Lewis Histo-Blood Group System and Associated Secretory Phenotypes

Review

~~

Vox Sang 1995;69:166-182

Stephen Henrya3 Rafael Oriol Bo Samuelsson a

Lewis Histo-Blood Group System and Associated Secretory Department of Clinical Chemistry and

Transfusion Medicine, Phenotypes University of Goteborg, Sweden; Department of Transfusion Medicine, Auckland Regional Blood Centre, Auckland, New Zealand; lNSERM U 178, Villejuif, France .................................................................................................

Abstract This review summarises present knowledge of the chemistry, immunology, genetics and clinical significance of antibodies in the Lewis and secretor histo- blood group systems. Although red cell serology has laid the foundations for these systems, more recent advances have been made by studying Lewis and related glycoconjugates with monoclonal antibodies, determining structures by mass spectrometry and NMR spectroscopy, identifying enzymes and their specificities, and identifying the genes by molecular biology. The expression of Lewis system antigens is dependent on Lewis and secretor loci. Fucosyltrans- ferases coded by genes at these loci compete and interact with each other and with other transferases to determine an individual's Lewis and secretor phenotype. Exocrine epithelial cells, mostly of endodermal origin, synthesise the Le- wis antigens which, as plasma glycolipids, are secondarily acquired by cells of the peripheral circulation. Phenotyping red cells is often regarded as a simple way of determining the Lewis and sometimes the secretor status of an individual; however, the red cell phenotype is influenced by many factors and may not neces- sarily reflect someone's Lewis and secretor genotypes. Two main red cell Lewis groups are usually found, Lewis negative and Lewis positive. In Lewis-negative individuals, the secretor genotype does not affect the Lewis phenotype, but in Lewis-positive individuals, the non-secretor genotype generates the Le(a+b-) phenotype, the secretor genotype causes the Le(a-b+) phenotype, and the partial secretor genotype gives rise to the Le(a+b+) phenotype. .....................

Introduction and General Background

In 1946, Mourant [ I ] found an antibody in the serum of Mrs. H. D. G. Lewis which agglutinated red blood cells of approximately 20% of normal blood donors. The antigen was initially referred to as Lewis and later Lewis a or Lea. Two ycars later, Andresen [2] described an antigen thought to be coded by an allele of Lea that was called Lewis b or Le". The genetics of the two Lewis antigens were poorly

understood until observations showed that the expression of this blood group system was related to the presence of soluble ABH substances in secretions [3,4]. Earlier, it had been found that 80% of a Caucasian population also have ABH antigens in their saliva. This salivary secretor character was found to be inherited as a dominant Mendelian trait [ 5 ] . It was shown that all donors with Le"-positive red cells were non-secretors ofABH in saliva, and that all donors with Le"- positive red cells were ABH secretors [ 3 ] . These facts, plus

Rcccivcd: June 16, 1994

received: Nov. 3, I994 Transfusion Medicine $ X . O O / O Accepted: Jan. 17. 1994

Dr. Steve Henry 0 1995 S.Karger A(;, l 3 w l Rcviscd manuscript Depanmcnt ofClinical Chcmistry and 0042 'J007/')5/0603 ( I I 6 6

University ofcioteborg S413 45 Giiteborg (Swedcn)

a family study of the secretor trait in the small proportion of individuals with the Le(a-b-) red cell phenotype, suggested that the three main Lewis red cell phenotypes found - Le (a+b-), Le(a-b+) and Le(a-b-) -were not the result of two alleles ( a and h) at a single Lewis locus, but were rather the result of the interaction of two genetically independent loci, Lewis (Le-le) and salivary ABH secretor (Se-se) [6].

The Lewis determinants are structurally related to determinants of the ABH blood group system, and at the serological level, Lewis is now known to be comprised of two major carbohydrate antigens, Led and Leb. Like ABH, they are made by sequential addition of specific monosaccharides on- to terminal saccharide precursor chains on glycolipid or glycoprotein carrier molecules [7]. Lewis and related antigens may occur as free oligosaccharides in milk and urine, or may be protein bound, commonly 0-linked via an N-acetylgalac- tosamine to a serine or threonine residue [8]. Lewis and related antigens are also present as glycolipids and are thought to be located mainly in the outer leaflet of the plasma membrane [9] and in the circulation, as plasma high- and low- density lipoproteins. Lewis determinants of the red cell are not synthesised by the red cell, but rather by exocrine epithelial cells, mostly of endodermal origin, which shed these antigens into the exocrine secretions and plasma. The digestive tract is probably a major, but not exclusive, site for synthesis of the Lewis plasma glycolipids and it is probable that mucosal cells shed into the intestinal lumen are digested, re- absorbed and their glycolipids transported to the plasma. The circulating Lewis glycolipids, carried in the plasma, are then acquired by red cells [lo-121, lymphocytes [I31 and platelets [ 141, thereby labelling these cells with Lewis antigens.

The Lewis and Secretor Genes

The Lewis locus is on the short arm of chromosome 19 [15, 161 quite a distance from Hand Se, which are closely linked on the long arm of the same chromosome [17,18]. No linkage has ever been detected between Se and Lewis [19].

The Lewis Genes The Le gene has been cloned and codes for an a-1,314-

fucosyltransferase that is expressed in exocrine secretions and transfers fucose to the subterminal (JGlcNAc unit of precursor chains [20-221. In addition to the Le gene, several alleles supposedly encoding non-functional transferases are known and are collectively termed Ze genes. These silent variants contain point mutations, most of which inactivate the cognate Lewis enzyme activity in the relevant Lewis- negative individuals [23-261.

The Secretor Genes The Se gene has recently been cloned. It codes for an

a-1,2-fucosyltransferase that transfers fucose to the terminal (3Gal unit of precursor chains [Rouquier and Lowe, unpubl. results]. The Se fucosyltransferase is expressed in salivary glands, where its presence is correlated with the secretion of ABH blood group substances in saliva (hence its name). The term ‘secretor’ refers only to the presence of large amounts of soluble A, B and H determinants in saliva, the ABH substances found depending on the ABO blood group of the individual.

Two different models for the control of the expression of the secretor gene have been proposed. The classical genetic regulator model proposed by Morgan and Watkins [reviewed in ref. 271 postulates the existence of one a-2-fucosyltransferase whose expression is under the control of one structural gene H and two regulatory genes, Se for saliva and Z for red cells. This model is sustained by an H-deficient pedigree in which a salivary ABH secretor child issued from a se/se, h/hxse/se, H/- couple [28]. The validity of the pedigree has, however, been questioned, on the basis of data later collected on more than 50 H-deficient families

The alternative to the regulator model is a simpler model composed of two structural genes Hand Se, in which each gene encodes a different a-2-fucosyltransferase [30]. This model is based on the fact that the three-dimensional con- formation of the type 1 and type 2 precursor chains strongly suggests that the a-2-fucosyltransferases working on type 1 or type 2 precursor chains must be different (fig. 1) [3 11. This is also supported by evidence that at least two different a-2-fucosyltransferases have been found, believed to be en- coded by the H and Se genes [31-341. In this model, the product of the Se gene must be expressed in epithelial tissues concerned with exocrine secretion, and the product of the H gene must be expressed in mesodermal tissues such as red cells [35]. Since the ABH antigens on red cells are mainly type 2, while type 1 ABH antigens predominate in saliva, the model of two structural genes, each encoding a different fucosyltransferase, accounts for all the genetic, tissue distribution and biochemical data in a more economical way than the previous three-gene model. The segregation of the H and Se genes in the H-deficient families of Reunion Island confirmed the adequacy of this model and showed that both genes are closely linked on the long arm of chromosome 19

Point mutations in the coding region of the H gene (FUT1) have been found to be responsible for red cell H- deficient phenotypes in both salivary ABH secretors and non-secretors [36], strongly suggesting that the two-gene

~ 9 1 .

~ 9 1 .

167

Fig. 1. Comparison of the accessibility to the 2' hydroxyl group (arrows) of the terminal galactose in type I (pDGall'+3flDGlcNAc) and type 2 (pDGall'-+4PDGlcNAc) precursor chains. The acetyl group of the subterminal PGlcNAc restricts access to the 2' hydroxyl group in type I , whereas it leaves a different and freer access to the same hydroxyl group in type 2. On the basis of this structural difference, Lemieux [31] proposed that the a-2-fucosyltransferases using type 1 and type 2 precursors as acceptors should be different. Also shown are the 3 and 4 hydroxyl groups on the GlcNAc where the Lewis enzyme can add fucose. It should be noted that hydroxyl hydrogen atoms are not shown. The three-dimensional model, produced by Per-Georg Nyholm, was obtained by hard-sphere exo-anomeric (HSEA) calculations.

structural model is correct. Furthermore, the recent cloning of the secretor gene [Lowe, pers. commun.] strongly sup- ports the two-gene structural model. Therefore, the authors of this paper favour this simpler structural model, and this is the context in which Se will be discussed.

A weak variant of the Se gene known as Sew is also sus- pected and believed to be the causative gene of the Le(a+b+) phenotype (see below). The Sew allele is predicted to be absent in white-race people but frequent in certain Orientals and in some dark-skinned populations (Polynesians, Aus- tralian aborigines). In addition to the Se andSe"genes, there is a further gene, se, which does not make a functional a-2- fucos yltransferase.

