Down-regulation of core 1  1,3-galactosyltransferase and Cosmc by Th2 cytokine alters O-glycosylation of IgA1

Abstract

Background. Patients with IgA nephropathy (IgAN) have an increased amount of abnormally O-glycosylated IgA1 in circulation, in glomerular deposits and produced by tissue cells in vitro. Although increased production of Th2 cytokines by peripheral blood lymphocytes and a functional abnormality of core 1 β1,3-galactosyltransferase (C1β3Gal-T) have been proposed as mechanisms underlying pathogenesis of IgAN, they are still obscure and are not connected.Methods. To clarify the effect of T-cell cytokines, we analysed the mRNA levels of C1β3Gal-T and its molecular chaperone Cosmc, C1β3Gal-T activity and subsequent O-glycosylation of IgA1 in a human B-cell line stimulated with these cytokines. The surface IgA1-positive human B-cell line was cultured with recombinant human IFN-γ, IL-2, IL-4 or IL-5. The production and glycosylation of IgA1 were determined by sandwich ELISA and enzyme-linked lectin binding assay, respectively. The mRNA levels of C1β3Gal-T and Cosmc were quantitatively measured by real-time PCR. C1β3Gal-T activity was analysed using high-performance liquid chromatography.Results. IgA1 production by IL-4-stimulated cells was significantly higher than controls or after IFN-γ or IL-5. The terminal glycosylation of secreted IgA1 was altered in response to IL-4. IL-4 stimulation significantly decreased the mRNA levels of both C1β3Gal-T and Cosmc and of C1β3Gal-T activity. IL-4 stimulation was clearly blocked by recombinant human IL-4 soluble receptor.Conclusions. It appears that Th2 cytokine IL-4 may play a key role in controlling glycosylation of the IgA1 hinge region.

Identification of Distinct Glycoforms of IgA1 in Plasma from Patients with Immunoglobulin A (IgA) Nephropathy and Healthy Individuals

“…The poor kinetic activity of T-synthase to the IgA1 coupled with deficiency of T-synthase could lead to a deficiency of galactose on IgA1 yet O-glycosylation of cellular glycoproteins could be relatively normal. Consistent with this are some studies proposing that patients with IgAN show decreased expression of Cosmc and/or T-synthase (8,34,36). However, we observed no significant differences in the percentage of IgA1 glycoforms lacking O-galactosylation between patients with IgAN and healthy controls.…”

Differential Expression of O-Glycans in CD4⁺ T Lymphocytes from Patients with Systemic Lupus Erythematosus

“…An increase of Tn antigen on the T cell surface could be related to a reduced expression of the enzyme C1GalT1 or its molecular chaperone Cosmc, which has been reported to be altered by the presence of cytokines such as IL-6 and IL-4 (Suzuki et al 2014;Yamada et al 2010 (Yamada et al 2010), which could explain the alterations of core 1 expression on CD4 + T cells from active SLE patients that we described herein.…”

O-Linked Glycosylation Determines the Nephritogenic Potential of IgA Rheumatoid Factor

“…In this regard, it is worth noting that a study reported the possible role of T-cell cytokine IL-4 in the regulation of O-glycosylation of the IgA1 hinge region. 23 Further understanding of the interplay between the structural characteristics of O-glycosylated IgA and their nephritogenic properties, as well as the molecular basis responsible for the regulation of IgA O-glycosylation, could help not only to improve our understanding of the immunopathologic mechanisms central to the development of IgAN but also to develop new therapeutic approaches for this disease.…”