Anti α1-3Gal antibodies and Gal content in gut microbiota in immune disorders and multiple sclerosis

Boussamet, Léo; Montassier, Emmanuel; Soulillou, Jean‐Paul; Berthelot, Laureline

doi:10.1016/j.clim.2021.108693

Cited by 6 publications

(7 citation statements)

References 109 publications

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“…Anti-Gal is one of the most abundant natural antibodies in humans, constituting ~1% of immunoglobulins [ 26 , 27 , 28 , 29 , 30 ]. It is produced throughout life, starting few months after birth [ 26 , 31 ], in response to antigenic stimulation by gastrointestinal bacteria [ 32 , 33 , 34 , 35 , 36 , 37 ]. Anti-Gal binds specifically to a carbohydrate antigen called the “α-gal epitope” with the structure Galα1-3Galβ1-4GlcNAc-R [ 29 , 38 , 39 , 40 , 41 ].…”

Section: Anti-gal and The α-Gal Nanoparticlesmentioning

confidence: 99%

α-Gal Nanoparticles Mediated Homing of Endogenous Stem Cells for Repair and Regeneration of External and Internal Injuries by Localized Complement Activation and Macrophage Recruitment

Galili¹,

Goldufsky²,

Schaer³

2022

IJMS

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This review discusses a novel experimental approach for the regeneration of original tissue structure by recruitment of endogenous stem-cells to injured sites following administration of α-gal nanoparticles, which harness the natural anti-Gal antibody. Anti-Gal is produced in large amounts in all humans, and it binds the multiple α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R) presented on α-gal nanoparticles. In situ binding of anti-Gal to α-gal nanoparticles activates the complement system and generates complement cleavage chemotactic-peptides that rapidly recruit macrophages. Macrophages reaching anti-Gal coated α-gal nanoparticles bind them via Fc/Fc receptor interaction and polarize into M2 pro-reparative macrophages. These macrophages secrete various cytokines that orchestrate regeneration of the injured tissue, including VEGF inducing neo-vascularization and cytokines directing homing of stem-cells to injury sites. Homing of stem-cells is also directed by interaction of complement cleavage peptides with their corresponding receptors on the stem-cells. Application of α-gal nanoparticles to skin wounds of anti-Gal producing mice results in decrease in healing time by half. Furthermore, α-gal nanoparticles treated wounds restore the normal structure of the injured skin without fibrosis or scar formation. Similarly, in a mouse model of occlusion/reperfusion myocardial-infarction, near complete regeneration after intramyocardial injection of α-gal nanoparticles was demonstrated, whereas hearts injected with saline display ~20% fibrosis and scar formation of the left ventricular wall. It is suggested that recruitment of stem-cells following anti-Gal/α-gal nanoparticles interaction in injured tissues may result in induction of localized regeneration facilitated by conducive microenvironments generated by pro-reparative macrophage secretions and “cues” provided by the extracellular matrix in the injury site.

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Section: Anti-gal and The α-Gal Nanoparticlesmentioning

confidence: 99%

α-Gal Nanoparticles Mediated Homing of Endogenous Stem Cells for Repair and Regeneration of External and Internal Injuries by Localized Complement Activation and Macrophage Recruitment

Galili¹,

Goldufsky²,

Schaer³

2022

IJMS

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“…As discussed above, a variety of pathogens bind the anti-Gal antibody and are neutralized or destroyed by this antibody because they present α-gal or α-gal–like epitopes (i.e., antigens with a structure resembling that of α-gal epitopes; thus, they bind anti-Gal). These include viruses that replicate in mammalian host cells containing active α1,3GT ( Geyer et al, 1984 ; Repik et al, 1994 ; Galili et al, 1996 ; Takeuchi et al, 1996 ; Welsh et al, 1998 ; Preece et al, 2002 ; Hayashi et al, 2004 ; Kim et al, 2007 ; Pipperger et al, 2019 ; Galili, 2020a ), bacteria ( Lüderitz et al, 1965 ; Galili et al, 1988b ; Whitfield et al, 1991 ; Mañez et al, 2001 ; Posekany et al, 2002 ; Han et al, 2012 ; Bernth Jensen et al, 2021 ; Boussamet et al, 2021 ), and protozoa such as Trypanosoma ( Milani and Travassos, 1988 ; Almeida et al, 1991 ), Leishmania ( Avila et al, 1989 ; Iniguez et al, 2017 ), and Plasmodium ( Ramasamy, 1988 ; Ravindran et al, 1988 ; Yilmaz et al, 2014 ). These observations raise the possibility that immunization for elevating anti-Gal titers in travelers to regions endemic for such zoonotic pathogens or in populations living in such regions may contribute to the immune protection by this antibody ( Yilmaz et al, 2014 ; Cabezas Cruz et al, 2016 ; Iniguez et al, 2017 ; Moura et al, 2017 ; Portillo et al, 2019 ; Hodžić et al, 2020 ).…”

