Review

Lewis group system review

M.R. Combs

Key Words: Lewis, Secretor, blood group, H, FUT2, FUT3 Le(a–b+) RBCs incubated with plasma from an Le(a–b–) donor. Mollison et al.13 demonstrated that the loss of Lewis The expression of Lewis blood group antigens depends on antigens may also occur in vivo. In 1969, Marcus and Cass14 the alleles inherited at two independent loci, FUT2 (Secre- confirmed that plasma Lewis antigens are glycosphingolip- tor [SE] gene) and FUT3 (Lewis [LE] gene). The Se and Le ids acquired by the RBC membrane from lipoproteins or alleles encode separate fucosyltransferases that interact aqueous dispersions. to form Lewis antigens in secretions and fluids. The Lewis For additional historic information and references, see antigens on RBCs are not integral to the membrane but the review by Watkins15 on the early investigations of gly- are passively adsorbed from the plasma. The antigens are coproteins that led to our current understanding of the ge- widely distributed in human tissue and fluids and are re- netic control, biosynthesis, and phenotypic interactions of ceptors for some pathogenic bacteria. Lewis are Lewis, ABO, H, and Secretor. rarely clinically significant, although there are rare reports of hemolytic transfusion reactions, hemolytic disease of the Genetics and Inheritance fetus and newborn, and renal transplant rejection. This re- The six antigens of the Lewis system are listed in view provides a general overview of the Lewis blood group Table 1. Expression of these antigens is determined by the system. An extensive overview by Daniels1 contains addi- alleles inherited at two independent loci, FUT2 (Secretor tional detailed information on the Lewis blood group sys- gene) and FUT3 (Lewis gene) Table 2. The FUT2 allele Se tem and related antigens. encodes a transferase that adds fucose to type 1 precursor chains in secretions and fluids to form type 1 H antigen. Be- History cause A and B terminal sugars may be added to type 1 H Anti-Lea was first described in 1946. Mourant2 reported chains, FUT2 also controls A and B antigen expression in a room temperature and 37°C directly agglutinating anti- secretions. The FUT2 allele se is nonfunctional. The FUT3 body in two women who delivered infants suspected of hav- allele Le encodes a different transferase that adds a fucose ing hemolytic disease of the fetus and newborn (HDFN). on type 1 precursor chains as well as on type 1 H chains. The The RBCs of one of the infants failed to react with the ma- FUT3 allele le is a nonfunctional allele. ternal serum; thus the antibodies were thought to be natu- Table 1. Lewis antigens rally occurring. This new agglutinated 25 percent Antigen ISBT symbol ISBT No. of 96 RBC samples from English people. Two years later, Andresen3 described the original anti- Lea LE1 007001 b Leb LE2 007002 Le . This antibody only reacted with group O or A2, Le(b+) RBCs. Brendemoen4 later reported an anti-Leb that reacted Leab LE3 007003 with all Le(b+) RBCs regardless of ABO group. The two anti- LebH LE4 007004 bodies described by Andresen and Brendemoen were later ALeb LE5 007005 named anti-LebH and anti-LebL, respectively.5 BLeb LE6 007006 In 1948, Grubb6 observed the correlation between the Lewis blood groups and Secretor. Twenty Le(a+) adults were all nonsecretors of ABH substances and 41 of 42 Le(a–) Table 2. Lewis phenotypes, prevalence, and inherited alleles persons were secretors. The Lewis and Secretor loci were Prevalence Genotype later shown by family studies to be genetically independent.7 Grubb and Morgan8 first showed that Lewis substances are FUT2 Red cell (Secre- FUT3 Substances in present in secretions and serum, suggesting that Lewis phenotype Whites Blacks tor) (Lewis) secretions 9 was a system of saliva and plasma antigens. Furthermore, Le(a+b–) 22 23 sese LeLe or Lea Lewis antibodies could be neutralized by these soluble sub- Lele 6,10,11 12 stances. In 1955, Sneath and Sneath suggested that Le(a–b+) 72 55 Sese or LeLe or Lea, Leb, ABH the fundamental expression of Lewis antigens is in the SeSe Lele plasma and that RBCs simply adsorb the Lewis antigens Le(a–b–) 6 22 Sese or lele ABH in vivo. When Le(a+b–) donor RBCs were transfused to SeSe an Le(a–b+) patient, donor cells separated by differential sese lele Type 1precursor were found to be Le(a+b+). The transfor- Le(a+b+) Rare* Rare* SewSew or LeLe or Lea, Leb, ABH mation could also be reproduced in vitro. In vitro studies Sewse Lele also showed the loss of Lewis antigens from Le(a+b–) and *Present in 10–40% of some Asian populations.

