Red blood cell blood group antigens: structure and function

Red Blood Cell Blood Group Antigens: Structure and Function Marion E. Reid and Narla Mohandas Red blood cell (RBC) blood group antigens are polymorphic, inherited, carbohydrate or protein structures located on the extracellular surface of the RBC membrane. They contribute to the architecture of the RBC membrane, and their individual function(s) are being slowly revealed. The biological qualities assigned to these RBC membrane structures are based on observed physiological alteration in RBCs that lack the component, by documenting similarities in its protein sequence (predicted from the nucleotide sequence of the gene) to proteins of known function and by extrapolation to identified functional homologues in other cells. The varied roles of RBC antigens include membrane structural integrity, the transport of molecules through the membrane, as receptors for extracellular ligands, adhesion molecules, enzymes, complement components and regulators, and in glycocalyx formation. Semin Hematol 41:93-117. © 2004 Elsevier Inc. All rights reserved.

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RYTHROCYTE blood group antigens are polymorphic, inherited, carbohydrate or protein structures located on the extracellular surface of the red blood cell (RBC) membrane. They are recognized by antibodies that are made in antigen-negative individuals after exposure to antigen-positive RBCs through transfusion or pregnancy. The production of blood group antibodies has led to the identification of numerous antigens and phenotypes, including natural knock-out (“null”) phenotypes. More than 250 known antigens have been assigned to 29 blood group systems, each encoded by genetically discrete genes (or closely linked gene families), which have been recognized by the International Society for Blood Transfusion (ISBT).1,2 Carbohydrates attached to proteins or lipids in specific linkages define antigens in the ABO, H, and P blood group systems. Antigens of the Lewis and Chido-Rodgers systems are acquired by the membrane from the plasma. Antigens of the remaining 24 blood group systems are located on integral RBC membrane proteins or on glycosylphosphatidylinositol (GPI)-linked proteins. Genes encoding 27 of the blood group systems have been cloned and sequenced,3 and the molecular bases of many antigens and phenotypes have been delineated (for details, see http://www.bioc.aecom.yu.edu/bgmut/index.htm). Only the genes encoding for the P and RAPH systems remain to be characterized. Table 1 lists the 29 ISBT-recognized blood group systems, the encoding genes, chromosome location, and the major antigens within each system. Years of meticulous studies using hemagglutination assays have provided not only a vast knowledge base regarding the nature of the various blood group antigens but also identified blood samples with unusual characteristics for detailed genetic and molecular analysis. Amino acid sequence, in most cases predicted from the nucleotide sequence, have provided insights into the topology and possible func-

tions of the proteins carrying the blood group antigens, but the biological significance of most of the blood group antigens has yet to be determined. In general, the polymorphisms that we recognize as blood group antigens and that have importance in transfusion medicine do not measurably alter the function of the specific component. The activities predicted for carrier proteins are usually based on sequence homology with proteins of known function, but their function in the mature RBC may not be the same as in other cells, or altered forms may serve as recognition signals in senescent RBCs or play roles during earlier stages of erythroid development. Many RBC membrane proteins with an extracellular component are glycosylated by N- and/or O-glycans. These carbohydrate structures form a negatively charged barrier, the glycocalyx, around the RBC. This barrier, which is approximately 10 to 15 nm deep, prevents spontaneous aggregation of the circulating RBCs, adhesion to endothelium, and protects against microbial invasion. The possible functions of the various components carrying blood group antigens can be divided into the following broad categories: membrane structural integrity, transport proteins, receptors for extracellular ligands, adhesive proteins, extracellular enzymes, complement regulators, and maintenance of surface charge in the glycocalyx. Table 2 lists the possible From the Laboratory of Immunochemistry and the Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY. Supported in part by National Institutes of Health Grants No. HL54459, HL54459, HL31579, and DK26263. Address correspondence to Marion Reid, PhD, Lindsley F. Kimball Research Institute, New York Blood Center, 310 E 67th St, New York, NY 10021. © 2004 Elsevier Inc. All rights reserved. 0037-1963/04/4102-0001$30.00/0 doi:10.1053/j.seminhematol.2004.01.001

Seminars in Hematology, Vol 41, No 2 (April), 2004: pp 93-117

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Table 1. Details of 29 Genetically Discrete Blood Group Systems Gene Name Name (No.)

Gene Location

ISBT

ISGN

Associated Antigens

Component Name

Copy No. per RBC

Carbohydrate GPA (CD235a); GPB (CD235b)

250,000 to ⬎ 1,000,000 GPA: 1,000,000; GPB: 200,000

Carbohydrate RhD (CD240D); RhCE (CD240CE)

500,000 RhD, RHCE combined: 100,000 to 200,000

Lutheran glycoprotein; BCAM (CD239) Kell glycoprotein (CD258)

1,500 to 4,000

ABO (001) MNS (002)

9q34.2 4q28.2-q31.1

ABO MNS

ABO GYP GYPB

P (003) Rh (004)

22q11.2-qter 1p36.13-p34.3

P1 RH

P1 RHD, RHCE

Lutheran (005)

19q13.2

LU

LU

Kell (006)

7q33

KEL

KEL

Lewis (007)

19p13.3

LE

FUT3

Duffy (008)

1q22-q23

FY

DARC

Kidd (009) Diego (010)

18q11-q12 17q21-q22

JK DI

SLC14A1 SLC4A1

Yt (011) Xg (012)

7q22 Xp22.32

YT XG

ACHE XG, MIC2

A, B, A, B, A1 M, N, S, s, U, He, Mia, Vw ⫹ 35 more P1 D, C, E, c, e, f, CW, V, G, ⫹ 36 more Lua, Lub, Lu3, Lu4, Aua, Aub ⫹ 12 more K, k, Kpa, Kpb, Ku, Jsa, Jsb ⫹ 17 more Lea, Leb, Leab, Lebh, ALeb, BLeb Fya, Fyb, Fy3, Fy4, Fy5, Fy6 Jka, Jkb, Jk3 Dia, Dib, Wra, Wrb, Wda, Rba ⫹ 14 more Yta, Ytb Xga, CD99

Scianna (013)

1p34

SC

ERMAP

Sc1, Sc2, Sc3, Rd

Dombrock (014)

12p13.2-p12.1

DO

DO

Colton (015)

7p14

CO

AQP1

Doa, Dob, Gya, Hy, Joa Coa, Cob, Co3

LandsteinerWiener (016)

19p13.3

LW

ICAM

LWa, LWab, LWb

Chido/Rodgers (017) Hh (018)

6p21.3

CH/RG

C4A, C4B

19q13.3

H

FUT1

CH1, CH2, Rg1 ⫹ 6 more H

Kx (019) Gerbich (020)

Xp21.1 2q14-q21

XK GE

XK GYPC

Cromer (021)

1q32

CROM

DAF

Knops (022)

1q32

KN

CR1

Indian (023)

11p13

IN

CD44

Kx Ge2, Ge3, Ge4, Wb, Lsa, Ana, Dha Cra, Tca, Tcb, Dra ⫹ 9 more Kna, Knb, McCa, Sla, Yka ⫹ 3 more Ina, Inb

Ok (024)

19pter-p13.2

OK

BSG

Oka

Raph (025) JMH (026) I (027) Globoside (028) GIL (029)

11p15.5 15q22.3-q23 6p24 3q25 9p13

MER2 JMH IGNT ␤GalN AcT1 GIL

MER2 SEMA-L IGNT B3GALT3 AQP3

MER2 JMH I P GIL

3,500 to 17,000

Carbohydrate

Not determined

Fy glycoprotein (CD234) Kidd glycoprotein Band 3 (CD233)

13,000 to 14,000

Acetylcholinesterase Xga glycoprotein CD99 Sc glycoprotein (ERMAP) Do glycoprotein (ART4) Channel-forming integral protein LW glycoprotein (ICAM-4) (CD242) C4A; C4B Carbohydrate (CD173) Xk glycoprotein GPC (CD236); GPD

14,000 to 18,000 1,000,000

10,000 9,000 Not determined Not determined 120,000 to 200,000 D⫹: 4,400 (adult) 5,150 (cord); D⫺: 2,835 (adult) 3,620 (cord) Not determined GP O adult: 1,700,000; lower on other ABO phenotypes 1,000 GPC: 135,000; GPD: 50,000

DAF (CD55)

20,000

CR1 (CD35)

20 to 1,500

Hermes antigen (CD44) Neurothelin, basoglin (CD147) Not defined H-Sema-L (CD108) Carbohydrate Carbohydrate AQP3

2,000 to 5,000 Not determined Not determined Not determined

Abbreviations: ISBT, International Society of Blood Transfusion; ISGN, International Society for Gene Nomenclature.

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functions of the structures carrying the blood groups, the type of membrane component, presence in other tissues, null phenotypes, and disease associations. This review focuses on the structures of the molecules that express RBC blood group antigens, their known or possible functions, and the potential biological significance of blood group polymorphisms.

