Central position of the human histo (blood) group O(H) and
pheno-type-determining enzymes in growth and infectious disease.
Peter Arend
Abstract:
Introduction.
Different origins of adaptive and germline-encoded immunoglobulins in blood group O(H) and non-O blood groups.
While the danger theory (12) suggests that there is no adaptive immunity without innate immun-ity, the bulk of human immunity is not acquired during one human lifetime but is considered to arise predominantly from evolutionary memory and survival mechanisms. Thus, an inborn origin has been postulated to explain isoagglutinin production in non-O blood groups (13)(14). In addition to adaptive, cross-reactive anti-AB production, which is mainly restricted to blood group O(H) individuals, the majority of anti-A/B immunoglobulins, especially the classic com-plement-binding anti-A and anti-B-reactive isoagglutinins, measured between 22 and 24°C, are independent of any blood group; they result from a primarily polyreactive, non-immune, germline-encoded IgM molecule, which in the non-O blood groups undergoes phenotype-specific glycosidic accommodation of the plasma proteins (14)(15). A proteomics analysis of O-GalNAc glycosylation in human serum identified 407 intact O-O-GalNAc glycopeptides from 93 glycoproteins (16). In blood group A individuals, these O-glycosylations are, apart from N-glycosylations, most likely dominated by phenotype-specific GalNAc enzymatic transfer via O-linkages to functional serine/threonine or tyrosine residues from the Fc region of the ancestral IgM molecule (17). The terminal serine appears to be the crucial structure (18), and any reduc-tion or exclusion of IgM anti-self reactivity thereby achieved, necessarily impairs the adaptive and innate defense processes (15). The key molecule of this phenotypic accommodation might be α2-macroglobulin, which is considered an evolutionarily conserved arm of the innate i m-mune system (19); it is functionally strongly connected to the structurally related IgM molecule (20), and exhibits ABO(H) reactivity in strict correlation with the cell surfaces (21)(22).
How blood group O(H) and A phenotype evolution and development may be molecularly related to growth and infection by different protozoan eukaryotes in light of the Duffy groups.
comprehensive study by Vasan et al. (2016) showed a positive association for blood group A individuals with cancer of the pancreas, breast, salivary glands, mouth, stomach and chronic lymphatic leukemia (25) and for blood group B individuals with cancer of the corpus uteri and the bladder, whereas an inverse association was observed for pharyngeal cancer, esophageal a d-enocarcinoma, and small intestinal cancer in blood group A individuals for pleural mesothelio-ma and myelomesothelio-mas in blood group B individuals. In two smesothelio-maller studies, regarding the O/O and A/A genotypes, in both cancer of the stomach (26) and that of the pancreas (27), the above posi-tive associations became even more clearer and finally are considered to be established. After all, blood group A individuals might be burdened with an overall increased risk in developing cancer when compared with blood group O(H), which currently is discussed to have a survival advantage when compared with non-O blood groups (28)(29).
When a species barrier is overcome by interspecies glycosylations (30), and ABO(H) gly-cotransferases accomplish the cross-species transmission of O-glycans in infectious diseases (31), the proposed principle of glycosidic, phenotypic accommodation may explain the pr o-nounced susceptibility of blood group A individuals to the life-threatening infections, character-izing the classic M. tropica, which is caused by P. falciparum. While M. tertiana or infection by P. vivax is the best-documented type of malaria, P. falciparum causes the most severe and fre-quently encountered diseases. For both malaria types, the risk of developing malaria is strongly associated with phenotype, but systematic reviews and intensive meta-analyses are restricted to M. tertiana and the Duffy blood group system, which has a genetically-determined special P.vivax receptor. This "Duffy-Antigen Receptor for Chemokines (DARC)" is a complex, poly-functional glycoprotein, which as a chemokine receptor binds a variety of chemokines, only to name the C-X-R (acute inflammation chemokine), C-C (chronic inflammation chemokine) and the IL-8 (interleukin 8), secreted by cells during inflammation (32)(33). DARC carries the 6 dif-ferent Duffy blood group antigens, as they are Fya, Fyb, Fy3, Fy4, Fy5 and Fy6 (34). The Duffy positive phenotypes Fy (a+b+), Fy (a+b-) and Fy (a-b+) belong mainly to Caucasian and Asian individuals, while the Fya allele likely represents the globally most prevalent allele (35). Fya individuals are highly susceptible to infections by P. vivax, whereas the Duffy negative pheno-type Fy (a-b-) group shows a strong resistance and is almost limited to Blacks (34). Consequent-ly, this type of malaria is extremely rare in Africa.