112 IMMUNOHEMATOLOGY, Volume 25, Number 3, 2009 Lewis system review

The phenotype Le(a+b–) is found in non- Fig. 1 Lewis antigen Type 1 Precursor Lea secretors (sese), i.e., individuals homozygous biosynthesis. Le for a nonfunctional FUT2 allele but who have A = A transferase; β β1,3 Gal 1,3 GlcNAc Gal GlcNAc inherited at least one Le allele (Lele or LeLe), B = B transferase; R R α1,4 which results in the fucosylation of type 1 Fuc = fucose; Se Fuc precursor chains to form Lea antigen (Fig. 1). Gal = galactose; GalNAc = N-acetylga- The FUT2 gene controls only H antigen ex- Type 1 H b lactosamine; Le pression in secretions, not Lewis; therefore, Le GlcNac = N-acetyl- β1,3 β1,3 Gal GlcNAc R Gal GlcNAc R individuals with the Le(a+b–) phenotype glucosamine; also have Lea in their saliva, but no H. α1,2 α1,2 α1,4 Le = Le transferase; Fuc Fuc Fuc The most common Lewis phenotype, R = upstream Le(a–b+), is attributable to inheritance of carbohydrate; at least one Se allele at the FUT2 locus (SeSe Se = Se transferase. A B or Sese) and one Le allele at the FUT3 locus (LeLe or Lele). The Le fucosyltransferase Type 1 A Type 1 B adds fucose to type 1 H chains, formed as a α1,3 β1,3 α1,3 β1,3 GalNAc Gal GlcNAc R Gal Gal GlcNAc R b result of the inheritance of Se, to form Le α1,2 α1,2 antigen (Fig. 1). Although small amounts of Fuc Fuc Lea antigen are formed from type 1 chain pre- Le Le cursors, Lea is rarely detectable on the RBCs. a b Le , Le , and H antigens are in the saliva, and, ALeb BLeb depending on ABO group, A and B antigens α1,3 β1,3 α1,3 β1,3 as well. GalNAc Gal GlcNAc R Gal Gal GlcNAc R The Le(a–b–) phenotype is found in in- α1,2 α1,4 α1,2 α1,4 dividuals homozygous for a nonfunctional Fuc Fuc Fuc Fuc Lewis gene (lele). Lewis antigens are absent from RBCs and saliva. These individuals may be secretors (Sese or SeSe) or nonsecretors (sese) of ABH. The Lewis gene (FUT3), located on the short arm of The Le(a+b+) phenotype is rare in Europeans but oc- chromosome 19,20 was cloned in 1990.25 An intronless cod- curs in 10 to 40 percent of some Asian populations.16 These ing region encodes the fucosyltransferase. Silent base sub- individuals have at least one Le allele and at least one weak stitutions that result in a functional enzyme and single base or inefficient Se allele (SewSew or Sewse). Sew results in par- substitutions that cause the Le(a–b–) phenotype have been tial or weak secretion of ABH.17 reviewed.22 Most single base substitutions that cause the Le(a–b–) phenotype are enzyme-inactivating, although one Molecular Basis results in an enzyme with altered substrate specificity.22 As In 1995 Rouquier et al. 18 cloned FUT2 and the pseudo- with FUT2, many FUT3 mutations show ethnic specificity. gene Sec1. These genes as well as the closely linked, highly For more information on FUT2 and FUT3 alleles, see www. homologous FUT1 (H gene), which determines H anti- ncbi.nlm.nih.gov/gv/mhc/xslcgi.cgi?cmd=bgmut/home.26 gen on RBCs, are located on the long arm of chromosome 19.19,20 The FUT2 gene consists of two exons, with exon 2 Biochemistry encoding the fucosyltransferase.21 Numerous FUT2 mu- The FUT2 allele Se encodes a transferase that adds a tations with ethnic associations have been described and terminal α1,2-linked fucose to galactose on type 1 precur- reviewed.22 Some mutations result in a functional FUT2 sor to form type 1 H antigen (Fig. 1). The FUT3 allele Le allele (Se), whereas a nonsense mutation, 428G>A (Trp- encodes a transferase that adds a subterminal α1,4-linked 143Stop) causes a common nonsecretor allele (se428) in fucose to the N-acetylglucosamine (GlcNAc) of type 1 chain Europeans, West Asians, and Africans.19,22 Other non- precursor to form Lea antigen. The Le enzyme may also add secretor alleles with ethnic specificity are caused by single