The Erythrocyte Membrane The erythrocyte membrane consists of lipids, proteins, and carbohydrates, which interact to form a dynamic and fluid structure with the strength and flexibility needed to survive 4 months in the circulation. Numerous cycles of extensive deformation are suffered as the RBC passages through narrow capillaries and sinusoids in the spleen, yet the RBC is without intracellular machinery to repair membrane damage.4 The RBC membrane is a composite structure with a lipid bilayer linked to a spectrin-based skeletal protein network by the interaction of cytoplasmic domains of bilayer-embedded membrane proteins with skeletal proteins. Cholesterol, phospholipids, and glycolipids form the bilayer, with hydrophobic tails facing inward and hydrophilic polar head groups outward on both extracellular and cytoplasmic faces of the membrane. The lipid molecules can diffuse rapidly within the plane of monolayers, but movement across the bilayer is rather slow (low rates of “flip-flop”), enabling the maintenance of membrane “sidedness.”5 Peripheral skeletal proteins form a two-dimensional protein network under the lipid bilayer (the membrane skeleton).6 The membrane skeleton is associated with the lipid bilayer through specific interactions between the skeletal proteins and the cytoplasmic domains of integral transmembrane proteins. The major and well-defined relationships include spectrin interaction with ankyrin, which in turn binds to the cytoplasmic domain of band 3 (anion exchanger, AE1), a multipass protein; and spectrin interaction with protein 4.1, which binds to the single-pass proteins glycophorin C (GPC) and glycophorin D (GPD). Some integral membrane proteins interact with other transmembrane proteins (such as band 3 with glycophorin A [GPA]; Kell with Kx; RhD and RHCE with RhAG), or with lipids (for example, Rh). Indeed, many of the proteins carrying blood group antigens associate with and reside in the milieu of the erythrocyte membrane as macromolecular complexes.7,8 Carbohydrates are essentially restricted to the extracellular surface of the RBC membrane, where they collectively form a negatively charged environment, the glycocalyx, which plays an important role in preventing red cell-red cell and RBC-endothelial interactions. The majority of carbohydrates are attached to lipids on a ceramide backbone and to proteins by linkages to aspar-

agine (N-linked) or to serine or threonine (O-linked) residues.9 Figure 1 depicts the membrane components that carry blood group antigens.

Terminology for Blood Groups A committee for terminology of RBC surface antigens, sanctioned by the ISBT, has established guidelines. Over time, notations devised to describe blood group antigens have changed. A single letter (A, D, K), a symbol with a superscript (Fya, Jkb, Lua), a symbol with a number (Fy3, Lu4, K12), and three or four letters (DAK, MAR, FPPT, TSEN) may be used within the same blood group system,1 creating very confusing terminology. Many components carrying blood group antigens have been assigned CD (cluster of differentiation) numbers. Here we use the terminology recommended by the ISBT.

Expression Pattern Many proteins and carbohydrate structures carrying blood group antigens are also expressed on nonerythroid cells: for examples, A, B, H, Kna (CD35), Ina (CD44), Oka (CD147), and Cromer-related antigens (CD55) have a wide tissue distribution.10,11 The ability to culture stem cells and to separate cells based on their staged differentiation, plus the availability of monoclonal antibodies, has enabled the timing of expression of blood group antigens during in vitro erythroid maturation. As the proerythroblasts differentiate into reticulocytes, the order of blood group antigen expression is as follows: GPC, Kell, RhAG, LW, RhCE, GPA, band 3, RhD, Lutheran, and Duffy.12 There is little information on the function of these various proteins during erythroid development.

Ontogeny Several blood group antigens are not expressed or are only weakly expressed on fetal RBCs and do not reach adult levels until approximately 2 years of age. Cord RBCs do not express Lea, Sda, Ch, Rg, or AnWj antigens. Cord red cells express the following antigens more weakly than do adult RBCs: A, B, H, P1, I, Leb, Lua, Lub, Yta, Vel, Doa, Dob, Gya, Hy, Joa, Xga, Kn, and Bg. In contrast, the i and LW antigens are more strongly expressed on cord RBCs than on adult cells.

Natural “Knockouts” in Humans The detection of an alloantibody to a high incidence antigen during compatibility or prenatal testing has led to the discovery of RBCs with null phenotypes. Null RBCs lack certain blood group antigens and usually also the specific carbohydrate or carrier protein is

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Table 2. Function, Structure, Tissue Distribution, and Disease Association for Some Components Carrying Blood Group Systems System Name

Function

Structure Membrane attachment; interacts with 4.1R and p55 Structure and transport Anion exchanger

Predicted Topology (no. of amino acids)

Present in Other Tissue

Null Phenotype

Disease Association

Gerbich

Type I single pass (GPC 128; GPD 107)

Fetal liver, renal endothelium, brain, cerebellum, ilium

Leach

Hereditary elliptocytosis, hemolytic anemia; decreased 4.1R and p55

Diego

Multipass with 14 spans (911)

1 case— transfusiondependent

Southeast Asian ovalocytosis, hereditary spherocytosis, renal tubular acidosis

Kx

Multipass with 10 passes (444)

Granulocytes, kidney: intercalated cells of distal and collecting tubules, testes Fetal liver, adult skeletal muscle, brain, pancreas, heart

McLeod

Rh

Multipass with 12 spans (RhD 417; RhCE 417)

Acanthocytosis, muscular dystrophy, hemolytic anemia; McLeod syndrome sometimes associated with CGD Hemolytic anemia, hereditary stomatocytosis, hematological malignancies

Kidd

Multipass with 10 passes (389)

Colton

Multipass with 6 spans (269)

GIL

Multipass with 6 spans (292)

Duffy

Multipass with 7 spans (338)

Binds hyaluronic acid, mediates adhesion of leukocytes

Indian

Type I single pass (341)

Binds laminin

Lutheran

Binds CD11/CD18; ligand for integrins

LandsteinerWiener

IgSF type I (Lu 597; BCAM 557) IgSF type I (241)

Fetal liver, placenta, arterial walls, marrow epithelium Blood cells, epidermis, blood/brain barrier

Possible adhesion molecule Adhesion molecules

Ok

IgSF type I (248)

All cells tested

Not described

Xg

JMH

Scianna

Type I (475)

Fibroblasts, fetal liver, spleen, thymus, adrenal, adult marrow Activated lymphocytes, neurons, epithelia, testes Erythroid-specific

Not described

Adhesion molecule Function in RBCs not known Possible adhesion molecules Binds microbes; glycocalyx; complement regulation; chaperone for band 3

type I single pass (Xg 180; CD99 163) GPI-linked (656)

MNS

Type I single pass (GPA 131; GPB 72)

Possible neurotransmitter; predicted topology

NH4 transport (?) or CO2 transport?

Transport Urea transporter

Water channel

Glycerol/water/urea transport Receptors/adhesion Chemokine/Plasmodium vivax receptor

Rhnull

Vasa recta endothelium; ?renal medulla vascular supply Kidney, liver, gall bladder, eye, capillary endothelium Kidney, liver, pancreas, lung, spleen, prostate Endothelial, and epithelial cells, Purkinje cells of brain, colon, lung, spleen, thyroid, thymus, collecting ducts of kidney Wide tissue distribution

Jk(a⫺b⫺)

Impaired urea transport, urine concentrating defect

Co(a⫺b⫺)

Monosomy 7, congenital dyserythropoietic anemia

GIL-negative

Fy(a⫺b⫺)

Resistance to P vivax invasion

1 case (?acquired) congenital dyserythropoietic anemia [also Yt(a⫺b⫺)] Lu(a⫺b⫺) recessive type

Depressed in pregnancy

LWnull also Rhnull

Not described

Increased expression possibly involved in vaso-occlusion in sickle cell disease Depressed in pregnancy and in some malignant diseases

Absent form PNH III RBCs

Sc:⫺1,⫺2,⫺3 Mk Mk (lack GPA & GPB) En(a⫺) (lack GPA) S⫺S⫺ (lack GPB)

Decreased P falciparum invasion; may be receptor for E coli

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Table 2. (Continued) Function

System Name

Enzymes Cleaves big Kell endothelin 3 to ET-3, a potent vasoconstrictor Acetylcholinesterase Yt

Enzymatic (ART4) Complement Complement regulation, binds C3b; disassembles C3/C5 convertase Complement regulation, binds C3b and C4b; mediates phagocytosis

Complement components

Other Glycocalyx

Predicted Topology (no. of amino acids) Type II single pass (732)

GPI-linked (557)

Present in Other Tissue Bone marrow, fetal liver, testes, brain, lymphoid tissue, heart Granulocytes, innervated tissue, including brain and muscle

Null Phenotype

Disease Association

Knull (K0)

1 case Absent from PNH III (?acquired) RBCs congenital dyserythropoietic anemia [also In(a⫺b⫺) Gy(a⫺) Absent from PNH III RBCs

Dombrock

GPI-linked (314)

WBCs

Cromer

GPI-linked (347)

Vascular endothelium, Inab epithelia GI, GU, CNS; soluble form in plasma and urine

Absent from PNH III RBCs; Dra is the receptor for uropathogenic E coli

Knops

Type I single pass (1998)

Antigens depressed in certain autoimmune and malignant conditions

Chido/Rodgers

Adsorbed from plasma

B lymphocytes, a subset of T lymphocytes, other nucleated blood cells, glomerular podocytes, follicular dendritic cells Plasma

ABO

Carbosyltransferases type II (354)

Glycocalyx

H

Glycocalyx

Lewis

Glycocalyx

I

Glycocalyx

GLOB

Unknown

RAPH

Epithelial cells, secretions, ectoderm, endoderm Fucosyl-transferase type II (365) Broad distribution; soluble—all fluids except CSF in secretors Fucosyltransferase type II (361) Blood cells, Adsorbed onto RBC gastrointestinal tract, skeletal muscle, kidney, adrenal N-acetylglucosaminyltransferase Broad tissue type II (400) distribution N-acetylgalactosaminyltransferase Blood cells; soluble type II (321) form in cyst fluid Unknown Fibroblasts; some cancer cells

Not reported

C4-deficient RBCs Certain phenotypes have predisposes for increased SLE susceptibility to some autoimmune conditions and infections Group O

Altered expression in some hematological disorders

Bombay (Oh)

Decreased in some tumor cells; increased in hematopoietic stress Increased expression in fucosisdosis; Lewis antibodies may be important in graft rejection Cateracts in Asians

Le(a⫺b⫺)

i (adult I–negative)

MER2-null

Receptor E coli and B19 parovirus The 3 known human anti-MER2 were made by Indian Jews with renal failure

Abbreviations: IgSF, immunoglobulin superfamily; GI, gastrointestinal; GU, genitourinary; CNS, central nervous system.

