Toll-Like Receptor 9 Stimulation Induces Aberrant Expression of a Proliferation-Inducing Ligand by Tonsillar Germinal Center B Cells in IgA Nephropathy

Abstract

The TNF family member a proliferation-inducing ligand (APRIL; also known as TNFSF13), produced by myeloid cells, participates in the generation and survival of antibody-producing plasma cells. We studied the potential role of APRIL in the pathogenesis of IgA nephropathy (IgAN). We found that a significant proportion of germinal centers (GCs) in tonsils of patients with IgAN contained cells aberrantly producing APRIL, contributing to an overall upregulation of tonsillar APRIL expression compared with that in tonsils of control patients with tonsillitis. In IgAN GC, antigen-experienced IgD+ B cells expressing a switched IgG/IgA B cell receptor produced APRIL. Notably, these GC B cells expressed mRNA encoding the common cleavable APRIL-a but also, the less frequent APRIL-d/z mRNA, which encodes a protein that lacks a furin cleavage site and is, thus, the uncleavable membrane-bound form. Significant correlation between TLR9 and APRIL expression levels existed in tonsils from patients with IgAN. In vitro, repeated TLR9 stimulation induced APRIL expression in tonsillar B cells from control patients with tonsillitis. Clinically, aberrant APRIL expression in tonsillar GC correlated with greater proteinuria, and patients with IgAN and aberrant APRIL overexpression in tonsillar GC responded well to tonsillectomy, with parallel decreases in serum levels of galactose-deficient IgA1. Taken together, our data indicate that antibody disorders in IgAN associate with TLR9-induced aberrant expression of APRIL in tonsillar GC B cells.

A proliferation‐inducing ligand increase precedes IgA nephropathy recurrence in kidney transplant recipients

“…Similar findings were reported in 166 IgAN patients by Zhai et al, who also identified that plasma APRIL level was positively correlated with Gd‐IgA1 levels, and by Han et al who discovered that APRIL levels increased the risk of ESRD in 637 patients with IgAN. Moreover, aberrant APRIL overexpression in tonsillar germinal centers of IgAN patients relate to a greater proteinuria . In our study, we demonstrated, for the first time, that APRIL could be an important component in the recurrence of IgAN after kidney transplantation.…”

“…In addition, in time, APRIL activation through “transmembrane activator and calcium‐modulating cyclophilin ligand interactor” (TACI) will induce IgA class switching on B cells in a T‐independent manner, whereas increasing plasma cells survival through “B‐cell maturation antigen” (BCMA) receptor . Continuous stimulation of B cells favors APRIL production by B cells themselves and, at a lower degree, TACI expression on B‐cell surface . In the end, APRIL promotes overproduction of IgA, mostly Gd‐IgA1, which will be the first hit for the IgAN activation .…”

“…26,28 Continuous stimulation of B cells favors APRIL production by B cells themselves and, at a lower degree, TACI expression on B-cell surface. 19,27 In the end, APRIL promotes overproduction of IgA, mostly Gd-IgA1, which will be the first hit for the IgAN activation. 19 This role of APRIL has been demonstrated in animal models and in human studies.…”

How to treat patients with chronic kidney disease: With special focus on IgA nephropathy

“…Percentages of stalk‐positive GC in the tonsils in this disease are significantly higher than those in chronic tonsillitis patients as controls. The relationship between the B cells in the GC and the production of glycan‐specific antibodies was observed in patients with IgA nephropathy . Recently, Suzuki et al (Abstract No.…”

Possible Mechanisms Underlying Epipharyngeal Abrasive Therapy (EAT) with ZnCl2 Solution for the Treatment of Autoimmune Diseases and Functional Somatic Syndrome

“…The range of presenting symptoms is summarized in Table 1, and can be classified into three broad classes, namely, inflammation-referred local symptoms, autoimmune-related symptoms, and neuroendocrine symptoms. With regard to autoimmune-related symptoms, recent pathophysiological studies have suggested that these immunological conditions might be triggered by pathogenic antigens in chronic tonsillitis which disturb the host-defense immune mechanisms [7][8][9]. As immunological characteristics of epipharyngeal lymphocytes are very similar to those of tonsillar lymphocytes [2], it is likely that epipharyngeal lymphocytes may play a role in triggering autoimmune diseases.…”