α1,4 fucose to the GlcNAc of type 1 H antigen to form Leb and multiple base deletions in FUT2. A missense mutation antigen (Fig. 1). Both Le and Se transferases prefer and 385A>T (Ile129Phe) causes a common enzyme-deficient compete for type 1 chain substrates in secretions and fluids. Se allele (Sew385) that is responsible for the Le(a+b+) phe- RBC Lewis antigen determinants are plasma glycosphingo- notype found in East and Southeast Asians.23 Three null lipids that are passively adsorbed onto cell membranes,14 FUT2 alleles attributable to gene recombination have been whereas Lewis antigens in secretions are glycoproteins.27 observed. One is the sedel allele, which is almost always The Le(a+b–) phenotype occurs in nonsecretors (sese) associated with an inactive FUT1 allele (h). Individuals who have at least one Le allele. Nonsecretors do not make homozygous for these alleles (sedelsedel and hh) have the type 1 H antigen; therefore the Le transferase adds α1,4 fu- classic Indian Bombay phenotype.24 cose to type 1 chain precursor to form Lea antigen only (Fig 1).

IMMUNOHEMATOLOGY, Volume 25, Number 3, 2009 113 M.R. Combs

In the Le(a–b+) phenotype, the Le transferase adds activity increases with age, these infants will ultimately type α1,4 fucose on type 1 H chain formed as a result of the Se Le(a–b+). By 1 year of age, 50 percent of children express transferase. The presence of both α1,2 fucose and α1,4 fu- their adult phenotype,35 and by age 2, the Lewis phenotype cose on GlcNAc results in Leb antigen expression. Although of most children will reflect their inheritedFUT2 and FUT3 the same α1,4 fucose when added to type 1 precursor results alleles.36 Lewis antigens are detectable in neonatal saliva. in Lea antigen, Lea is not expressed on the α1,4 fucosylated As in adults, secretors have Lea and Leb, nonsecretors have type 1 H structure (Fig. 1). Most type 1 chain is converted Lea.35 to Leb and adsorbed on the RBC membrane, resulting in the Le(a–b+) RBC phenotype. However, small amounts Pregnancy of Lea antigen are made as a result of the addition of α1,4 Lewis-positive women may become transiently Le(a– fucose by the Le transferase to type 1 precursor chains be- b–) during pregnancy and may produce Lewis antibod- fore Se transferase is able to add α1,2 fucose. Once the α1,4 ies.29,37 Decreased expression of Lewis antigens during preg- fucose is added to form Lea, steric hindrance prevents fur- nancy was first reported by Brendemoen.38 The increased ther fucosylation by Se transferase (to form Leb) or A and incidence of the Le(a–b–) phenotype during pregnancy B transferases.28 Some monoclonal or potent anti-Lea may may be a result of increased concentration of plasma lipo- react with this adsorbed Lea antigen on apparent Le(a–b+) proteins during pregnancy. In pregnant women, the ratio RBCs.29 of lipoprotein to RBC mass increases more than fourfold so In the Le(a–b–) phenotype, Lewis antigens are not de- that much more Lewis glycolipid is attached to plasma lipo- tectable in saliva or on the RBCs. Nonsecretors (sese and protein than is available for the RBC surface. Leb glycolipid lele) produce only type 1 chain precursors. In secretors, in plasma only decreases slightly during pregnancy; there- type 1 H chains will be produced, which can be further fuco- fore, decreased expression of Leb on RBCs is not caused by sylated by A and B transferases (Fig. 1). decreased blood levels of Leb glycolipid.39 In the Le(a+b+) phenotype, Lea is formed at the expense of Leb owing to ineffective competition of the Sew gene prod- Lewis Antigen Distribution uct for type 1 precursor. This results in more Lea antigen Lewis antigens are widely distributed in the human and less Leb antigen than is found in individuals with a nor- body and are often called “histo-blood group