Immunochemistry, Genetics and Relation to Human Disease

Despite the recognized importance of the ABO and Lewis antigens in blood typing and trans­fusion, few physicians appreciate the extraordinary complexity of this system and its association with human disease. These antigens are found in secretions throughout the body and on the surface of epithelial and endothelial cells. Current interest in kidney transplantation has directed attention to their presence in the renal vascular endothelium. ABO incompatibility between mother and fetus may produce infertility or hemolytic disease of the newborn, and persons of certain blood groups have an increased susceptibility to peptic ulcer or gastric cancer. The purpose of this review is to summarize current concepts of the immunochemistry and the genetics of the ABO and Lewis system and their relation to human biology and disease. Earlier work in these areas has been summarized in monographs and books, (1,2) and more extensive reviews of individual aspects, such as the immunochemistry, are available elsewhere. (3)

Before a detailed account of the immunochemistry and genetics is presented, a brief summary will be given to orient the general reader. The A and B antigens were originally detected on erythrocytes by means of isoagglutinins in the serum of persons lacking these determinants. These antigens are synthesized from a common intermediate, H substance, by addition of a single sugar to the noreducing end of H oligosaccharide chains, and the immunologic reactivity of the H antigen is markedly decreased by the additional sugar. There is no O antigen; Group O erythrocytes and the saliva of Group O secretors contain the H antigen, but the designation Group O erythrocytes has been retained for historical reasons. Approximately 75 per cent of white persons secrete glycoproteins containing the same A, B or H antigens present on their erythrocytes.

The Lewis antigens, Lea and Leb, are also found on erythrocytes and glycoproteins. These antigens appear on the same glycoproteins as the ABH determinants, but their synthesis is regulated by the in­dependent gene Le. The operation of these independent genes on a common substrate results in a complex phenotypic interaction, which will be con­sidered in a subsequent section of this review.

Our current knowledge of the inmmunochemistry of the ABH and Lewis antigens is mainly the result of several decades of systematic investigation by two laboratories, that of Morgan and Watkins at the Lister Institute in England, and Kabat's group at Columbia University College of Physicians and Surgeons in the United States. These studies were performed on water-soluble substances isolated from secretions, primarily from ovarian-cyst fluid.

The ABH substances purified from secretions are glycoproteins composed of approximately 80 per cent carbohydrate and 20 per cent amino acids. (1,34) They are heterodisperse, with an average molecular weight of 300,000, (5-7) but the molecules of different sizes have similar composition and serological properties. (6)  The glycoproteins contain a peptide  back­bone to which multiple oligosaccharide chains are attached through an alkali-labile glycosidic bond (8,9) to the hydroxyl group of serine or threonine. (16)  Most of the oligosaccharide chains are linked to the backbone through an N-acetylgalactosamine residue.­ The carbohydrate moiety of the ABH and Lewis glycoproteins consists primarily of four sugars, D-­galactose, L-fucose, N-acetyl-D-galactosamine and N-acetyl-D-glucosamine (Table 1). A small amount of N-acetylneuraminic acid (sialic acid), generally less than 1% but occasionally as much as 18 % (12) is found in many cysts. This sugar does not appear to have blood group specificity and in high concentrations may interfere with the expression of blood group activity. The amino acid compositions of the different blood group glycoproteins are similar to each other, and unrelated to blood-group specificity. Serine and threonine constitute more than 40 per cent of the total amino acids,(5,13) and proline and alanine are also present in relatively large amounts, but aromatic and sulfur­ containing amino acids are virtually absent.

The ABH and Lewis glycoproteins possess a common basic structure, and their blood-group specificity is determined by the sequence and linkage of sugars at the terminal nonreducing end of the carbohydrate chains. The number of chains bearing antigenic determinants has been estimated at 40 to 100 per 300,000 molecular weight. (14,15) The structures of these antigenic determinants, which have recently been elucidated by hapten-inhibition studies.