Lewis Antigens and Their Defining Antibodies

Type 1 Precursor Chain or Le" The main Lewis-related epitope found in red cell Lewis-

negative ABH non-secretors (le/le, se/!e) is the type 1 precursor, which is also known as the Le" antigen (although it is not formed by the action of Lewis genes). The Le" antigen is found on red cells and in plasma and was originally defined by the ARM serum, which preferentially agglutinates Le(a- b-) non-secretor red cells [37,38]. Previously, in 1957, Iseki

et al. [39] produced a rabbit polyclonal antibody, which after absorption agglutinated all Le(a-b-) cells, and named this antibody anti-Le". In light of its pattern of reactivity, the true specificity was probably anti-Le" + Led. Le Pendu et al. [40] have shown that in rabbits, antibodies raised either to synthetic GalPl-3GlcNAc coupled to bovine albumin, or to saliva from a red cell Le(a-b-) non-secretor, then affinity-purified onto G a l ~ l + 3 G l c N A c ~ l +R immunoadsor- bents, had the same pattern of reactivity as the ARM sera. The chemical structure responsible for Lec was suggested to be the type 1 chain core saccharide [40] although this was later debated [41]. The problem faced in defining the Le' epitope is that it is difficult to define a single structural epitope using polyclonal antiserum. When polyclonal antisera are prepared, they preferentially recognise a branched elongated structure [41, 421 which is present in saliva, plasma and on red cells of Le(a-b-) ABH non-secretors. In contrast, monoclonal and affinity-purified antibodies can be prepared to a simpler structure (Gal~1--+3GlcNAcfiI + R ) which is also present in saliva, plasma and on red cells of Le(a-b-) ABH non-secretors but which, in its most simple form (lactotetraosylceramide), does not contribute to the agglutination of red cells [4345] . Lactotetraosylceramide (Lec-4) however is clearly the precursor to Led (H type 1) and Lea, and is detected in the plasma of Le(a-b-) non-se-

I68 Henry/Oriol/Samuelsson Lewis and Secretor

I Anti - Leac ,-Plasma- rSmall Intestinel

Lane Sample Code

Gud Web 046 TWi Hen Did 078

RBC AEH Secretor phenotype phenotype

Le(a-b) nonsecretor Le(a-b) nonsecretor Le(a-b) partial secretor Le(a-b-) secretor Le(a+b) nonsecretor Le(a-b+) seuetor Le(a+b+) partial secretor

Glycollpld source

Plasma Plasma Plasma Plasma Plasma Plasma Plasma

8 529 Le(a-b) nonsecretor Small intestine 9 Bre Le(a-b) secretor Small intestine

10 536 Le(a+b) Small intestine 11 578 b(a-b+) Small intestine 12 076 Le(a+b+) Small intestine

II Anti - Leab r-Plasma.-, r-Small Intestinel

1 2 3 4 5 6 7 8 9 1 0 1 1 12

~e'-4

~ e ~ - 5

9 10

1 2 3 4 5 6 7 8 9 1 0 1 1 12

1 1 1 Ant i-LebH -Plasma-- rSmal l Intestinel

I ,

1 2 3 4 5 6 7 8 9 1 0 1 1 1 2

Fig. 2. Thin-layer chromatogram montage of non-acid glycolipids from plasma and small intestinal epithelial cells from group 0 individuals with various Lewis and secretor phenotypes. Glycolipids have been separated on high-per- formance thin-layer Chromatography plates using a ch1oroform:rnethanol:water (60:35: 8) eluant and immunostained with radiolabelled anti-Lewis antibodies. Slight differences seen in mobilities represent experimental differences between plates. Plate I = Anti-Le", plate 11 = anti-Le"h, plate 111 = anti-LebH.

cretors but not secretors (fig. 2); it reacts with polyclonal anti-Le' when separated by thin-layer chromatography [42] and it can be elongated in Le(a-b-) ABH non-secretors to form the branched antigen (with Galljl+3GlcNAc~l+R on one of its branches; see fig. 3) which, when absorbed on to red cells will react with polyclonal anti-Lee.

The inability of lactotetraosylceramide to cause red cell agglutination is perhaps not surprising when it is considered how close to the cell surface the epitope would be - reactivity may be sterically hindered. There is, however, little doubt that the branched structures are relatively major glycolipids and immunogens in Lewis-negative non-secretors,

and that they are probably responsible for the agglutination of red cells via the LeC epitope and/or other epitopes, if polyclonal antisera are used. These branched structures also appear to be absent or poorly expressed on cord red cells because human anti-Le' (ARM) [38] and goat anti-Le' [37] react only with adult Le(a-b-) cells. In the agglutination of red cells, branched Le' structures bearing several epitopes (including Gal~1--+3GlcNAc~l+R) are the targets of monoclonal, affinity-purified and polyclonal antibodies, although polyclonal antibodies appear to be directed to more than just the Gal~1+3GlcNAc~1 -+R epitope [unpubl. obs.]. It is therefore appropriate to define the minimum

169

Galpl-3GlcNAcpl-3Galp 14Glcpl-lCer

Galp 1-3GlcNAcp 1-3Galp1-4Glc~1-1Cer 4

Fucal

Galj31-3GlcNAcpl-3Galp 1-4Glcpl-1Cer 2

Fucal

Gal~l-3GlcNAc~l-3Gal~l-4Glc~l-1Cer 2 4

Fucal Fucal

GalNAcal-3Galp 1-3GlcNAcp 1-3Galp 1-4Glcp 1 -1Cer 2

Fucal

GalNAcal-3Gal~l-3GlcNAc~l-3Gal~l-4Glc~l-lCer 2 4

Fucal Fucal

Gala 1-3GlcNAcpl Y 3,6Galp 1-3GlcNAcp 1-3Galp 1 4Glcp 1-1 Cer

a Galp 1 -4GlcNAcp 1

3 Fucal

Type 1 precursor, LeC, or lactotetraosylceramide

Lea or Lea-5

H type 1, Led, or H-5-1

Leb or Leb-6

A type 1 , ALed or A-6-1

ALeb or A-7-1

Branched LeC blood-group active nonaglycosylceramide [41]

Fig. 3. Common type 1 Lewis and related glycolipid antigens (not shown are B type 1 and BLeh). Cer = Ceramidc; Glc =glucose; Gal = galactose; GlcNAc = N-acetylglucosamine; Fuc = fucose.

requirement for a Le' antigen as a terminal Gal(31 -3GlcNAcfil +R structure, while the immunodominant Le' antigen of adult red cells is present on a branched precursor (see fig. 3 ) .

H IJpe 1 or Le" The second precursor to Lewis structures is monofuco-

sylated H type I, also known as Le" or Le"" [46,47] (fig. 3), which is formed by the action of the secretor transferase on thc type 1 precursor (fig. 4). This is the main antigen found on red cells and i n plasma ofgroup 0 Lewis-negative ABH secretors ( l d e , Se/-) [37,38,42] (fig. 2). Anti-Led was originally defined in 1970 by Potapov [48], who described an antibody raised in goats which, after absorption, showed anti-Le" activity; that is, the antibody reacted preferentially with the red cells from Le(a-b-) secretors. This antigen is also a precursor for ABO, and in group A, B and AB indi-

viduals it may also be converted into the corresponding type 1 A or B structures, A-6-1 (ALe") and B-6-1 (BLe") (fig. 3) according to the A or B phenotype ofthe individual.

Le" The monofucosylated Led antigen (fig. 3 ) is made by the

enzyme product of the Le gene acting on the type 1 precursor (Le'; fig. 4), and is found on the red cells of Lewis-positive ABH non-secretors, and to a lesser extent in Lewis-positive secretors (fig. 2). Lea is believed to be an unsuitable substrate for modification by the Se and ABO transferases. Anti-Lea reagents are usually easy to obtain and red cell phenotyping is straightforward. An analysis of anti-Le" monoclonal antibodies showed, as expected, that they do not cross-react at all with the H structure, but they do cross- react with the type 1 precursor chain (Le') [49] (see also fig. 5 ) .

170 HenryiOrioliSamuelsson Lewis and Secretor

Fig. 4. Simplified schematic diagram of a cyclic pathway for the formation of type 1 Lewis and extended Lewis structures [from ref. 421. The internal reducing side of these precursors is coupled to the carrier (R) which can be carbohydrate, glycolipid or glycoprotein molecules of different sizes. Known transferases of each step are indicated in italics near the solid pathway lines (Le = the Lewis a-3/4-fucosyltransferase(s); Se = the secretor a-2-fucosyltransferase (s); A and B = the ABO system glycosyltransferases). Other pathways which may be operating are symbolised by the dashed lines. The precursor can represent many different structures and the elongated/branched product on each cycle may become a suitable precursor for utilisation by the Le and Se transferases or it may be diverted to another pathway. The elongating/branching step can be represented by different transferases. As can be seen, the Lewis, secretor, elongat- ingibranching transferases and alternative pathways compete. It is proposed that fucosylation ofthe precursor removes it from the extendingibranching pathway. Fucosylated products may be able to re-enter the chain extension pathway, albeit less efficiently than non-fucosylated products.

Le" The difucosylated Leh antigen (fig. 3) is also made by the

product of the Le gene; however, the precursor is H type 1 (Led). The formation of Leh is therefore the result of the epistatic interaction of the products of Se and Le genes (fig. 4), and Leh is a major Lewis-related epitope found in red cell Lewis-positive ABH secretors (Le/-, Se/-; fig. 2).

Red cell phenotyping for Leh is more complex than for Led, because strong anti-Leh reagents are difficult to obtain and they all cross-react with Le" andlor H, the two components of the Leh antigen (fig. 5) . At one extreme, the antibodies have Leah specificity and at the other they have LehH

specificity. Even anti-Leh reagents that seem to be highly specific by agglutination always have some degree of cross- reactivity when reacted with related synthetic oligosaccharides or isolated glycolipids [42,49-521 making a clear definition of anti-Leh activity rather complex. As regards anti- Lehl' activity, it is interesting to note that monoclonal anti- LehH reagents react better with isolated ALeh and BLeh structures than do anti-LehL reagents [49]. This suggests that the different reactivity seen with Al, AZ, B and 0 Le(a-b+) red cells using anti-LehH may be due either to an inability to react with ALeh and BLeh antigens only when they are on the red cell membrane, or to a lower avidity of anti-Leb".

171

Fig. 5. Schematic two-dimensional representation of the frontal projections of Lewis antigens following the axis of the linkage between the PGal and the OGlcNAc of the precursor (empty boxes) [adapted with permission from ref. 401. The fucose in a-1,2 linkage is that of Se or H (large-point-filled box) and the fucose in a-1,3/4 linkage is that of Lewis (small-point-filled box). The fucose of Lewis in Lea leaves free access to the right side of the Lc' precursor chain, showing why cross-reactivity can be expected between these two epitopes. The fucoses ofSe and Lewis shield the upper part of the Le' precursor chain like a roof. This explains why anti-Leb reagents do not cross-react with the precursor. As Leb is a compound antigen of Le" and Led, it can be seen why cross-reactions with these two epitopes occur. Although the type 1 and type 2 precursors vary markedly in their ability to accept a terminal fucose due to structural differences (see fig. I ) , the type 2 precursor once fucosylated (to form LeX and Ley) resemble their type 1 isomers (Le" and Leh), and hence the cross-reactivity sometimes found between Lea and LeX, and between Leb and Ley.

An analysis of anti-Leh reagents showed a whole range of different cross-reaction patterns including H, Lea, Ley and precursor disaccharide chains, with each reagent showing slightly different areas and degrees of overlap in reactivity [49]. It has been suggested that the finding of an anti-Leh reagent that reacts only with Leh and which does not cross- react with either of its closely related Led or H epitopes is unlikely [49] (see also fig. 5).