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Figure 1. Model of RBC membrane components carrying blood group antigens. The various antigens determinants are represented by the carbohydrate moieties attached to lipids or to proteins, protein backbone alone, or by both protein backbone and the attached carbohydrate moieties. Most protein blood group antigens are carried on integral transmembrane (type I, type II, and multi-pass) proteins; however, a few are carried on glycosylphosphatidylinositol (GPI)-linked proteins, and antigens in one system (Ch/Rg) are adsorbed from the plasma. The components carrying blood group antigens are named with the blood group system in parentheses.

absent. These natural “knockout” models have revealed insights into the function of membrane proteins.

Membrane Proteins With Structural Function Several blood group systems are carried on proteins that have structural functions and thus are involved in the maintenance of the bioconcave discoid shape and membrane material properties of the RBC (Table 3). The absence of GPC and GPD, band 3, Kx, Rh, or Lutheran proteins result in morphological changes. Proteins carrying Diego, Kx, and Rh antigens also are involved in transport of molecules across the lipid bilayer (Tables 1 and 2).

Gerbich Blood Group System and GPC and GPD The Gerbich (Ge) antigens, three of high incidence (Ge2, Ge3, and Ge4) and four of low incidence (Wb, Lsa, Ana, and Dha), are carried on the extracellular

domain of GPC and/or GPD.13 GPC and GPD are type I membrane glycoproteins encoded by the GYPC gene on chromosome 2. GPD is generated from the same mRNA as GPC by means of an alternate initiation codon.14,15 GPC is a 32-kd protein bearing one Nlinked oligosaccharide and approximately 12 O-linked oligosaccharides in the N-terminal, extracellular domain. The desialylated form of GPC is exposed on the surface of early erythroid progenitors (erthrocyte burst-forming unit [BFU-E]) and is a useful marker of early normal or leukemic erythroid differentiation.16 Normally, glycosylated GPC first appears at the later erythroctye colony-forming unit (CFU-E) stage (17). The transmembrane domain passes through the lipid bilayer as a single ␣-helix. The cytoplasmic domain of GPC forms a complex with protein 4.1 (4.1R) and p55 and is a major site of attachment of the spectrin-actin– based skeleton to the plasma membrane. Residues Tyr94 to Arg166 of the 30-kd membrane binding domain of 4.1R interact with the positively charged amino acid residues 82 to

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RBC Blood Group Antigens

Table 3. RBC Changes Associated With Protein-Based Null Phenotypes (natural knock-outs) Blood Group System

Morphological Gerbich

Phenotype

Lu(a⫺b⫺) recessive

GPC and GPD (reduced protein 4.1 and p55) Band 3, protein 4.1 (reduced GPA) Xk (reduced Kell) RhD, RhCE, LW (reduced RhAG; CD47; GPB) LU glycoprotein/B-CAM (reduced CD44)

Jk(a⫺b⫺)

Kidd glycoprotein

Colton

Co(a⫺b⫺)

Aquaporin-1

MNS

En(a⫺) U⫺ MkMk

GPA GPB GPA, GPB

D⫺ Knull (K0) Fy(a⫺b⫺) LW(a⫺b⫺) Sc:⫺1,⫺2,⫺3 Gy(a⫺) Inab Gil⫺

RhD Kell glycoprotein Duffy glycoprotein LW glycoprotein ERMAP Dombrock glycoprotein DAF Aquaporin-3

Diego Kx Rh Lutheran Other changes Kidd

No observed change Rh Kell Duffy LW Scianna Dombrock Cromer Gil

Leach (Ge⫺2⫺3⫺4)

Absent (reduced) Protein(s)

McLeod Rhnull

98 in the cytoplasmic domain of GPC and the corresponding residues 61 to 77 of GPD.18-23 Amino acid residues 112 to 128 of GPC and residues 91 to 107 of GPD bind to the PDZ domain of p55, which is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins.24,25 Residues Tyr214 to Glu246 of the 4.1R membrane binding domain bind to p55 at a positively charged, 39 –amino acid segment located between the SH3 domain and the guanylate kinase domain of p55.26 The complex of GPC/GPD, 4.1R, and p55 is important in maintaining cell shape and membrane mechanical stability, since absence of GPC and GPD (the Ge:⫺2,⫺3,⫺4 or Leach phenotype) results in elliptocytosis with decreased membrane stability.20,27 GPC and GPD are expressed in a variety of tissues (Table 2) but at lower levels than in erythroid cells and with different glycosylation patterns28,29; they may have an analogous function in the membrane mechanics of non-erythroid cells. Mutations in exon 1, exon 2, or exon 3 of GYPC modify the N-terminal extracellular domain of GPC and GPD and thus alter the antigenicity of RBCs but do not affect cellular mechanical properties.29,30 Examples include Ge-type RBCs that lack amino acids encoded by exon 2; Yus-type RBCs that lack amino acids encoded by exon 3; and Wb⫹ RBCs that have a missense muta-

In Vivo Change

Elliptocytosis Poikilocytosis Acanthocytosis Stomatocytosis, spherocytosis Acanthocytosis in dominant type

Impaired urea transport Urine concentrating defect Reduced osmotic water permeability Increased glycosylation of band 3 [En(a⫺) and MkMk]

Some have GI abnormalities

tion of GYPC, converting Asn at position 8 to Ser, thereby precluding N-glycosylation at this site.31,32 These variant forms of GPC have the normal cytoplasmic domain, which can interact with 4.1R and p55. The variant RBCs have normal levels of 4.1R and are normocytic. By contrast, in the Leach phenotype there is complete loss of GPC and GPD secondary to deletion of exons 3 and 427,33 or a frameshift mutation33; affected individuals do not have significant hemolysis, but a proportion of their RBCs are elliptocytic34,35 and exhibit decreased membrane deformability and mechanical stability (⬃50% as measured by ektacytometry)20,36 (see article by Gallagher in this issue). GPC-deficient RBCs are also partially deficient in 4.1R and p5522,37 and thus the disturbance in membrane mechanical properties exhibited by Leach RBCs likely derives from a defective GPC/GPD/4.1R/p55 complex. Individuals with homozygous 4.1R deficiency also exhibit low GPC (⬃70%) in their elliptocytic RBCs,38,39 emphasizing that the cellular content of each component of the ternary complex depends on the expression level of the others.

Membrane Proteins With Both Structural and Transport Function A critical function of the cell membrane is to transport water-soluble molecules across the hydrophobic

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lipid bilayer, in order to bring nutrients into the RBC, remove waste products, and control ion gradients. Specialized transmembrane transport proteins carry out this key function. Membrane transport proteins can be classified as carrier proteins that physically move a solute across the membrane, and channel proteins that form a hydrophobic pore in the membrane through which the specific solute or ion passes. The proteins that carry blood group antigens Diego, Rh, Kidd, Colton, and GIL have membrane transport function. They are multipass proteins with the NH2terminus and COOH-terminus both oriented to the cytoplasmic side of the lipid bilayer; the protein associated with Kx also may have this structure and function.

Diego Blood Group System and Anion Transport Antigens of the Diego system are carried on band 3 (synonyms include anion transporter, AE1, and SLC4A1), a transmembrane protein that traverses the membrane 12 or 14 times40-42 and which transports anions.43 The Diego antigens are derived from amino acid substitutions within band 3. The Dia/Dib polymorphism is associated with a Leu854Pro substitution, and expression of Wra/Wrb is associated with Lys658Glu. For expression, Wrb requires the interaction of band 3 and GPA.44,45 The N-glycan on the fourth extracellular loop of band 3 (Asn642) carries more than half of the mature red cell A, B, H, and I antigens. With the exception of the Dia/Dib polymorphism, the Diego blood group polymorphisms are not associated directly with any functional alteration of band 3. Band 3 is a major integral membrane protein, comprising 25% to 30% of the RBC membrane protein (⬃1.2 million copies per RBC); it resides in the membrane as a dimer. Residues 1 through 403 form the 43-kd NH2-terminal cytoplasmic domain; this residue functions as an anchor point for the membrane skeleton through interactions with the peripheral membrane proteins ankyrin, 4.1R, and protein 4.2, and as a binding reservoir for hemoglobin, denatured hemoglobin, the glycolytic enzymes glyceraldehyde 3-phosphate dehydrogenase, phosphofructokinase and aldose, as well as for catalase and hemichromes.46 Residues 509 to 911 form a channel that exchanges HCO3⫺ and Cl⫺, facilitating the critical function of RBCs in CO2 uptake in tissues and subsequent release of CO2 in the lungs (a huge number of bicarbonate and chloride anions are exchanged: ⬃20 billion/second per RBC). Although HCO3⫺ and Cl⫺ are the predominant physiologically relevant anions exchanged by band 3, the specificity of the channel is broad, and larger anions such as sulfate, phosphate, pyruvate, and su-

