Induction of Cytolytic Anti-Gal Antibodies in α-1,3-Galactosyltransferase Gene Knockout Mice by Oral Inoculation with<i>Escherichia coli</i>O86:B7 Bacteria

Posekany, Karla J.; Pittman, H. Keith; Bradfield, John F.; Haisch, Carl E.; Verbanac, Kathryn M.

doi:10.1128/iai.70.11.6215-6222.2002

Cited by 69 publications

(54 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Briefly, a strain of E. coli. (O86:B7) that has been shown to bind alpha gal antibodies [25] was incubated over night and the next day a fixed amount of the bacterial suspension was incubated with functional complement and supplemented either with heat inactivated serum from pooled cirrhotic patients (20 patients/pool) or heat inactivated normal serum. Figure 3B shows the pattern of bacterial growth in the presence of serum.…”

Section: Resultsmentioning

confidence: 99%

Altered Functionality of Anti-Bacterial Antibodies in Patients with Chronic Hepatitis C Virus Infection

et al. 2013

View full text Add to dashboard Cite

BackgroundUsing comparative glycoproteomics, we have previously identified a glycoprotein that is altered in both amount and glycosylation as a function of liver cirrhosis. The altered glycoprotein is an agalactosylated (G0) immunoglobulin G molecule (IgG) that recognizes the heterophilic alpha-gal epitope. Since the alpha gal epitope is found on gut enterobacteria, it has been hypothesized that anti-gal antibodies are generated as a result of increased bacterial exposure in patients with liver disease.MethodsThe N-linked glycosylation of anti-gal IgG molecules from patients with fibrosis and cirrhosis was determined and the effector function of anti-bacterial antibodies from over 100 patients examined. In addition, markers of microbial exposure were determined.ResultsSurprisingly, the subset of agalactosylated anti-gal antibodies described here, was impaired in their ability to mediate complement mediated lysis and inhibited the complement-mediated destruction of common gut bacteria. In an analysis of serum from more than 100 patients with liver disease, we have shown that those with increased levels of this modified anti-gal antibody had increased levels of markers of bacterial exposure.ConclusionsAnti-gal antibodies in patients with liver cirrhosis were reduced in their ability to mediate complement mediated lysis of target cells. As bacterial infection is a major complication in patients with cirrhosis and bacterial products such as LPS are thought to play a major role in the development and progression of liver fibrosis, this finding has many clinical implications in the etiology, prognosis and treatment of liver disease.

show abstract

Section: Resultsmentioning

confidence: 99%

Altered Functionality of Anti-Bacterial Antibodies in Patients with Chronic Hepatitis C Virus Infection

et al. 2013

View full text Add to dashboard Cite

show abstract

“…However, Thall et al, [28] Posekany et al, [29] Chiang et al, [30] and Dor et al [31] in multiple studies found that cytotoxic anti-Gal α 3Gal antibodies may be induced in concentrations at levels as high as milligrams per milliliter in α 3GalT1 −/− mice and pigs without acute or chronic rejection of self-organs or self-blood vessels, opposite to the implication of this assertion. Paradoxically, Christiansen et al [20] acknowledged that they had generated anti-iGb3 monoclonal antibodies in α 3GalT −/− mice that express the functional iGb3 enzyme.…”

Section: Discussionmentioning

confidence: 99%

Lack of iGb3 and Isoglobo-Series Glycosphingolipids in Pig Organs Used for Xenotransplantation: Implications for Natural Killer T-Cell Biology

