Is sialylation of IgA the agent provocateur of IgA nephropathy?

In IgA nephropathy (IgAN), the mechanisms responsible for deposition of IgA1 in the glomerular mesangium, and subsequent initiation of glomerular injury in some patients, remain unclear. Much research evidence now demonstrates that the O-glycosylation of IgA1 is abnormal in IgAN, and that this is potentially pathogenic. However, the exact nature of the O-glycoyslation abnormality, and the metabolic processes resulting in its production, are not well understood. Progress in this field has partly been limited by the lack of a suitable animal model, because the IgA of laboratory animals is not O-glycosylated. In this paper, Suzuki and colleagues have established B cell lines from patients with IgAN that produce IgA1 with abnormal O-glycosylation. This has allowed them to show that abnormal IgA1 carries an increased proportion of O-glycans terminating in sialic acid rather than the normal galactose units (Figure 1), and that this is associated with increased mRNA expression and activity of the sialylating enzyme ST6GalNAcII, and decreased expression and activity of the galactosylating enzyme C1GalT1. These findings contribute new insights to the study of defective IgA1 O-galactosylation and mark a significant step forward in the field of IgAN research

SELDI-TOF mass spectrometry to identify urinary biomarkers of deep vein thrombosis;Journal Article

SELDI-TOF mass spectrometry to identify urinary biomarkers of deep vein thrombosis;Journal Articl

a, b, c Area under the curve of tacrolimus, MMF and prednisone over the study period from t₀ to t₆.

<p>a, b, c Area under the curve of tacrolimus, MMF and prednisone over the study period from t₀ to t₆.</p

Effect of Immunosuppressive Drugs on the Changes of Serum Galactose-Deficient IgA1 in Patients with IgA Nephropathy.

Galactose-deficient IgA1 (Gd-IgA1) and IgA-IgG complexes are known to play an important role in the pathogenesis of IgA nephropathy (IgAN). We aimed therefore to determine the impact of immunosuppression on the serum levels of Gd-IgA1, total IgA1 and IgA-IgG complexes in IgAN patients. In a retrospective study, serum samples from IgAN patients collected before transplantation (t0) and at 3- and 6-month posttransplant (t3 & t6) were used to measure the levels of Gd-IgA1, total IgA1 and IgA-IgG complexes. The area under the curves (AUC) of immunosuppressants was calculated by the plot of plasma trough level or dosage of each immunosuppressant versus time and was interpreted as the extent of drug exposure. Thirty-six out of 64 IgAN patients, who underwent kidney transplantation between 2005 and 2012, were enrolled. From t0 to t3, serum Gd-IgA1 and total IgA1 decreased significantly (24.7 AU (18.6-36.1) to 17.2 (13.1-29.5) (p<0.0001); 4.1 mg/ml (3.6-5.1) to 3.4 (3.0-4.1) (p = 0.0005)), whereas IgA-IgG complexes remained similar. From t3 to t6, Gd-IgA1 and IgA-IgG complexes significantly increased (17.2 AU (13.1-29.5) to 23.9 (16.8-32.0) (p = 0.0143); OD 0.16 (0.06-0.31) to 0.26 (0.14-0.35) (p = 0.0242)), while total IgA1 remained similar. According to median regression analysis, AUC of prednisone t0-6 was significantly associated with the decrease of Gd-IgA1 t0-6 (P = 0.01) and IgA1 t0-6 (p = 0.002), whereas AUC of tacrolimus t0-6 was associated with the decrease of IgA1 t0-6 (p = 0.02). AUC of prednisone t0-3 was associated with the decrease of IgA-IgG complexes t0-3 (p = 0.0036). The association of AUC prednisone t0-6 with Gd-IgA1 t0-6 remained highly significant after adjustment for other immunosuppressants (p = 0.0036). Serum levels of Gd-IgA1, total IgA1 and IgA-IgG in patients with IgAN vary according to the changing degrees of immunosuppression. The exposure to prednisone most clearly influenced the serum levels of Gd-IgA1

Patient characteristics.

<p>Patient characteristics.</p

B cell O-galactosyltransferase activity, and expression of O-glycosylation genes in bone marrow in IgA nephropathy

In IgA nephropathy pathogenic IgA1 is likely derived from bone marrow cells and exhibits reduced O-galactosylation. Defective O-galactosylation may arise from compromised expression or function of the enzyme β-galactosyltransferase and/or its molecular chaperone (Cosmc). We measured B cell O-galactosylation activity and the relative gene expression of β-galactosyltransferase and Cosmc in peripheral blood and bone marrow taken from patientswith IgA nephropathy and controls. O-galactosylation activity was measured in peripheral and bone marrow cells controls by the incorporation of radiolabelled galactose into an asialo-mucin acceptor. Gene expression of β-galactosyltransferase and Cosmc was measured by real time PCR and related to that of the enzyme GalNAc-T2, which synthesizes the core O-glycan. Neither the B cell O-galactosylation activity nor the gene expression of the enzyme or chaperone were different between patients and controls. However, the relationships between the O-glycosylation of serum IgA1, galactosylation activity and β-galactosyltransferase gene expression showed different patterns in IgA nephropathy and controls. In IgA nephropathy, O-galactosylation activity correlated with β-galactosyltransferase gene expression, but not with IgA1 O-glycosylation, suggesting that factors other than the availability of β-galactosyltransferase or Cosmc are responsible for altered IgA1 O-glycosylation

Gd-IgA1, total IgA1 and IgA-IgG complexes in recurrent and non-recurrent patients at t0, t3 and t6.

<p>Gd-IgA1, total IgA1 and IgA-IgG complexes in recurrent and non-recurrent patients at t0, t3 and t6.</p

a, b, and c. Changes of galactose-deficient IgA1, total IgA1 and IgA-IgG complexes over time under influence of changing degrees of immunosuppression with tacrolimus, mycophenolate mofetil (MMF) and prednisone.

<p>Boxes represent the median 50% of patients, lower and upper box ends are the 25th and 75th percentiles, and the middle bar represents the median. Whiskers link the lower/ upper box ends with the 5th and the 95th percentile. Outliers are represented by a closed circle.</p

Area under the curve of immunosuppressants.

<p>Area under the curve of immunosuppressants.</p