Abstract
TLR7 has been linked to the pathogenesis of glomerulonephritis, but its precise roles are not clear. In this study, we evaluated the roles of TLR7 in IgA nephropathy (IgAN). TLR7 proteins were abundant in CD19+ B cells infiltrated in the kidneys of patients with IgAN. The intensities of both intrarenal TLR7 and CD19 proteins were closely associated with kidney function (estimated glomerular filtration rate [eGFR] and serum creatinine concentration) and renal histopathology (tubular atrophy, leukocyte infiltration, tubulointerstitial fibrosis, and global glomerulosclerosis) in patients with IgAN. Meanwhile, TLR7 mRNA levels were significantly increased in peripheral blood B cells of patients with IgAN. TLR7+CD19+ B cells expressed inflammatory cytokines (IL-6 and IL-12) in kidneys and produced high levels of IgA1 and galactose deficient-IgA1 (Gd-IgA1) in peripheral blood of patients with IgAN. Mechanistically, TLR7 activated B cells to produce high levels of Gd-IgA1 via the TLR7-GALNT2 axis in IgAN. Protein levels of GALNT2 were increased by overexpression of TLR7, while they were reduced by TLR7 knockdown in B cells. GALNT2 overexpression augmented Gd-IgA1 production in B cells derived from patients with IgAN. Taken together, high TLR7 expression in B cells has dual roles in the development and progression of IgAN, by facilitating renal inflammation and Gd-IgA1 antibody synthesis.
Highlights
IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, with about 25%–30% patients developing end-stage renal disease within 20 years [1, 2]
Renal biopsy specimens from non-chronic kidney disease (CKD) donors (n = 8) and patients with IgAN (n = 89), minimal change disease (MCD) (n = 9), or membranous nephropathy (MN) (n = 11) were analyzed for TLR7 expression
The mean intensities of renal TLR7 were higher in patients with impaired estimated glomerular filtration rate than in patients with normal eGFR (P < 0.001) in IgAN (Figure 1C), indicating that TLR7 was more involved in patients with IgAN exhibiting renal damage
Summary
IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, with about 25%–30% patients developing end-stage renal disease within 20 years [1, 2]. The most significant feature of IgAN is the mesangial deposition of polymeric galactose-deficient IgA1 (Gd-IgA1) immune complexes [3], which contain terminal β1,3 galactose (Gal) deficiency and exposed N-acetylgalactosamine (GalNAc) residues in O-glycans of the hinge region of IgA1 [2, 4]. B cells in the mucosal immune system could mature into plasma B cells in response to pathogen stimulation, resulting in IgA1 and IgA2 secretion to form dimeric IgA1, IgA2, or large polymeric IgA1 antibodies. These IgA1-producing B cells enter the circulation and migrate along the mucosa, bone marrow, and kidney, becoming tissue-resident lymphocytes [13]. The addition of Gal is mediated by core β1,3-galactosyltransferase (C1GALT1) via its chaperone, COSMC [18, 19]
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