大山 友香子

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide with most patients progressing to kidney failure. Although its pathophysiology remains incompletely understood, deposition of IgA-containing immune complexes in the glomerular mesangium induces mesangial cell proliferation and overproduction of extracellular matrix components and cytokines and chemokines, that lead to glomerular injury. The properties of nephritogenic IgA1 include abnormal glycosylation of its polymeric forms and its capacity to bind IgG autoantibodies to form immune complexes. Nephritogenic IgA1 is thought to be secreted by B cells originating from or residing in mucosa-associated lymphoid tissues (MALT), such as gut-associated lymphoid tissues (GALT) and nasopharynx-associated lymphoid tissues (NALT). However, little is known how the immune abnormalities in MALT elevate the circulatory levels of nephritogenic IgA. This review summarizes fundamental insights into IgA production and its regulation in MALT in general, provides an overview of the immune abnormalities in the MALT of patients with IgAN relevant to the production of abnormally glycosylated IgA, and summarizes relevant emerging treatments tested in clinical trials.

BACKGROUND: IgA nephropathy (IgAN) is a mucosal immune-associated disease characterized by the overproduction of galactose-deficient IgA1 (Gd-IgA1) and formation of nephritogenic immune complexes. Epstein-Barr virus (EBV), which preferentially infects IgA+ B cells, has been implicated in IgAN pathogenesis, although its role remains unclear. Given mucosa involvement, we characterized breast milk B cells as available representatives of mucosal tissue to better understand the pathogenesis of IgAN. METHODS: We performed a phenotypic analysis of B cells (CD19+), plasmablasts (CD38+), and CD138+ cells (representing migrating pre-plasma cells, CPC) in the breast milk of IgAN and healthy mothers (HC). EBV infection of cells was detected by using EBV-encoded RNA (EBER). B cell differentiation, IgA/Gd-IgA1 expression, and homing-related markers were characterized using complementary cytometric and microscopic approaches. RESULTS: Breast milk from mothers with IgAN contains a significantly higher proportion of EBER+ B cells compared with HC. Moreover, the proportion of EBER+ CPCs in the breast milk of IgAN mothers is significantly higher than in HC. B cells present in the breast milk of mothers with IgAN exhibit a higher expression of the mucosal homing receptor CCR9 compared to B cells from HC. IgA+ B cells from healthy mothers exhibit a higher overall frequency of surface Gd-IgA1 expression and lack CD138 marker and thus could be classified as memory B cells or plasmablasts considering their class-switched phenotype. In contrast, breast milk from IgAN mothers was enriched for Gd-IgA1+ CD138+ CPC cells, indicating a shift toward terminally differentiated antibody-producing cells. These findings suggest disease-associated alterations in B cell differentiation and compartmentalization rather than increased mucosal Gd-IgA1 production per se. CONCLUSION: Despite the limited number of analyzed samples, we detected interesting differences in B cells in the breast milk of IgAN mothers and HC. The analysis of B cell populations in the breast milk of IgAN mothers indicates EBV-associated B cell dysregulation. The enrichment of EBV+ CPC and Gd-IgA1+ CPC in the breast milk of IgAN mothers agrees with a former model proposing aberrant mucosal B cell differentiation and trafficking involvement in IgAN pathogenesis.

BACKGROUND: IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis. Elevation in the blood levels of aberrantly glycosylated IgA1 is a crucial initial step in IgAN pathogenesis. Here, we aimed to determine the longitudinal changes in the serum levels of IgA1 O- and N-glycoforms in patients with IgAN receiving different treatments. METHODS: We enrolled Japanese patients diagnosed with primary IgAN: 10 patients who underwent tonsillectomy and corticosteroid therapy (T-CST), 7 who received corticosteroid therapy (CST), 8 who received conservative therapy (CO), and 5 with other renal diseases who received corticosteroid therapy (ORD) as disease controls. IgA was purified from patient sera collected at diagnosis and post-treatment. After sample preparation, O-glycoforms of the hinge region (HR) and N-glycoforms of the fragment crystallizable region were analyzed using high-resolution mass spectrometry (MS). RESULTS: The MS analysis of O-glycoforms of IgA1 showed that the relative abundance of IgA1 with 3GalNAc3Gal, which we previously identified as a characteristic IgA1 O-glycoform in IgAN, decreased post-treatment only in the T-CST group (P = 0.0195). Regarding N-glycoforms, the relative abundance of fucosylated N-glycan at asparagine (Asn)340 increased in the IgAN group compared with that in the ORD group (P = 0.0189) and decreased post-treatment only in the T-CST group (P = 0.0195). CONCLUSION: The MS analysis of O- and N-glycoforms of IgA1 revealed substantial changes in their abundance in the T-CST group but not in the CST, CO, and ORD groups. Our study provides new insights into how specific treatments alter the IgA1 glycoform abundance.

Galactose (Gal)-deficient IgA1 (Gd-IgA1) is involved in IgA nephropathy (IgAN) pathogenesis. To reflect racial differences in clinical characteristics, we assessed disease- and race-specific heterogeneity in the O-glycosylation of the IgA1 hinge region (HR). We determined serum Gd-IgA1 levels in Caucasians (healthy controls [HCs], n = 31; IgAN patients, n = 63) and Asians (HCs, n = 20; IgAN patients, n = 60) and analyzed profiles of serum IgA1 HR O-glycoforms. Elevated serum Gd-IgA1 levels and reduced number of Gal residues per HR were observed in Caucasians. Reduced number of N-acetylgalactosamine (GalNAc) residues per HR and elevated relative abundance of IgA1 with three HR O-glycans were common features in IgAN patients; these features were associated with elevated blood pressure and reduced renal function. We speculate that the mechanisms underlying the reduced GalNAc content in IgA1 HR may be relevant to IgAN pathogenesis.