THE MALT

Every cell have a cytoskeleton, a system of fibers that maintains cell structure, shape and allows the movements.

Cytoskeleton is made of microtubules, intermediate filaments as keratins and microfilaments.

Keratins are abundant in epithelial cells.

The M cells were first identified by J.F Schmedtje using Electron microscopy in rabbit appendix tissue. The discovery of the M cells we owe it to Owen & Jones,1974. Studying the Peyer’s Patches (PPs) of human small intestine they found the presence of microfolds on the apical surface of the M cells. The function of gatekeepers was discovered.

It has been said that Intestinal epithelial cells in the Follicle associated epithelium (FAE) originate from stem cells in crypts located between a villus and a Peyer's Patch (PP) dome. Each crypt harbours a demilune in front of the pathologist eye made of stem cells that generate distinct cell types from two distinct recognized axes of migration and differentiation according to Heath, 1996.

Garvarieli et al stated that cells on the FAE side of the crypt move into the dome and differentiate into absorptive enterocytes and M cells. The fact that is not clear yet is whether crypt cells commit early to FAE and M-cell phenotypes or whether a factor act later to induce further differentiation of enterocytes in M-cells. As has been hypothesized with the immune response and the need of the M-cells.

In order to make this simple, Cells on one side of the crypt differentiate into absorptive enterocytes, goblet (mucus), and enteroendocrine cells. These cells migrate to the villi. The cells on the follicle-facing side of the same crypt acquire features of M cells and distinct follicle-associated enterocytes.

The M cells emerge from the crypt, they maturate and begin endocytic activity, fail to assemble brush borders, and allow the entrance of immune cells in their characteristic intraepithelial pocket. These observations suggest that inductive factors from the follicle act early in the differentiation pathway, inducing crypt cells to commit to FAE phenotypes.

Further studies that have been performed on the basis of differentiated expression of glycoconjugates on M cell membranes could show that a subpopulation of crypt cells seems to be predetermined as M cells before acquiring the corresponding morphological features.

Recent studies demonstrated that human intestinal epithelial cells may be converted into functional M cells in vitro by interaction with PPs derived lymphocytes. A fast increase of M cell numbers at distinct sites of the FAE occurs rapidly after exposure to bacteria. At the light of this results the suggested name Epithelial immune cells looks accurate.

Epithelial cells in the crypt region surrounding GALT follicles have been reported to display a gene expression profile distinct from those in the villous region, which is thought to be due to their interaction with GALT. RANKL has been demonstrated a promoter of M cell differentiation.

GALT receives its supply of antigens directly from the mucosal surface across the intestinal epithelium overlaying the GALT lymphoid follicles called “follicle-associated epithelium”(FAE).

M cells are positive for the monoclonal antibody sialyl-Lewis-A antigen, Galectin-9, GP2 at the apical surface. Hallmarks used for recognizing these cells.

Morphology and microanatomy of M cells

• Poorly organized or reduced brush border.
• Short irregular microvilli.
• Thin glycocalyx.
• Presence of a pocket in the basolateral surface (intraepithelial invagination).
• Contains B, T and or Dendritic cells.
• Transepithelial transport, transcytosis.
• Less enzymatic activity (Fig 1).

M cells in the follicle-associated epithelium transport foreign macromolecules and microorganisms to antigen-presenting cells within and under the epithelial barrier.

Fig. 1. M cell, secret door, enterocyte and goblet cell.

COMPARISON BETWEEN M CELLS AND ENTEROCYTES

CHARACTERISTIC	M CELL	ENTEROCYTE
Glicocalix	Thin and rudimentary	Thick, filamentous and well developed
Microvilli	Few Short, irregular or microfolds	Abundant Large Digestive enzymes
Brush border	Poorly organized	Well organized and abundant
Enzymes	Reduced lisozomal sizes and enzymes (acid phosphatases)	Normal
Function	APC, add in immune response, transcytosis, phagocytosis	To Absorb nutrients from the intestine
Histogenesis	Epithelial	Epithelial

The acid phosphatases are lysosomal enzymes that hydrolyse phosphomonoesters at low pH, releasing phosphoric acid.

THE SECRET DOOR

The M cells can be seen as a secret door to enter rapidly and trigger a immune response. It is well known the mechanism of transcytosis for antigen transport and the way it should aid the immune response induction and the antigen that it’s been transporting to the releasing of costimulatory signals for T and B cell proliferation (Pappo & Mahlman, 1993).

 

Sansonetti & Phalipon (1999) postulated that the M cells can be considered a potential Achilles heel, or a double-edged sword, therefore can be used by microorganisms to deceive the immune response and enter the epithelium probably via the secret door offered by these cells as a rout of entry. Theory reinforced considering studies in Salmonella spp. in translocate murine M cells (Jones et al., 1994).

It is considered that the M cell surface structure changes not only in accordance with enfolded lymphocytes and the uptake of antigenic materials, but also according to the organ in which M cells are present and whether inflammation is present or not. These cells represent an important gateway for the intestinal immune system by delivering luminal antigens through the follicle-associated epithelium to the underlying immune cells.

According to Lügering et al (2004), M cell pocket provides a specialized microenvironment composed of memory T (CD4⁺ CD45R0⁺) and memory B (sIgD^–CD20⁺) cells partially expressing the proliferation antigen Ki-67. Significant elevation of M cell-associated TCRαβ, CD4 and B cells during chronic intestinal inflammation was demonstrated. This raise the hypothesis: increase in B cells and CD4⁺ T cells reflects an elevated antigen uptake and processing during intestinal inflammation through M cells.

The expansion of CD4- and TCRαβ-positive T cells as well as the elevated expression of interleukin-4 by Peyer Patche’s lymphocytes suggests that a specific microenvironment is more likely to induce M cell differentiation from epithelial cells rather than a specific cell population.

The way the door or gateway is created is secondary to the intermediate filaments, which are also responsible for the shape of the cell. The intermediate filaments, forms an arch around the pocket and a thick network around the nucleus.

Elucidation of the molecular architecture of M cell apical surfaces and interaction with microorganism is important for understanding the strategies that pathogens use to exploit this pathway and for utilizing M cell transport for delivery of vaccines to the mucosal immune system.

                

        Fig 2. Microphotogtaph of intestinal dome area and epithelial coat. 

 The black arrow highlights the secret door or gateway.

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