There are two types of backbone structures, Type I chains, which contain galactose linked -(1-3) to N-acetylglucosamine, and Type 2 chains in which the linkage is -(1-4).(3) Oligosaccharides with these nonreducing terminal ends do not possess blood-group specificity, but can be detected immunologically by their cross-reaction with horse antiserum prepared against Type 14 pneumococcal polysaccharide.(16,17) A glycoprotein with oligosaccharide chains terminating with either of these sequences has been termed a “precursor substance," and a substance of this type has been isolated from ovarian-cyst fluid.(3) The presence of fucose on C-2 of the terminal galactose of either Type 1 or Type 2 chain produces an H determinant.(8-9,18-19) The presence of fucose linked to C-4 of N-acetylglucosamine in a Type I chain results in Lea activity, (20.21) but a Type 2 oligosaccharide containing fucose linked to C-3 of N-acetylglucosamine has very weak Lea activity.(21)  The simultaneous presence of both fucose substituents on a Type I chain results in the appearance of a new antigenic specificity, Leb , and loss of most of the H and Lea activities.(22)  Type 2 difucosyl chains have weak Leb activity.(22,23)

The A determinant consists of the Type 1 or 2 H structure plus a terminal nonreducing N-acetylgalactosamine-linked alpha(1-3) to galactose.(20.21,24) Similarly, the B determinant consists of the H structure plus a terminal alpha(1-3) galactose residue. (18,19,24)  H activity is lost when the additional sugars are added. The Type 2 Group A determinant containing two fucose residues has much less A activity than the monofucosyl Type 2 determinant shown in Figure 1, (18,19)  possibly because of conformational changes produced in the nonreducing end of the determinant. Isolation of a difucosyl Type I Group A determinant has not been reported. The unbranched trisaccharide

        alpha (1->3)      beta (1->3)

(GalNAc ------------aGal -----------aGNAc)

has appreciable A activity but it is less active than the fucose containing tetrasaccharide depicted in Figure 1. (19) It is not clear whether the fucose residue makes contact with the antibody binding site or stabilizes a particular conformation of the terminal trisaccharide but is not itself in contact with the antibody.

The structures of most of the ABH and Lewis determinants have been established, but the complete structure of the glycoproteins remains to be ascertained. There are at least four types of oligo­saccharide chains that have blood-group specificity, Type 1 and 2, monofucosyl and difucosyl chains (as noted above in the Group A determinant), and very short chains without blood-group activity may also exist. (21) The various types of oligosaccharide chain may not be distributed equally among the glycopro­tein molecules synthesized by a single individual. (25) Moreover, Lloyd et al (21) recently isolated a branched oligosaccharide containing both Type 1 and Type 2 chains, and they proposed the existence of "megalosaccharide" chains that contain two determinants.

Most glycoproteins isolated from a single cyst have multiple specificities. For example, an A1 glycoprotein usually has strong A1 and Leb properties, and weak H and Lea activity. The evidence available indicates that most of these diverse speci­ficities are present on each molecule, rather than segregated on different molecules. (26,27) This was shown by precipitation of a blood-group substance with an antibody specific for a single determinant, and the demonstration that the other specificities were removed from the supernatant. Since each oligosaccharide depicted in Figure 1 has only one strong haptenic activity, it is likely that the multiple specificities result from different chains attached to a common backbone. In the example noted above, the Leb and H activities would result from the presence of incomplete chains that lack the terminal N-­acetylgalactosamine. In addition, some antibodies may be able to react with an internal determinant in a completed chain. (28)