peroxide are also transported, although at much slower rates.47 Several potent and experimentally useful inhibitors of band 3 anion transport are known, the most commonly employed being stilbene disulfonates, such as 4,4⬘-diisothiocyanostilbene2,2⬘-disulfonate (DIDS).47 The COOH terminus, like the NH2 terminus, is on the cytoplasmic side of the membrane and binds carbonic anhydrase II.48 Band 3 contributes to maintaining the structural integrity of the RBC membrane. Deficiency of band 3 causes membrane surface area loss and alterations in the RBC shape, as spherocytosis. Approximately one fifth of human cases of hereditary spherocytosis (HS) result from deficiency of band 3 (see Eber and Lux in this issue).49-52 Numerous mutations identified in the band 3 gene in HS lead to decreased synthesis, altered membrane insertion, decreased protein stability, and inability to bind protein 4.2.6,53 Mice completely deficient in band 3 that survive gestation have a severe spherocytic hemolytic anemia, closely resembling severe HS in humans. These mice have undetectable amounts of protein 4.2 and GPA54,55 but normal spectrin, actin, and protein 4.1 and normal membrane skeleton architecture by electron microscopy.55 These observations indicate that band 3 is, surprisingly, not required for membrane skeleton assembly but functions in stabilizing membrane lipids. Loss of this function may be critical to the pathogenesis of HS. In addition to mouse models, there is a recessive form of HS in cattle with mild to moderate hemolytic anemia and complete deficiency of band 3, due to a nonsense mutation at codon 646.56 The cattle, like band 3– deficient mice, have defective anion transport, lack protein 4.2, and have reduced numbers of intramembrane particles by electron microscopy. In contrast to spherocytic morphology associated with reduced amounts of band 3 assembled onto the RBC membrane, deletion of amino acids 401 to 408 in band 3 causes Southeast Asian ovalocytosis (SAO),57-59 an autosomal-dominant condition characterized by rounded elliptocytic cells, mild or absent hemolysis, and the presence of unusually rigid and heat-tolerant RBCs. Red cells in SAO resist malarial invasion, and they show altered expression of several blood group antigens60 (see article by Gallagher in this issue). SAO band 3 protein has an abnormal N-glycan, is misfolded in the membrane, and does not transport anions or bind transport inhibitors such as H2DIDS or eosin maleimide.61,62 No SAO homozygote has been found, suggesting lethality. The altered membrane organization may be responsible63 for the selective depression of several blood group antigens, including S, s, U, Ena; D, C, e; Kpb; Jka, Jkb; Dib, Wrb; Xga; Sc1; IF and IT antigens. SAO is found predominantly in Melanesia and Malaya and may have an incidence of up to 25% in some popula-

RBC Blood Group Antigens

tions.60 SAO RBCs deplete intracellular adenosine triphosphate (ATP) more readily than do normal red cells, and ATP depletion correlates with the inability of Plasmodium falciparum to invade the RBCs. On storage at 4°C, SAO RBCs become markedly permeable to monovalent cations, and the increased activity of the sodium pump results in the rapid loss of ATP.64 Mutation of band 3 Arg589 in transmembrane (TM) domain 6, Ser613 in TM 7, and an 11–amino acid deletion in the COOH-terminal domain have been independently associated with the autosomaldominant form of distal renal tubular acidosis (dRTA), characterized by impaired distal nephron secretion of hydrogen ions.65-68 The phenotype is believed to result from faulty targeting of band 3 to the apical rather than the basolateral membrane of collecting tubule type A intercalated cells, not to a defect in anion transport.69 Mutation of Gly701 (located in the intracellular loop between TM8 and TM9) is associated with autosomal recessively inherited dRTA, with the phenotype again deriving from faulty band 3 trafficking. Incomplete processing of the band 3 N-linked lactosaminoglycan moiety due to a deficiency in the relevant glycosyltransferase(s) occurs in congenital dyserythropoietic anemia type II (CDA II or hereditary erythroblast multinuclearity with positive acid serum test [HEMPAS]), although it is probably not the primary molecular defect. The phenotype of binucleate/multinucleate erythroblasts in the bone marrow and a characteristic RBC membrane dysmorphology is believed to derive from both decreased anion transport and increased band 3 aggregation in the membrane.70 A rare Pro868 to Leu mutation in TM14 of band 3 causes hereditary acanthocytosis; affected RBCs exhibit decreased ankyrin binding and increased anion transport.6 In addition to these functions, band 3 also may be involved in RBC senescence. Hemichromes, a partially denatured form of hemoglobin, bind to band 3 more avidly than does hemoglobin, resulting in the formation of hemichrome-band 3 aggregates.71,72 This clustering of band 3 is believed to generate a cell surface epitope identified by autologous IgG antibodies, which may act as a signal for the removal of aged or defective RBCs from the circulation by phagocytosis.73,74 Band 3 clustering can generate multivalent epitopes comprised of surface sialylated poly-Nacetyllactosaminyl chains, which in turn can be recognized by anti– band 3 IgG autoantibodies and by macrophages directly.75,76 There is considerable evidence that antibodies are bound to band 3 in aged and pathological RBCs.6 Antibodies to senescent antigen, resident on the band 3 carbohydrate,77,78 likely bind to aggregated or oligomerized band 3.74,79-82 Band 3 clusters have been visualized by immunofluorescence microscopy and detected by biochemical methods in aged RBCs.79,80 Aggregation probably results

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from cumulative oxidative damage because similar damage, including the binding of autologous IgG, takes place on oxidized RBCs or RBCs containing Heinz bodies, a product of oxidative denaturation of hemoglobin.6 Senescent antigen also is exposed on RBCs infected with P falciparum.83,84

Kx Blood Group System Kx, the single antigen of the Kx system, is carried by the Xk protein, which is encoded by XK, a gene on the short arm of the X chromosome. While Xk protein has structural but not sequence similarity with a family of proteins involved in transport of neurotransmitters, its transport substrate(s) have not been defined.85,86 In the RBC membrane, the Xk protein is covalently linked to the Kell glycoprotein (a type II membrane protein with endopeptidase activity) by a disulfide bond, thereby forming a stable complex.87,88 Male hemizygotes who lack Xk on their RBCs (McLeod syndrome) have weak expression of Kell antigens, variable echinocytosis or acanthocytosis (8% to 85%), and mild compensated hemolytic anemia (3% to 7% reticulocytes).89-91 Some tear drop erythrocytes and bizarre poikilocytes are also present. Female heterozygotes have occasional acanthocytes (as expected from X-chromosome inactivation) and very mild hemolysis.89,90 The abnormal shape is apparently due to an alteration of lipid or protein in the inner bilayer, because it can be corrected by substances like chlorpromazine, which accumulate between inner bilayer lipids.92 In the fifth decade, patients with McLeod syndrome develop a myopathy or neuropathy or both,93-98 first manifest as areflexia and an elevated serum creatine phosphokinase (CPK)94 but later progressive.98,99 In the sixth decade, a cardiomyopathy (cardiomegaly) or neuropathy (dystonic or choreiform movements, with or without peripheral neuropathy, psychiatric disturbances, and seizures) may appear. Imaging studies show caudate atrophy and decreased dopamine D2receptors.93,95,97,100-103 At this stage the disease is sometimes confused with chorea-acanthocytosis.96 The skeletal muscle myopathy is usually not evident clinically, although changes may be seen in biopsy specimens.98,104-106 (For more information about the McLeod Syndrome, see www.nefo.med.uni-muenchen. de/⬃adanek/McLeod.html). The exact cause of the membrane defect in McLeod syndrome is yet to be defined. Protein and lipid composition is normal,107-109 but the density of intramembranous particles (IMPs) is increased.109 Band 3, the major IMP protein, may be abnormally dissociated in McLeod RBCs compared to normal red cells, where it exists primarily as dimers and tetramers.110 There is also increased phosphorylation of some lipids and membrane proteins, especially band

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3, spectrin, phosphatidic acid and polyphosphoinositides.108 The Xk gene is less than 500 kb distal to the chronic granulomatous disease (CGD) locus on the X chromosome. As a consequence, some males have both CGD and McLeod syndrome, due to deletions that encompass both loci. Absence of Xk protein also has been attributed to various splice site or framehift mutations in XK.85,111,112

Rh Blood Group System The Rh blood group system is comprised of at least 45 independent antigens carried by two nonglycosylated, palmitoylated proteins encoded by variant forms of two homologous genes, RHD and RHCE, located on chromosome 1.113,114 RHD encodes the D antigen and RHCE encodes the CcEe set of antigens. Rh antigen expression at the RBC surface requires the presence of the Rh-associated glycoprotein (RhAG), which exhibits 36% sequence identity with Rh proteins and is encoded by a gene located on chromosome 6. RhD, RhCE, and RhAG form a core complex in the RBC membrane that is stabilized by NH2terminal and COOH-terminal domain associations. In addition to the interaction between the three Rh subunits, the Rh core complex also contains several other proteins: LW glycoprotein (ICAM-4), integrinassociated protein (IAP, CD47), GPB, and possibly Duffy protein. Although the function of the Rh protein complex in the normal RBC is not known, the complex may act as ammonium transporter, based on a weak homology to the Mep/Ant family of proteins and a single complementation study in yeast.115,116 The Rh proteins also might facilitate diffusion of CO2 gas.117-120 However, there is not yet definitive evidence of the transport function of Rh protein complex in the RBC membrane. The importance of Rh complex in regulating RBC membrane structure is revealed by the rare Rhnull phenotype, which exhibits stomatocytic and spherocytic morphology with loss of membrane surface area, cell dehydration, cation permeability abnormalities, and shortened RBC survival leading to a compensated hemolytic anemia (chromium 51–labeled RBC half-life of 10 to 14 days).121-123 Osmotic fragility is only mildly increased but ektacytometry shows a significant loss of membrane surface, particularly in denser (and presumably older) cells.123 RBC membrane K⫹ or Rb⫹ (a K⫹ analogue) permeability is about twice normal, compatible with a mild xerocytosis syndrome.123,124 Indeed, in one patient a majority of the Rhnull RBCs were dense and K⫹-depleted; however, in another case, cation and water concentrations were normal.122 Stomatocytosis and hemolysis are also features of Rhmod disease. The Rhnull phenotype has two distinct

genetic backgrounds. The amorph type of Rhnull is the result of inactivating mutations in RHCE in tandem with a deleted RHD, but with no alteration in RHAG. The less rare regulator type of Rhnull and also the Rhmod phenotype (in which the Rh antigens are suppressed) have normal RHD and RHCE but are associated with diverse mutations in RHAG. These mutations result in the generation of defective RhAG glycoproteins that are absent or reduced in the RBC membrane.113,114

Membrane Proteins With Transport Function Proteins carrying Kidd, Colton, and GIL antigens pass through the lipid bilayer multiple times and function as transporters (Tables 1 and 2).