Section: Vaccines Elevating Anti-gal Titers For Protection Against Zoonotic Viruses and Pathogens Presenting α-Gal Or α-Gal–like Epitopesmentioning

confidence: 99%

“…As indicated above, anti-Gal binds to α-gal epitopes on glycans ( Galili et al, 1984 ; Galili et al, 1985 ; Galili et al, 1987 ; Towbin et al, 1987 ; Avila et al, 1989 ; Teneberg et al, 1996 ; McMorrow et al, 1997 ; Teranishi et al, 2002 ; Bovin, 2013 ) and is naturally produced in monkeys of Asia and Africa (Old-World monkeys), apes, and humans, all of which have evolved in the Eurasia–Africa landmass (referred to as the Old World) and lack α-gal epitopes ( Galili et al, 1984 ; Spiro and Bhoyroo, 1984 ; Galili et al, 1985 ; Galili et al, 1987 ; Towbin et al, 1987 ; Galili et al, 1988a ; Avila et al, 1989 ; McMorrow et al, 1997 ; Teranishi et al, 2002 ; Galili, 2019 ). In humans, anti-Gal crosses the placenta and is constantly produced throughout life, starting a few months after birth ( Galili et al, 1984 ; Wang et al, 1995 ), as a result of continuous antigenic stimulation by gastrointestinal bacteria which present glycans with structures similar to that of the α-gal epitope ( Lüderitz et al, 1965 ; Galili et al, 1988b ; Whitfield et al, 1991 ; Mañez et al, 2001 ; Posekany et al, 2002 ; Han et al, 2012 ; Boussamet et al, 2021 ). In the circulation, as many as 1% of quiescent B lymphocytes can produce anti-Gal following activation ( Galili et al, 1993 ).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, 20–30 mya, the early α-gal epitope–synthesizing Old-World primates were eliminated, whereas the progeny lacking these epitopes survived to evolve into present-day Old-World monkeys, apes, and humans ( Galili et al, 1987 ; Galili et al, 1988a ; Galili, 2019 ). Since anti-Gal was found to bind to a variety of bacteria ( Lüderitz et al, 1965 ; Galili et al, 1988b ; Whitfield et al, 1991 ; Mañez et al, 2001 ; Posekany et al, 2002 ; Han et al, 2012 ; Bernth Jensen et al, 2021 ; Boussamet et al, 2021 ) and to protozoa including Trypanosoma ( Milani and Travassos, 1988 ; Almeida et al, 1991 ), Leishmania ( Avila et al, 1989 ), and Plasmodium ( Ramasamy, 1988 ; Yilmaz et al, 2014 ), one cannot exclude the possibility that such pathogens could cause this evolutionary selection process eliminating ancestral Old-World primates synthesizing α-gal epitopes. Alternatively, high-affinity binding of a pathogen to α-gal epitopes on cells, as recently shown with Plasmodium yoelii sporozoites (a rodent pathogen) ( Poole et al, 2021 ), could have a similar selective effect.…”

Section: Introductionmentioning

confidence: 99%

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

Galili

2021

Front. Mol. Biosci.

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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.

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“…Primates, including apes, and Old-World monkeys, do not express the αGal epitopes due to an evolutive inactivation of the gene coding for the α1,3-galactosyltransferase enzyme ( 13 , 14 ); consequently, they naturally produce these antibodies. Some evidence links their origin to the gut microbiota ( 15 , 16 ). αGal residue is expressed in glycolipids and glycoproteins of the cell membrane of different microorganisms, including viruses, bacteria, and protozoans ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

Poly-L-Lysine-Based αGal-Glycoconjugates for Treating Anti-αGal IgE-Mediated Diseases

Olivera-Ardid¹,

Bello-Gil²,

Tuzikov

et al. 2022

Front. Immunol.

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Anti-αGal IgE antibodies mediate a spreading allergic condition known as αGal-syndrome (AGS). People exposed to hard tick bites are sensitized to αGal, producing elevated levels of anti-αGal IgE, which are responsible for AGS. This work presents an immunotherapy based on polymeric αGal-glycoconjugates for potentially treating allergic disorders by selectively inhibiting anti-αGal IgE antibodies. We synthesized a set of αGal-glycoconjugates, based on poly-L-lysine of different degrees of polymerization (DP1000, DP600, and DP100), to specifically inhibit in vitro the anti-αGal IgE antibodies in the serum of αGal-sensitized patients (n=13). Moreover, an animal model for αGal sensitization in GalT-KO mice was developed by intradermal administration of hard tick’ salivary gland extract, mimicking the sensitization mechanism postulated in humans. The in vitro exposure to all polymeric glycoconjugates (5-10-20-50-100 µg/mL) mainly inhibited anti-αGal IgE and IgM isotypes, with a lower inhibition effect on the IgA and IgG, respectively. We demonstrated a differential anti-αGal isotype inhibition as a function of the length of the poly-L-lysine and the number of αGal residues exposed in the glycoconjugates. These results defined a minimum of 27 αGal residues to inhibit most of the induced anti-αGal IgE in vitro. Furthermore, the αGal-glycoconjugate DP1000-RA0118 (10 mg/kg sc.) showed a high capacity to remove the anti-αGal IgE antibodies (≥75% on average) induced in GalT-KO mice, together with similar inhibition for circulating anti-αGal IgG and IgM. Our study suggests the potential clinical use of poly-L-lysine-based αGal-glycoconjugates for treating allergic disorders mediated by anti-αGal IgE antibodies.

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Anti α1-3Gal antibodies and Gal content in gut microbiota in immune disorders and multiple sclerosis

Cited by 6 publications

References 109 publications

α-Gal Nanoparticles Mediated Homing of Endogenous Stem Cells for Repair and Regeneration of External and Internal Injuries by Localized Complement Activation and Macrophage Recruitment

α-Gal Nanoparticles Mediated Homing of Endogenous Stem Cells for Repair and Regeneration of External and Internal Injuries by Localized Complement Activation and Macrophage Recruitment

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

Poly-L-Lysine-Based αGal-Glycoconjugates for Treating Anti-αGal IgE-Mediated Diseases

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