antigens.” mal Se gene.17 Lewis antigens are found on the pancreas, stomach, and Because Le transferase can add fucose to type 1 H chain large and small intestine mucosa; skeletal muscle; renal as well as to type 1 A and type 1 B chains, additional Lewis cortex; and adrenal glands. See Ravn and Dabelsteen40 for determinants such as ALeb, BLeb, and LebH may be expressed an extensive review of the tissue distribution of histo-blood depending on an individual’s ABO group (Fig. 1).30,31 These group antigens. antigens are defined by single antibodies, not separable In addition to saliva and plasma, Lewis antigens are mixtures of antibodies. LebH is present on cells with strong present in other fluids such as human milk,41 urine, gas- 42 43 H antigen expression, i.e., group O and A2, Le(b+) RBCs. trointestinal juices and seminal fluid, ovarian cyst fluid, The determinant involves type 1 H antigen and the Le α1,4 and amniotic fluid.44 As with RBCs, Lewis antigens on lym- fucose.16 ALeb is formed when Le transferase adds fucose to phocytes14 and platelets45 are acquired from the plasma. type 1 A chains; BLeb is formed when Le transferase adds The gastrointestinal tract may be the primary source of fucose to type 1 B chains (Fig. 1). plasma Lewis antigens.46 This is evident in a report of eight Leab is a determinant expressed on Le(a+) or Le(b+) patients with intestinal failure and resections of the ileum adult RBCs. The antigen is also present on cord samples and or jejunum, all with Le(a–b–) RBCs.47 Recipients of from infants who have inherited Le, suggesting that the an- bone marrow,48 kidney,49 and liver transplants50 maintain tigen is formed early in embryonic development.16 The com- their own RBC Lewis phenotypes, suggesting that these mon determinant is within the α1,4 fucose added by the Le organs are not primary sources of plasma Lewis antigens. transferase.32 Antibodies Infants Lewis antibodies are most often found in individuals Most newborns type Le(a–b–) during the first month with Le(a–b–) RBCs; their sera may contain a mixture of of life, although Lewis antigens can sometimes be detected anti-Lea, -Leb, and -Leab. Anti-Lea is usually found in Le(a– on cord RBCs with more sensitive techniques33,34 or the use b–) individuals who are ABH secretors.51 Le(a–b+) individ- of anti-Leab. If Le is inherited, only very low levels of the Le uals do not make anti-Lea because small amounts of Lea are fucosyltransferase are present at the site of production of present. plasma Lewis antigens. The Le fucosyltransferase becomes There are two major types of anti-Leb. The most com- active before the Se fucosyltransferase; therefore Lea devel- mon, anti-LebH, reacts preferentially with Le(b+) RBCs with ops first, and RBCs may type as Le(a+b–) followed by a tran- stronger H antigen expression, such as group O or A2 RBCs. sient Le(a+b+) phenotype if Se is inherited.33,35 As secretor Anti-LebL reacts with all Le(b+) RBCs regardless of ABO

114 IMMUNOHEMATOLOGY, Volume 25, Number 3, 2009 Lewis system review group. Anti-Leb is usually found in Le(a–b–) individuals are frequently detected and may cross the placenta. Spital- who are nonsecretors of ABH.51 Anti-Leb is rarely produced nik et al. 55 detected IgG anti-Lea by hemagglutination in 13 by people with Le(a+b-) RBCs. These individuals are typi- of 13 maternal samples and in 12 of the 13 cord samples by bH 4, 52,53 cally group A1 or A1B with anti-Le . enzyme-linked immunosorbent assay. They concluded that Other Lewis antibodies include anti-ALeb and -BLeb the rare incidence of HDFN is attributable to poor expres- which react with the compound antigens on group A or B sion of Lewis antigens on fetal cells instead of the frequently RBCs. Anti-Leab occurs mainly in Le(a–b–) secretors who cited low incidence of IgG Lewis