Kidd Blood Group System and Transport of Urea The three common phenotypes [Jk(a⫹b⫺), Jk(a⫺b⫹) and Jk(a⫹b⫹)] of the Kidd blood group system are encoded by two co-dominant alleles. The rare Jk(a⫺b⫺) null phenotype is most abundant in Polynesians and Finns. That the Kidd glycoprotein might transport urea stemmed from the observation that Jk(a⫺b⫺) RBCs are relatively resistant to lysis by 2 mol/L urea.125 Indeed the Kidd glycoprotein is the urea transporter in the RBC membrane,126,127 which functions by rapidly transporting urea into and out of red cells as they pass through the high urea concentration in the renal medulla, thereby preventing RBC dehydration.128. Urea transport across Kiddnull RBC membranes is approximately a thousand times slower than across normal membranes,129 but no phenotypic changes in either RBC shape or survival are associated with the absence of Kidd glycoprotein. Two patients with Jk(a⫺b⫺) RBCs had an impaired ability to maximally concentrate urine.130 Two Jk(a⫺b⫺) individuals (one Caucasian, one of Chinese origin) were found to have different intronic splice site mutations in a Jkb allele that caused exon skipping and the production of truncated proteins. Expression studies using Xenopus oocytes showed that such proteins are not transported to the plasma membrane and that they do not facilitate urea transport.131 A different missense mutation, identified in three Finnish families, may alter N-glycosylation which in turn could affect the gross conformation of the Kidd glycoprotein and its insertion into the membrane.132

Colton Blood Group System and Transport of Water The Colton system consists of Coa, an antigen of high incidence (99.9%) and antithetical to the less com-

RBC Blood Group Antigens

mon Cob (incidence of 10% in most populations), and the Co3 antigen that is present on all RBCs except those of the very rare null phenotype, Co(a⫺b⫺). Membranes of RBCs and some kidney tubules differ from those of most other cells in their high water permeability, due to a molecular water channel protein.133,134 This protein, designated aquaporin-1 (AQP-1), carries antigens in the Colton blood group system. The suggested function of AQP-1 is to facilitate rehydration of RBCs after their shrinkage in the hypertonic environment of the renal medulla.135 AQP-1, a 28-kd channel-forming integral protein (CHIP-28), is a member of the major integral protein (MIP) family and the main water channel in RBCs.136,137 The protein has been crystalized and the tetrameric complex forms an “hour-glass” structure in the RBC membrane.138 Absence of AQP-1 was thought to be incompatible with life, but the identification of Co(a⫺b⫺) individuals by serologists provided natural knockout models. Four such probands have been tested.139,140 Human RBCs lacking AQP-1 exhibit markedly reduced osmotic water permeability but no obvious phenotypic abnormality, and Co(a⫺b⫺) individuals are apparently healthy. Defective urinary concentrating ability as well as decreased pulmonary vascular permeability occur with complete deficiency of AQP⫺1.141,142 Reconstitution of the recombinant protein into Xenopus oocytes136 or liposomes133 confirmed its function as a waterselective channel. AQP-1 knockout mice appear normal but after water deprivation for 36 hours become severely dehydrated and lethargic.143

GIL Blood Group System and Transport of Glycerol, Water, and Urea Aquaporin-3 (AQP-3) is also a MIP channel-forming molecule and differs from AQP-1 in that it transports glycerol, water, and urea.144 AQP-3 also traverses the RBC membrane six times with both NH2- and COOH-termini located towards the cytoplasm. APQ-3 is expressed in kidney, liver, pancreas, lung, spleen, and prostate.145 The blood group antigen, GIL,146 was shown to be expressed on APQ-3 in two individuals whose plasma contained antibodies to this high incidence antigen.147 Both had the same G to A nucleotide substitution in intron 5, leading to skipping of exon 5 and failure to express APQ-3. Studies of glycerol permeability in AQP-3– deficient RBCs have suggested that another protein is also involved in glycerol transport. GILnull RBCs are not associated with any overt functional defect, and mouse RBCs, which lack an equivalent AQP3 molecule, transport glycerol efficiently.148

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Membrane Proteins as Receptors for Ligands, Parasites, Bacteria, and Viruses Based on their structure or function in other cells, some proteins in the RBC membrane that carry blood group antigens appear to be receptors for specific ligands and/or microbes, suggesting they play a direct role in pathogenesis of infectious diseases (Tables 1 and 2).

Duffy Blood Group System The Fya and Fyb antigens of the Duffy blood group system are encoded by two alleles, FY A and FY B. There are four major phenotypes: Fy(a⫹b⫺), Fy(a⫺b⫹), Fy(a⫹b⫹), and Fy(a⫺b⫺).149 The Fy(a⫺b⫺) phenotype, rare in most populations, is predominant among black populations, particularly those originating in West Africa, in whom the incidence of may reach 100%. Duffy blood group antigens are carried on the Duffy glycoprotein. The Duffy glycoprotein is a promiscuous chemokine receptor in RBCs.150 It binds a variety of proinflammatory cytokines of both the C-X-C class (acute inflammation) and the C-C class (chronic inflammation), including interleukin-8 (IL-8), melanoma growth stimulatory activity (MGSA), monocyte chemotactic protein 1 (MCP-1) and a factor regulated on activation, normal T-expressed and secreted (RANTES).151-154 Although the Duffy glycoprotein is predicted to have seven membrane-spanning domains, it does not appear to function as a transport molecule. A major structural difference compared to other RBC channel forming molecules is that the NH2-terminal region of the glycoprotein is oriented on the extracellular surface of the membrane.155 The Duffy glycoprotein is the receptor for the malarial parasite, Plasmodium vivax.156,157 Because Fy(a⫺b⫺) RBCs are refractory to invasion by P vivax merozoites, likely this phenotype, at least in Africa, evolved under selective pressure to circumvent the infection.158 The function of Duffy glycoprotein in normal RBC physiology remains to be defined. The lack of Duffy glycoprotein in RBCs from black Africans is the result of a mutation in the promoter region of FYB, which disrupts a binding site for the erythroid transcription factor GATA-1 and prevents expression of the Duffy gene in erythroid tissue.159 To date, blacks with a mutated GATA box have been shown to carry FYB and therefore Fyb is expressed on their non-erythroid tissues. In one study, Fy(a⫺b⫺) African-Americans had decreased allograft survival if they also experienced delayed graft function.160 Fy(a⫺b⫺) due to an FYA allele with a mutated GATA box, has been found in Papua New Guinea, another malaria-endemic region.161 In Caucasians the Fy(a⫺b⫺) phenotype is the result of premature stop codons that silence the FY gene, and the Duffy glycoprotein is missing from

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all tissues.162,163 This “true” Duffy null phenotype has no obvious hematological or immunological abnormalities. FY knockout mice show only blunted neutrophil response on exposure to bacterial lipopolysaccharide, but the susceptibility to S aureus was identical to wild-type. Thus Duffy appears to be functionally redundant.164 An increase in inflammatory infiltrates in the lung and liver was observed in FY knockout mice challenged with lipopolysaccharide.165 In studies of patients with sickle cell disease, elevated levels of IL-8 were noted in acute chest syndrome; of 20 patients, 19 were Fy(a⫺b⫺) and 14 had elevated levels of IL-8.166 Whether the frequency of Fy(a⫺b⫺) in this small group reflects a risk for the development of acute lung syndrome is controversial, as the frequency of Fy(a⫺b⫺) among West African blacks is approximately 75%. MCP-1 levels in healthy adults were higher in males versus females and Fy antigen–positive individuals versus Fy(a⫺b⫺) donors.167 Whether variation in MCP-1 levels poses a risk for certain chemokine-associated diseases is unknown. Another phenotype called Fyx, which is not uncommon in Caucasians, is due to a mutation in the FYB gene (168-171). The resulting amino acid change (residue 89) is located in the first intracellular cytoplasmic loop and decreases the amount of protein in the membrane and results in reduced expression of Fyb, Fy3, and Fy6 antigens and reduced chemokine binding. The weak expression of Fyx is due to an instability of the mature glycoprotein as it translocates to the plasma membrane (150). The Duffy glycoprotein may have a role in enhancing leukocyte recruitment to sites of inflammation by facilitating movement of chemokines across the endothelium (172). It may also function in the lung parenchyma during inflammation (173)

