**4.2 M cells**

The cytoplasm of M cells forms a thin membrane-like structure in the upper part of the cytoplasm that separates the inner space of the intestine from the space below the epithelium, hence it is also called the membrane epithelial cell. In other words, these cells have a large envelope in which many immune cells, such as antigen-supplying cells, are located in this envelope, closest to the intestinal tract (**Figure 2**).

An important role of M cells is the transfer of antigen to the O-MALT. These cells are not presenting of antigen, but only its transporter. These cells endocytose the antigen not specifically, but selectively, meaning that not every antigen can pass through M cells. M cells select and pass antigens based on molecular load, hydrophobicity, and viability.

Since the transfer of antigen by M cells can play an important role in the first stage of the immune response, the factors that affect this transfer are very important in choosing a mucosal immunization strategy. M cells make up between 10% in humans and animals and up to 50% in rabbits around the follicular epithelial cells (FAE) [35]. Areas specific to endocytosis are present between irregular or shallow short microvilli on the upper surface of the M cell [36]. These cells lack some of the digestive enzymes present on the anterior membrane of enterocytes. However, M cell membranes contain many glycoconjugates compounds that can be suitable binding sites for lectin-like microbial surface molecules [36–38]. These cells endocytose and transmit microorganisms, particles, and lectins that selectively attach to their apical membrane with high efficiency [36], in other words, substances that bind to mucosal surfaces elicit a strong secretory response. For example, oral administration of lectin leads to the production of anti-lectin-specific IgA. While

#### **Figure 2.**

*M cell. The basement membrane of the M cell begins to form an intracellular envelope. M cells first transfer antigens from the airways and gastrointestinal tract to the envelope and then to the defense cells located beneath the epithelium.*

the administration of the same amount of another immunogen that does not have adhesion and binding properties is ineffective [39].

The reason for the lack of adverse responses to food antigens and the normal intestinal flora should be sought in the inability of M cells to transmit soluble luminal antigens and nonadherent particles [40]. It seems that the introduction of small but frequent oral or inhaled amounts of soluble immunogens leads to tolerance [41].

Some viruses, bacteria, and protozoa, such as Cryptosporidium, selectively attach to M cells and transmit well. Among these viruses, only reovirus type I, poliovirus, and HIV 1 bind specifically to the upper membrane of M cells. These viruses do not attach to cell surfaces in the FAE or the epithelium of the villi.

In reovirus type I, one of the outer capsid proteins (δ1 or μ1), after being activated by the proteolytic process in the gastrointestinal tract, causes the virus to contact the M cell.

In animals, large numbers of gram-negative pathogens and *Streptococcus pyogenes* bind selectively or preferably to M cells. Some viruses (such as rotaviruses and transmissible gastroenteritis viruses), as well as bacteria such as *Escherichia coli* [42], Yersinia pseudo-tuberculosis, *Vibrio cholerae* [43–45], Shigella [46], *Yersinia enterocolitica* [47], and *Campylobacter jejuni* [48], have proliferated in M cells after infiltration and they cause local infection and inflammation. M cells use a carbohydrate-lectin detection system with multiple receptors to identify a variety of pathogenic microorganisms in the gut.

The cell surface of M is increased due to the presence of accessible membrane regions and specific binding regions of large ligands and is therefore different from other epithelial cells.

In the gut, immunoglobulins also bind specifically to M cells [49], so that for the first time in suckling rabbits, accumulation of milk slgA was observed on M cells of Peyer's patches.

Both Fc and Fab IgG fragments attach to the M cell. Lectins present on the surface of M cells identify abundant oligosaccharides present on immunoglobulins. Specific binding and transport of immunoglobulins by M cells may be involved in the regulation of immune responses. slgA usually prevents antigens and microorganisms from coming into contact with mucosal surfaces. The Fc Domain IgA molecule is hydrophilic (hydrophilic and hair-phosphatic) and binds IgA (attached to microorganisms) to epithelial cells. The Fc properties of the IgA molecule prevent the colonization of pathogens (without causing inflammation).