Tvpe I LewidABH Combined Antigens In group A, B and AB Lewis-positive secretor-positive

individuals, some H type 1 is modified to make type 1 A or B antigens. In 1958, an antibody (Magard) that reacted with A type I , or ALed (fig. 3), was described by its reactivity with A, and A] Le(a-b-) secretor red cells [53]. A monoclonal antibody directed to the A type 1 antigen has been used to determine the presence of this glycolipid antigen on red cells [54]. The product of the Le gene can also utilise the type 1 A or B antigens to form the compound antigens ALeb and/or BLeb (fig. 3 ) according to the ABO phenotype of the individual [54-561. It is believed that these antigens cannot be formed by the action of the A and/or B glycosyltransferases on the Leh-antigen. An antibody directed to the difu-

cosylated A type 1 antigen (ALeb), known as Siedler, reacting only with A, and A,B red cells of the Le(a-b+) phenotype was reported in 1968 [57]. Later, a monoclonal antibody of the same specificity was used to determine the presence of this glycolipid antigen on red cells [54]. Al- though BLed and BLeb antigens are known to exist, only antibodies directed to BLed have been reported so far [13].

An antibody in humans that defines the very unusual compound antigen known as ILeb" has been described on two occasions [58, 591. This unusual antibody deserves mention because it obviously detects a branchedlextended Lewis structure that is present on the red cell membrane, but which is not detected in plasma. Extended branched Lewis structures have been described to be tumour-associated carbohydrate antigens, and are also found in plasma, especially that of Polynesians [42,52,60-62.1. Whether some of these extended antigens will react with this antibody is unknown, but highly probable.

Related Type 2 Lewis Antigens, L 8 (X) and Ley (Y) The Lea and Leb epitopes present on type 1 structures are

for many transfusion laboratories the only two components of the Lewis blood group system. If, however, the Le a-314-

172 HenryiOrioliSamueIsson Lewis and Secretor

fucosyltransferase acts on the type 2 chain precursor structure (where the terminal disaccharide linkage of the precursor is (S1,4 rather than (31,3), isomers of Lewis structures are formed. These are referred to as the LeX (X), Ley (Y), ALeY (AY) and BLeY (BY) structures, and are recognised as important markers of the cell membrane [7, 21, 27, 631. Al- though the type 2 Lewis antigens can be made by the Lewis transferase (FUT3) [20], they are usually formed by several non-Lewis a-3-fucosyltransferases (FUT4, FUT.5, FUT6,

From a serological perspective, the type 2 Lewis LeX and Ley antigens are not agglutinating epitopes on red cells, but they are often present in the same samples as type 1 Lea and Leb structures. For example, minor amounts of LeX glycolipid have been detected in the plasma of 0 Le(a-b-) non- secretors [71]. Despite the different profiles of the precursors presented to antibodies and enzymes [72] the fucosylated products of type 1 and type 2 precursors have common features which can cross-react with antibodies directed either to type 1 or type 2 structures (see fig. 5) [49,50].

FUT7) [64-701.

The So-Culled ‘Infant L8Antibody’ The term anti-LeX as proposed by Arcilla and Sturgeon

[73] to define the particular population of antibodies reacting equally well with Lea and Leb in the adult, and Lea on infant red cells, should not be used; this leads to confusion with antibodies specific for the LeX (X) structure that is defined as the type 2 isomer of Le”. The former so-called anti- LeX specificity corresponds to the specificity anti-Leab (LE3) [74], in which antibodies agglutinate red cells ofboth adult phenotypes Le(a+b-) and Le(a-b+) with the same in- tensity. Evidence has been presented that anti-Leab mainly recognises the Fucal,4 added by the Lewis transferase, a property which enables the antibody to react with both Lea and Le” determinants. In addition, anti-Leab can recognise small amounts of Lea structures present on cord red cells and red cells from Lewis-positive infants [75]. This anti- Leah antibody reacts only with those cord cells that have a genotype which includes the Le gene, regardless of secretor genotype. In many respects, this antibody could be considered as the ‘true’ anti-Lewis reagent because it detects the antigenic product of the Lewis transferase without regard to the presence of a terminal fucose.

Siulvluted Structures Sialylated structures of both the type 1 (Lea) and type 2

(Le’) antigens are also known to exist. Although these will not be discussed here, it should be noted that sialic acid can be added in a2-3 linkage to the peripheral (SGal of any of the type 1 or type 2 precursor chains [27,64,70].

Biosynthesis of Type 1 Lewis and Related Antigens

Formation of the Lewis antigens is a complex process involving the Lewis, secretor and other gene products which (when present) interact and compete to produce the known Lea and Leh epitopes. A simplified overview of the peripheral biochemical structures and interactions of transferases, resulting in the known Lewis and secretory antigens, is shown in figure 4. Glycolipid profiles relating to red cell phenotype for plasma and small intestine are shown in figure 2.

The sequences of events described (fig. 4) are, however, not common to all tissues of an individual or even the same tissue during development. For example, in Lewis-positive secretors [Le(a-b+)], type 1 ABH and Leh are well expressed in the small intestine [76], expressed in the proxi- mal half of the colon, but are present only to a limited extent in distal colonic mucosa [77-791. In the adult colon, the Se transferase is believed to be repressed and essentially only Lea is expressed in Lewis-positive individuals, irrespective of the ABH secretor status. In contrast, in the fetal colon and rectum, ABH-related carbohydrate antigens carried by type 1 chain core structures are expressed, with Leb expression being directly related to the secretor status of the individual [80]. However, from birth there is a gradual disap- pearance or appreciable reduction of these antigens in the distal colon, with the exception of Lea, which remains expressed [79, 801. The Le” antigens which are expressed by fetal colonocytes, but which have disappeared from normal adult colonocytes, may reappear (derepression) in adults on colonic cancer cells [78,79].

Lewis and Secretor Phenotyping

Red Cell Lewis Antigens About one third of the total Lewis-active glycolipid in

whole blood is associated with the red cell, and the rest is found in the plasma [81]. The concentration of Leb glycolipid in serum has been estimated to range from 0.1 to 4.0 pgl ml[82].

As a consequence of the secondary acquisition of Lewis antigens, the red cell phenotype may be changed in disease and other conditions. Altered red cell expression may be seen in patients with cancer of the pancreas, stomach, bile ducts, breast, colon and bladder [83-871. In addition, the red cell phenotype may also change in women who become pregnant and in patients who develop alcoholic cirrhosis, alcoholic pancreatitis, viral and parasite infections [82, 88- 911. Various mechanisms have been attributed to these dis-

173

cordancies, including a decrease in the relative concentration of Lewis-blood-group-active glycolipids in pregnancy, abnormal lipid metabolism, and changes in triglycerides and high-density lipoproteins.

Red cells can also change and acquire a different type 1 ABH and Lewis phenotype if they are incubated in vitro in plasma of a different phenotype, or acquired in vivo by transfusion [lo], or after bone marrow transplantation into a recipient of a different ABO or Lewis phenotype [92,93].

Genetic factors may also be involved in the expression of the red cell Lewis phenotype. For example, a single point mutation giving a leucine to arginine substitution in the transmembrane domain of the Lewis enzyme modifies the anchoring of the enzyme in the Golgi membrane. This mutation, when present at a double dose, reduces the amount of Le" and Le" glycolipids adsorbed on red cells giving the dis- cordant erythrocyte Le(a-b-) phenotype in individuals with normal expression of Led and Leb antigens in saliva [25].

Sulivury ABH and Lewis Substances The common distinction between secretors and non-se-

cretors of ABH andor Lewis substances is made by inhib- iting an antiserum with saliva in an inhibition test [94]. Many variables influence the detection of salivary substances. These include the ABO and Lewis group, dilution of saliva, potency, source, cross-reactivity of antiserum, immunoglobulin class, quality control and methodology [94-971.

The salivary inhibition test, used to differentiate ABH secretors from ABH non-secretors, needs to be sufficiently insensitive so as not to detect the low levels of ABH substances present in non-secretor saliva [97-991, while being sufficiently sensitive to detect low levels of ABH substances that may be the result of an inefficient secretor gene [IOO], or in different ABO types [94]. Determination of the level of ABH substances in saliva, especially in partial secretors, can be difficult unless carefully standardised techniques are used [96, 97, 100-1031. Similarly, low levels of Lewis antigens in the saliva of Lewis-negative individuals [38, 1041, and other related substances can also inhibit Lewis antiserum. Some monoclonal reagents, although specific for a given determinant on the intact red cell, may be neutralised by a related epitope in saliva, i.e. Led substance will neutralise most monoclonal anti-LehL reagents [51].

However, using properly standardised techniques, the ranges of concentration in blood group substances are, for the most part, the products of individual characteristics rather than sampling and methodological variables [97]. It should also be noted that the lectin Ulex euvopaeus which is used in salivary inhibition assays shows specificity forthe H type 2 determinant and does not cross-react with H type I

[46, 1051. However, most of the H type 2 in saliva is under the control of the Se gene [31].

Lewis and Secretor Phenotypes

In white races, about 90% are Lewis positive and Lewis negatives range from 6-10%, while, independently, secretors of ABH represent almost 80% and non-secretors are close to 20%. The frequencies of the three main red cell Le- wis phenotypes for European Caucasians are Le(a+b- ) 22%, Le(a-b+) 72% and Le(a-b-) 6% [94]. These frequencies vary markedly in other populations; for example, the Lewis-negative phenotype is almost 30% of American Blacks [106], and in some African populations can reach up to 40% [107]. The non-secretor phenotype is virtually absent in all South American Indians and Orientals [107]. The Le(a+b+) phenotype and partial secretory phenotypes which are absent or rare in most other adult populations [I071 are frequent in Polynesians [loo, 1081, Australian aborigines [109], Chinese [102, 1101, Japanese [83, 1031 and Blacks [Ill].

In populations where the Le(a+b+) phenotype is frequent, Leb detectability depends on the potency, type of antiserum used [112,113] and technique [114]: many allegedly Le(a+b-) individuals are in fact Le(a+b+) [52, 60, 1001. With different commercial anti-Lewis antisera, we have found that the same Polynesian individuals may be pheno- typed as Le(a-b-) and Le(a-b+), or Le(a+b-) and Le (a+b+), or Le(a-b+) and Le(a+b+) [112,113]. These anoma- lous phenotypes can represent up to 15% of results, and so cast doubt on actual phenotype frequencies that have been reported for some populations. The same phenomenon occurs in the Chinese, where the frequency of Le(a+b-) varies from 0 to 10% and Le(a+b+) from 13 to 25% when different antisera are used [ 1151.

Le(u-b-) At the serological level, individuals who have not inher-

ited a coding Lewis genotype (le/le; about 6-lo%), do not make detectable Lewis antigens and the red cells phenotype as Le(a-b-). There is little or no serologically detectable Le" or Leb antigen in the saliva or plasma, although trace amounts of Lewis activity and cross-reactivity can be detected [38, 42, 104, 1161. Lea has been found in Le(a-b-) non-secretors' plasma and intestinal samples (fig. 2) [42, 1171 while Leb can be indentified in the Le(a-b-) secretor samples (fig. 2) [42,76,118] and in other tissues [ I 191.