MNS Blood Group System and GPA and GPB The integral membrane glycoproteins GPA and GPB account for the majority of the surface charge of the RBC. Their extracellular domains contain an abundance of sialic acid, which generates a layer of negative charge at the cell surface, preventing adherence of RBCs to each other and to vessel walls. Surface epitopes of the glycophorins, including variants generated by protein defects, are the basis for a wide diversity of blood group antigens in the MNS system. GPA also serves as a receptor for infective agents such as P falciparum and may function as a chaperone, facilitating the targeting of specific integral membrane proteins to the plasma membrane. The glycophorins belong to the broad family of integral membrane proteins that pass through the lipid bilayer as a single ␣-helix. Because the “single-pass” membrane

proteins include growth factor receptors and receptor kinases, the glycophorins have been considered candidate mediators of transmembrane signaling in RBCs. GPA was the first membrane protein to have its complete amino acid sequence determined. Amino acids 1 to 61 give rise to the extracellular NH2terminal domain, which contains a complex oligosaccharide attached to Asn26174 and 15 serine or threonine O-linked tetrasaccharides with sialic acid moieties.175,176 The carbohydrate component of GPA is 60% of its molecular mass. The transmembrane domain of GPA, amino acids 62 to 95, interacts with negatively charged lipids, such as phosphatidylserine and phosphatidylinositol.177,178 Self-association of the L75I76XXG79V80XXG83V84XXT87 motif within the transmembrane domain results in homodimerization into a right-handed pair of ␣-helices.179,180 By nuclear magnetic resonance spectroscopy, Ile76, Val80, and Val84 on the ␣-helix of one monomer interface with Leu75, Gly79, Gly83, and Thr87 on the second monomer181; this dimeric interaction resists dissociation by detergents. A sequence in the transmembrane domain of GPA is important for horizontal interactions with band 3,182 and GPA may function as a chaperone for membrane targeting of band 3.183 A specific role for the cytoplasmic domain of GPA (amino acids 96 to 131) has not been defined. Treatment of RBCs with antibodies to GPA induces cellular rigidity on ektacytometry, and the quantity of GPA associated with the membrane skeleton increases.184 Both changes are dependent on the presence of the cytoplasmic tail of GPA, suggesting that the cytoplasmic domain binds to the membrane skeleton in response to a transmembrane signal initiated by antibody treatment.185 Cellular rigidity induced by adherence of pathogens to glycophorins could serve to heighten reticuloendothelial clearance of infected cells.185 GPA has been used as a specific marker for the erythroid lineage due to its presence in proerythroblasts.186 In addition, assays to gauge radiation exposure and consequent somatic mutation have been developed based on measuring the frequencies of variant GPA phenotypes in RBCs.187,188

Band 3 and GPA Are Functionally Associated GPA and band 3 have a physiological association. Expression of the Wrb blood group antigen (the receptor for P falciparum) requires the interaction between GPA and Glu658 of band 3. A GPA Ala65Pro mutation (HAG antigen) and a Glu63Lys mutation (MARS antigen) in GPA cause aberrant Wrb antigen expression.189 The co-expression of GPA and band 3 in Xenopus oocytes facilitates the expression of band 3 and enhances anion transport. Mutation in band 3

RBC Blood Group Antigens

at Gly701 leads to impaired protein targeting to the cell surface in Xenopus oocytes; the aberrant phenotype is rescued by co-expression of the mutant band 3 with GPA, consistent with a chaperone-like role for GPA in band 3 targeting.190 RBCs lacking GPA have altered band 3 glycosylation. RBCs from band 3 knock-out mice are completely deficient in GPA, emphasizing the potential relevance of band 3-GPA interactions during erythropoiesis and in mature RBCs.191 The gene for GPB lies just downstream of GPA on chromosome 4 and probably arose by gene duplication.192,193 The first 26 amino acids of the extracellular NH2-terminal domain are identical to the N blood group form of GPA.194 GPB also carries the S, s, and U blood group antigens but lacks the N-linked complex oligosaccharide. Distally, GPB lacks a portion of the extracellular domain corresponding to exon 3 of GPA and almost the entire cytoplasmic domain. GPB is reduced in Rhnull RBCs. Because GPB is expressed exclusively in RBCs, the GPB promoter has been the subject of transcriptional regulation studies. Repression of the GPB promoter in nonerythroid cells is accomplished by the binding of a ubiquitous factor that recognizes a GATA motif centered at position ⫺75 of the promoter195; the Ku70 protein may function as the GPB repressor.196 Erythroid-specific derepression of the GPB promoter is mediated by the erythroid transcription factor hGATA-1.196 Complete loss of GPA, GPB, or both by gene deletion gives rise to En(a⫺), (S⫺s⫺), and MkMk RBCs, respectively. En(a⫺) RBCs, for example, are completely deficient in GPA. The affected cells compensate for a potential 60% loss of surface charge by increasing glycosylation of band 3, such that the overall surface charge is only reduced by about 20%.197 Given the proximity and homology of GPA, GPB, and GPE genes, hybrid glycophorin molecules are generated by recombination events during meiosis. None of the GPA and GPB variants produce detectable changes in erythropoiesis or in the shape, function, or lifespan of affected RBCs. Indeed, rare individuals with complete absence of GPA and GPB exhibit no apparent erythrocyte abnormalities.198 The major function of GPA could be to confer surface charge to the RBC membrane, preventing red cell–red cell interactions that are detrimental to blood flow. GPA is a likely RBC surface attachment site for P falciparum.199,200 Alternative pathways for malarial invasion of RBCs depend on the strain of P falciparum and the ability of the parasite to switch its invasion requirements.201 For example, sialic acid– dependent invasion results from binding of merozoite protein EBA-175 to the Neu5Ac(␣2,3)-Gal moiety on the O-linked tetrasaccharides of GPA.202 Another sialic acid– dependent but EBA-175–independent pathway is believed to involve merozoite binding to GPB.203 GPA binds the C4 component of complement204

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and may provide limited protection to RBCs from complement-induced lysis by inhibiting the formation or binding of the C5b-C7 complex.205 In vitro, K562 cells transfected with GPA are protected from natural killer cells.206

Membrane Proteins That Act as Adhesion Proteins Cell adhesion molecules are crucial for many physiological processes in embryogenesis, as well as in pathological processes such as inflammation, wound healing, and cancer. While adhesion molecules have no obvious function on mature RBCs, they likely play a key role in cell-to-cell or cell-matrix interaction during erythropoiesis or in hematopoietic cell maturation. Rare people with Lutheran null or LW null phenotypes have no known phenotype, and no genetic null phenotypes for Indian, Ok, or Xg are known (Table 1 and 2).

Indian Blood Group System Antigens of the Indian system are carried on CD44, a type I, single-pass, integral membrane protein. CD44 appears to be the major human hyaluronan receptor and also may bind fibrinogen, laminin, some forms of collagen, and osteopontin.207-209 CD44-hyaluronan interaction may be required for adhesion of lymphoid cells and primitive erythroid progenitor cells to bone marrow stroma in lymphopoiesis and erythropoiesis. Isoforms of CD44, the result of alternative splicing (CD44v), are associated with the ability of cancer cells to metastasize.210 Soluble forms of CD44 have been found in serum of cancer patients; in some non-Hodgkin’s lymphoma, a correlation between clinical severity and CD44 levels was observed.211 The In(a⫺b⫺) phenotype was described in a patient with a novel form of CDA and CD44 deficiency,212 but it was not possible to determine if the phenotype was genetic or related to the patient’s hematological disorder. Positively charged motifs (SRRRC and QKKKL) on CD44, which are homologous to the interacting peptides found in band 3, bind to the membrane binding domain of 4.1R.213 Analogous to band 3, 4.1R competes with ankyrin for CD44 binding and may thus regulate CD44-ankyrin interactions.213 Ca2⫹-dependent and -independent calmodulin binding sites are located within the 4.1R membrane binding domain,214 and 4.1R membrane binding domain interactions with transmembrane proteins are subject to regulation by Ca2⫹-calmodulin.