It was known early in the century that ABH substances occur in human tissues and secretions in two forms, water-soluble and alcohol-soluble, and that persons with these substances  in saliva (secretors) have more water-soluble substances in their tissues than those lacking the substance in their saliva (nonsecretors). These studies have been extended and refined in recent years by the use of sensi­tive mixed agglutination and immunoflourescence technics that allow precise localization of the substances to individual cells. Immunofluorescent staining has revealed ABH substances in the cell membranes of all vascular endothelial  cells, and certain epithelial cells. (62) The membrane antigens are alcohol soluble and occur in secretors and nonsecretors alike. The positive epithelia are stratified or pseudostratified, and include the skin, tongue, esophagus, lower genitourinary tract and uterine cervix. (62)

ABH substances are secreted by mucous glands in many organs, including the upper respiratory tract, the gastrointestinal tract from the esophagus through the colon and the uterine cervix. (62) The synthesis of blood-group substances in superficial glands of the gastric and small-intestine mucosa is regulated by the secretor gene. Large amounts of ABH material are found all secretors,(63-67) but abundant Leb substance and no ABH substance is seen in non-secretors. Glands situated more deeply in the mucosa of the pylorus and small intestine (Brunner's glands) produce A and B substances without regard to secretor status. (64,66) These substances are not extracted by fixation of the tissues with alcohol and are probably glycoproteins.  The gastric parietal glands also produce A and B substances in both secretors and nonsecretors, but this material is alcohol soluble and is probably glycosphingolipid in nature.(117)

The prostate glands and the lactating mammary glands of secretors also produce ABH substances.(66) The pattern of secretion by the breast is unusual in that abundant H substance is produced by secretors of all ABH phenotypes, but much less A substance, and virtually no B substance, is detectable in the breast or in milk. (69) Synthesis of ABH substances in the exocrine acini of the pancreas and the secre­tory cells, of sweat glands is not regulated by the secretor gene. ABH substances are detectable in the plasma of nonsecretors and secretors; the latter tend to have higher titers, but there is considerable overlap between the two groups. (70,71)

Blood Group A and B glycoproteins have been isolated from urine by King, (72) and Lundblad and Berggard. (73) These materials are similar to ovarian ­cyst glycoproteins in their chemical composition, but the preparation of Lundblad contained glucose, which has not been detected in other human blood group glycoproteins. The glucose could be a constituent of a glycoprotein contaminant since no evidence was presented that the glucose-containing material was precipitable by specific antiserum. In another study, Lundblad (174) isolated pentasaccharides with A and B activity from urine. Both types of oligosaccharide contained one glucose residue on the reducing end, and the A compound had in addition one mole! each of N-acetylgalactosamine and galactose, and two moles of fucose. The origin of these materials is unknown. Blood-group substances have been detected in the collecting tubules and calyxes of secretors, but it is not clear whether they are synthesized by the kidney or merely excreted. The membranes of epithelial cells of the lower urinary tract contained alcohol-soluble ABH antigens, presumably glycosphingolipids, and it has been suggested that the urinary oligosaccharides may be derived from a cell-membrane substance.(73) 

Szulman (75,76) has studied the appearance of ABH substances in cell membranes and secretions of human embryos. The membrane substances are found first in the epithelium all vascular endothelium of the youngest embryos examined, estimated at about five weeks of gestational age. At this time all epithelia contain the ABH substances except those of the nervous system, adrenal glands and liver. The antigens disappear from these epithelia in an orderly and predictable manner as evidences of morphologic differentiation appear, and by about the end of the third intrauterine month, the-adult pattern of distribution is achieved. ABH substances appear in secretions at eight to nine weeks' ovulation age in the salivary glands and stomach, and then appear throughout the gastrointestinal tract and other characteristic locations.

