellular responses of platelets, endothelial cells, and monocytes stimulate the proliferation of smooth muscle cells. As this cycle proceeds, cellular debris rich in lipids, as well as additional extracellular matrix proteins, accumulate in the subendothelial space, and an atherosclerotic plaque forms. For many years, it has been observed that erythrocytes from patients with diabetes demonstrate abnormal adhesion to endothelial cells. In I98 1, Wautier et al showed that RBCs from patients with diabetes adhered to cultured umbilical vein endothelial cells
136
Marilyn]. Tel&
significantly more than did normal erythrocytes.125 Furthermore, the degree of increased adhesion observed for individual patients was related to the degree of vascular complications. 125These studies led to the hypothesis that a diabetes-related abnormality of BBCs contributes to diabetic vascular disease. Adhesion of RBCs has been shown to lead to prostacyclin release’26 and has been associated with morphologic changes in cultured endothelial cells. 127 One process known to lead to biochemical abnormalities of RBC membranes is nonenzymatic glycation. This reaction affects protein amine groups: in the presence of high glucose concentrations, aldimines are formed and then undergo rearrangements to form ketoamines. Eventually, glucose-derived crosslinks can be formed, leading to production of advanced glycation end products (AGES). Thus, although glycosylated hemoglobin is traditionally measured as an indication of long-term glucose control, the presence of these AGES is similarly the result of the control or lack of control of glucose levels. 124 AGES appear to mediate adhesion to endothelial cells, and endothelial cells have a specific receptor for these moieties. This receptor (RAGE) was cloned in 1992 and was shown to be an IgSF molecule containing one V-type and two C2-type domains, as well as a single transmembrane domain.79 Occupation of this receptor with appropriate ligands produced a positive feedback loop involving increased expression of RAGE and cellular activation.92 Infusion of soluble RAGE in mice was able to block the accelerated atherosclerosis otherwise observed92J28; thus, RBC adhesion to endothelial cells via the AGE-RAGE ligand-receptor pair is likely to have a pathogenic role in the vascular disease associated with diabetes. Work is now proceeding to determine what pharmacologic interventions in addition to tight glucose control can disrupt the AGE-RAGE pathway of endothelial damage.58J34 It also remains to be determined whether RBCs from diabetic individuals have additional abnormalities that affect erythrocyte adhesion or cell-cell interactions. Some investigators have found subtle cell surface abnormalities in RBCs from patients with diabetes. Decreased membrane fluidity and increased lipid peroxidation have been associated with the condition,76 as has a decreased RBC life spana One study demonstrated that RBCs from diabetic individuals express less CD59 on their surfaces,129 while
studies of the expression of acetylcholinesterase, another GPI-linked protein, have produced contradictory results. Whether the expression and function of transmembrane proteins, and especially adhesion molecules, is affected by diabetes remains to be determined. In addition, RBCs in diabetics are relatively deficient in reduced glutarhione, a fact that may predispose to oxidative damage to membrane proteins and lipids. ’ l8 Oxidative stress can in turn increase the formation of glycation end products.58
RBC Adhesion
in Sickle Cell Disease
The stereotypical painful crises and multiorgan darnage characteristic of sickle cell disease result from vaso-occlusion. Sickle cell vaso-occlusion follows both directly and indirectly from the unique properties of the mutant gene product hemoglobin S. When deoxygenated hemoglobin S undergoes polymerization, accumulation of elongated hemoglobin crystals produces cell deformation and reduces elasticity, thus preventing RBCs from passing through capillaries and the small vascular spaces of the spleen. However, increased polymerization of hemoglobin S above a baseline state is likely not the cause of vaso-occlusive crises.34 The tendency of sickle RBCs to form abnormal cell-cell and cell-extracellular matrix adhesions, together with abnormal activation of the coagulation system, are felt to be key factors in pathogenesis (Fig &23,37,51,53,66
Endothelial damage is also characteristic of sickle cell disease. Evidence of such damage includes the presence of increased numbers of circulating endothelial cells, their activated phenotype, and the fact that contact of sickle RBCs with endothelial cells in vitro causes activation and alteration of the phenotype of endothelial cells.17,68,95J01J02When the endothelial lining of blood vessels is severely damaged, the matrix of subendothelial proteins may become exposed to flowing blood, thus making ECM components as well as endothelial cells themselves likely targets for sickle RBC attachment. The adhesive interactions observed in various experimental systems appear to involve BBC adhesion to both endothelial cells as well as to ECM components. 34,50Both static assays and tests under flow conditions document sickle cell adhesion to laminin, thrombospondin,62,‘20 and fibronectinG4 as well as to endothelial cells in culture.53 However,
137
RBC Su f&e Adhesion iVfolecu~s
Altered Membrane Proteins and Surface Properties of Sickle RBC jx_(,_ (__*j=---- -“-~-.l.>m * l-;__lql_lxtll .+ ___._- ^“-b, Activation of =.---v-?-m --=w Increased RBC Adhesion ~ *‘+ Coagulation / 1’ Adhesion to Endotheliu&nd Subendothelium Matrix H Increased Gelation ; .” 4 --;>>*<~~’ *i ‘I ‘,? I*
St Mechanic!! Obstruction~=+~~~$&,ed Tr&Sit Time B #’ ‘9 \? 3 *I’ gb\*, ks ;u a. --*,* P ‘%+-“yv& -x ‘**-------~-~ Endothelial Damage/Activation
Figure 2. Pathways involving RBC adhesion in vasoocclusion. RBCs from patients with sickle cell disease exhibit a number of surface abnormalities, including membrane protein alterations and derangement of normal lipid sidedness, with exposure of phosphatidylserine. These alterations have been hypothesized to contribute to activation of the coagulation system, as well as to RBC adhesion to endothelial cells and extracellular matrixcomponents. Adhesion of RBCs appears to contribute to a cycle of endothelial damage, leading to more cellular adhesion. Delayed transit time of RBCs containing hemoglobin S may then lead to increased gelation and further derangement of the red cell surface.
