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The Roles of Peyer's Patches and Microfold Cells in the Gut Immune System: Relevance to Autoimmune Diseases - PubMed

  • ️Tue Jan 01 2019

Review

The Roles of Peyer's Patches and Microfold Cells in the Gut Immune System: Relevance to Autoimmune Diseases

Nobuhide Kobayashi et al. Front Immunol. 2019.

Abstract

Microfold (M) cells are located in the epithelium covering mucosa-associated lymphoid tissues, such as the Peyer's patches (PPs) of the small intestine. M cells actively transport luminal antigens to the underlying lymphoid follicles to initiate an immune response. The molecular machinery of M-cell differentiation and function has been vigorously investigated over the last decade. Studies have shed light on the role of M cells in the mucosal immune system and have revealed that antigen uptake by M cells contributes to not only mucosal but also systemic immune responses. However, M-cell studies usually focus on infectious diseases; the contribution of M cells to autoimmune diseases has remained largely unexplored. Accumulating evidence suggests that dysbiosis of the intestinal microbiota is implicated in multiple systemic diseases, including autoimmune diseases. This implies that the uptake of microorganisms by M cells in PPs may play a role in the pathogenesis of autoimmune diseases. We provide an outline of the current understanding of M-cell biology and subsequently discuss the potential contribution of M cells and PPs to the induction of systemic autoimmunity, beyond the mucosal immune response.

Keywords: Peyer's patch; autoimmune disease; intestinal epithelial cell; intestinal microbiota; microfold cell; mucosal immunity.

Copyright © 2019 Kobayashi, Takahashi, Takano, Kimura and Hase.

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Figures

Figure 1
Figure 1

Whole-mount immunostaining of M cells in FAE of a PP (Left) and a cecal patch (Right). M cells were classified into two populations based on the expression of the molecular markers Spi-B (red) and GP2 (green). Spi-B+ single-positive cells are immature M cells located near the crypt and have low ability to take up luminal antigens. Spi-B+GP2+ double-positive cells are functionally mature M cells that are located near the top of the FAE dome of PP and have high uptake capacity. In cecal patches, Spi-B+GP2+ double-positive cells are rarely detected. See Kimura et al. (8) for details.

Figure 2
Figure 2

Scheme of differentiation of M cells in PP. (A) RANKL expressed on M-cell inducer (MCi) cells initiate the differentiation of M cells. RANK signaling induces the transcription factor Spi-B and Sox8 parallelly. Spi-B+Sox8+GP2− cells are immature M cells that have low uptake activity. Sox8 directly induces the expression of GP2. GP2+ cells are mature M cells that have high uptake activity. (B) Signaling pathway of M-cell differentiation. RANKL signaling activates canonical NF-κB (p50/RelA) through TRAF6. Canonical NF-κB signaling is required for the activation of non-canonical NF-κB (p52/RelB), which regulates early M-cell marker genes. p52/RelB directly upregulates the expression of transcription factors Spi-B and Sox8. Sox8 directly binds to the Gp2 promoter. Both Spi-B and Sox8 are required for Gp2 expression and M-cell maturation.

Figure 3
Figure 3

Hypothetical model of autoantibody production mediated by M cells. SFB is delivered to CD11bhi and CD11bhi CD11chi cell subsets in PP via M cell-mediated transcytosis. The M cells engulf SFB, which induces the differentiation of Tfh cells. Tfh cells egress from the PP and migrate to the systemic lymphoid tissues where autoimmune responses predominantly occur, leading to the production of autoantibodies to glucose-6-phosphate isomerase and thus, exacerbation of arthritis. It is unlikely that SFB induces Tfh differentiation by molecularly mimicking the glucose-6-phosphate isomerase antigen. C. jejuni also can be taken up by M cells. B cells directly recognize C. jejuni LOS, probably through Toll-like receptor 4 (TLR4) engagement, and produce LOS-specific antibodies. LOS is structurally homologous to GM1 ganglioside, which can lead to the production of anti-GM1 antibodies. Anti-GM1 antibodies are associated with some forms of GBS. Likely, C. jejuni-derived protein antigens are also involved in the pathogenesis of GBS through the activation of Tfh and B cells. Pancreatic acinar cells secrete GP2 to the lumen, where it binds FimH-positive bacteria. FimH-positive bacteria with GP2 are taken up by M cells via receptor GP2. Antigen-presenting cells (APCs) recognize GP2 on the surfaces of bacteria and start producing anti-GP2 autoantibodies. Anti-GP2 autoantibodies may target GP2-expressing pancreatic cells to cause pancreatitis.

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