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Immunoglobulin A (Chan in J Allergy Clin Immunol 134:1394–14014e4, 2014), the second most abundant immunoglobulin in serum, plays an important role in mucosal homeostasis. In human serum, there are two subclasses of IgA, IgA1 (≅ 90%) and IgA2 (≅ 10%), transcribed from two distinct heavy chain constant regions. This study evaluated the serum concentrations of total IgA, IgA1, and IgA2, and total IgG, IgG1, IgG2, IgG3, and IgG4 in T2-high asthmatics compared to healthy controls and the presence of gender-related variations of immunoglobulins. Total IgA levels were increased in asthmatics compared to controls. Even more marked was the increase in total IgA in male asthmatics compared to healthy male donors. IgA1 were increased only in male, but not in female asthmatics, compared to controls. Concentrations of IgG2, but not IgG1, IgG3, and IgG4, were reduced in asthmatics compared to controls. IgG4 levels were reduced in female compared to male asthmatics. In female asthmatics, IgA and IgA1 levels were increased in postmenopause compared to premenopause. IgA concentrations were augmented in mild, but not severe asthmatics. A positive correlation was found between IgA levels and the age of patients and an inverse correlation between serum concentrations of IgA2 and IgE in asthmatics. A positive correlation between total IgA or IgA2 and IgG2 was found in asthmatics. These results highlight a gender dimorphism in IgA subclasses in male and female T2-high asthmatics. More adequate consideration of immunological gender disparity in asthma may open new opportunities in personalized medicine by optimizing diagnosis and targeted therapy. [ABSTRACT FROM AUTHOR]

IgA nephropathy is the most common form of glomerulonephritis in many parts of the world and remains an important cause of end-stage renal disease. Current evidence suggests that IgA nephropathy is not due to a single pathogenic insult, but rather the result of multiple sequential pathogenic “hits”. An abnormally increased level of circulating poorly O-galactosylated IgA1 and the production of O-glycan-specific antibodies leads to the formation of IgA1-containing immune complexes, and their subsequent mesangial deposition results in inflammation and glomerular injury. While this general framework has formed the foundation of our current understanding of the pathogenesis of IgA nephropathy, much work is ongoing to try to precisely define the genetic, epigenetic, immunological, and molecular basis of IgA nephropathy. In particular, the precise origin of poorly O-galactosylated IgA1 and the inciting factors for the production of O-glycan-specific antibodies continue to be intensely evaluated. The mechanisms responsible for mesangial IgA1 deposition and subsequent renal injury also remain incompletely understood. In this review, we summarize the current understanding of the key steps involved in the pathogenesis of IgA nephropathy. It is hoped that further advances in our understanding of this common glomerulonephritis will lead to novel diagnostic and prognostic biomarkers, and targeted therapies to ameliorate disease progression. [ABSTRACT FROM AUTHOR]

Objective: The proteins BAFF, ST6GALNAC2, C1GALT1, and COSMC in peripheral blood mononuclear cells (PBMCs) and plasma levels of IgA1 and galactose-deficient IgA1 (Gd-IgA1) are potential biomarkers for IgAN nephropathy. In this study, we comparatively studied the changes of those biomarkers before and after tonsillectomy. Methods: Peripheral blood samples were obtained from 16 IgAN patients with pre- and post-tonsillectomy. IgAN was diagnosed based on results from analysis of percutaneous renal biopsy tissue. Peripheral blood samples from three patients without renal diseases (non-IgAN), before and after tonsillectomy, and 16 healthy controls were also examined. BAFF, ST6GALNAC2, C1GALT1, and COSMC mRNA levels in PBMCs were detected using real-time PCR. Plasma IgA1 content was measured by ELISA. Gd-IgA1 levels were determined using the VV lectin-ELISA method. Results: BAFF, ST6GALNAC2, C1GALT1, and COSMC mRNA levels and the plasma concentrations of IgA1 and Gd-IgA1 in IgAN patients before tonsillectomy were significantly higher than those in healthy controls ( P < 0.05). Tonsillectomy significantly increased the expression of BAFF and ST6GALNAC2, and plasma IgA1 level, while it downregulated that of C1GALT1 and COSMC ( P < 0.05). However, in non-IgAN patients, tonsillectomy did not affect the mRNA levels of BAFF, ST6GALNAC2, C1GALT1, and COSMC, plasma IgA1 content and Gd-IgA1 level. Positive correlations were established between BAFF and IgA1 ( r = 0.604, P < 0.01) and between ST6GALNAC2 and Gd-IgA1 ( r = 0.623, P < 0.01). Conclusions: Tonsillectomy changes the mRNA levels of BAFF, ST6GALNAC2, C1GALT1, and COSMC in PBMCs, as well as the plasma IgA1 level in IgAN patients. BAFF and ST6GALNAC2 might regulate IgA1 secretion and O-glycosylation. [ABSTRACT FROM AUTHOR]