normally bear a relatively large number of known or putative adhesion molecules, including CD44 (a hyaluronan receptor that can alsoact asa ligand for fibronectin, laminin, and collagen),2,47,59 IAP (a thrombospondin receptor),40,75LW (ICAM-4, an ICAM- homolog),8,9and B-CAM/LU (a laminin receptor).24,82,85J20J33 Sickle RBCs may be more adhesivedue to increasedexpressionof theseadhesion moleculesor due to activation of usually quiescent proteins. Examples abound of cell surface receptors that require activation before they becomecapableof binding their ligands. It has been well demonstrated that CD44 in resting lymphocytes or in transfected cellsexhibits little adhesionto hyaluronan, while the samecellsexposedto various stimuli, such asphorbol estersthat activate protein kinaseC, show markedly increasedhyaluronan binding.l l7 The cytoplasmic portion of CD44 is known to be required for this effect to 0ccut-.7~,~~7 In addition, binding of some antibody ligands (but not others) has a similar effect on CD44, in both nucleated cells and erythrocytes.73.1
sickle cell adhesionto fibronectin and thrombospondin is much weaker than is adhesionto laminin.52~71 The causesof increasedstickinessof sickle RBCs may be multiple. Several investigators have shown that hemoglobin SS-containing, but not hemoglobin AA- or AS-containing reticulocytes, bear the integrin a&t, a moleculecapableof binding fibronectirP and VCAM-1, aswell asglycoprotein n/: which in some circumstancesis a receptorfor collagenand thrombospondin. As has already been discussed,all RBCs
17
The interaction of sicklered cellswith laminin via the B-CAM/LU receptor is the best characterized adhesionphenomenonknown to involve sickleRBCs. B-CAM/LU mediatesa high-affinity interaction of sickleRBCs with laminin, ableto resistshearstresses presentin both small and medium caliber vessels,as shown when recombinant B-CAM/LU is expressed in transfected cells (Fig 3).120In addition, the fifth IgSF domain of B-CAM/LU has been identified as responsible for the interaction with laminin,
1 0.9
Figure 3. Adhesion to immobilized laminin of murine erythroleukemia (MEL) cells expressing either vector alone or a construct encoding recombinant B-CAM. MEL cells transfected with vector alone adhered only minimally to laminin in a variable-height flow chamber.120 However, cells expressing recombinant B-CAM adhered to laminin with a critical shear stress (level at which 50% of cells remain attached) of >lO dyne/cm*.
-Vector
0
2
4
6 Shear
8 Stress.
10 dyne/cmA2
12
14
16
h!adel
but the epitope involved has not been precisely defined.‘33 The process producing alteration of BCAM/LU so that it binds laminin on sickle RBCs could be due to one or more of several factors. Sickle RBCs express an increased B-CAMILU copy number,133 but the scale of this overexpression is not in accord with the degree of increased adhesion sickle RBCs exhibit. Other factors could include association of B-CAM/LU molecules with each other or with other altered membrane proteins, or more direct alteration of the cytoplasmic domain of B-CAM/LU by phosphorylation or by association with other proteins. Much research remains to be accomplished to determine how the adhesion molecules of sickle RBCs are rendered active and how this activity can be interrupted to reverse or prevent vaso-occlusion.
Summary The progressive characterization of the erythrocyte membrane at a molecular level, along with the identification of the functions of the various proteins, has led to the recognition that both immature and mature RBCs express a large number of adhesion molecules. We have yet to discover which adhesive interactions are critical for normal erythroid differentiation and if these adhesive interactions regulate release of RBCs from the bone marrow. We do not yet know whether disruption of any of these adhesive interactions produce abnormal or deficient erythroid differentiation. Nor do we understand how, in disorders such as sickle cell disease, what regulates the activity or inactivity of RBC adhesion molecules. Nevertheless, as many of the molecules implicated in adhesion have now been well characterized at a molecular level, the answers to these questions should be well within our reach.
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