Immunoglobulin Superfamily of Glycoproteins At least six proteins in the RBC membrane belong to the immunoglobulin superfamily of glycoproteins:

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these are the glycoproteins carrying Lutheran, LW, Scianna, and Ok blood groups, as well as CD47 and CD58, which have no known polymorphisms in humans. The immunoglobulin superfamily glycoproteins primarily function as receptors and adhesion molecules.215,216

Lutheran Blood Group System The Lutheran blood group glycoprotein is the receptor on erythroid cells for the extracellular matrix protein, laminin. The glycoprotein consists of five disulfide-bonded extracellular, immunoglobulin superfamily domains, a single hydrophobic transmembrane domain, and a cytoplasmic tail. Two isoforms of this type I membrane protein (85 kd [Lu] and 78 kd [BCAM] isoforms) are expressed by alternative splicing of a single gene; both bind laminin. The two isoforms are distinguished by differences in their cytoplasmic domains; the 78-kd isoform has a truncated cytoplasmic tail.217-221 While the function of the Lutheran glycoprotein in normal RBCs remains to be defined, it mediates adhesion of sickle red cells to laminin.222-225 RBCs from patients with sickle cell disease express approximately one and a half times more Lutheran glycoprotein than do normal RBCs, and the level of laminin binding to RBCs correlates with the level of Lutheran expression. Laminin ␣-5 ⫺/⫺ mice have a dramatic decrease in Lutheran glycoprotein in diverse tissues.226-228 Lutheran glycoprotein is expressed late during erythroid differentiation and it may play a functional role in mediating erythroblast-extracellular matrix interactions in the marrow that regulate egress of reticulocytes into the circulation. The cytoplasmic region of Lutheran glycoprotein interacts with the membrane cytoskeleton.229 Three genetic backgrounds generate the Lu(a⫺b⫺) phenotype: homozygosity for a recessive gene Lu, a dominant supressor gene InLu, and an X-linked recessive gene XS. Only the autosomal recessive type of Lu(a⫺b⫺) can be considered a true null phenotype, because weak expression of Lutheran antigens can be demonstrated for the two other types. A nonsense mutation generating a stop codon was identified in one Lu(a⫺b⫺) individual who was therefore almost certain to lack the Lu glycoproteins, yet there were no obvious disease manifestations.230 About 1 person in 5,000231,232 inherits In(Lu), which is located on chromosome 11p. The In(Lu) gene product has broad regulatory functions: it inhibits expression of CD44 (an adhesive protein carrying the Indian blood group), MER2 (a common RBC antigen), CR1 (the C3b/C4b complement receptor carrying the Knops blood group), AnWj (the erythroid Haemophilus influenzae receptor), and the glycolipid antigens P1 and i, as well as the Lutheran antigens.233 Second, although some of these proteins (like CD44) are widely

expressed, the action of In(Lu) is limited to erythroid cells.234 Patients with the In(Lu) Lu(a⫺b⫺) phenotype have abnormally shaped RBCs; the morphology varies from normal or mild poikilocytosis (bumpy, irregular cells) to marked acanthocytosis. No hemolysis or anemia is evident. Osmotic fragility of fresh In(Lu) Lu(a⫺b⫺) RBCs is normal but during in vitro incubation RBCs lose K⫹ and become osmotically resistant.231 The molecular mechanisms responsible for this cation loss and for the regulatory effects of the In(Lu) protein are not known, mostly because the In(Lu) gene has not been cloned. Whether the reduced Lu glycoprotein, some other protein, or disruption of a complex on the RBC membrane is responsible for the maintenance of normal red cell morphology is yet to be determined.

LW Blood Group System The LW glycoprotein (also termed intracellular adhesion molecule-4 [ICAM-4]) consists of two extracellular immunoglobulin superfamily domains, which show strong sequence homology with the protein superfamily of intracellular adhesion molecules (ICAMs).235 The 40- to 42-kd LW glycoprotein is encoded by a gene on chromosome 19. Extracellular domains of LW glycoprotein interact with integrins LFA1 (CD11/CD18)236 and ␣4␤1 and ␣V integrins.237 In contrast to Lutheran glycoprotein, which is expressed late during erythroid development, LW glycoprotein appears early in erythropoiesis before GPA and about the same time as RhAG.238 LW glycoprotein may function in erythroblast-macrophage interactions (in erythroblastic islands) that are critical for erythropoiesis.239 LW also binds to a similar integrin, ␣IIb/␤3. Platelets adhered better to ICAM-4 –positive than to ICAM-4 –negative (LWnull) cells; immobilized RBCs and platelets deficient in GPIIb/IIIa did not bind to ICAM-4 – coated microtiter wells.240,241 There is no evidence that platelets and RBCs interact in vivo, but these molecules may participate in pathological states such as vaso-occlusion in sickle cell disease. The proband and her brother who have the rare inherited LWnull phenotype are apparently normal. The gene responsible for this LWnull phenotype has a 10 – bp deletion and a premature stop codon in the first exon.242 Transient loss of LW antigen from RBCs has been reported in pregnancy and in lymphoma, leukemia, sarcoma, and other malignancies.243 The LW protein is part of the Rh complex and is present on D-negative RBCs at about half the copy number as on D-positive RBCs. In cord blood the number of copies of LW glycoprotein per red cell is equal in D-positive and D-negative RBCs and is higher than in adults.

RBC Blood Group Antigens

Ok Blood Group System a

The RBC antigen, Ok , is located on the Ok glycoprotein, a leukocyte activation antigen with two immunoglobulin superfamily domains.244 The function of the Ok glycoprotein (synonyms: CD147, neurothelin, basigin) in RBCs is unknown, although conserved sequence homologies within the cytoplasmic and transmembrane domains suggest that it could be a component of a signal transduction complex.245,246 Knockout mice show that basigin is required for embryo implantation and expressed during spermatogenesis.247 Basigin is expressed in testes during spermatogenesis but it is also present in azoospermic men with the Sertoli cell– only syndrome.248 Basigin may bind mannoside-containing glycoconjugates.249 The Oka antigen occurs with a high incidence and the only known Ok(a⫺) individuals (eight probands) are Japanese. The Ok(a⫺) phenotype is the result of a single amino acid substitution in the Ok glycoprotein.245

Scianna Blood Group System Human erythrocyte membrane-associated protein (ERMAP) is expressed exclusively on erythroid cells and carries Scianna blood group antigens.250 ERMAP is predicted to have one extracellular transmembrane immunoglobulin-like domain; the intracellular region has a conserved B30.2 domain and multiple kinase-dependent phosphorylation consensus motifs.251 Therefore, ERMAP is likely a receptor/signal transduction molecule specific for erythroid cells.252

Xg Blood Group System The Xg glycoprotein is homologous with CD99, which has adhesion properties and is thought to be important in hemopoietic cell differentiation. CD99 also may mediate apoptosis of immature thymocytes.253-255 The function of Xg glycoprotein in RBCs is not known. The difference between the Xg(a⫹) and Xg(a⫺) blood groups is associated with the level of the Xga antigen and, presumably, Xg glycoprotein on the RBC surface rather than a different gene product. Xga antigen escapes X-chromosome inactivation due to the expression of a duplicate gene, MIC2, which lies telomeric and in the pseudoautosomal region of the X chromosome. MIC2 (synonyms: CD99, E2) is expressed on all cells and is an adhesion molecule on T cells.256 A portion of CD99 activates a caspase-independent apoptosis pathway in T cells.257

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molecules are part of plasma membrane complexes that are associated with intracellular protein kinases.257 Like other GPI-linked molecules, CD108 on RBCs may be a receptor that plays a role in signal transduction.

Membrane Proteins That Function as Enzymes Kell Blood Group System Kell glycoprotein is a 93-kd, single-pass type II membrane protein encoded by a gene on chromosome 7q33.259 It has sequence homology with a family of neutral endopeptidases and is an endothelin-3– converting enzyme; in addition to this activity, Kell glycoprotein can also cleave the precursors of endothelin-1 and endothelin-2, but much less effectively.260 Endothelins are potent vasoactive peptides involved both in the regulation of vascular tone and in developmental processes. The Kell glycoprotein may participate in the early stages of hematopoiesis or cell lineage determination.261 The Kell glycoprotein carries the antigens in the Kell blood group system. In contrast to the pathology seen in Xk-deficient RBCs, Kell glycoprotein deficiency does not result in RBC alterations107 (Tables 1 and 2). The Kell system consists of five sets of high-incidence and low-incidence antigens (K/k; Kpa/Kpb/ Kpc; Jsa/Jsb; K11/K17; K14/K24), three low-incidence antigens (Ula; K23; VLAN), and 10 high-incidence antigens (Ku; Km; K12; K13; K16; K18; K19; K22; TOU, RAZ). The antigens are associated with a single amino acid substitution of the Kell glycoprotein. The k to K substitution of Thr to Met disrupts the motif for N-glycosylation and may explain the relatively high immunogenicity of the K antigen.262

Yt Blood Group System Yt antigens reside on acetylcholinesterase (AChE).263,264 The RBC isoform of AChE is GPIlinked and is present in the membrane as a dimer. Its function in RBCs is not known but the molecule is enzymatically active; the Yta/Ytb polymorphism (which results from a single amino acid substitution)265 does not affect the enzymatic activity of AchE.264 Yt(a⫺b⫺) RBCs have no obvious abnormalities. AChE is a conventional type I transmembrane protein on neuronal cells, likely from alternate splicing of the mRNA.263

JMH Blood Group System

Dombrock Blood Group System

The JMH antigen is carried on the GPI-linked protein CD108, expressed on RBCs, some activated lymphocytes, neurons, epithelia, and testes.257,258 CD108

The Dombrock blood group antigens reside on ADPribosyltransferase, a GPI-linked glycoprotein. This enzyme (ART4) acts as a regulator of protein function

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through post-translational modification of the addition of adenosine diphosphate (ADP)-ribose to a target molecule.266 Despite extensive investigation, the RBC Dombrock glycoprotein has yet to be shown to have enzymatic activity. The polymorphism leading to the Doa/Dob antigens was identified as an amino acid substitution when the candidate gene was sequenced.267 Various mutation events lead to the Donull phenotype with no obvious deleterious effect on RBC structure or function.268

