scholarly journals Biosynthesis of α-Gal Epitopes (Galα1-3Galβ1-4GlcNAc-R) and Their Unique Potential in Future α-Gal Therapies

2021 ◽  
Vol 8 ◽  
Author(s):  
Uri Galili

The α-gal epitope is a carbohydrate antigen which appeared early in mammalian evolution and is synthesized in large amounts by the glycosylation enzyme α1,3galactosyltransferase (α1,3GT) in non-primate mammals, lemurs, and New-World monkeys. Ancestral Old-World monkeys and apes synthesizing α-gal epitopes underwent complete extinction 20–30 million years ago, and their mutated progeny lacking α-gal epitopes survived. Humans, apes, and Old-World monkeys which evolved from the surviving progeny lack α-gal epitopes and produce the natural anti-Gal antibody which binds specifically to α-gal epitopes. Because of this reciprocal distribution of the α-gal epitope and anti-Gal in mammals, transplantation of organs from non-primate mammals (e.g., pig xenografts) into Old-World monkeys or humans results in hyperacute rejection following anti-Gal binding to α-gal epitopes on xenograft cells. The in vivo immunocomplexing between anti-Gal and α-gal epitopes on molecules, pathogens, cells, or nanoparticles may be harnessed for development of novel immunotherapies (referred to as “α-gal therapies”) in various clinical settings because such immune complexes induce several beneficial immune processes. These immune processes include localized activation of the complement system which can destroy pathogens and generate chemotactic peptides that recruit antigen-presenting cells (APCs) such as macrophages and dendritic cells, targeting of antigens presenting α-gal epitopes for extensive uptake by APCs, and activation of recruited macrophages into pro-reparative macrophages. Some of the suggested α-gal therapies associated with these immune processes are as follows: 1. Increasing efficacy of enveloped-virus vaccines by synthesizing α-gal epitopes on vaccinating inactivated viruses, thereby targeting them for extensive uptake by APCs. 2. Conversion of autologous tumors into antitumor vaccines by expression of α-gal epitopes on tumor cell membranes. 3. Accelerating healing of external and internal injuries by α-gal nanoparticles which decrease the healing time and diminish scar formation. 4. Increasing anti-Gal–mediated protection against zoonotic viruses presenting α-gal epitopes and against protozoa, such as Trypanosoma, Leishmania, and Plasmodium, by vaccination for elevating production of the anti-Gal antibody. The efficacy and safety of these therapies were demonstrated in transgenic mice and pigs lacking α-gal epitopes and producing anti-Gal, raising the possibility that these α-gal therapies may be considered for further evaluation in clinical trials.

Antibodies ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 25 ◽  
Author(s):  
Uri Galili

Human natural antibodies to mammalian carbohydrate antigens (MCA) bind to carbohydrate-antigens synthesized in other mammalian species and protect against zoonotic virus infections. Three such anti-MCA antibodies are: (1) anti-Gal, also produced in Old-World monkeys and apes, binds to α-gal epitopes synthesized in non-primate mammals, lemurs, and New-World monkeys; (2) anti-Neu5Gc binds to Neu5Gc (N-glycolyl-neuraminic acid) synthesized in apes, Old-World monkeys, and many non-primate mammals; and (3) anti-Forssman binds to Forssman-antigen synthesized in various mammals. Anti-viral protection by anti-MCA antibodies is feasible because carbohydrate chains of virus envelopes are synthesized by host glycosylation machinery and thus are similar to those of their mammalian hosts. Analysis of MCA glycosyltransferase genes suggests that anti-Gal appeared in ancestral Old-World primates following catastrophic selection processes in which parental populations synthesizing α-gal epitopes were eliminated in enveloped virus epidemics. However, few mutated offspring in which the α1,3galactosyltransferase gene was accidentally inactivated produced natural anti-Gal that destroyed viruses presenting α-gal epitopes, thereby preventing extinction of mutated offspring. Similarly, few mutated hominin offspring that ceased to synthesize Neu5Gc produced anti-Neu5Gc, which destroyed viruses presenting Neu5Gc synthesized in parental hominin populations. A present-day example for few humans having mutations that prevent synthesis of a common carbohydrate antigen (produced in >99.99% of humans) is blood-group Bombay individuals with mutations inactivating H-transferase; thus, they cannot synthesize blood-group O (H-antigen) but produce anti-H antibody. Anti-MCA antibodies prevented past extinctions mediated by enveloped virus epidemics, presently protect against zoonotic-viruses, and may protect in future epidemics. Travelers to regions with endemic zoonotic viruses may benefit from vaccinations elevating protective anti-MCA antibody titers.