antibodies. are group A1, B, or A1B. This antibody reacts with Lewis- Two cases of mild HDFN caused by Lewis antibodies positive RBCs from adults as well as cord RBCs from in- have been reported. The first reported case attributable to fants with an Le allele.16 anti-Lea caused a positive DAT with anti-Lea in the eluate Most Lewis antibodies are naturally occurring IgM. and hyperbilirubinemia. The infant’s RBCs initially typed Some may have an IgG component,54–56 and there are rare as Le(a–b+), which was speculated to be caused by blocking examples of pure IgG Lewis antibodies.57 Although most of the antigen by the maternal antibody. Four days later the Lewis antibodies are naturally occurring, some may be RBCs typed Le(a+b+) The 42-week gestation was speculat- stimulated by RBC transfusion. Cheng and Lukomskyi58 ed to have allowed stronger development of Lea antigen, and reported on two patients who exhibited Lewis antibodies the mildness was thought to be caused by partial neutraliza- after massive RBC transfusions of presumably Lewis- tion of the maternal antibody by Lea substance in the fetal positive units. One patient exhibited IgG anti-Lea and the plasma.72 Neonatal jaundice developed in a case of HDFN other had IgM and IgG anti-Leb. There was no evidence of caused by anti-Leb. The antibody was IgM and IgG and was hemolysis in either patient. hemolytic in vitro. An eluate prepared from the newborn’s In patients with 37°C reactive anti-Lea or anti-Leb, the DAT-positive RBCs contained anti-Leb.73 antibody titer may rise after RBC transfusion.13,59,60 In spite of this, Lewis antibodies are rarely implicated in hemolytic Clinical Significance transfusion reactions. Anti-Lea is more frequently associ- Lewis antigens are receptors for pathogenic bacteria. ated with acute hemolytic transfusion reactions61-64 than is In particular, Leb and type 1 H mediate attachment of Helico- anti-Leb.65,66 Three cases of delayed hemolytic transfusion bacter pylori,74 a gram-negative bacterium associated with reactions (DHTR) have been claimed.67–69 Hemolytic trans- gastritis, gastric and duodenal ulcers, adenocarcinoma,75 fusion reactions are rare because most Lewis antibodies are and immune thrombocytopenic pupura.76 Leb and type 1 not active at 37°C, transfused RBCs lose their Lewis anti- H are also receptors for Norwalk virus that causes gastro- gens into the recipient’s plasma, and there is neutralization enteritis.77 Conversely, lack of Lewis antigens, i.e., the of recipient Lewis antibodies by Lewis substance in donor Le(a–b–) phenotype, is associated with an increased suscep- plasma before the antibodies can bind to the RBCs of the tibility to infections by Candida spp,78 and uropathogenic recipient.13,59 Escherichia coli.79 Because most Lewis antibodies are IgM, they react best The Le(a–b–) phenotype is also associated with an in- in agglutination tests at room temperature and occasion- creased risk of cardiovascular disease.80 The mechanism for ally in agglutination tests at 37°C. Reactivity with anti- this association is unclear, but it may be mediated through human globulin (AHG) may be related to IgG or caused elevated triglycerides,80 insulin resistance syndrome,81 or by bound complement if polyspecific AHG reagent is used. obesity,82 each of which is also associated with the Le(a–b–) Lewis antibodies may demonstrate complement activation phenotype. by causing in vitro lysis of Lewis-positive RBCs, especially The Le(a–b–), Bombay phenotype occurs in patients with the use of enzyme-treated RBCs or fresh serum. To with leukocyte adhesion deficiency syndromes (LADII). aid Lewis antibody detection and identification, plasma A mutation in the GDP-fucose transporter results in and saliva Lewis substances or commercial sources of solu- hypofucosylation of