Tahiri

Hawke

et al. 2013

Journal of Carbohydrate Chemistry

View full text Add to dashboard Cite

α-1,3-Terminated galactose residues on glycoproteins and glycosphingolipids are recognized by natural anti-α-1,3-galactose antibodies in human serum and cause hyperacute rejection in pig-to-human xenotransplantation. Genetic depletion of α-1,3-galactosyltransferase-1 in pigs abolishes the hyperacute rejection reaction. However, the isoglobotriosylceramide (iGb3) synthase in pigs may produce additional α-1,3-terminated galactose residues on glycosphingolipids. In both α-1,3-galactosyltranserase-1 knockout mice and pigs, cytotoxic anti-α-1,3-galactose antibodies could be induced; thus, a paradox exists that anti-α-1,3-galactose antibodies are present in animals with functional iGb3 synthases. Furthermore, iGb3 has been found to be an endogenous antigen for natural killer T (NKT) cells, an innate type of lymphocyte that may initiate the adaptive immune responses. It has been reasoned that iGb3 may trigger the activation of NKT cells and cause the rejection of α-1,3-galactosyltransferase-1-deficient organs through the potent stimulatory effects of NKT cells on adaptive immune cells (see ref.[20]). In this study, we examined the expression of iGb3 and the isoglobo-series glycosphingolipids in pig organs, including the heart, liver, pancreas, and kidney, by ion-trap mass spectrometry, which has a sensitivity of measuring 1% iGb3 among Gb3 isomers, when 5 μg/mL of the total iGb3/Gb3 mixture is present (see ref.[35]). We did not detect iGb3 or other isoglobo-series glycosphingolipids in any of these organs, although they were readily detected in mouse and human thymus and dendritic cells. The lack of iGb3 and isoglobo-series glycosphingolipids in pig organs indicates that iGb3 is unlikely to be a relevant immune epitope in xenotransplantation.

show abstract

“…Inactivation of the α1,3GT gene, resulting in suppression of α-gal expression in ancestral Old World primates would have eliminated immune tolerance to this epitope and thus enable production of the anti-Gal antibody as means of protection against the pathogen(s) expressing α-gal epitopes. This possibility is supported by the following observations: i) enveloped viruses propagated in cells with active α1,3GT express α-gal epitopes on their glycoproteins, whereas the same virus propagated in cells lacking α1,3GT, do not express α-gal epitopes [55][56][57]; ii) bacteria and protozoa have been found to express carbohydrate epitopes with structures similar to the α-gal epitopes, as indicated by their ability to bind anti-Gal [30,[58][59][60]; and iii) anti-Gal has been shown to destroy viruses and protozoa expressing α-gal epitopes [61][62][63].…”

Section: Possible Causes For the Evolutionary Inactivation Of α13gtmentioning

confidence: 98%

“…Individuals successfully suppressing α-gal epitope expression would have lost immune tolerance to the α-gal epitope and would have produced the natural anti-Gal antibody in response to antigenic stimulation by gastrointestinal bacteria expressing carbohydrate epitopes with structures similar to that of the α-gal epitope. Currently, such antigenic stimulation in humans is mediated by a number of bacterial strains in the intestinal flora [30,58].…”

Section: Possible Causes For the Evolutionary Inactivation Of α13gtmentioning

confidence: 99%

The Galα1,3Galβ1,4GlcNAc-R (α-Gal) epitope: A carbohydrate of unique evolution and clinical relevance

Macher

Galili

2008

Biochimica et Biophysica Acta (BBA) - General Subjects

368

337

View full text Add to dashboard Cite

In 1985, we reported that a naturally occurring human antibody (anti-Gal), produced as the most abundant antibody (1% of immunoglobulins) throughout the life of all individuals, recognizes a carbohydrate epitope Galα1-3Galβ1-4GlcNAc-R (the α-gal epitope). Since that time, an extensive literature has developed on discoveries related to the α-gal epitope and the anti-Gal antibody, including the barrier they form in xenotransplantation and their reciprocity in mammalian evolution. This review covers these topics and new avenues of clinical importance related to this (α-gal epitope/ anti-Gal) unique antigen/antibody system in improving the efficacy of viral vaccines and in immunotherapy against cancer.

show abstract

Induction of Cytolytic Anti-Gal Antibodies in α-1,3-Galactosyltransferase Gene Knockout Mice by Oral Inoculation withEscherichia coliO86:B7 Bacteria

Cited by 69 publications

References 38 publications

Altered Functionality of Anti-Bacterial Antibodies in Patients with Chronic Hepatitis C Virus Infection

Altered Functionality of Anti-Bacterial Antibodies in Patients with Chronic Hepatitis C Virus Infection

Lack of iGb3 and Isoglobo-Series Glycosphingolipids in Pig Organs Used for Xenotransplantation: Implications for Natural Killer T-Cell Biology

The Galα1,3Galβ1,4GlcNAc-R (α-Gal) epitope: A carbohydrate of unique evolution and clinical relevance

Contact Info

Product

Resources

About