IgA nephropathy, described in 1968 as IgA-IgG immune-complex disease, is an autoimmune disease. Galactose-deficient IgA1 is recognized by unique autoantibodies, resulting in the formation of pathogenic immune complexes that ultimately induce glomerular injury. Thus, formation of the galactose-deficient IgA1-containing immune complexes is a critical factor in the pathogenesis of IgA nephropathy. Studies of molecular defects of IgA1 can define new biomarkers specific for IgA nephropathy that can be developed into clinical assays to aid in the diagnosis, assessment of prognosis, and monitoring of disease progression. [ABSTRACT FROM AUTHOR]

In celiac disease, gluten ingestion provokes small-bowel mucosal injury and production of IgA autoantibodies against transglutaminase 2 (TG2). It has been suggested that in celiac patients IgA could mediate the transepithelial passage of gluten peptides in a mechanism involving the transferrin receptor. As IgA1 with galactose-deficient O-linked glycans has elevated affinity for the transferrin receptor, we assessed whether total serum IgA1 and IgA1 anti-TG2 autoantibodies in celiac patients are aberrantly glycosylated. We report that males with celiac disease have higher total serum levels of galactose-deficient IgA1 than non-celiac males. Furthermore, O-glycans of the disease-specific TG2 IgA1 autoantibodies in celiac patients exhibited elevated galactose deficiency. A gluten-free diet had no effect on the total serum levels of galactose-deficient IgA1, whereas the amount of galactose-deficient anti-TG2 IgA1 decreased. Thus, the undergalactosylated IgA1 molecules are not pathognomonic for celiac disease, but galactose deficiency in IgA1 could be an aggravating factor. [ABSTRACT FROM AUTHOR]

IgA nephropathy (IgAN), the most common form of primary glomerulonephritis worldwide, is defined by predominant IgA1 deposits in the glomerular mesangium. Among abnormalities of the IgA immune system reported so far in IgAN, aberrant O-linked glycosylation in the hinge region of IgA1 is the most consistent finding. IgA1 molecules bearing abnormal glycosylation have been found in serum, in tonsillar lymphocytes, and in eluate from mesangial deposits, and characterized by decreased O-linked N-acetylgalactosamine residues with or without alteration in the terminal sialylation of the O-linked sugars. IgA1 with incomplete galactosylation has a tendency to accumulate in glomerular mesangium by self-aggregation or immune complex formation. Glomerular mesangial cells exposed to immune complexes of these IgA1 can proliferate and secrete cytokines, chemokines, growth factors, and extracellular matrix components promoting inflammatory reactions in the glomeruli. Although genes encoding enzymes involved in the O-glycosylation process, such as C1GALT1, have been reported to be responsible for susceptibility to IgAN, recent evidence suggests that the abnormality is restricted to a small fraction of B cell populations and arises from dysregulated IgA1 production and secretion in mucosal immune system. This review will focus on and discuss the role of incompleteness of IgA1 O-galactosylation in the pathogenesis of IgAN and propose a possible mechanism in which abnormal IgA1 occurs in IgAN. [ABSTRACT FROM AUTHOR]

IgA nephropathy and Henoch-Schönlein purpura nephritis (HSPN) are related diseases characterized by deposits of IgA1-containing immune complexes in the renal mesangium. Adult patients with IgA nephropathy have aberrantly glycosylated IgA1 (galactose-deficient O-linked glycans) in the circulation and renal deposits. However, IgA1 glycosylation has not been studied in pediatric patients with IgA nephropathy. Using our quantitative lectin enzyme-linked immunosorbent assay (ELISA) test, we measured serum levels of galactose-deficient IgA1 of children with IgA nephropathy and HSPN and controls. Children with IgA nephropathy and HSPN had serum levels higher than those of healthy children or renal-disease controls with C1q nephropathy. Furthermore, lectin ELISA identified patients with HSPN whose clinical course mimicked that of IgA nephropathy. In summary, pediatric patients with IgA nephropathy and HSPN have an aberrancy in the glycosylation in IgA1 O-linked glycans that is similar to that in adults with IgA nephropathy. [ABSTRACT FROM AUTHOR]

The T-cell immunoglobulin- and mucin-domain-containing molecules (Tim) have been implicated in the pathogenesis of immune diseases. In this study, we used quantitative realtime reverse transcription-polymerase chain reaction to examine the Tim-1 mRNA expression in peripheral blood mononuclear cells from Henoch-Schönlein purpura patients. The results showed that Tim-1 mRNA expression was significantly higher in patients, which was closely correlated with serum TNF-α, IL-4 levels, IgA1 levels. [ABSTRACT FROM AUTHOR]