and southeast Asia. These infections appear to be limited to certain ethnic groups (36), although episodes of global distributions, involving life-threatening disease, are a widely discussed prob-lem (37). Statistically significant, life-threatening infections are diagnosed in blood group A in-dividuals when compared with blood group O(H) (38), although in areas, where this type of ma-laria is endemic, blood group O(H) may be the largest group of gametocyte carriers, sometimes even suffering from mild disease (39). P. falciparum differs from the other human malaria spe-cies in that infected RBC do not remain in the circulation for the entire life cycle; when young parasites mature to the trophozoite stage, infected RBC adhere to endothelial cells in the micro-circulation (40); and aside from RBC rosette formation, this phenomenon, termed “sequestra-tion”, appears to characterize the life-threatening disease in P. falciparum infections and occurs rarely in those of the "nonsequestering" P. vivax, ovale and knowlesie.
While Duffy positive individuals are susceptible to P. vivax infections, and human blood blood group A individuals are highly susceptible to severe infections by P. falciparum, the DARC protein appears, in contrast to the cancer susceptibility of blood group A, to exert a marked growth regulating activity in different types of cancer (41)(42); this was explained by suppressing the activation of transcription factor STAT3 (signal transducer and activator of tra n-scription 3) through the inhibition of CXCR2 (a chemokine adaptor protein) signaling (43). Functional or structural relations of the DARC protein to the non-immune IgM or isoagglutinins of the ABO(H) blood group system are unknown. A natural anti-Duffy-reactive IgM occurs ex-tremely rarely, and the naturally-occurring anti-Duffy antibody arises as an adaptive IgG, main-ly caused by repeating infections and incompatible blood transfusions.
transferase activity (52)(53), representing a potential anti-malaria drug target during the asexual intraerythrocytic stage (57)(58). Thus, SERA, detected decades ago (59), is accepted as a puta-tive antigen precursor, while heterologous O-GalNAc glycosylation, which most likely utilize trans-species-compatible serine positions on the pathogen, might explain the preferred binding of special Plasmodium strains; moreover, the pronounced susceptibility of blood group A indi-viduals to severe malaria (60) suggests the formation of anti-Tn-reactive structures (15), provid-ing a new molecular definition of an immunological (therapeutic) target.
Blood group O(H) individuals, who are unable to complete this self-destructive, likely tran-sient hybrid connection, maintain natural (anti-A/Tn-cross-reactive?) antibodies against this con-nection (15), and the suggested metabolic pathways may explain the growth inhibition caused by P. malariae. While Maeda et al. explain the growth-regulating activity of the DARC protein in cancerogenesis via down-regulation of the CXCR2 signaling and reduction of STAT3 activation (43), Salanti et al. presented a concept, according to which an evolutionarily refined parasite-derived protein may be exploited to target a common, complex malignancy-associated glycosa-minoglycan modification (61), expressing multiple (assumingly "A-like" or Tn-configurated?) GalNAc residues. Thus, because SERAs are common to all human-specific Plasmodium species (44) (45), it is hypothesized that the heterologous glycosylation of cancerous GalNAc residues upon exposure to a serine (kinase) surplus of "pathogen" (55)(59) may initiate the growth inhibi-tion caused by malaria infecinhibi-tions.
