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Editorial
. 2020 Aug 20;5(10):1620-1624.
doi: 10.1016/j.ekir.2020.08.009. eCollection 2020 Oct.

Why Target the Gut to Treat IgA Nephropathy?

Jonathan Barratt  1 , Brad H Rovin  2 , Daniel Cattran  3 , Jürgen Floege  4 , Richard Lafayette  5 , Vladimir Tesar  6 , Hernán Trimarchi  7 , Hong Zhang  8 ; NefIgArd Study Steering Committee
Affiliations
Editorial

Why Target the Gut to Treat IgA Nephropathy?

Jonathan Barratt et al. Kidney Int Rep. .
No abstract available

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Figures

Figure 1
Figure 1
The Peyer’s patch, mucosal IgA synthesis, IgA nephropathy (IgAN), and a role for NEFECON in the treatment of IgAN. The Peyer’s patches are concentrated in the terminal ileum and are the major antigen sampling and inductive sites of the gut-associated lymphoid tissue (GALT). Antigens are taken up by specialized M cells in the follicle-associated epithelium overlaying the Peyer’s patches. Subepithelial dome-resident dendritic cells (DCs) then take up and process these antigens, and after priming, naïve CD4+ T cells differentiate into helper T cells. T follicular helper (Tfh) cells interact with cognate B cells at the B cell follicular border. Next, Tfh cells colocalize with B cells in the B-cell follicle in close proximity to the follicular dendritic cell (FDC) network, and this allows the formation of a germinal center. In the germinal center, the antigen-specific B cells undergo class switching to IgA1 and somatic hypermutation to generate high-affinity antibodies. B-cell class switching to IgA1 is stimulated through T-cell CD40L binding to B-cell CD40, together with the action of transforming growth factor (TGF)-β. In parallel, T-independent IgA class switching may also occur, which involves dendritic cell activation of naïve B cells. Toll-like receptor (TLR) ligand-activated DCs secrete factors that induce IgA1 class switch, including B-cell–activating factor (BAFF), A proliferation-inducing ligand (APRIL), and TGF-β. The resulting IgA1+ long-lived plasma cells and memory B cells generated within the germinal center leave the Peyer’s patch and migrate to the mesenteric lymph nodes and then to the blood, from where plasma cells home to effector sites in the lamina propria of the small and large intestine. In the lamina propria IgA1+ B cells may sequentially switch to IgA2 expression in response to APRIL and interleukin (IL)-10 released by TLR-activated epithelial cells. In the lamina propria, additional IgM+ IgD+ B cells can undergo direct class switching from IgM to IgA1 or IgA2 in response to BAFF or APRIL and IL-10. IgAN is associated with an increase in circulating mucosal-type IgA1, which is believed to be due to an underlying dysregulation in mucosal IgA synthesis. This results in an increase in circulating poorly O-galactosylated dimeric and polymeric IgA1, which results in the formation of large IgA1 immune complexes with a propensity to accumulate in the kidney and cause nephritis. Most IgA1 in the glomeruli does not contain a secretory component and, therefore, has not been secreted across a mucosal surface, even though evidence suggests it is derived from the GALT. Potential mechanisms for GALT-derived IgA1 to directly enter the circulation rather than being secreted are either direct passage of mucosally synthesised (but not secreted) IgA1 into the circulation and/or displacement of GALT-derived B cells to systemic sites such as the bone marrow, where they secrete mucosal-type IgA1 directly into the circulation. Immune complex formation may be amplified further by the formation of IgA and IgG anti-IgA autoantibodies. These autoantibodies are directed against the poorly O-galactosylated hinge region of the IgA1 molecule. NEFECON is designed to deliver a targeted dose of budesonide to the Peyer’s patches of the terminal ileum, where it is hypothesized to reduce the formation of the IgA molecules that ultimately drive immune complex formation in IgAN. CD, cluster of differentiation; FDA, Food and Drug Administration; IgA-IC, IgA immune complex; IL, interleukin; M, microfold; SEM, scanning electron microscope.
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References

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