Le(a-b-) individuals can be subdivided into salivary ABH secretors and ABH non-secretors, depending on the

I74 Henry/Oriol/Samuelsson Lewis and Secretor

presence or absence of a Se gene. Le(a-b-) ABH secretors express the H type 1 (Led), while Le(a-b-) non-secretors express only the type 1 precursor (Le') antigen [31, 37, 120, 1211.

Immunochemical analysis of glycolipids in plasma shows that the type 1 precursor (Le') is present and H type 1 is absent in the Le(a-b-) non-secretors, while in Le(a-b-) secretors the reverse is true, with H type 1 being present and type 1 precursor absent (fig. 2) [42]. This result is consistent with the accepted biosynthetic pathway where type 1 precursor (Le') is fucosylated by the Se transferase to form H type I (Le"; see fig. 4). One of the more interesting observations in the Lewis negatives is a tendency to produce elongated precursor chains (fig. 2) when the Se fucosyltransferase is absent or inefficient [41,42]. In contrast, in the presence of a normal efficient secretor fucosyltransferase, complete conversion of precursor (Le '5 Led) occurs, which appears to preclude the precursor from being extended (see

The Le(a-b-) and Le(a-6-c-d-) phenotypes and Plas- ma a-3-L-Fucosyltransjerase (FUT6) Deficiency. The Le (a-b-c-d--) phenotype may be secondary to interactions of the products of the A or B and secretor genes, where the H type 1 (Led) formed is modified into A and/or B type 1 antigens. The phenotype is also seen in cord blood samples [37, 381, but this probably represents the non-expression of the branched Le' antigen on cord cells, although this remains to be provcd. In the paper associating the Le(a-b-c-d-) phenotype with a-3-L-fucosyltransferase deficiency [ill], there is evidence of ABH and secretor (Se%) transferases which, of course, questions the claim that the Le(a-b-c-d-) phenotype is a consequence of the failure to express plasma a-3-L-fucosy ltransferase.

There is little doubt that rare deficiency of the plasma tr-3-L-fucosyltransferase (FUT6) is associated with the Le (a-b-) red cell phenotype [29,122]. Thirty-three of 34 plasma a-3-L-fucosyltransferase-deficient individuals were Lewis negative on red cells and saliva, suggesting strong linkage disequilibrium between the FUT3 (Lewis) and FUT6 genes encoding these enzymes [66]. This is in good agreement with the recent finding that FUT3 and FUT6 are closely linked on chromosome 19 [123].

fig. 4).

Le(o t h - ) In Caucasians, the Le(a+b-) phenotype is usually clear

and easily defined, but in other populations where the Le (a+b+) phenotype is common, the Leh reaction of some Le (a+b+) red cells may have become so weak as to be undetected by many reagents.

Le(a + b +) At the serological level, the Le(a+b+) phenotype is usu-

ally easily recognised. Reactions with both anti-Le" and anti-Leb are usually strong, although a whole range of reactions exists. At one infrequent extreme, red cells appear as Le(a+b+) with a weak Lea reaction. These individuals often have normal levels of secretory substances and red cell Le" is only detected by potent reagents. Unless they have partial secretion of ABH substances, they should be considered as Le(a-b+). More commonly, the Lea and Leb reactions are of similar score, and these individuals are usually partial secretors [loo]. At the other extreme, but commonly, many Leb reactions of Le(a+b+) cells have become so weak as to be undetectable, and these individuals may phenotype as Le (a+b-) partial ABH secretors, and sometimes Le(a+b-) non-secretors [52]. Despite an apparent Le(a+b-) frequency of up to 26% in Polynesians using polyclonal antisera [IOS], we now believe this phenotype is virtually absent in Polynesians [loo]. Immunochemically, we have identified Leb glycolipids in two Le(a+b-) Polynesian samples, one of which is an apparent non-secretor, and the other a partial secretor [52]. The patterns of reactivity found resembled those ofLe(a+b+) samples (fig. 2) [52,60]. This undetected Leh is analogous to the serological non-detection of Le" on Le(a-b+) cells, but is much more significant because it represents the failure to detect a genetic polymorphism (that is, the presence of the product of a secretor transferase).

In Polynesian individuals of the Le(a+b+) phenotype, both Le"5 and Leh-6 are clearly demonstrated in the plasma, small intestine (fig. 2) and red cell glycolipid prepara- tions [52, 601. The same result was obtained for a Reunion Islander [52] and two Chinese plasma samples [60] of the Le(a+b+) phenotype. This copresence of Led and Leb in Le (a+b+) samples is in marked contrast to Caucasians with normal Lewis phenotypes who have predominantly either Lea or Leb present on red cells or in plasma.

There thus appears to be a quantitative basis for the unusual serology encountered in Polynesians. Lea is formed at the expense of Leb, and the more Lea formed the less Leh, hence a greater likelihood of not detecting Leh. When the number of available Le" antigens is reduced even further by competition with the A and B glycosyltransferases, Le" should be even more difficult to detect. This indeed does appear to be the case, as the Le(a+b+) phenotype is detected more frequently in group 0 subjects [IOS, 109,1241. Howev- er, the Le(a+b+) phenotype is still frequently found in group A, donors [log].

It has been postulated that the Le(a+b+) phenotype and partial secretion are the result of a change in the equilibrium of action of secretor- and Lewis-gene-specified transferases

175

[52, 100,1031. Although the Le(a+b+) phenotype, and associated partial secretion, could theoretically be caused by a more efficient than usual Le gene, the finding of Le(a-b-) partial secretors by other investigators [42,94,125] and our- selves [52,100], suggests independence of the gene causing Le( a+b+) from the Lewis loci. As a consequence we believe that the Le(a+b+) phenotype and reduced secretion of salivary ABH substances seen in Polynesians is the result of an inefficient or weak secretor gene (Sew) as originally postulated for Australian aborigines by Sturgeon and Arcilla [103]. The phenotypic result of this changed equilibrium is Le(a+b+) red cells and partial ABH secretion, or Le(a+b-) red cells and partial to negative ABH secretion, when the shift is further in favour of the Le gene [52,100].

Another observation related to the Le(a+b+) phenotype is the tendency to produce more elongated glycolipids than Le(a-b+) individuals. By fractionating and weighing glycolipids from the small intestine of a Le(a+b+) and a Le(a-b+) individual, we were able to measure a 2.5-fold increase in elongated glycoconjugates in the Le(a+b+) phenotype [117]. The formation of these large glycolipids is compat- ible with the concept of a weak secretor gene. The product of a Sew gene might lead to only partial formation of H antigen and allow increased production of Led and increased elongation of precursor chains to occur before precursor chain elongation is terminated by addition of the secretor fucosyl residue (see fig. 4).

Le(u-h +) Although red cells phenotype as Le(a-b+), they do in

fact have low levels of Lea, but it is generally insufficient to be detected by routine phenotyping reagents. Immuno- chemically it can be seen that these individuals convert almost all their H type l into Le” (fig. 2), and any type l A or B formed is mostly converted into the compound structures ALeb and/or BLeb [56,121].

Injant Lewis Phenotypes Additional complexities arise when infants are consid-

ered, where it appears that there is a differing penetrance of the Se gene during the first few years of life, which causes a change in some infants’ red cell phenotypes [103]. It is believed that during the first month of life, the Lewis enzyme activity is very weak and red cells type as Le(a-b-). At this early age, only very strong anti-Leab reagents [75] and some monoclonals [126] will detect positive reactions on red cells of babies with the Le gene. Then, in genetically appropriate individuals, Lewis activity increases before secretor activity and red cells type as weak Le(a+b-). Later, the Lewis activity continues to increase and some secretor activity ap-

pears, enough to make some Le” epitopes and give the Le (a+b+) phenotype, but not enough to transform most molecules into Le”. This Le(a+b+) phenotype is very common in children, representing up to 37% of Lewis phenotypes of infants aged 1-24 months [106, 1271. The secretory phenotype of Le(a+b+) infants is fully expressed, unlike the partial secretor phenotype associated with Le(a+b+) adults [103,128]. Finally, at about 2 years of age, both enzyme ac- tivities reach the normal adult levels and the red cell phenotype is transformed into the adult Le(a-b+), because most serum Lewis glycolipids are transformed into the difucosylated Le” structure [129].

Makela and Makela [130] demonstrated that the plasma of newborn infants would not transform Le(a-b-) red cells of adults into Lewis positives, but Le(a-b-) red cells of infants could be transformed into Lewis positives with Lewis- positive adult plasma. This demonstrates that a plasma Lewis glycolipid deficiency is the reason for the failure of infants to express detectable Lewis antigens. Although in pregnancy the large increase in lipoprotein relative to red cell mass can cause the Le(a-b-) phenotype to occur [82], this does not appear to be the cause in infants. Rather it appears that the Lewis transferase is poorly expressed in some tissues of the neonate [65], and a reduced level of circulating Lewis glycolipids is therefore responsible for the Le(a- b-) phenotype.

Tissue Expression of Lewis

Despite the fact that Lea and Le” were discovered on red cells, they are more widely expressed on epithelial tissues and are better called histo-blood group antigens. However, for any given phenotype, not all adult organs express the same antigens in the same proportions, and each organ has its own particular maturational changes in expression of ABH and Lewis at different stages of ontogeny. The expression of Lewis antigens in tissues is reviewed in detail else- where [129,131]. In brief, in adults, endodermal tissues (e.g. epithelial tissues concerned with exocrine secretion, including most of the cells of digestive, respiratory and urinary epithelia) express mainly type 1 and type 2 ABH antigens under control of the products of the Le and Se genes [21]. Ectodermal (e.g. epidermis) and mesodermally derived tissues (which include red cells and vascular endothelium) express mainly type 2 ABH antigens independent of the Le and Se genes, although there are some exceptions [21].

176 HenryiOrioliSamuelsson Lewis and Secretor

Tissue Origin ofplasma Lewis Glycolipids The site of synthesis of the plasma glycolipids is uncer-

tain but it has been suggested that they may originate from the intestinal tract [82]. This is based on the observation that human small intestinal mucosal scrapings and epithelial cells contain large amounts of blood group ABH and Lewis glycolipids [55,76,117,132,133]. In general, immunochemical staining of glycolipids is very similar between plasmas and intestinal fractions of the same phenotype (fig. 2) suggesting, at least, that similar glycosyltransferase mechanisms are responsible for the epitopes formed. However, staining patterns are not identical, with a single ceramide species predominating in the intestine, while a more heterogenous ceramide distribution is seen in plasma [60, 1171. The different Lewis glycolipid ceramide patterns in plasma and intestine suggest that either the intestinal tract is not the only origin of plasma glycolipids, or that a transport mechanism from intestine to plasma discriminates between ceramide species. Alternatively, the glycolipids in the study above represent an entire scraping of the intestinal tract without regard to maturity or location of the cells. It has been shown (in rat) that there are quantitative and glycolipid ceramide differences between cells at the bottom of the crypts and those near the top [134]. It is therefore possible that plasma and intestinal glycolipid profiles may be identical if only those cells extruded into the lumen are studied. More probably other exocrine organs such as liver, kidney, and pancreas also contribute to the plasma glycolipids, which could account for the more heterogenous ceramide composition of plasma glycolipids.