glycoproteins. Clinically, these pa- ble substances may be used to neutralize Lewis antibodies, tients have leukocytosis, severe infections, and mental and and enzyme-treated RBCs may be used to enhance Lewis growth retardation, thereby demonstrating the broad im- antibody reactivity. pact of glycoprotein fucosylation.83,84 Transfusion services vary in their selection of RBC The role of Lewis in renal transplantation is contro- units for patients with Lewis antibodies. Some provide versial. Oriol et al.85 reported that Lewis-negative renal al- antigen-negative units if Lewis antibodies are hemolytic lograft recipients have a significantly lower graft survival in vitro, agglutinating at 37°C or reacting in the IAT with rate than do Lewis-positive recipients. Other investigators anti-IgG. In general, however, the selection of antiglobulin have found that renal transplant recipients who receive a crossmatch-compatible blood for patients with Lewis anti- Lewis-matched kidney have the best survival.86–88 Although bodies is recommended and considered safe.70,71 these reports suggest that cytotoxic Lewis antibodies may Lewis antibodies rarely cause HDFN. Although most play a role in renal transplant survival, other investigators are IgM and cannot cross the placenta, IgG Lewis antibodies have reported that Lewis phenotype compatibility does not

IMMUNOHEMATOLOGY, Volume 25, Number 3, 2009 115 M.R. Combs affect survival.89,90 Detectable Lewis antibodies in renal 16. Reid ME, Lomas-Francis C. The blood group antigen transplant recipients, however, have been associated with factsbook. 2nd ed. San Diego, CA: Academic Press, antibody-mediated graft rejection.91-93 2004. In summary, the Lewis blood group system is inter- 17. Henry SM, Benny AG, Woodfield DG. Investigation of esting and complex; the antigens are widely distributed in Lewis phenotypes in Polynesians: evidence of a weak se- human tissue and fluid; and the expression of most Lewis cretor phenotype. Vox Sang 1990;58:61–6. antigens requires the interaction of transferases from more 18. Rouquier S, Lowe JB, Kelly RJ, et al. Molecular cloning of than one blood group system. Lewis antibodies are rarely a human genomic region containing the H blood group clinically significant; however, there is growing evidence α(1,2)fucosyltransferase gene and two H locus-related that the presence or absence of Lewis antigens in an indi- DNA restriction fragments: isolation of a candidate gene vidual can be clinically significant, and this is the focus of for the human Secretor blood group locus. J Biol Chem much of the current research and investigation involving 1995;270:4632–9. the Lewis blood group system. 19. Kelly RJ, Rouquier S, Giorgi D, et al. Sequence and ex- pression of a candidate for the human secretor blood References α(1,2)-fucosyltransferase gene (FUT2). J Biol Chem 1. Daniels G. Human blood groups. 2nd ed. Oxford: Black- 1995;270:4640–9. well Science, 2002. 20. Reguigne-Arnould I, Couillin P, Mollicone R, et al. 2. Mourant AE. A ‘new’ human blood group antigen of fre- Relative positions of two clusters of human α-L- quent occurrence. 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Fol Hered Path 1959;8:261–96. sis for erythrocyte Le(a+b+) and salivary ABH partial- 6. Grubb R. Correlation between Lewis blood group and se- secretor phenotypes: expression of a FUT2 secretor allele cretor character in man. Nature 1948;162:933. with an A→T mutation at nucleotide 385 correlates with 7. Sanger R, Race RR. The Lutheran-secretor linkage in reduced alpha(1,2) fucosyltransferase activity. Glycoconj man: support for Mohr’s findings. Heredity 1958;12:513– J 1996;13:985–93. 20. 24. Koda Y, Soejima M, Johnson PH, et al. Missense muta- 8. Grubb R, Morgan WTJ. The “Lewis” blood group char- tion of FUT1 and deletion of FUT2 are responsible for acters of erythrocytes and body fluids. Br J Exp Pathol Indian Bombay Phenotype of ABO blood group system. 