Glycosphingolipids Gb3 and iGb3

Porubský, Štefan; Luckow, Bruno; Bonrouhi, Mahnaz; Speak, Anneliese O.; Cerundolo, Vincenzo; Platt, Frances M.; Gröne, Hermann–Josef

doi:10.1007/s00292-008-1040-0

Cited by 3 publications

(1 citation statement)

References 20 publications

(26 reference statements)

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“…In infection models, iNKT cell recognition of iGb3 has been identified as an important trigger for inducing Th1 response by iNKT cells (31). However, iNKT cells may recognize different endogenous Ags (43) and therefore the microenvironment of different tissues or types of inflammation (e.g., Th1 vs Th2) encountered may be instrumental in determining the phenotype of iNKT cytokine production. In this regard, endogenous ligand(s) involved in IL-5 production by IL-2 is an area to be further investigated in the future.…”

Section: Discussionmentioning

confidence: 99%

Invariant NKT Cells Biased for IL-5 Production Act as Crucial Regulators of Inflammation

Sakuishi

Oki

Araki

et al. 2007

The Journal of Immunology

100

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Although invariant NKT (iNKT) cells play a regulatory role in the pathogenesis of autoimmune diseases and allergy, an initial trigger for their regulatory responses remains elusive. In this study, we report that a proportion of human CD4+ iNKT cell clones produce enormous amounts of IL-5 and IL-13 when cocultured with CD1d+ APC in the presence of IL-2. Such IL-5 bias was never observed when we stimulated the same clones with α-galactosylceramide or anti-CD3 Ab. Suboptimal TCR stimulation by plate-bound anti-CD3 Ab was found to mimic the effect of CD1d+ APC, indicating the role of TCR signaling for selective induction of IL-5. Interestingly, DNA microarray analysis identified IL-5 and IL-13 as the most highly up-regulated genes, whereas other cytokines produced by iNKT cells, such as IL-4 and IL-10, were not significantly induced. Moreover, iNKT cells from BALB/c mice showed similar IL-5 responses after stimulation with IL-2 ex vivo or in vivo. The iNKT cell subset producing IL-5 and IL-13 could play a major role in the development of allergic disease or asthma and also in the immune regulation of Th1 inflammation.

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Section: Discussionmentioning

confidence: 99%

Invariant NKT Cells Biased for IL-5 Production Act as Crucial Regulators of Inflammation

Sakuishi

Oki

Araki

et al. 2007

The Journal of Immunology

100

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Non-α1,3Gal Carbohydrate Antigenic Epitopes

Kim

2024

Glycoimmunology in Xenotransplantation

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Therapeutic Uses of Bacterial Subunit Toxins

Lingwood

2021

Toxins

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The B subunit pentamer verotoxin (VT aka Shiga toxin-Stx) binding to its cellular glycosphingolipid (GSL) receptor, globotriaosyl ceramide (Gb3) mediates internalization and the subsequent receptor mediated retrograde intracellular traffic of the AB5 subunit holotoxin to the endoplasmic reticulum. Subunit separation and cytosolic A subunit transit via the ER retrotranslocon as a misfolded protein mimic, then inhibits protein synthesis to kill cells, which can cause hemolytic uremic syndrome clinically. This represents one of the most studied systems of prokaryotic hijacking of eukaryotic biology. Similarly, the interaction of cholera AB5 toxin with its GSL receptor, GM1 ganglioside, is the key component of the gastrointestinal pathogenesis of cholera and follows the same retrograde transport pathway for A subunit cytosol access. Although both VT and CT are the cause of major pathology worldwide, the toxin–receptor interaction is itself being manipulated to generate new approaches to control, rather than cause, disease. This arena comprises two areas: anti neoplasia, and protein misfolding diseases. CT/CTB subunit immunomodulatory function and anti-cancer toxin immunoconjugates will not be considered here. In the verotoxin case, it is clear that Gb3 (and VT targeting) is upregulated in many human cancers and that there is a relationship between GSL expression and cancer drug resistance. While both verotoxin and cholera toxin similarly hijack the intracellular ERAD quality control system of nascent protein folding, the more widespread cell expression of GM1 makes cholera the toxin of choice as the means to more widely utilise ERAD targeting to ameliorate genetic diseases of protein misfolding. Gb3 is primarily expressed in human renal tissue. Glomerular endothelial cells are the primary VT target but Gb3 is expressed in other endothelial beds, notably brain endothelial cells which can mediate the encephalopathy primarily associated with VT2-producing E. coli infection. The Gb3 levels can be regulated by cytokines released during EHEC infection, which complicate pathogenesis. Significantly Gb3 is upregulated in the neovasculature of many tumours, irrespective of tumour Gb3 status. Gb3 is markedly increased in pancreatic, ovarian, breast, testicular, renal, astrocytic, gastric, colorectal, cervical, sarcoma and meningeal cancer relative to the normal tissue. VT has been shown to be effective in mouse xenograft models of renal, astrocytoma, ovarian, colorectal, meningioma, and breast cancer. These studies are herein reviewed. Both CT and VT (and several other bacterial toxins) access the cell cytosol via cell surface ->ER transport. Once in the ER they interface with the protein folding homeostatic quality control pathway of the cell -ERAD, (ER associated degradation), which ensures that only correctly folded nascent proteins are allowed to progress to their cellular destinations. Misfolded proteins are translocated through the ER membrane and degraded by cytosolic proteosome. VT and CT A subunits have a C terminal misfolded protein mimic sequence to hijack this transporter to enter the cytosol. This interface between exogenous toxin and genetically encoded endogenous mutant misfolded proteins, provides a new therapeutic basis for the treatment of such genetic diseases, e.g., Cystic fibrosis, Gaucher disease, Krabbe disease, Fabry disease, Tay-Sachs disease and many more. Studies showing the efficacy of this approach in animal models of such diseases are presented.

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Glycosphingolipids Gb3 and iGb3

Cited by 3 publications

References 20 publications

Invariant NKT Cells Biased for IL-5 Production Act as Crucial Regulators of Inflammation

Invariant NKT Cells Biased for IL-5 Production Act as Crucial Regulators of Inflammation

Non-α1,3Gal Carbohydrate Antigenic Epitopes

Therapeutic Uses of Bacterial Subunit Toxins

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