Clinical Significance of Lewis Antibodies

Lewis antibodies are quite common, and may be frequently detected in the general population as part of serological pretransfusion testing [124, 1351. They are present in as many as 3% ofprenatal sera [135,136]. The majority of Lewis antibodies are probably naturally occurring, although the antibodies can be stimulated by transfusion [137]. It is generally assumed that most Lewis antibodies are IgM. However, it has been determined that most sera containing Lewis antibodies have an IgG component and that, rarely, some are entirely IgG [135,138,139].

Anti-Led is not made by Le(a-b+) individuals because they also have the Lea antigen. In contrast, subjects with the Le(a+b-) phenotype do not have Leb antigens and can make anti-Leh, albeit infrequently [135,138-1401. Most examples of anti-Le" are formed by subjects of the Le(a-b-) ABH secretor phenotype, whereas most examples of anti-Leb are

formed by Le(a-b-) ABH non-secretors [104]. At first, this may seem surprising, but when it is appreciated that Le(a- b-) non-secretors make small amounts of Led, and Le(a-b-) secretors make small amounts of Leb [42], this is not un- expected.

The majority of Lewis antibodies are weak, reacting op- timally at temperatures lower than 37"C, and hence are of no clinical significance in blood transfusion. Led antibodies (and some anti-Leb) usually bind complement in vitro and often bring about the lysis of cells, especially enzyme-treated cells. These antibodies are only clinically significant if they are capable of reacting at 30-37"C, and on rare occasions anti-Lea has been blamed for haemolytic transfusion reactions [reviewed in ref. 94,124,1401. When a Lewis antibody is encountered in compatibility tests, blood for transfusion can safely be selected on the basis of in vitro compatibility at 37°C [140, 1411. The reason the great majority of Lewis antibodies do not cause a problem in vivo is because they are often weak and neutralised by Lewis substances in plasma before they can bind to red cells [ 1241. Although it is known that the Lewis antibody titre may rise considerably after an incompatible transfusion [ 1421, secondary re- sponses to these transfused red cells are rare, probably because the transfused red cells lose their Lewis antigens into the plasma as readily as they acquire them, and therefore acquire the phenotype of the recipient [lo, 941. Only two cases of delayed haemolytic transfusion reaction involving Lewis antibodies have been claimed [143, 1441. There is, however, no other evidence to support the notion that phe- notyped blood should be provided for individuals with Lewis antibodies, and blood can be issued safely on the basis of cross-match compatibility.

Haemolytic Disease of the Newborn (HDN) and Autoimmune Haemolytic Anaemia Lewis antibodies do not cause HDN although two cases

of mild HDN have been claimed [145, 1461. Two other examples of Lewis antibodies have been reported to sensitise red cells, but without evidence of a haemolytic process [147, 1481. The virtual absence of HDN due to Lewis antibodies is probably because of the poor expression of Lewis antigens on fetal red cells. Lewis antibodies are also not implicated in autoimmune haemolytic anaemia, although there are re- ports of Lewis-reactive autoantibodies sensitising red cells, but without causing haemolysis [88,149,150].

Lewis Antibodies and Renal Allograft Rejection Kidneys synthesise Lewis antigens independently [ 1511

and some centres have shown that Lewis-negative renal allograft recipients have a significantly lower renal allograft

177

survival rate than Lewis-positive individuals [152]. Renal allograft rejection has been shown to be associated with the presence of Lewis antibodies [149], many of which are only demonstrable by ELISA assays [ 1531. Lewis antibodies have also been associated with renal failure. In an unusual case, immunocompetent cells from a Le(a-b-) bone marrow transplantation were shown to produce anti-Le”, which was suggested to be associated with the development of renal failure in the recipient [154].

Other Antibodies Other antibodies to Lewis-related structures such as anti-

Le‘, -Led, -ALed, -ALeh, -BLed, -BLeb and -ILebH seem to be benign to red cells, as no report of these antibodies causing HDN or transfusion reactions can be found. These antibodies may however be lymphocytotoxic, as has been observed for antibodies directed to Lea, Le’, ALe’, ALed and BLed

It is of interest to note that four unusual Lewis antibodies occurred in patients with cancer. Anti-ALed (Magard) was found in a patient suffering from cancer ofthe stomach [53], anti-lacto-N-tetraose (Le‘) was found in a patient suffering from bronchogenic carcinoma [44], anti-ILe”” was first described in a patient who had metastatic carcinoma of the bladder [59] and an autoanti-Led was made by a Le(a-b+) individual who had carcinoma of the oesophagus [150]. It is also of note that the anti-lacto-N-tetraose was credited to be in part responsible for the regression of the patient’s tumour. Recently, monoclonal antibodies directed to fucosylated type 1 Lewis products have inhibited adhesion of colon carcinoma cells to vascular endothelium [155], and have been shown to have anti-tumour effects both in vitro and in vivo [ 1561.

~ 3 1 .

Final Comment

Much has been learned over the last 50 years about the Lewis and secretor systems, yet many questions remain un- answered. The overall impression is that Lewis and secretor carbohydrate polymorphisms of cell surfaces mu,v represent an advantage at the population level, for adaptation to a hos- tile foreign environment. We cannot say as yet that one his- to-blood group confers a greater survival potential than another, but the richness ofbiological systems and their capac- ity for adaptation resides in their diversity.

Unlike most of the blood group antigens, the Lewis system is unusual because the antigens are not biosynthesised per se on the red cells, but are rather absorbed from plasma. This secondary acquisition of glycolipids from the plasma

is not always straightforward, with underlying processes and diseases affecting the acquired red cell phenotype. I n many instances, it is clear that red cells might not be the optimal target cells for phenotyping, and that other samples such as saliva, epithelial cells, urine, tissue or genomic DNA would be more informative. Although the Lewis and secretor systems do not constitute clinically important systems to many transfusionists, these systems have a very real but not yet fully understood significance at the tissue level. Only by carefully and correctly defining phenotypes, char- acterising the glycoconjugates normally found in humans, and determining the genes and specificities of the glycosyltransferases involved, will it be possible to unravel the in- tricate biological relationships of carbohydrate blood group antigens with disease.

Acknowledgements

Per-Georg Nyholm, Medical Biochemistry, is gratefully acknowl- edged for the three-dimensional model shown in figure 1. The work reported by the authors of this review was supported by grants from thc New Zealand MedicaliHealth Research Council (grants 90137 and 921 44), the Swedish Medical Research Council (grants 6521 and 104.36). the IngaBritt and Arne Lundberg Foundation, the French Centre Na- tional de la Recherche Scientifique and Groupement de Recherche ct d’Etudes sur les Genomes (grant 57/94).

Addendum

The coding sequence of the secretor gene (FUT2) has now bccn published [157, 1581, confirming the two structural gene model for t/ and Sr [30]. The secretor gene codes for a 332 amino acid long poly- peptide which shares 68% sequence identity with the C-terminal 292 residues of the H fucosyltransferase. The non-secretor phenotype is the result of the homozygous presence of an enzyme-inactivating non- sense mutation (TrpI4’ -+ stop). Furthermore, we have identified in Po- lynesians, a second non-secretor allele and a candidate mutation for the Se“ allele (unpubl. results).

I78 HenryiOriollSamuelsson Lewis and Secretor

References

1 Mourant AE: A 'new' human blood group antigen of frequent occurrence. Nature 1946;158: 237 23X.

2 Andresen PH: The blood group system L. A new blood group L2: A case of epistasy within the hlood groups. Acta Pathol Microbiol Scand 1948;162:728.

3 Grubb R : Correlation between Lewis blood group and secretor character in man. Nature 1948: 1 ~ 9 3 3 .

4 Brcndemoen OJ: Further studies of agglutination and inhibition in the Lea-Leb system. J MedClin 1950;36:335-341.

5 Schiff F, Sasaki H: Der Ausscheidungstypus, ein auf serologischem Wege nachweisbares mendelndes Merkmal. Klin Wochenschr 1932; 11: 1426-1429.

6 Ceppellini R, Siniscalo M: Una nuova ipotcsi genetica per i l sistema Lewis secretore e suoi reflcssi nei riguardi di alcune evidence di linkage conalfri loci. Rev lnst Sieroter ltal 1955;30: 43 I - 445.

7 Clausen H. Hakomori S: ABH and related his- to-blood group antigens: Imniunochemical differences i n carrier isotypes and their distribution. Vox Sang 1989;56: 1-20.

8 lwase H: Variety and microheterogeneity in the carbohydrate chains of glycoproteins. Int J Bio- cheni 1988;20:479491.

9 Hakomori S: Chemistry of glycosphingolipids; In: Kanfer JN, Hakomori S (eds): Sphingolipid Biochemistry. New York, Plenum, 1983, pp I - 165.

10 Sneath JS, Sneath PHA: Transformation ofthe Lewis groups ofhuman red cells. Nature 1955; 176: 172.

1 1 Marcus DM, Cass LE: Glycosphingolipids with Lewis hlood group activity: Uptake by human erythrocytes. Science 1969;164:553-555.

12 Crookston MC: Blood Group Antigens Ac- quired from plasma. New York: Liss, 1980.

I3 Oriol R, Danilovs J, Leinieux R, Terasaki P, Ber- noco D: Lymphocytotoxic definition of combined ABH and Lewis antigens and their trans- fer from bcra to lymphocytes. Hum lmmunol 1980;3:195 205.

14 Dunstan RA, Marcus B, Simpson MD, Rosse WF: Le" blood group antigens on human platelets. Am J Clin Pathol 1985;83:90-94.

15 Weitkamp LR, Johnson E, Guttomsen SA: Probable genetic linkage between the loci for the Lewis blood group and complement C3. Cy- togenct Cell Genet 1974:13:183-184.

16 Whitehead AS, Solomon E, Chambers S, Bodmer WF. Povey S, Fey G: Assignment ofthe structural gene for the third component of human complement to chromosome 19. Proc Natl Acad Sci (JSA 1982;79:5021-5025.

17 Rouquier S. Giorgi D, Bergmann A, Brandriff B, Lcnnon G: The fucosyltransferase locus FUTl m a p distal to apolipoprotein loci E and C2 on human chromosome 19. Cytogenct Cell Genet 1994;66:70-71.

pp90 114.

18 Reguigne-Amould I, Coullin P, Mollicone R, Faure S, Fletcher A, Kelly RJ, Lowe JB, Oriol R: Relative positions of two clusters of human cc-l-fucosyltransferases in 19q (FUT I -FUT2) and 19p (FUT6-FUT3-FUTS) within the micro- satellite genetic map of chromosome 19. Cyto- genet Cell Genet, in press.

