Differential Recognition of Diet-Derived Neu5Gc-Neoantigens on Glycan Microarrays by Carbohydrate-Specific Pooled Human IgG and IgA Antibodies
Shani Leviatan Ben‐AryeChristoph SchneiderHai YuSalam BashirXi ChenStephan von GuntenVered Padler‐Karavani
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Abstract:
Sialic acids (Sias) cover vertebrate cell surface glycans. N-Acetylneuraminic acid (Neu5Ac) and its hydroxylated form N-glycolylneuraminic acid (Neu5Gc) are common Sia in mammals. Humans cannot synthesize Neu5Gc but accumulate it on cells through red-meat rich diets, generating numerous immunogenic Neu5Gc-neoantigens. Consequently, humans have diverse anti-Neu5Gc antibodies affecting xenotransplantation, cancer, atherosclerosis, and infertility. Anti-Neu5Gc antibodies circulate as IgG, IgM, and IgA isotypes; however, repertoires of the different isotypes in a large population have not been studied yet. Here, we used glycan microarrays to investigate anti-Neu5Gc IgGs and IgAs in intravenous immunoglobulin (IVIG) or pooled human IgA, respectively. Binding patterns on microarrays fabricated with Neu5Gc- and Neu5Ac-glycans, together with inhibition assays, revealed that different IVIG preparations have highly specific anti-Neu5Gc IgG reactivity with closely related repertoires, while IgAs show cross-reactivity against several Neu5Ac-glycans. Such different anti-Neu5Gc IgG/IgA repertoires in individuals could possibly mediate distinctive effects on human diseases.Keywords:
Xenotransplantation
Xenotransplantation is a hot topic currently, since the demand for diverse organs is increasing in patients.Among many species, pigs are suitable animals for xenotranplantation as they share many anatomical and physiological characteristics with humans.This review article provides an overview of porcine xenotransplantation and the rejection of pig xenotransplants in primates, and use of genetically modified and cloned pigs in xenotransplantation.It also highlights major target organs in porcine xenotransplantation and virus infection in xenotransplantation. (
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Objective To summarize the research progress of xenotransplantation. Methods Domestic and international publications about xenotransplantation were summarized and reviewed. Results Hyperacute xenograft rejection was a huge problem for xenotransplantation,but it could be alleviated if the organs or tissues of donor were genetically modified. So far the graft survival time differed greatly due to characteristics of different organ. Conclusions By reviewing the studies of relevant papers about xenotransplantation,a comprehensive understanding of research background and a suitable research direction of xenotransplantation can be supplied. The graft organs or tissues from genetically modified donors are expected to avoid or alleviate hyperacute xenograft rejection.
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The aim of xenotransplantation is to allow the transplantation of animal organs or cells to humans. This approach would immediately eliminate the human organ shortage that is responsible for a significant mortality of patients on the waiting list for transplantation of organs. The immune differences between pig and human induce an immediate rejection of porcine tissues by humans. This rejection has recently been partially controlled by genetic engineering of pigs, the use of new immunosuppressive drugs and encapsulation of isolated cells. However, due to the risk of transmission of animal infectious agents to humans, the WHO recommends that clinical application of xenotransplantation only takes place if adequate regulations are in place.
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The aim of xenotransplantation is to allow the transplantation of animal organs or cells to humans. This approach would immediately eliminate the human organ shortage that is responsible for a significant mortality of patients on the waiting list for transplantation of organs. The immune differences between pig and human induce an immediate rejection of porcine tissues by humans. This rejection has recently been partially controlled by genetic engineering of pigs, the use of new immunosuppressive drugs and encapsulation of isolated cells. However, due to the risk of transmission of animal infectious agents to humans, the WHO recommends that clinical application of xenotransplantation only takes place if adequate regulations are in place.
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Ganglioside GAA-7 exhibits higher neurite outgrowth than ganglioside GM1a and most echinodermatous gangliosides (EGs) when tested on neuron-like rat adrenal pheochromocytoma (PC12) cells in the presence of nerve growth factor (NGF). The unique structure of GAA-7 glycan, containing an uncommon sialic acid (8-O-methyl-N-glycolylneuraminic acid) and sialic acid-α-2,3-GalNAc linkage, makes it challenging to synthesize. We recently developed a streamlined method to chemoenzymatically synthesize GAA-7 glycan and employed this modular strategy to efficiently prepare a library of GAA-7 glycan analogues incorporating N-modified or 8-methoxyl sialic acids. Most of these synthetic glycans exhibited moderate efficacy in promoting neuronal differentiation of PC12 cells. Among them, the analogue containing common sialic acid shows greater potential than the GAA-7 glycan itself. This result reveals that methoxy modification is not essential for neurite outgrowth. Consequently, the readily available analogue presents a promising model for further biological investigations.
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Antibodies against pig antigens mediate much of the pig xenograft rejection process in humans and in evolutionarily related primates. The main, and possibly the only, natural antibody that induces rejection of pig xenografts is anti-Gal, which interacts with α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R) on pig cells. However, in xenograft recipients there are two types of elicited (ie, induced) anti-pig antibodies that are detrimental to the xenograft: 1) elicited anti-Gal IgG, which displays approximately 100-fold increase in activity in comparison with the natural anti-Gal, and 2) anti–non-gal antibodies against a large number of immunogenic pig proteins. If complement activation is prevented, these antibodies destroy xenograft cells, primarily via the antibody-dependent cell-mediated cytotoxicity mechanism. Progress in xenotransplantation requires the development of novel methods for preventing the production of these natural and elicited antibodies.
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