1949;30:198-208. Biochem Biophys Res Commun 1997;238:21-5. 9. Grubb R. Some aspects of the complexity of the blood 25. Kukowska-Latallo JF, Larsen RD, Nair RP, Lowe JB. groups ABO. Rev Hematol 1950;5:268–75. A cloned human cDNA determines expression of a 10. Grubb R. Observations on the human group system mouse stage-specific embryonic antigen and the Lewis Lewis. Acta Path Microbiol Scand 1951;28:61–81. blood group α(1,3/1,4)fucosyltransferase. Genes Dev 11. Brendemoen OJ. Studies of agglutination and inhibition 1990;4:1288–303. in two Lewis antibodies. J Lab Clin Med 1949;34:538– 26. Blumenfeld OO, Patnaik SK. Allelic genes of blood group 42. antigens: a source of human mutations and cSNPs docu- 12. Sneath JS, Sneath PHA. Transformation of the Lewis mented in the Blood Group Antigen Gene Mutation Da- groups of human red cells. Nature 1955;176:172. tabase. Hum Mutat 2004;23:8–16. 13. Mollison PL, Polley MJ, Crome P. Temporary suppres- 27. Watkins WM. Blood-group substances. Science sion of Lewis blood-group antibodies to permit incom- 1966;152:172–81. patible transfusion. Lancet 1963;1:909–12. 28. Kobata A, Grollman EF, Ginsberg V. An enzymatic ba- 14. Marcus DM, Cass LE. 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41. Watkins WM, Morgan WT. Specific inhibition stud- cies and immunoglobulin classes of the Lewis, P1, and ies relating to the Lewis blood-group system. Nature MN system antibodies. Lab Med 1983;14:422–6. 1957;180:1038–40. 57. Mollison PL, Engelfriet CP, Contreras M. Blood transfu- 42. McConnell RB. Lewis blood group substances in body sion in clinical medicine. 10th ed. Oxford: Blackwell Sci- fluids. Istituto GM (ed.) Proc 2nd Congr Hum Genet, ence, 1997. Rome, Italy 1961:858–61. 58. Cheng MS, Lukomskyi L. Lewis antibody following a 43. Morgan WT. A contribution to human biochemical ge- massive . Vox Sang 1989;57:155–6. netics; the chemical basis of blood-group specificity. 59. Hossaini AA. Neutralization of Lewis antibodies in vivo Proc R Soc Lond B Biol Sci 1960;151:308–47. and transfusion of Lewis incompatible blood. Am J Clin 44. Arcilla MB, Sturgeon P. Lewis and ABH substances in Pathol 1972;57:489–93. amniotic fluid obtained by amniocentesis. Pediatr Res 60. Holburn AM. Quantitative studies with (125I) IgM anti- 1972;6:853–8. Lea. Immunology 1973;24:1019–26. 45. Dunstan RA, Simpson MB, Rosse WF. Lea blood 61. de Vries SI, Smitskamp HS. Haemolytic transfu- group antigen on human . Am J Clin Pathol sion reactions due to anti-Lewisa agglutinin. Br Med J 1985;83:90–4. 1951;1:280–1. 46. Hanfland P, Graham HA. Immunochemistry of the 62. Brendemoen OJ, Aas K. Hemolytic transfusion reac- Lewis-blood-group systems: partial characterization tion probably caused by anti-Lea. Acta Med Scand of Lea-, Leb-, and H-Type 1(LedH)-blood-group active 1952;141:458–60.

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63. Roy RB, Wesley RH, Fitzgerald JD. Haemolytic transfu- 80. Hein HO, Sorensen H, Suadicani P, et al. The Lewis sion reaction caused by anti-Lea. Vox Sang 1960;5:546– blood group—a new genetic marker of ischaemic heart 50. disease. J Intern Med 1992;232:481–7. 64. Mollison PL, Cutbush M. Use of isotope-labeled red 81. Clausen JO, Hein HO, Suadicdani P, et al. Lewis phe- cells to demonstrate incompatibility in vivo. Lancet notypes and the insulin resistance syndrome in young 1955;268:1290–5. healthy white men and women. Am J Hypertens 65. Quiroga H, Leite A, Baia F, et al. Clinically significant 1995;8:1060–6. anti-Leb.(abstract) Vox Sang 2000;78(Suppl 1):P125. 