group O(H), which is commonly observed within Caucasian populations and is associated with a reduced overall risk of developing cancer, may come into play. Hypothetically, the virtual geno-type O/O Fy (a+b+) has the lowest risk but does not occur alone in any population, while the A/A Fy (a-b-) genotype carries the highest risk, and the A/A Fy (a+b+) and other ABO(H)/Duffy allelic mixtures balance these risks. Together, the data reported in one previous study (64) reflect the mixed impact of different genotypes, resulting in at least two blood group systems associated with a risk of cancer development: the ABO(H) and Duffy groups. The risk of developing any disease is rarely associated with a single phenotype, and given the lack of reliable data concern-ing P. falciparum and P. vivax infections and their outcomes in blood group A and O(H) indi-viduals and/or genotypes specified in parallel with Duffy groups, any further molecular biologi-cal explanations for the differing susceptibilities of the Duffy Fya phenotype and blood group A individuals to Plasmodium infections and cancer remain speculative.
Glycosidic accommodation between host and pathogen promotes infections by eukaryotic and prokaryotic pathogens.
Conclusions.
O-glycosylations, which with similar peptide backbones are used by lower metazoans, such as mol-lusks and the fruit fly Drosophila melanogaster (95)(96), moreover, in the snail Helix pomatia are associated with the release of a hexamerically (97) structured Tn-complementary, hemagglutinat-ing defense protein. In 1973, Hammarström demonstrated that the bindhemagglutinat-ing patterns and capacity of this molluscan protein to bind human blood group A RBCs are strikingly similar to those of the mammalian IgM molecule (98), giving rise to speculation regarding an evolutionary relationship with the mammalian non-immune anti-A-reactive IgM molecule, while its germline, similar to that of the polyreactive ancestral IgM of the human blood group O(H), appears not to be burdened with A/B phenotypic accommodations; indeed, Helix pomatia and other snails never develop can-cer. An even stronger immunity, involving a clinically relevant anti-H-reactive, complement-binding IgM and likely higher anti-A/Tn levels, may be exerted by the "real" blood group O or Oh Bombay type (h/h; se/se), based on a mutational meltdown of the H and Se gene functions on chromosome 19, encoding the α1,2 L-fucosyltransferases (FUT1/FUT2); however, the extremely small population size of the classic Bombay type suggests an affected reproductive health and proves a negative evolutionary role. While the background of these mutations has been discussed controversially, and studies on the functions of α1,2 L-fucosyltransferases in murine fertility (99) may not be extrapolable to human phenotype development, primates use different pathways for critical fucosylation events (100), and human α1,2 L-fucosyltransferase genes exclusively accom-plish the expression of ABO antigens (101). After all, the normal blood group O(H), based on α1,2 L-fucosylations, stresses its central position in the evolution of primates by representing the most frequent blood group within the ABO(H) system worldwide, and may confer a general sur-vival advantage resulting from superior complex immunity in which human-specific nonimmune anti-A-reactive IgM or isoagglutinin appears to be identified as an authentic complementary pro-tein to the trans-species, developmental Tn epitope (15). This complement-binding propro-tein may exert its immunological power during major ABO(H)-incompatible transfusions, mirroring its precise role in internal defense processes, which are affected through the phenotypic, identical glycosylation of cell surfaces and plasma proteins in non-O blood groups.
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Figure 1
Fig. 1. Spontaneous variations in the production of anti-A/B isoagglutinins in 21 individuals suffering from ulcerative colitis (blood group A = 11, blood group 0 = 10) and 42 normal ind- viduals (blood group A = 22, blood group O = 20) were investigated under double-blind conditions. The grade of immunization and dominance of the 7S (IgG) conglutinating and 19S (IgM) agglutinating immunoglobulins were determined by measuring conglutinin and agglutinin titer and their quotients at three different temperatures. Using the non-parametric Wilcoxon procedure, the minimally elevated anti-B-reactive IgG and IgM levels in blood group A plasma remained within normal range, whereas blood group O patients exhibited the statistically