2020 ◽  
Vol 21 (18) ◽  
pp. 6702
Author(s):  
Uri Galili

The glycans on enveloped viruses are synthesized by host-cell machinery. Some of these glycans on zoonotic viruses of mammalian reservoirs are recognized by human natural antibodies that may protect against such viruses. These antibodies are produced mostly against carbohydrate antigens on gastrointestinal bacteria and fortuitously, they bind to carbohydrate antigens synthesized in other mammals, neutralize and destroy viruses presenting these antigens. Two such antibodies are: anti-Gal binding to α-gal epitopes synthesized in non-primate mammals, lemurs, and New World monkeys, and anti-N-glycolyl neuraminic acid (anti-Neu5Gc) binding to N-glycolyl-neuraminic acid (Neu5Gc) synthesized in apes, Old World monkeys, and many non-primate mammals. Anti-Gal appeared in Old World primates following accidental inactivation of the α1,3galactosyltransferase gene 20–30 million years ago. Anti-Neu5Gc appeared in hominins following the inactivation of the cytidine-monophosphate-N-acetyl-neuraminic acid hydroxylase gene, which led to the loss of Neu5Gc <6 million-years-ago. It is suggested that an epidemic of a lethal virus eliminated ancestral Old World-primates synthesizing α-gal epitopes, whereas few mutated offspring lacking α-gal epitopes and producing anti-Gal survived because anti-Gal destroyed viruses presenting α-gal epitopes, following replication in parental populations. Similarly, anti-Neu5Gc protected few mutated hominins lacking Neu5Gc in lethal virus epidemics that eliminated parental hominins synthesizing Neu5Gc. Since α-gal epitopes are presented on many zoonotic viruses it is suggested that vaccines elevating anti-Gal titers may be of protective significance in areas endemic for such zoonotic viruses. This protection would be during the non-primate mammal to human virus transmission, but not in subsequent human to human transmission where the virus presents human glycans. In addition, production of viral vaccines presenting multiple α-gal epitopes increases their immunogenicity because of effective anti-Gal-mediated targeting of vaccines to antigen presenting cells for extensive uptake of the vaccine by these cells.


1989 ◽  
Vol 146 (1) ◽  
pp. 21-38 ◽  
Author(s):  
J. D. Mollon

The disabilities experienced by colour-blind people show us the biological advantages of colour vision in detecting targets, in segregating the visual field and in identifying particular objects or states. Human dichromats have especial difficulty in detecting coloured fruit against dappled foliage that varies randomly in luminosity; it is suggested that yellow and orange tropical fruits have co-evolved with the trichromatic colour vision of Old World monkeys. It is argued that the colour vision of man and of the Old World monkeys depends on two subsystems that remain parallel and independent at early stages of the visual pathway. The primordial subsystem, which is shared with most mammals, depends on a comparison of the rates of quantum catch in the short- and middle-wave cones; this system exists almost exclusively for colour vision, although the chromatic signals carry with them a local sign that allows them to sustain several of the functions of spatiochromatic vision. The second subsystem arose from the phylogenetically recent duplication of a gene on the X-chromosome, and depends on a comparison of the rates of quantum catch in the long- and middle-wave receptors. At the early stages of the visual pathway, this chromatic information is carried by a channel that is also sensitive to spatial contrast. The New World monkeys have taken a different route to trichromacy: in species that are basically dichromatic, heterozygous females gain trichromacy as a result of X-chromosome inactivation, which ensures that different photopigments are expressed in two subsets of retinal photoreceptor.


2021 ◽  
Author(s):  
Asheley H. B. Pereira ◽  
Claudia A. A. Lopes ◽  
Thalita A. Pissinatti ◽  
Ana C. A. Pinto ◽  
Daniel R. A. Oliveira ◽  
...  

Abstract Herein we present the pathological findings of different tuberculosis stages in Old and New World monkeys kept under human care in Rio de Janeiro, Brazil and naturally infected with Mycobacterium tuberculosis Complex. Fifteen nonhuman primates from five different colonies were incorporated into the study. There are 60% (9/15) Old World Monkeys and 40% (6/15) New World Monkeys. According to the gross and histopathologic findings, the lesions in nonhuman primates of this study are classified into the chronic-active, extrapulmonary, early-activation or latent-reactivation tuberculosis stage. Among the Old World Monkey, 66.7% (6/9) of nonhuman primates, all rhesus monkeys (Macaca mulatta), showed severe granulomatous pneumonia. In all Old World Monkeys cases, typical granulomas were seen in at least one organ regardless of the stage of the disease. In the New World Monkeys, the typical pulmonary granulomas were seen in 16.7% (1/6) of the cases, just in the latent-reactivation stage in Uta Hick’s Bearded Saki (Chiropotes utahickae). In this study, 66.7% (6/9) of Old World Monkeys (OWM) and 83.3% (5/6) of New World Monkeys (NWM) showed pulmonary changes at the histological evaluation. The tuberculosis diagnosis in the nonhuman primates in this study was based on pathological, immunohistochemical, molecular, and bacteriological culture. Although the typical presentation was observed in some cases, the absence of pulmonary granuloma did not exclude the tuberculosis occurrence in nonhuman primates of the Old and New World. Tuberculosis should be included as a cause of interstitial pneumonia with foamy macrophages infiltration in the New World nonhuman primates. Due to the high sensitivity of immunohistochemistry with Anti-Mycobacterium tuberculosis, we suggest the addition of this technique as a diagnostic tool of tuberculosis in the nonhuman primates even when the typical changes are not seen.


