Abstract
IgA nephropathy (IgAN) is a leading cause of kidney failure, yet little is known about the immunopathogenesis of this disease. IgAN is characterized by deposition of IgA in the kidney glomeruli, but the source and stimulus for IgA production are not known. Clinical and experimental data suggest a role for aberrant immune responses to mucosal microbiota in IgAN, and in some countries with high disease prevalence, tonsillectomy is regarded as standard-of-care therapy. To evaluate the relationship between microbiota and mucosal immune responses, we characterized the tonsil microbiota in patients with IgAN versus nonrelated household-matched control group participants and identified increased carriage of the genus Neisseria and elevated Neisseria-targeted serum IgA in IgAN patients. We reverse-translated these findings in experimental IgAN driven by BAFF overexpression in BAFF-transgenic mice rendered susceptible to Neisseria infection by introduction of a humanized CEACAM-1 transgene (B × hC-Tg). Colonization of B × hC-Tg mice with Neisseria yielded augmented levels of systemic Neisseria-specific IgA. Using a custom ELISPOT assay, we discovered anti-Neisseria–specific IgA-secreting cells within the kidneys of these mice. These findings suggest a role for cytokine-driven aberrant mucosal immune responses to oropharyngeal pathobionts, such as Neisseria, in the immunopathogenesis of IgAN. Furthermore, in the presence of excess BAFF, pathobiont-specific IgA can be produced in situ within the kidney.
Highlights
The mechanisms underlying the pathogenesis of immunoglobulin A nephropathy (IgAN) are poorly understood, yet it is one of the most common causes of kidney failure
We previously reported that the cytokine APRIL (TNFSF13) was elevated in the serum of IgA nephropathy (IgAN) patients compared to controls in two independent cohorts[8]
The diagnostic hallmark of IgAN is the deposition of nephritogenic galactose-deficient IgA containing immune complexes in the glomerular mesangium, the origin of and trigger for pathogenic Gd-IgA1 are not known
Summary
The mechanisms underlying the pathogenesis of immunoglobulin A nephropathy (IgAN) are poorly understood, yet it is one of the most common causes of kidney failure. Our previous studies of a murine IgAN model suggest that commensal microbial colonization is essential for the development of IgAN in mice overexpressing the TNF-family BAFF[7, 8]. We hypothesized that in the setting of high levels of BAFF/APRIL, mucosal-derived IgAsecreting cells are recruited to the kidney and contribute to development of IgAN To test this hypothesis we characterized the tonsil and stool microbiome profiles of a large cohort of patients with IgAN compared to household-matched non-related control subjects. We identified increased tonsil Neisseria carriage and enhanced production of anti-Neisseria-targeted IgA in the blood of our patient cohort We reverse translated these observations into an experimental IgAN model and found that elevated levels of BAFF provoke an enhanced IgA-biased systemic immune response to mucosal Neisseria exposure. Our findings are the first to show that a maladaptive host response to a commensal organism is associated with IgAN disease and recruitment of mucosal-derived IgA-secreting cells to the kidney
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