82. Hein HO, Suadicani P, Gyntelberg F. The Lewis blood 66. Jesse JK, Sheek KJ. Anti-Leb implicated in acute hemo- group—a new genetic marker of obesity. Int J Obes lytic transfusion reaction: a rare occurrence. (abstract) (Lond) 2005;29:540–2. Transfusion 2000;40(Suppl):115S. 83. Hirschberg CB. Golgi nucleotide sugar transport and leu- 67. Pineda AA, Taswel HG, Brzica SM. Delayed hemolytic kocyte adhesion deficiency II. J Clin Invest 2001;108:3– transfusion reaction. An immunological hazard of blood 6. transfusion. Transfusion 1978;18:1–7. 84. Luhn K, Wild MK, Eckhardt M, et al. The gene defective 68. Weir AB, Woods LL, Chesney C, Neitzer G. Delayed in leukocyte adhesion deficiency II encodes a putative hemolytic transfusion reaction caused by anti-LebH anti- GDP-fucose transporter. Nat Genet 2001;28:69–72. body. Vox Sang 1987;53:105–7. 85. Oriol R, Opelz G, Chun C, Terasaki PI. The Lewis sys- 69. Contreras M, Mollison PL. Delayed haemolytic trans- tem and kidney transplantation. Transplantation fusion reactions caused by anti-LebH. Vox Sang 1980;29:397–400. 1989;56:290. 86. Oriol R, Cartron J-P, Yvart J, et al. The Lewis system: 70. Waheed A, Kennedy MS, Gerhan S, Senhauser DA. new histocompatibility antigens in renal transplanta- Transfusion significance of Lewis system antibodies. Am tion. Lancet 1978;1:574-5. J Clin Pathol 1981;76:294–8. 87. Salmon C, Cartron J-P, Rouger P. The human blood 71. Poole J, Daniels G. Blood group antibodies and their groups. New York: Masson, 1984. significance in . Transfus Med Rev 88. Fischer E, Lenhard V, Romer W, et al. Influence of Lewis 2007;21:58–71. blood group system on clinical kidney transplantation. 72. Carreras Vescio LA, Torres OW, Virgilio OS, Pizzolato M. Proc Eur Dial Transplant Assoc 1979;16:377–82. Mild hemolytic disease of newborn due to anti-Lewisa. 89. Posner MP, McGeorge MB, Mendez-Picon G, et al. The Vox Sang 1993;64:194–5. importance of the Lewis system in cadaver renal trans- 73. Bharucha ZS, Joshi SR, Bhatia HM. Hemolytic disease of plantation. Transplantation 1986;41:474–7. the newborn due to anti-Leb. Vox Sang 1981;41:36–9. 90. Gratama JW, Hendriks GF, Persijn GG, et al. The in- 74. Boren T, Falk P, Roth KA, et al. Attachment of Helico- teraction between Lewis blood group system and bacter pylori to human gastric epithelium mediated by HLA-matching in renal transplantation. Transplanta- blood group antigens. Science 1993;262:1892–5. tion.1988;45:926–9. 75. Goodwin CS, Mendall MM, Northfield TC. Helicobacter 91. Williams G, Pegrum GD, Evans CA. Lewis antigens in re- pylori infection. Lancet 1997;349:265–9. nal transplantation. Lancet 1978;1:878. 76. Franchini M, Veneri D. Helicobacter pylori infection and 92. Spitalnik S, Pfaff W, Cowles J, et al. Correlation of immune thrombocytopenic purpura: an update. Helico- humoral immunity to Lewis blood group antigens bacter 2004;9:342–6. with renal transplantation rejection. Transplantation 77. Hutson AM, Atmar RL, Marcus DM, Estes MK. Norwalk 1984:37:265–8. virus-like particle hemagglutination by binding to H 93. Boratynska M, Banasik M, Halon A, et al. Blood group histo-blood group antigens. J Virol 2003;77:405–15. Lewis alloantibodies cause antibody-mediated rejec- 78. Hilton E, Chandrasekaran V, Rindos P, Isenberg HD. tion in renal transplant recipients. Transplant Proc Association of recurrent candidal vaginitis with in- 2007;39:2711–14. heritance of Lewis blood group antigens. J Infect Dis 1995;172:1616–19. Martha Rae Combs, MT(ASCP)SBB, Analytical Specialist, 79. Stapleton A, Nudelman E, Clausen H, et al. Binding of uro- Technical Director of Immunohematology, Duke Universi- pathogenic Escherichia coli R45 to glycolipids extracted ty Hospital, Transfusion Service, Box 2928, Room 1720N, from vaginal epithelial cells is dependent on histo-blood 2424 Erwin Road, Durham, NC 27710. group secretor status. J Clin Invest 1992;90:965–72.

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