1970 ◽  
Vol 116 (3) ◽  
pp. 437-443 ◽  
Author(s):  
R. H. Adamson ◽  
J. W. Bridges ◽  
M. E. Evans ◽  
R. T. Williams

1. The fate of (-)-quinic acid has been investigated in 22 species of animals including man. 2. In man and three species of Old World monkeys, i.e. rhesus monkey, baboon and green monkey, oral quinic acid was extensively aromatized (20–60%) and excreted in the urine as hippuric acid, which was determined fluorimetrically. 3. In three species of New World monkeys, i.e. squirrel monkey, spider monkey and capuchin, in three species of lemurs, i.e. bushbaby, slow loris and tree shrew, in the dog, cat, ferret, rabbit, rat, mouse, guinea pig, hamster, lemming, fruit bat, hedgehog and pigeon, oral quinic acid was not extensively aromatized (0–5%). 4. In the rhesus monkey, injected quinic acid was not aromatized, but largely excreted unchanged. 5. In rhesus monkeys pretreated with neomycin to suppress gut flora, the aromatization of oral quinic acid was considerably suppressed. 6. In rats and rhesus monkeys [14C]quinic acid was used and this confirmed its low aromatization in rats and its high aromatization in the monkeys. 7. Shikimic acid given orally was excreted as hippuric acid (26–56%) in rhesus monkeys, but not in rats. 8. The results support the view that quinic acid and shikimic acid are aromatized by the gut flora in man and the Old World monkeys.


2019 ◽  
Author(s):  
Silvia Spadacenta ◽  
Peter W. Dicke ◽  
Peter Thier

ABSTRACTThe ability to extract the direction of the other’s gaze allows us to shift our attention to an object of interest to the other and to establish joint attention. By mapping one’s own expectations, desires and intentions on the object of joint attention, humans develop a Theory of (the other’s) Mind (TOM), a functional sequence possibly disrupted in autism. Although old world monkeys probably do not possess a TOM, they follow the other’s gaze and they establish joint attention. Gaze following of both humans and old world monkeys fulfills Fodor’s criteria of a domain specific function and is orchestrated by very similar cortical architectures, strongly suggesting homology. Also new world monkeys, a primate suborder that split from the old world monkey line about 35 million years ago, have complex social structures. One member of this group, the common marmoset (Callithrix jacchus), has received increasing interest as a potential model in studies of normal and disturbed human social cognition. Marmosets are known to follow human head-gaze. However, the question is if they use gaze following to establish joint attention with conspecifics. Here we show that this is indeed the case. In a free choice task, head-restrained marmosets prefer objects gazed at by a conspecific and, moreover, they exhibit considerably shorter choice reaction times for the same objects. These findings support the assumption of an evolutionary old domain specific faculty shared within the primate order and they underline the potential value of marmosets in studies of normal and disturbed joint attention.HIGHLIGHTSCommon marmosets follow the head gaze of conspecifics in order to establish joint attention.Brief exposures to head gaze are sufficient to reallocate an animal’s attention.The tendency to follow the other’s gaze competes with the attractional binding of the conspecific’s face


2020 ◽  
Vol 29 (18) ◽  
pp. 3032-3043
Author(s):  
F Isabella Zampeta ◽  
Monica Sonzogni ◽  
Eva Niggl ◽  
Bas Lendemeijer ◽  
Hilde Smeenk ◽  
...  