19 Ball SP, Tongue N, Gibdud A, Le Pendu J, Mol- licone R, Gerard G, Oriol R: The human chromosome 19 linkage group FUTl (H). FUT2 (SE), LE, LU, PEPD, C3, APOC2, D 19ST and D19S9.Ann HumGenet 1991;55:225-233.

20 Kukowska-Latallo JF, Larsen RD, Nair RP, Lowe JB: A cloned human cDNA determines expression of a mouse stage-specific embryonic antigen and the Lewis blood group a(1,3/1,4)fucosyltransferase. Genes Dev 1990;4: 1288-1 303.

21 Oriol R; Le Pendu J, Mollicone R: Genetics of ABO, H, Lewis, X and related antigens. Vox Sang I986;5 1 : 161-1 7 I .

22 Prieels JF', Monnom D, Dolmans M, Beyer TA, Hill RL: Copurification of Lewis blood group N-acetylglucosaminide a 1-4 fucosyltransferase and N-acetylglucosamide a 1-3 fucosyltransferase from human milk. J Biol Chem

23 Elmgren A, Rydberg L, Larson G: Genetic het- erogeneity among Lewis negative individuals. Biochem Biophys Res Commun 1993;196: 5 15-520.

24 KO& Y, Kimura H, Mekada E: Analysis of Le- wis fucosyltransferase genes from the human gastric mucosa of Lewis-positive and -negative individuals. Blood 1993;82:2915-2919,

25 Mollicone R, Reguigne I, Kelly RJ, Fletcher A, Watt J, Chatfield S, Aziz A, Cameron HS, West- on BW, Lowe JB, Oriol R: Molecular basis for Lewis a( 1,3/1,4)fucosyltransferase gene deficiency (FUT3). J Biol Chem 1994;269:20987- 20994.

26 Nishihara S, Yazawa S, lwasaki H. Nakazato M, Kudo T, Ando T, Narimatsu H: a( 1,3/1,4)fucosyltransferase (FucT-Ill) gene is inactivated by a single amino acid substitution in Lewis histo- blood type negative individuals. Biochem Bio- phys Res Commun 1993; 196:624-63 I .

27 Watkins WM: Biochemistry and genetics ofthe ABO, Lewis, and P blood group systems. Adv Hum Genet 1980;lO: 1-136.

28 Levine P, Robinson E, Celano M, Briggs 0, Fal- kinburg L: Gene interactions resulting suppression of blood group substance B. Blood 1955: 10:1100-1108.

29 Oriol R: Genetic control of the fucosylation of ABH precursor chains: Evidence for new epistatic interactions in different cells and tissues. J lmmunogenet 1990:17:235-245.

30 Oriol R, Danilovs J, Hawkins BR: A new genetic model proposing that the Se gene is a structural gene closely linked to the Hgene. Am J Hum Genet 1981;33:42143 I.

31 Le Pcndu J, Lemieux RU, Lambert F, Dalix AM, Oriol R: Distribution of H type 1 and H type 2 antigenic determinants in human sera and saliva. Am J Hum Genet 1982:34:402415.

1981;256:10456-10463.

32 Betteridge A, Watkins WM: Variant forms of a a-2-l-f~icosyltransferase in human submaxil- lary glands from hlood group ABH 'secretor' and 'nonsecretor' individuals. Glyconconj J 1985;2:

33 Kumazaki T, Yoshida A: Biochemical evidence that secretor gene, Se, is a structural gene encoding a specific fucosyltransferase. Proc Natl Acad Sci USA 1984;8 1 :4 193-4197,

34 Le Pendu J, Cartron JP, Lemieux RU, Oriol R: The presence of at least two different H-blood- group-related PDGal a-2-l-fucosyltransferases in human serum and the genetics of blood group H substances. Am J Hum Genet 1985;37: 749-760.

35 Oriol R, Le Pendu J , Sparkes RS, Sparkes MC, Crist M, Gale RP, Terasaki PI, Bemoco M: In- sights into expression of ABH and Lewis antigens through human bone marrow transplantation. Am J HumGenet 1981;33:551-560.

36 Kelly RJ, Emst LK, Larsen RD, Bryant JG, Robinson JS, Lowe JB: Molecular basis for H blood group deficiency in Bombay (0,)) and pa- rahombay individuals. Proc Natl Acad Sci USA 1994;9 I :5843-5847.

37 Graham HA, Hirsch HF, Davies DM: Genetic and immunochemical relationships between soluble and cell-bound antigens of the Lewis system; in Mohn J, Plunkett RW, Cunningham R, Lambert R (eds): Human Blood Groups. Basel, Karger, 1977, pp 257-267.

38 Gunson HH, Latham V: An agglutinin in human serum reacting with cells from Le(a-b) non- secretor individuals. Vox Sang 1972;22:344- 354.

39 lseki S, Masaki S, Shubasaki K: Studies on the Lewis blood group system. I : Le' blood group factor. Proc Imp Acad Jpn 1957;33:492497.

40 Le Pendu J, Lemieux RU, Oriol R: Purification of anti-Le' antibodies with specificity for pDGal( I-3)PDGlcNAcO- using a synthetic immunoadsorbent. Vox Sang l982;43: 188- 195.

41 Hanfland P, Kordowicz M, Peter-Katalinic J, Pfannschmidt G, Crawford RJ, Graham HA, Egge H: lmmunochemistry ofthe Lewis hlood- group system: Isolation and structures of Le- wis-c active and related glycosphingolipids from the plasma of blood-group 0 Le(a-b-) nonsecretors. Arch Biochem Biophys 1986; 246:655-672.

42 Henry SM, Oriol R, Samuelsson BE: Detection and characterisation of Lewis antigens in plasma of Lewis negative individuals: Evidence for extended structure formation as a result of reduced fucosyltransferase competition. Vox Sang 1994;67:387-386.

43 Gooi HC. Williams LK, Uemura K, Hounsell EF, Mcllhinney RAJ, Feizi T: A marker of human foetal endoderm defined by a monoclonal antibody involves type 1 blood group chains. Mol lmmunol 1983:20:607-613.

61-78.

179

44 Kabat EA, Liao J, Shyong J, Osserman EF: A monoclonal IgM macroglobulin with specificity for lacto-N-tetraose in a patient with bronchogenic carcinoma. J lmmunol 1982; 128: 540-544.

45 Picard JK, Loveday D, Feizi T Evidence for sialylated type 1 blood group chains on human erythrocyte membranes revealed by agglutination of neuraminidase-treated erythrocytes with Waldcnstrom's macroglobulin IgM"'"' and hy- bridoma antibody FC 10.2. Vox Sang 1985;48: 26 ~ - 3 3.

46 Graham HA, Sinay P, Hirsch HF, Jacquinet JC: Inhibition of anti-LedH and Uleu anti-H lectin with oligosaccharides. 19th Congr Int Soc Blood Transfus, 1978; p 552.

47 Hanfland F', Graham H: lmmunochemistry ofthe Lewis blood group system: Partial characterization of Le", Le" and H type I (Led'') blood group active glycosphingolipids from human plasma. Arch Biochem Biophys 1981;210:383-395.

48 Potapov MI: Detection ofthe antigen of the Le- wis system, characteristic of the erythrocytes of the secretory group Le(a-b-). Problem Haema- to1 (IJSSR) 1970;l 1:4549.

49 Good AH, Yau 0, Lamontagne LR, Oriol R: Serological and chemical specificities oftwelve monoclonal anti-Led and anti-Leh antibodies. Vox Sang 1992;62: 180-1 89.

SO FranCois A, Sansonetti N , Mollicone R, Le Pen- dti J, Galton J ; Jaulmes B, Oriol R: Heterogenei- ty ofLewis antibodies: A comparison of the rc- action o f human and animal reagents with synthetic oligosaccharides. Vox Sang I986;50: 227-234.

51 Fraser RIH, Mackie A, lnglis G , Murphy MT, Mitchell R: Characterisation of anti-glycocon- ,jugate monoclonal antibodies; in Rouger F', An- stee D, Salmon C (eds): First International Workshop on Monoclonal Antibodies against Human Red Blood Cell and Related Antigens. Paris, Arnette, 1987, pp 633-639.

52 Henry SM, Woodfield DG. Samuelsson BE, Oriol R: Plasma and red cell glycolipid patterns of Le(a+b+) and Le(a+lr-) Polynesians as further evidence of a weak secretor gene, Se". Vox Sang 1993;65:62-69.

53 Andresen J: Modifying influence ofthe secretor gcnc on the development ofthe ABH substance: A contribution to the conception of the Lewis group system. Vox Sang 1958;3:251-261.

54 Clausen H, Levery SB, McKibbon JM, Hako- mori S: Blood group A determinants with mono- and difucosyl type 1 chain in human erythrocyte membranes. Biochemistry 1985; 24:3518~-3586.

55 Breimer ME, Karlsson K-A, Samuelsson BE: Characterization of a human intestinal difucosyl heptaglycosylceramide with a blood group B determinant and a type 1 carbohydrate chain. J Biol Chcm 1982;257:1079-1085.

56 Lindstrom K, Breimer ME, Jovall PA, Lanne B, Piinlott W, Samuelsson BE: Non-acid glycosphingolipid expression in plasma of an A, Le (a-b+) secretor human individual: Identifica- tion ofan ALch heptaglycosylceramide as a major blood group component. J Biochem 1992; I I1:337 345.

57 Seaman MJ, Chalmers DG, Franks D: Siedler: An antibody which reacts with A, Le(a-b+) red cells. Vox Sang 1968;15:25-30.

58 Branch D, Powers T A second example of anti- ILeh". Transfusion 1979;19:353.

59 Tegoli J, Cortez M, Jensen L, Marsh WL: A new antibody, anti-ILehH, specific for a determinant formed by the combined action of the I, Le, Se and H gene products. Vox Sang 1971;21:397- 404.

60 Henry SM, Oriol R, Samuelsson BE: Expres- sion of Lewis histo-blood group glycolipids in the plasma of individuals of Le(a+b+) and partial secretor phenotypes. Glycoconj 1994; 1 1 : 593-599.

61 Stroud MR, Levery SB, Nudelman ED, Salyan MEK, Towell JA, Roberts CE, Watanabe M, Hakomori S: Extended type I chain glycosphingolipids: Dimeric Led (II14V4Fuc2Lcb) as human tumour-associated antigen. J Biol Chem 1991 ;266:8439-8446.

62 Stroud MR, Levery SB, Salyan MEK, Roberts CE, Hakomori S: Extended type 1 chainglycos- phingolipid antigens: Isolation and characterization of trifucosyl-Leh antigen (I1I4V4Vl'Fuc3 Lc,). Eur J Biochem 1992;203:577-586.