The use of antigenic markers for cultured cells was covered in a recent review by Franks (77) and the occurrence of ABH antigens in human cells was examined in detail. When human cell lines possessing ABH antigens are grown in tissue culture, the A and B antigens are lost, but  specificity is retained. (7,11,79) This contrasts with the retention of A and B antigens in established cell lines of many animal species, and the stability of other antigens, such as the H-2 system in mice.(77) Chessin et al.  claimed that loss of the B antigen from human amnion cells could be prevented by supillernentation of the medium with several sugars that are constituents of blood-group substances, but this work could not be reproduced by another group.(81)

Human serum alkaline phosphatases can be separated into two major zones by electrophoresis in starch gel.(83,84) The rapidly migrating component is present in all serums and is thought to originate in liver, and possibly bone, whereas the enzyme with slower mobility originates in the small intestine. The intestinal enzyme call be differentiated other serum alkaline phosphatases by several criteria in addition to electrophoretic mobility. (113) It is inhibited by L-phenylalanine (85,86) and resistant to treatment With neuraminidase (87) and differs antigenically from the other enzymes. (88-89) Arfors, Beckman and Lundin (91) first pointed out that the slower phosphatase band occurs almost exclusively in the serum of Group B and O secretors, and is almost never found in those of Group A secretors or in nonsecretors of any type. They also presented data implicating at least one of her independent locus in regulating the appearance of the intestinal phospha­tase in serum.(90) These findings have been extended and confirmed by several groups in studies of populations in many parts of the world.(92-116)

With more sensitive techniques for demonstrating alkaline phosphatase activity, it was found that small amounts of this enzyme are present in the serums of 10 to 15 per cent of Group A secretors, and a smaller number of nonsecretors. (93,114) The serums of approximately 70 to 80 per cent of Group O and B secretors contain this enzyme, in much larger quantities than in the Group A secretors or nonsecretors. Group AB persons are intermediate in percentage of positive persons and in quantities of phosphatase in serum.

The concentration of the intestinal phosphatase is lowest in the serum during fasting and rises after ingestion of fat, reaching a peak at about seven to eight hours.(118) This increase is most marked in Group O and B secretors, but it is detectable in most people. The concentration of intestinal alkaline phosphatase in human thoracic-duct lymph rises after a fatty meal, and presumably most of the intestinal phosphatase enters the blood by way of the lymphatic system.(100) Schreffier  and Langnall et al (102) measured the alkaline phosphatase concentration in the mucosa of the human small intestine. The former found no correlation between alkaline phosphatase levels and ABO groups or secretor type, but the latter observed that Group O and B secretors had the highest mean concentration of alkaline phosphatase, Group A secretors had the next highest concentration, and nonsecretors had the lowest amount; in that study,  however, there was a marked overlap between the three groups in the range of enzyme activity, and the differences observed were much smaller than those found in se­rum. In view of these data it seems likely that the ABO and secretor genes influence the rate at which the intestinal phosphatase enters the blood, or its catabolism, rather than its synthesis in the intestine.(103)

As noted previously, cattle and sheep erythrocytes contain antigens similar to human A and H determinants. An analogous association has been found between serum alkaline phosphatase and blood­group polymorphisms in these species. (104-107)

The association of ABO and secretor types with this serum enzyme polymorphism is of particular interest because of the association of the same traits with certain diseases of the gastrointestinal tract. Elucidation of the mechanism by which the blood­group genes participate in producing the alkaline phosphatase polymorphism may provide a lead to their role in the physiology and pathology of the gastrointestinal tract.

Beckman and Zoschkel have recently reported an association between blood Group A and a polymorphism of human serum acid phosphatases. Two major bands of acid phosphatase activity call be re­solved by starch-gel electrophoresis, and the concentration of the enzyme with the greater anodal mobility was higher in persons of blood Group A or AB than in those of B or O.