Antigens of these complexes are reabsorbed and evaluated by macrophages and lymphocytes inside or below the epithelium (containing Fcα receptors) [50–52]. This event intensifies the secretory immune response against pathogens that have not been effectively eliminated from the gut. However, convincing evidence of the ultimate fate of IgA or IgA-Antigen complexes is not available after uptake by M cells but it is speculated that Fcα receptors on the surface of mucosal cells may play a role in other stages of the mucosal immune response. IgA reacts with lactoferrin and lactoperoxidase through the FC region, thereby enhancing the function of these nonspecific defense elements.

#### **4.3 Antigen transfer**

M cells absorb adhesive molecules such as lectins and ferritin through membrane clathrin vesicles and discharge them into vesicular or tubular structures similar to the cytoplasmic apex endosomes (above the epithelial pocket) [36]. In this part of the cell structure, vesicular endosomes are rarely found and no structures are containing acid phosphatase [53]. During transfers, endocytic materials do

#### *Mucosal Immunology DOI: http://dx.doi.org/10.5772/intechopen.98863*

not decompose extensively. However, the presence of endosomal hydrolase in M cell transport vesicles has not been ruled out. The apical vesicles of M cells are acidic [54].

Proteins and microbes that have entered the M cell vesicles are discharged out of the epithelial cell by the exocytosis membrane up to 10 minutes after vertebral endocytosis [36, 55].

Exocytic vesicles originate from endosomal intermediate components and structures. Lysosomes are present in the pericardial Golgi of M cells, but endocytic materials of the apical membrane have not been observed in these areas.

M cells shorten their transport path by lifting the lateral membrane toward the apex and shortening the lateral endosomes directly to specific regions of the lateral base (**Figure 2**). The intraepithelial membrane of M cells is different from the lateral membrane (which attaches to the adjacent cell) and the basement membrane (which attaches to the basal lamina).

For example, it has been shown that Na/K ATPase pumps are concentrated in the lateral part (not in the envelope membrane of M cells. It is said that the presence of a specific population of lymphocytes in the M cell envelope indicates the presence of specific lymphocyte receptors in the envelope membrane (**Figure 2**). The mechanism of distribution of specific lymphoid cells in this area is still unknown The pattern of glycosylation determines the specificity of M cells. The structure of LPS in *salmonella typhi* morium fimbriae plays a role in binding to M cells.

M cells, make up a small population of epithelial cells. However, their ability to transmit intestinal adhesive particles is remarkable.

#### **4.4 M cells, areas of infiltration of pathogenic microorganisms**

M cells have developed their non-specific mechanisms for binding and absorption of intestinal material so that the mucosal immune system can access a variety of microorganisms and particles. The ability of M cells to bind to bacteria such as *Vibrio cholerae* allows the immune system to sample these non-invasive pathogens well and to organize the appropriate secretory immune response. The secretion of sIgA anti-cholera toxin (CT) plays an important role in limiting the course of the disease and preventing the recurrence of infection [56–58].

Many pathogenic bacteria and viruses that attach to M cells use this intraepithelial transport pathway as an invasion pathway. For example, reoviruses and polioviruses reach the Peyer's patches by selectively binding to the apex of the M cells [59, 60]. *Salmonella typhimurium* in mice and *Salmonella typhi* in humans are gram-negative pathogens that transmit to M cells attached to Peyer's patches and cause disease [45]. An effective mucosal immune response against Salmonella cannot prevent the organism from spreading to the liver and spleen. Therefore, with intestinal infiltration into the host, the systemic spread of the disease will occur. In addition, early transport of *Shigella flexneri* [46] and *Yersinia enterocolitica* [47] causes these organisms to enter the lamina propria by invading the lateral basal surfaces of epithelial cells and infecting mucosal macrophages.

O-MALT contains IgA-producing plasma cell precursors and is the center of the mucosal IgA response. After being transfected by M cells, the antigens first encounter the antigen-presenting cells and the lymphocytes in the cell's inner envelope [7]. In the dome area below the FAE, IgM+ B cells, CD4 + T cells, dendritic cells, and macrophages form a cellular network by which antigens are absorbed, processed, and delivered to lymphocytes. After activation, the process of maturation and differentiation of B cells occurs in O-MALT.