63 Hakomori S: Biochemical basis oftumor-associated carbohydrate antigens: Current trends, fu- ture perspectives, and clinical applications. Im- munol Allergy Clin N Am 1990;10:78 1-802.

64 Mollicone R, Gibaud A, Franqois A, Ratcliffe M, Oriol R: Acceptor specificity and tissue distribution of three human u-3-fucosyltransferases. EurJ Biochem 1990;191:169-176.

65 Mollicone R, Candelier JJ, Mennesson B, Couillin P, Venot AP, Oriol R: Five specificity patterns of ( 1-3)-cr-l-fucosyltransferase activity defined by use of synthetic oligosaccharide acceptors: Differential expression of the enzymes during human embryonic development and in adult tissues. Carbohydr Res 1992;228: 265-276.

66 Mollicone R, Reguigne I, Fletcher A, Aziz A, Rustam M, Weston BW, Kelly RJ, Lowe JB, Oriol R: Molecular basis of plasma u( 1,3)fucosyltransferase gene deficiency (FUT6). J Biol Chem 1994;269: 12662-1 267 I.

67 Weston BW, Smith PL, Kelly RJ, Lowe JB: Mo- lecular cloning of a fourth member of a human a( 1,3)fucosyltransferase gene family. J Biol Chem 1992;267:24575-24584.

68 Weston BW, Nair RP, Larsen RD, Lowe JB: Iso- lation of a novel a( 1,3)fucosyltransferase gene and molecular comparison to human Lewis blood group a( 1,3/1,4) fucosyltransferase gene. J Biol Chem 1992;267:4 I 5 2 4 160.

69 Natsuka S, Gersten KM, Zenita K, Kannagi R, Lowe JB: Molecular cloning of a cDNA encoding a novel human leukocyte a( 1,3)fucosyltransferase capable of synthesizing the sialyl Lewis x determinant. J Biol Chem 1994;269: 16789-16794.

70 Sasaki K, Kurata K, Funayama K, Nagata M, Watanabe E, Ohta S, Hanai N, Nishi T Expres- sion cloning of a novel al,3-fucosyltransferase that is involved in the biosynthesis of the sialyl Lewis x carbohydrate determinants in leuko- cytes. J Biol Chem 1994;269: 14730-14737.

71 Pfannschmidt G, Peter-Katalinic J, Kordowicz M, Heinz E, Dabrowski J, Dabrowski U, Hanf- land P: Structures of fucose-containing ceramide pentasaccharides from the plasma of blood group 0 Le(a-b-) nonsecretors. FEBS Lett 1984; 174:55-60 (Corrigenda FEBS Lett 1984; 177:305).

72 Lemieux RU: Human blood groups and carbohydrate chemistry. Chem Soc Rev 1978;7:423- 452.

73 Arcilla MB, Sturgeon P: Le', the spurned antigen ofthe Lewis blood group system. Vox Sang 1974;26:425438.

74 ISBT: Blood Group Tcrminology 1990. Vow Sang 1990;58:152-169.

75 Schenkel-Brunner H, Hanfland P: Immunochc- mistry of the Lewis blood-group system. I l l : Studies on the molecular basis of the Leh property. Vox Sang 1981;40:358-366,

76 Bjork S, Breinier ME, Hansson GC, Karlsson K-A, Leffler H: Structures of blood group glycosphingolipids of human small intestinc: A rc- lation between the expression of fucolipids of epithelial cells and the ABO, Le and Se phenotypes of the donor. J Biol Chem 1987:262:

77 Holgersson J, Stromherg N, Breimer M: Cilyco- lipids of human large intestine: Diffcrcnce in glycolipid expression relation to anatomical lo- calization, epithelialinon-epithelial tissue and ABO, Le and Se phenotypes ofthe donors. Bio- chimie 3988;70:1565-1574.

78 Itzkowitz S: Carbohydrate changes in colon cancer. APMIS Suppl 1992;100:173--180.

79 Yuan M, ltzkowitz SH, Palckar A, Shamsuddin AM, Phelps PC, Trump BF, Kim YS: Distribu- tion of blood group antigens A, B, H, Lewis,', and Lewish in human normal, fetal, and malignant colonic tissue. Cancer Res 1985;45:4499 451 1.

80 Szulman AE, Marcus DM: The histological distribution of the blood group substances in inan as disclosed by immunofluorescence. VI: The Le" and Leh antigens during fetal development, Lab Invest 1973;28:565-574.

8 I Rohr TE, Smith DF, Zopf DA, Ginsburg V: Le"- active glycolipid in human plasma: Mcasurc- ment by radioimmunoassay. Arch Biochcrn Biophys 1980;199:265-269.

82 Hammar L, Mansson S, Rohr T, Chester T, Ginsburg V, Lundblad A, Zopf D: Lewis phenotypes of erythrocytes and LC" active glycolipid in serum of pregnant women. Vox Sang I98 I ; 40:21-33.

83 Hirano K, Kawa S, Oguchi H, Kobayashi T, Yo- nekura H, Homma T Loss of Lewis antigen expression on erythrocytes on some cancer patients with high serum C A - 1 9 4 levels. J Natl Cancer Inst 1987;79:1261-1268.

84 Langkilde NC, Wolf H, 0rntoft TF: Lewis negative phenotype and bladder cancer. Lancet 1990;335:926.

85 Langkilde NC, Wolf H, Meldgard P, 0mtoft TF: Frequency and mechanism of Lewis antigen expression in human urinary bladder and colon carcinoma patients. Br J Cancer 1991;63:583 586.

6158-6765.

I80 Henry/Oriol/SamueIsson Lewis and Secretor

86 Langkilde NC, Wolf H, Omtoft TF: Lewis antigen expression in benign and malignant tissues from RBC Le(a-b) cancer patients. Br J Haematol I99 I ;79:493499.

87 Rowe G R McGregor M, Napier JAF: Lewis negative genotype and breast cancer risk. Lan- cet 1989;2:227-228.

88 Brendemoen OJ: Some factors influencing Rh immunization during pregnancy. Acta Pathol Microbiol Scand 1952;3 1:579-583.

89 Lee CH; Hagen MA, Chong BH, Grace CS, Rozenburg MC: The Lewis system and secretor status in autoimmune hemolytic anemia complicating infectious mononucleosis. Transfusion I980;20:585-588.

90 Makni S, Dalix AM, Caillard T, Compagnon B. Le Pendu J , Ayed K, Oriol R: Discordance between red cell and saliva Lewis phenotypes in patients with hydatid cysts. Exp Clin Immu- nogcnet 1987;4:136-143.

91 Stigendal L. Olsson R, Rydberg L, Samuels- son BE: Blood group Lewis phenotype on erythrocytes and in saliva in alcoholic pancreatitis and chronic liver disease. J Clin Pathol 1984;37:778-782.

92 Lindstrom K, Shanwell A. Jacobsson A. Lonnqvist B, Samuelsson BE: Alterations of glycosphingolipid-based blood group antigen expression on erythrocytes and in plasma studied on consecutive samples after a blood group 0 to A bone marrow transplantation. Glyco- biology l992;2:529-534.

93 Needs ME. McCarthy DM, Barrett J: ABH and Lewis antigen and antibody expression after bone marrow transplantation. Acta Haematol 1987;78: 13-1 6.

94 Race RR. Sanger R: Groups in Man, ed 6. Ox- ford. Blackwell Scientific, 1975.

95 Milne RW, Dawes C: The relative contribu- tions of different salivary glands to the blood group activity of whole saliva in humans. Vox Sang I973;25:298-307.

96 Surgeon F', McQuiston D, van Camp S: Quanti- tative studies on salivary blood group substances. I: Methodology and physiological variables. Vox Sang 1973;24:97-113.

97 Sturgeon P, McQuiston D, van Camp S: Quan- titative studies on salivary blood group substances. 1 1 : Normal values. Vox Sang 1973;24: 114-125.

98 Fiori A, Giusti GV, Panari G: Gel filtration of ABH blood group substances. II: Individual gel chromatographic patterns of ABH substances in the saliva of secretors and non-secretors. J Chromatogr 1971;55:351-363.

99 Le Pendu J, Oriol R, Lambert F, Dalix AM, Le- mieux RU: Competition between ABO and Le gene specified enzymes. 11: Quantitative analysis of A and B antigens in saliva of ABH non- secretors. Vox Sang 1983;43:421425.

I00 Henry SM, Benny AG, Woodfield DG: Investi- gation of Polynesian Lewis phenotypes: Evi- dence of a weak secretor phenotype. Vox Sang 1990;58:h 1-66,

101 Boettcher B, Kenny R: A quantitative study of Le", A and H antigens in saliva of Australian Caucasians and Aborigines. Hum Hered 197 I ; 2 1334-345.

102 Broadbeny RE, Lin-Chu M: The Lewis blood group system among Chinese in Taiwan. Hum Hered 1991;41:290-294.

103 Sturgeon P, Arcilla MB: Studies on the secretion of blood group substances. I: Observa- tions on the red cell phenotype Le(a+b+x+). Vox Sang 1970;18:301-322.

104 Miller EB, Rosenfield RE, Vogel P, Haber G, Gibbel N: The Lewis blood factors in Amer- ican Negroes. Am J Phys Anthropol 1954;12: 427443.

105 Hindsgaul 0, Norberg T, Le Pendu J, Lemieux RU: Synthesis of type2 human blood group determinants: The H, X and Y haptens and var- iations of the H type 2 determinant as probes for the combining site of the lectin I of Uiex europaeus. Carbohydr Res 1982;109:109-142.

106 Molthan L: Lewis phenotypes of American Caucasians, American Negroes and their children. Vox Sang 1980;39:327-330.

107 Mourant AE, Kopec A, Domaniewska-Sobc- zak K: The Distribution of Human Blood Groups and Other Polymorphisms, ed 2. Ox- ford, Oxford University Press, 1976, pp 548- 576.

108 Henry SM, Simpson LA, Woodfield DG: The Le(a+b+) phenotype in Polynesians. Hum Hered 1988;38:1 11-1 16.

109 Vos GH, Comley P: Red cell and saliva studies for the evaluation of ABH and Lewis factors among the Caucasians and Aboriginal populations of Westem Australia. Acta Genct 1967; I7:495-5 10.

110 Lin-Chu M, Broadberry RE, Chang FJ: The distribution of blood group antigens and al- loantibodies among Chinese in Taiwan. Trans- fusion 1988;28:350-352,

1 I 1 Greenwell P, Johnson PH, Edwards JM, Reed RM, Moores PP, Bird A, Graham HA, Watkins WM: Association of human Lewis blood group Le(a-bc-d-) with the failure of expression of a-3-L fucosyltransferase. Blood Trans- fus lmmunohaematol I986;29:233-249.