Since the initial reports of Aird et al.(110) of the association of peptic ulcer and gastric carcinoma with ABO blood groups, a voluminous literature has accumulated oil these topics, and it has been tabulated and analyzed in several reviews.(117) The most prominent findings are all increased frequency of peptic ulcer in Group O persons and in non­secretors of all ABO groups,(112-116) and of gastric carcinoma and pernicious anemia in people with blood Group A. (117-119) The excessive rate of duodenal ulcer in Group O people has been estimated   about 35 per cent and at about 20 per cent for gastric ulcer. Duodenal ulcers are about 50 per cent more likely to develop in nonsecretors than in secretors. Taking the liability of the group least susceptible, to duodenal ulcer, A, B and AB secretors, as 1.0, the relative liability of 0 nonsecretors has been estimated at 2.5: 1, A and B nonsecretors as 1.60: 1, and O secretors at 1.35:1.(112) More recent studies have   demonstrated that Group O subjects have an excessive rate of bleeding, perforation and development of stomach ulcers, but no correlation was found between these complications and secretor status.(120,121)

Group A persons, on the other hand, have an excessive rate of gastric cancer of about 20 per cent, and a 25 per cent increase in pernicious anemia Although these data have been obtained by independent groups of investigators in many parts of the world, the methodology and conclusions of these studies have been criticized by Wiener. (122)

It is likely that many factors, genetic and environmental, contribute to the pathogenesis of these dis­eases, and it is hoped that the associations noted above will lead to an understanding of some of these factors. Studies of gastric function in relation to blood group and secretor type have provided lit­tle enlightenment to date. No correlation has been found between ABO group or secretor type and the production of  glycoproteins by the stomach.(123) There have been two reports (124,125) that the serum pepsinogen level was higher in normal persons of Group O than in those of Group A.

The occurrence of hemolytic disease of the new­born caused by ABO incompatibility was not firmly established for some years after the recognition of the role of Rh incompatibility in this syndrome. The reasons for this belated recognition were the difficulties in detecting sensitization of the infant's red cells and the mild, self-limited nature of the disease in most cases. It has been estimated that approximately 5 per cent of newborn infants may have positive  antiglobulin tests caused by ABO in­compatibility  but only 0.5 per cent give evidence of clinical disease, and only 0.2 per cent require exchange transfusion. (128)

As first noted by Rosenfield,(121)  ABO erythroblastosis occurs almost exclusively in A, and B offspring of O mother's. The major reason for this is that Group O persons have more IgG anti-A and anti-B antibodies than those of other blood groups, and among the major immunoglobulin classes, only IgG antibodies cross the placenta. In contrast to Rh erythroblastosis, severe hemolytic disease may occur in the first ABO-incompatible pregnancy, and infants with incompatible blood types born subsequently may he less severely affected. Although the blood of infants with ABO erythroblastosis may exhibit more striking hematologic changes than that of infants with Rh disease, including the presence of spherocytes, ABO hemolytic disease tends to be self­limited, and, if treatment is necessary, only one exchange transfusion is generally required. In 1943 Levine (131) suggested that ABO incompatibility between mother and fetus may reduce the frequency of isoimmunization to Rh and other antigens.

Extensive reviews of the clinical features and management  of ABO erytbroblastosis are available. (133,134) In view of the dramatic reduction in the incidence of Rh erythroblastosis achieved by post­partum treatment of nonsensitized mothers with human gamma globulin containing anti-Rh antibodies, (135,136)  ABO incompatibility may become the commonest cause of clinical erythroblastosis in the future.

The possible effects of ABO incompatibility on infertility and fetal loss have been the subject of speculation and conflicting reports for several decades. The weight of evidence now indicates that ABO incompatibility between mother and fetus results in a small but significant decrease in fertility. (131,137-143)    The mechanism postulated for prevention of fertilization is damage of ABO-incompatible sperm by isoagglutinins in the secretions of the uterine cervix. (138,145) If multiple samples of cervical mucus are examined, more than 63 per cent of women exhibit isoagglutinin activity, primarily in the IgG immunoglobulin class. (146,147) There is some evidence for local production of these antibodies, since the titer and serologic properties of the antibodies in cervical secretions may not correlate directly with serum antibodies. (146,148,149) Although some investigators have reported that ABO antigens were present on sperm of all men, recent work indicates that they are found only on the sperm of secretors. (151,152) The anti­gens appear to be acquired from the seminal secre­tions and are not readily washed off in vitro. Nonsecretor sperm can acquire ABO antigens in vitro from seminal plasma, saliva or solutions of purified blood-group glycoproteins.(112) ABO incompatibility between wife and husband was found to be more frequent in infertile than in fertile couples in some series,(138) but not in al (143) and the issue remains unresolved. Consideration of the secretor status of the husband, and the serological properties of the cervical isoagglutinins, may help future studies resolve this problem. It should be mentioned in passing that additional immunologic factors maybe involved in infertility, (153) including immunization of women to other antigens in semen or on sperm and autoimmunity to sperm in males.