Complement Elements and Regulatory Proteins Cromer Blood Group System Antigens in the Cromer blood group system are located on decay accelerating factor (DAF, CD55), which is attached to the RBC membrane through a GPI anchor. The DAF glycoprotein is arranged into four extracellular short consensus repeat domains, each with about 60 amino acid residues. The Cromer system has two sets of antithetical antigens: Tca/Tcb/ Tcc and WESa/ WESb. Nine of the antigens (Cra, Tca, Dra, Esa, IFC, WESb, UMC, GUTI and SERF) are of high incidence and three (Tcb, Tcc, and WESa) are of low incidence. The amino acids required for expression of these antigens have been determined, and with the exception of Dra are due to a single amino acid change.269,270 DAF is present on all cells that are in contact with plasma (including blood cells and vascular endothelium), on epithelia of the gastrointestinal and urinary tracts, and in the nervous system. DAF is strongly expressed on the apical surface of trophoblasts271 and will absorb antibodies in the Cromer system from maternal serum, explaining the lack of HDN due to Cromer antibodies. Although DAF is not expressed on paroxysmal nocturnal hemoglobinuria (PNH) III RBCs, this deficiency is not the cause of their susceptibility to hemolysis. DAF functions to accelerate the decay of both C3 and C5 convertases regardless of whether they are the products of the classical or alternative pathways. Thus, DAF inhibits the amplification stage of complement activation and protects cells from complementmediated damage. DAF is a receptor for Escherichia coli and enterovirus.140,272,273 DAF is also found in plasma and other body fluids and prevents the activation of C4b2a by inhibiting the deposition of C3b on the surface of RBCs.274 Together with membrane cofactor protein (MCP), DAF catalyzes factor I–mediated cleavage of C3b that binds to RBCs.275-277 RBCs from individuals with the Inab phenotype, the null phenotype of the Cromer system, do not have significant complement-induced lysis in vivo.278 Although protein-loosing enteropathy has been re-

ported with the Inab phenotype, there is no clear disease association with this phenotype. The Dr(a⫺) variant RBCs express inherited Cromer antigens very weakly.

Knops Blood Group System Antigens of this system are carried on complement receptor 1 (CR1; CD35). CR1 is a type I single-pass membrane glycoprotein and a member of a large family of proteins known as the complement control protein (CCP) family. The CR1 glycoprotein consists of up to 30 repeated and disulfide-bonded domains called CCP modules. These modules, also termed short consensus repeats, are organized into four regions called long homologus repeats (LHRs), each region consisting of seven short consensus repeats.279 Most importantly, CR1 copy number on RBCs varies greatly among healthy individuals. Less than 100 copies per RBC are not detected using conventional blood group antibodies for the antigens expressed on this receptor molecule. Knops antigen expression is variable among different individuals, as is the number of CR1 molecules per RBC.280 Like DAF, the CR1 gene is located within the regulation of complement activation (RCA) cluster on chromosome 1 at 1q32. CR1 has four allotypes, A, B, C, and D. The most frequent allotypes are A (82%) and B (18%); the others are exceedingly rare. Soluble CR1 (sCR1) is present in low levels in plasma.281 CR1 protects RBCs from autohemolysis by inhibiting the classical and alternative complement pathways through cleavage of C4b and C3b. CR1 binds immune complexes, which are removed by the reticuloendothelial system in the liver and spleen without damaging RBC integrity.140,273,282 Acquired deficiencies of CR1 have been described in patients with systemic lupus erythromatosis, rheumatic diseases, and other malignant and inflammatory disorders. Low levels of CR1 on RBCs may cause deposition of immune complexes on blood vessel walls with subsequent damage to the vessels.283 Kna and McCa are common antigens with a similar prevalence (⬎90%) in different populations. However, the Sla antigen is of high prevalence in whites (98%) but of much lower occurrence among blacks (60%). In vitro rosetting of P falciparum is reduced in uninfected cells that are Sl(a⫺) or have low CR1 levels, suggesting that the Sl(a⫺) phenotype might confer resistance to malaria.284

Chido/Rodgers Blood Group System The complement elements C4A and C4B carry the Rodgers and Chido antigens, respectively, and are adsorbed onto RBCs from plasma. C4, the fourth component of complement, is involved in classical pathway activation. Functionally, C4A is more effec-

RBC Blood Group Antigens

Table 4. Components Carrying Blood Group Antigens That Serve as Receptors for Infectious Agents Receptor

Proteins Duffy Glycophorin A AnWj Cromer Knops (S1a) Carbohydrates Lewis P (Globoside) P1, Pk

Infectious Agent/Micro-organism

Plasmodium vivax Plasmodium falciparum Hemophilus influenzae Escherichia coli, enteroviruses Plasmodium falciparum Helicobacter pylori Parvovirus B19 Escherichia coli

tive than C4B in solubilizing immune complexes and inhibiting immune precipitation. C4B binds more efficiently to the RBC, thus causing hemolysis. Of 18 cases with total C4 deficiency (Ch/Rgnull), 14 had lupus; C4A null occurs in numerous other autoimmune diseases such as Graves’ disease, rheumatoid arthritis, and Sjo¨ rgen syndrome.285 C4B null gene has been associated with IgA nephropathy and rheumatoid arthritis as well as increased susceptibility to bacterial meningitis in children.286

ABO Blood Group System ABO antigens are the most clinically significant human alloantigens in transfusion medicine, yet their physiology remains to be elucidated. The antigens of the ABO system, which are not the primary gene product, require the sequential action of glycosyltransferases for expression. Lack of A, B, and H antigens on RBCs, as in individuals with the Bombay phenotype (Oh), does not affect erythrocyte function, integrity, or survival,287 nor are there reports of increased propensity to infection or disease in these individuals. The carbohydrate antigens A, B, H, Le, and P1 are present on many human cells other than RBCs and are also found in animals, bacteria, and even in some plants. On red cells, these antigens contribute to glycocalyx but otherwise their function is unknown.85

Lewis Blood Group System Lewis antigens (Lea and Leb) on RBCs are derived from plasma and not synthesized by the RBC.289 Lewis antigens are expressed in many human tissues including gastric surface mucous cells. Helicobacter pylori, the major causative agent of gastric ulcers, binds to gastric surface mucous cells that contain fucose, specifically Leb and H (type 1 chain) antigens, with Leb the predominant receptor for the organism.290 H pylori mimics cell surface glycomolecules present in gastric mucosa through the expression of

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Lewis antigens, facilitating H pylori infection. Most strains of H pylori express Lex and Ley (the type 2 chain structures) and a small minority of strains express Lea and Leb antigens on type 1 chains. The binding moiety of H pylori, Bab A (blood group antigen binding adhesin), has been purified and Bab A may mediate H pylori adherence to gastric epithelium as an important bacterial virulence factor.291 In transgenic mice expressing a human receptor for H pylori in their gastric mucosa, H pylori attachment resulted in production of autoantibodies directed at Lex. Lex epitopes are common to both H pylori and gastric parietal acid–secreting cells. Chronic type B gastritis as well as gastric and dudenal ulcers may develop due to an autoimmune process or through an inflammatory response to H pylori colonization.292 Lewis determinants on H pylori, the host Lewis phenotype type, and the severity of the inflammatory response have been correlated.293 Factors other than Lewis expression must influence disease progression, because isolates of H pylori that do not express Lewis antigens colonize gastric mucosa and cause infection, and individuals with the Le(a⫹b⫺) phenotype can become infected with H pylori and develop ulcers. Carbohydrate chains expressing Leb in blood group A⫺ and B⫺ individuals, unlike those of group O individuals, are frequently substituted with the A or B active sugar; these substituted chains do not permit binding of H pylori. This biochemical difference may explain earlier observations that group O individuals have a higher incidence of ulcers than those of group A or B.290 Lewis antigens may act as receptors for other infectious pathogens. Lex (an isomer of Lea) and Ley (an isomer of Leb) were found as neoantigens on malignant tissues294; their presence and the density apparently correlated with tumor metastatic potential.

Globoside Blood Group System The P antigen is the receptor for parvovirus B19, which specifically infects erythroid progenitors. B19 causes erythema infectosum (fifth disease) in normal children and adults, and worsening of anemia as transient aplastic crisis in patients with hemolysis, and chronic hypoplastic anemia if the host is unable to mount an effective neutralizing antibody response.295,296 P-fimbriated strains of E coli, often responsible for pyelonephritis, express both P-binding and Pk-binding molecules at the tips of their pili, which bind to P and Pk antigens through the disaccharide Gal␣1-4Gal.297

Raph Blood Group System MER2 was first identified as a blood group antigen using monoclonal antibodies. More than 92% of RBCs are MER2⫹. When the human antibody was

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found, the antigen was renamed Raph. Anti-MER2 found in three Raph-negative individuals with renal failure suggests that MER2 might be required for normal renal function.298

Infectious Diseases and Blood Group Antigens Some blood group antigens are expressed on tissues other than RBCs, including the epithelium of the gastrointestinal and urogenital tracts and lungs, which are exposed to multiple micro-organisms. Several carbohydrate and protein antigens have been shown to act as adhesion or receptor molecules for infectious agents (Table 4).

Conclusion In this review we have described the function of many of the protein components of the RBC membrane. The same protein or homologous proteins in other tissues may have defined functions, beyond the scope of this review and described elsewhere.140,273,299 It is important to consider that a component in the RBC membrane does not exist in isolation and interactions within microenvironments of the membrane may be important to functionality. Blood group polymorphisms generally do not affect the biological function of the component and in fact usually occur in the relatively nonconserved regions—thus, variations can be tolerated. Notable exceptions are Leb and Sla, which bind Helicobacter pylori and Plasmodium falciparum, respectively, where the specific antigen is required for the binding of the microbe. Some blood group phenotypes appear to confer a selective advantage: an example is the Fy(a⫺b⫺) in areas where certain forms of malaria are endemic. Other components, like CR1 and GPA, may be present in the RBC membrane to efficiently remove microbes from the circulation, thereby protecting the host from infection.

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