Abstract The human UBE3A gene, which is essential for normal neurodevelopment, encodes three Ubiquitin E3 ligase A (UBE3A) protein isoforms. However, the subcellular localization and relative abundance of these human UBE3A isoforms are unknown. We found, as previously reported in mice, that UBE3A is predominantly nuclear in human neurons. However, this conserved subcellular distribution is achieved by strikingly distinct cis-acting mechanisms. A single amino-acid deletion in the N-terminus of human hUBE3A-Iso3, which is homologous to cytosolic mouse mUBE3A-Iso2, results in its translocation to the nucleus. This singe amino-acid deletion is shared with apes and Old World monkeys and was preceded by the appearance of the cytosolic hUBE3A-Iso2 isoform. This hUBE3A-Iso2 isoform arose after the lineage of New World monkeys and Old World monkeys separated from the Tarsiers (Tarsiidae). Due to the loss of a single nucleotide in a non-coding exon, this exon became in frame with the remainder of the UBE3A protein. RNA-seq analysis of human brain samples showed that the human UBE3A isoforms arise by alternative splicing. Consistent with the predominant nuclear enrichment of UBE3A in human neurons, the two nuclear-localized isoforms, hUBE3A-Iso1 and -Iso3, are the most abundantly expressed isoforms of UBE3A, while hUBE3A-Iso2 maintains a small pool of cytosolic UBE3A. Our findings provide new insight into UBE3A localization and evolution and may have important implications for gene therapy approaches in Angelman syndrome.


2005 ◽  
Vol 35 (2) ◽  
pp. 399-409 ◽  
Author(s):  
Ying Li ◽  
Chun Ye ◽  
Peng Shi ◽  
Xiao-Ju Zou ◽  
Rui Xiao ◽  
...  

The growth hormone (GH) gene family represents an erratic and complex evolutionary pattern, involving many evolutionary events, such as multiple gene duplications, positive selection, the birth-and-death process and gene conversions. In the present study, we cloned and sequenced GH-like genes from three species of New World monkeys (NWM). Phylogenetic analysis strongly suggest monophyly for NWM GH-like genes with respect to those of Old World monkeys (OWM) and hominoids, indicating that independent gene duplications have occurred in NWM GH-like genes. There are three main clusters of genes in putatively functional NWM GH-like genes, according to our gene tree. Comparison of the ratios of nonsynonymous and synonymous substitutions revealed that these three clusters of genes evolved under different kinds of selective pressures. Detailed analysis of the evolution of pseudogenes showed that the evolutionary pattern of this gene family in platyrrhines is in agreement with the so-called birth-and-death process.


1993 ◽  
Vol 10 (5) ◽  
pp. 827-855 ◽  
Author(s):  
Marcello G. P. Rosa ◽  
Juliana G. M. Soares ◽  
Mario Fiorani ◽  
Ricardo Gattass

AbstractCortical projections to the middle temporal (MT) visual area were studied by injecting the retrogradely transported fluorescent tracer Fast Blue into MT in adult New World monkeys (Cebus apella). Injection sites were selected based on electrophysiological recordings, and covered eccentricities from 2–70 deg, in both the upper and lower visual fields. The position and laminar distribution of labeled cell bodies were correlated with myeloarchitectonic boundaries and displayed in flat reconstructions of the neocortex. Topographically organized projections were found to arise mainly from the primary, second, third, and fourth visual areas (V1, V2, V3, and V4). Coarsely topographic patterns were observed in transitional V4 (V4t), in the parieto-occipital and parieto-occipital medial areas (PO and POm), and in the temporal ventral posterior area (TVP). In addition, widespread or nontopographic label was found in visual areas of the superior temporal sulcus (medial superior temporal, MST, and fundus of superior temporal, FST), annectent gyrus (dorsointermediate area, DI; and dorsomedial area, DM), intraparietal sulcus (lateral intraparietal, LIP; posterior intraparietal, PIP; and ventral intraparietal, VIP), and in the frontal eye field (FEF). Label in PO, POm, and PIP was found only after injections in the representation of the peripheral visual field (>10 deg), and label in V4 and FST was more extensive after injections in the central representation. The projections from V1 and V2 originated predominantly from neurons in supragranular layers, whereas those from V3, V4t, DM, DI, POm, and FEF consisted of intermixed patches with either supragranular or infragranular predominance. All of the other projections were predominantly infragranular. Invasion of area MST by the injection site led to the labeling of further pathways, including substantial projections from the dorsal prelunate area (DP) and from an ensemble of areas located along the medial wall of the hemisphere. In addition, weaker projections were observed from the parieto-occipital dorsal area (POd), area 7a, area prostriata, the posterior bank of the arcuate sulcus, and areas in the anterior part of the lateral sulcus. Despite the different nomenclatures and areal boundaries recognized by different models of simian cortical organization, the pattern of projections to area MT is remarkably similar among primates. Our results provide evidence for the existence of many homologous areas in the extrastriate visual cortex of New and Old World monkeys.


1968 ◽  
Vol 27 (3_suppl) ◽  
pp. 1031-1034 ◽  
Author(s):  
Roger T. Davis ◽  
Robert W. Leary

40 Ss drawn from 7 species of monkey, and Lemur catta were trained to solve bent-wire detour problems. Old World monkeys were significantly more proficient than New World monkeys or lemurs, but members of the latter two groups did not differ significantly from each other. The results are compared with those obtained with children, apes, and raccoons.


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