The loss or suppression of the red-cell  antigen has been observed in a number of patients with leukemia.(2,161) These patients had normal  phenotypes before the onset of the leukemia, and in the course of their disease the A, antigen became extremely weak. The decrease in strength of the Al antigen was accompanied by an increased reactivity with anti-H reagents, so that the cells reacted like O cells. The saliva of the patients who were secretors contained normal amounts of A, antigen, indicating that the alteration occurred in hematopoietic cells. Selective loss of the A, antigen in a Type A (113) patient has also been observed, and there is one report of loss of the B antigen in an AB patient.(166) Somatic mutation, caused by the disease or the treatment, has been suggested as the cause of these alterations . (163,164,166)

Acquisition of a "B-like" antigen has been noted in patients with carcinoma of the colon or rectum and in a few patients with other malignant processes or infections. (2,167,168)  Their serums contained anti-B that did not react with their own red cells. Many bacteria possess lipopolysaccharides with blood Group B activity, (161) and these substances adhere firmly to red cells in vitro.(170) It was proposed that altered permeability of the diseased areas per­mitted the bacteria] substances to enter the blood and adsorb to erythrocytes, and this phenomenon has been observed in the course of an enteritis caused by Escherichia Coli. (171) However, Marsh (172) reported that certain bacterial filtrates contained enzymes capable of causing the appearance of B antigen in A or 0 red cells, and this mechanism may also have a role.

In 1956 Glynn et al.(173) suggested that the secretor status of the host may bell) determine whether rheumatic fever followed streptococcal pharyngitis. Their data indicated that secretors were less liable to rheumatic fever than nonsecretors, but they noted no correlation with ABO blood group. (174,175) Others reported fewer cases of rheumatic fever and rheumatic heart disease in Group O individuals, as well as in secretors (176-178). A study of patients undergoing tonsillectomy for treatment of chronic tonsillitis revealed no deficit of Group O persons or secretors.

Since many microorganisms contain antigens similar to the ABH determinants  correlations have been sought between blood groups and susceptibility to infectious diseases. Two mechanisms might affect the prevalence or course of an infectious disease: if the infectious agent possessed an A antigen  Group A persons might be partially tolerant to the micro-organism and consequently exhibit an ineffective immune response. 

Group A patients were reported to be more sus­ceptible to myocardial infarction,(189) gallstones, cirrhosis of the liver,(191) diabetes mellitus (191, 193)  and tumors of the salivary glands (194,195) pancreas(196) and ovary(197) than persons with other blood groups. Amyotrophic lateral sclerosis was reported to be more common in Group B secretors than in other blood types.(198) The influence of the ABO blood groups on natural selection was considered in several reviews.(15,195,188)

Conclusions

The human ABH and Lewis blood-group antigens occur in secretions and cell membranes throughout the body. The specific antigenic determinants are oligosaccharide chains, which are linked to a polypeptide backbone in glycoprotein molecule's or to sphingoside in glycosphingolipids. The blood-group genes control the synthesis of enzymes that catalyze the addition of single sugar residues to the non-reducing end of these oligosaccharide chains. There is a statistical association between certain blood-group phenotypes and increased susceptibility to a number of diseases.

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