112 Henry SM, Simpson LA, Benny AG, Wood- field DG: Investigation of Polynesian Lewis phenotypes: Variability in detection of Lewis antigens by monoclonal, goat and human antisera. NZ J Med Lab Techno1 1989;43:64-67.

113 Henry SM, Dent AM, Harding Y: Detection of an Leh epitope peculiar to Polynesians; in Chester MA, Johnson U, Lundblad A, Low B, Messeter L, Samuelsson B (eds): Proceedings of the Second International Workshop and Symposium on Monoclonal Antibodies against Red Blood Cells and Related Antigens. Lund, Secretariat, 1990, p 75.

114 Henry SM, Dent AM, Harding Y: Ability to demonstrate Poynesian Leh antigen using one- stage and two-stage enzyme techniques; in Chester MA, Johnson U, Lundblad A, Low B, Messeter L, Samuelsson B (eds): Proceedings of the Second International Workshop and Symposium on Monoclonal Antibodies against Human Red Blood Cells and Related Antigens. Lund, Secretariat, 1990, P 76.

115 Lin-Chu M, Broadbeny RE: The Lewis phenotypes among Chinese in Taiwan; in Chester MA, Johnson U, Lundblad A, Low B, Mess- eter L, Samuelsson B (eds): Proceedings of the Second International Workshop and Symposi- um on Monoclonal Antibodies against Human Red Blood Cells and Related Antigens. Lund, Secretariat, 1990; p 79.

116 Holbum AM: Quantitative studies with ['ZSI]lgM anti-Le". Immunology 1973;24:1019- 1026.

I17 Henry SM, Samuelsson BE, Oriol R: Immu- nochemical and immunohistological expression of Lewis histo-blood group antigens in small intestine including individuals of the Le (a+b+) and Le(a-b) nonsecretor phenotypes. Glycoconj 1994; 1 1 :600-607.

1 I8 Henry SM, Jovall PA, Ghardashkhani S, Gus- tavsson ML, Samuelsson BE: Structural and immunochemical identification of Leh glycolipids in the plasma ofa group 0 Le(a-lr) secretor. Glycoconj J, in press.

1 19 Omtoft TF, Holmes EH, Johnson P, Hakomori S, Clausen H: Differential tissue expression of the Lewis blood group antigens: Enzymatic, immunohistologic, and immunochemical evidence for Lewis a and b antigen expression in Le(a-b-) individuals. Blood 1991;77: 1389- 1396.

120 Jovall PA, Lindstrom K, Pascher I, Pimlott W, Samuelsson BE: Identification of a blood group A active hexaglycosylceramide with a type 1 carbohydrate chain in plasma of an A, Le(a-b-) secretor. Arch Biochem Biophys 1987;257:409-415.

121 Lindstrom K, Rydberg L, Samuelsson BE: Biochemical and immunochemical studies of the expression of glycosphingolipid-based ABH and related antigens in normal cells and in plasma. Ann lnst Pasteur 1987;138:857- 861.

122 Watkins WM, Greenwell P, Yates AD, Johnson PH: Regulation of expression of carbohydrate blood group antigens. Biochimie 1988;70: 1597-1611.

123 Nishihara S, Nakazato M, Kudo T, Kimura H, Ando T, Narimatsu H: Human a-1,3 fucosyltransferase (FucT-VI) gene is located at only 13kb 3' to the Lewis type fucosyltransferase (FubT-Ill) gene on chromosome 19. Biochem Biophys Res Commun 1993; 190:42-46.

124 Mollison PL, Engelfriet CP, Contreras M: Blood Transfusion in Clinical Medicine, ed 9. Oxford, Blackwell Scientific, 1993.

125 LewisM,KaitaH,ChownB:The bloodgroups of a Japanese population. Am J Hum Genet 1957;9:274-283.

126 Lin M, Shieh SH: Postnatal development of red cell Le" and Leh antigens in Chinese infants. Vox Sang 1994;66:137-140.

127 Cutbush M, Giblett ER, Mollison PL: Demon- stration of the phenotype Le(a+b+) in infants and adults. Br J Haematol 1956;2:210-220.

128 Lawler SD, Marshall R: Lewis and secretor characters in infancy. Vox Sang 1961;6:541- 554.

181

I29 Oriol R: ABO, Hh, Lewis and secretion: Serol- ogy, genetics and tissue distrubution: in Car- tron JP, Rouger P (eds): Blood Cell Biochem- istry: Molecular Basis of Major Blood Group Antigens. New York, Plenum, 1994, pp 37-73.

130 Mikela 0, Makela P: Leh antigen: Studies on its occurrence in red cells, plasma and saliva. Ann Med Exp Biol 1956:34:157-162.

131 Holgersson J, Breimer ME. Samuelsson BE: Basic biochemistry of cell surface carbohy- drates and aspects of tissue distribution of his- to-blood group ABH and related glycosphingolipids. APMIS Suppl 1994;100:18-27.

I32 McKibbin JM, Spencer WA, Smith EL, Mans- son J, Karlsson K, Samuelsson BE, Li Y, Li S: Lewis blood group fucolipids and their isomers from human and canine intestine. J Biol Chem I982;257:755-760.

133 Smith EL, Bowdler AJ. Bull RW, McKibbon JM: Human blood group activity of human and canine intestinal glycolipids containing fucose. Immunology I973:25:621-629.

I34 Ureimcr ME, Hansson GC, Karlsson K-A, Lef- tler H: Glycosphingolipids and the differentia- tion of intestinal epithelium. Exp Cells Res 198 1;135: 1-13.

135 Molthan L, Strohm PL, Gross BM, Paradis DJ: Frequencies and immunoglobulin classes of the Lewis, P, , and MN system antibodies. Lab Med 1983; I4:422-426.

I16 Perkins RP: The significance ofanti-Lewis antibodies in pregnancy. Am J Obstet Gynecol 1970; IO7:28-32.

137 Cheng MS, Lukomskyi L: Lewis antibody following a massive blood transfusion. Vox Sang 198957: 155--156.

13X Holburn AM: IgG anti-Le'. Br J Haematol 1974;27:489-500,

139 Spitalnik SL, Cowles JW, Cox MT, Blumberg N: Detection of IgG anti-Lewis(a) antibodies in cord sera by kinetic Elisa. Vox Sang 1985; 48:235-238.

140 lssitt PD: The Lewis System; in Applied Blood Group Serology, ed 3. Miami, Montgomery Scientific Publications, 1985,pp 169-191.

141 Waheed A, Kennedy MS, Gerhan S, Senhauser DA: Transfusion significance of Lewis system antibodies. Am J Clin Pathol 198 1 ;76:294- 298.

142 Mollison PL, Polley MJ, Crome P: Temporary suppression of Lewis blood-group antibodies to permit incompatible transfusion. Lancet 1963;i:909-912.

143 Pineda AA, Taswel HF, Brzica SM: Delayed hemolytic transfusion reaction. An immuno- logical hazard of blood transfusion. Transfu- sion 1978;18:1-7.

144 Weir AB, Woods LL, Chesney C, Neitzer G: Delayed hemolytic trailsfusion reaction caused by anti-Le'" antibody. Vox Sang 1987; 53:105-107.

145 Carreras Vescio LA, Torres OW, Virgilio OS, Pizzolato M: Mild hemolytic disease of newborn due to anti-Lewisd. Vox Sang 1993;64: 194-1 95.

146 Bharucha ZS, Joshi SR, Bhatia HM: Hernolyt- ic disease of the newborn due to anti-Leh. Vox Sang 1981;41:36-39.

147 Abhyankar S, Silfen S, Rao SP, Vinciguerra C, Dimiaio TM: Positive cord blood 'DAT' due to anti-Le": Absence of hemolytic disease of the newborn. Am J Pediatr Hematol Oncol 1989;

148 Kelsall GA. Vos GH: A case of haemolytic disease of the new-born due to anti-Le'. Med J Aust 1962;49:598-599.

149 Giles CM, Poole J: Auto-anti-Leh in the serum of a renal dialysis patient. Clin Lab Haematol 1979;1:239-242.

I 50 Judd WJ, Steiner EA, Friedman BA, Oberman HA: Anti-Le" as an autoantibody in the serum of a Le(a-b+) individual. Transfusion 1978; I8:436440.

I 1: 184-185.

151 Oriol R, Cartron JP, Cartron J, Mulct C: Bio- synthesis of ABH and Lewis antigcns in normal and transplanted kidneys. Transplantation

1.52 Oriol R, Opelz G, Chun C, Terasaki PI: Thc Lewis system and kidney transplantation. Transplantation 1980;29:397--400.

153 Spitalnik S, Pfaff W, Cowles J , Ireland JE. Scornik JC, Blumberg N: Correlation of hu- moral immunity to Lewis blood group antigens with renal transplantation rejection. Transplantation 1984;37:265-268.

154 Blajchman MA, King DJ, Heddle NM, Sinyal DP, Walker IR, Brain MC: Association ofrenal failure with Lewis incompatibility after alloge- neic bone marrow transplantation. Am J Mcd

1980;29: 184-188.

1985;79: 143-146. 155 Dejana E, Martin-Padura 1, Lauri D, Bern

ni S, Bani MR, Garofalo A, Giavazzi R, Mag- nani J, Mantovani A, Menard S: Endothclial leukocyte adhesion molecule-I dependent adhesion of colon carcinoma cells to vascular endothelium is inhibited by an antibody to Lewk fucosylated type 1 carbohydrate chain. Lab In- vest 1992:66:324-330.

156 Watanabe M, Ohishi T, Kuzuoka M, Nudel- man ED, Stroud MR, Kubota T, Kodaira S, Abe 0, Hirohashi S, Shimosata Y, Hakomori S: In vitro and in vivo antitumor effects ofmu- rine monoclonal antibody NCC-ST-42 I reacting with dimeric Le" (LcVLe") epitope. Cancer Res 1991;51:2199-2204.

157 Rouquier S, Lowe JB. Kelly RJ, Fertitta AL, Lennon GG, Giorgi D: Molecular cloning ofn human genomic region containing the f-l blood group a( 1,2)fucosyltransferase gene and two H locus-related DNA restriction fragments. Isolation of a candidate for the human Secre/or blood group locus. J Biol Chem 1995:270:

158 Kelly RJ, Rouquier S, Giorgi D, Lennon GG, Lowe JB: Sequence and expression of a cand- date for the human Srtrrtor blood group a( 1,2)fucosyltransfcrase gene (FUT2). Homo- zygosity for an enzyme-inactivating nonsensc mutation commonly correlates with the non- secretor phenotype. J Biol Chcm 1995;270: 46404649.

4632-4639.

Henry/Oriol/Samuelsson Lewis and Secretor

Lewis Histo-Blood Group System and Associated Secretory Phenotypes

Documents

Transcript of Lewis Histo-Blood Group System and Associated Secretory Phenotypes