**8. Mechanisms of secretory IgA protection**

#### **8.1 Immune exclusion**

Secretory IgA dimer is responsible for binding to microorganisms in the intestine and mucosal surfaces of the gastrointestinal tract, respiratory tract, and genital tract [67, 68].

The slgA-antigen complex can be easily trapped in mucus, excreted by bowel movements, and the beat of cilia of the respiratory tract. Also, the sIgA can directly block the microbial binding sites to epithelial cells [69].

The basic way of protection by sIgA is the same as immune exclusion. Therefore, the presence of appropriate levels of specific sIgA can only cause protection (even in the absence of other immunological mechanisms) [2].

#### **9. Respiratory mucosa**

The airways are an important route for the entry of pathogen antigens, allergens, and airborne particles. The upper respiratory tract mucosa contains the nasal lymphatic tissue (NALT), the bronchial lymphatic tissue (BALT), and the airway lymph nodes, and the lower respiratory tract mucosa contains the smaller airway lymph nodes and alveoli.

The immune system is present in the airways like other mucous membranes and plays an important role in regulating homeostasis and preventing harmful immune responses to harmless antigens. The respiratory system also contains specialized and organized mucosal tissues such as the palatine, lingual, pharyngeal, and adenoids, which form a ring-like structure called the "Waldeyer's ring" in the pathway of air and food antigens (**Figure 6**).

The extensive vascular network of the respiratory system provides a favorable environment for the migration of lymphocytes and the passage of blood vessels to the lung tissue. Leukocytes do not follow the conventional method of homing in lymphoid tissues and do not have processes such as rolling and attaching to the endothelium and passing through the HEV.

One of the defense mechanisms in the mucosa is physical and mechanical defense, which is seen in the respiratory system as a mechanism of clearance of the ciliary mucosa (mucociliary). The most abundant cells in the upper airways are ciliated epithelial cells that form the physical barrier [2, 5].

#### **Figure 6.**

*Waldeyer's ring. The tonsils and adenoids form a ring of lymphatic tissue in the gastrointestinal tract and airways called the Waldeyer's ring.*

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

Goblet cells are present in the margins of ciliated epithelial cells and are responsible for secreting mucus.

The mucus layer is directed to the upper respiratory tract by the movement of the cilium, so that suspended particles and pathogens are excreted or swallowed through sneezing and coughing which is called mucociliary clearance. Various cells in the respiratory tract, such as ciliated epithelial cells, alveoli, and immune cells located subepithelial, can produce and secrete antimicrobial peptides such as defensins, cathelicidins, collectins, and protease inhibitors [5].

#### **9.1 Waldeyer's ring**

The tonsils and adenoids are a great place to trap antigens from the mouth and nose. In humans, the Waldeyer's ring forms a network of lymphatic tissue in the nasopharyngeal mucosa, which is the structure of NALT. The epithelial surface of the tonsils and adenoids is the site of antigen entry due to its proximity to the external environment.

The palatine tonsils are two oval masses of secondary lymphatic tissue that are located in pairs behind the oral cavity and at the beginning of the oropharynx and are the entry point for respiratory and gastrointestinal antigens. The tonsils have several depressions called crypts. The presence of crypts increases the surface of the tonsils and the ability to remove antigens. The outer layer of each crypt is composed of epithelial cells, which have M-like cells present and perform the function of antigen uptake and transport through the epithelium. Below the epithelium of each crypt is one or more secondary lymph follicles.

Most cell populations of NALT lymphatic structures are composed of T and B lymphocytes and to a lesser extent dendritic cells and macrophages. NALT is structurally similar to MALT and has FAE-containing cells similar to M goblet and IELs. Lymphatic follicles are also seen in the subepithelial layer. Most tonsils located in the tonsils are B cells that turn into antibody-producing plasma cells (often IgA). The number of CD4 + T cells in this area is very low and IEL lymphocytes CD8 + T is found as CD8 + αβT or in the unusual phenotypes CD8αα + αβ T and CD8αα + γδ T.

Lymphatic tissues along the airways form the BALT structure. The upper airways have more organized lymphatic structures than the lower airways. In the lungs, active immune cells migrate mainly to the mediastinal and cervical lymph nodes, which enlarge in the face of infectious agents. In the BALT structure, the number of M and IEL cells in the overlying epithelium is very rare and there are no goblet cells in this area. In BALT, similar to MALT, lymph follicles are seen. B cells located inside the follicles usually have a memory phenotype and are mostly IgA+ . In the absence of infection, BALT is difficult to detect. Therefore, BALT is considered a secondary structure in cases of infection [4, 5].

#### **9.2 Regulation of immune responses by airway epithelial cells**

Airway epithelial cells specialize in regulating immune responses in the respiratory tract. While these cells can detect pathogenic microbes, they do not respond to harmless antigens and cause respiratory homeostasis These cells produce antimicrobial peptides, inflammatory cytokines, and chemokines, and express much lower levels of TLRs than the gastrointestinal epithelium, However, the expression of these TLRs is strongly influenced by TNF-α and IFN-γ [5].

#### **9.3 Dendritic cells in the respiratory mucosa**

BALT and NALT have a large number of DCs. These cells help maintain homeostasis by detecting and differentiating between pathogenic and harmless antigens

and by inducing tolerance to their antigens. Airway DCs are often of the myeloid class, but plasmacytoid DCs are rarely seen.

There is also a population of positive langerin DCs in the upper airways that are somewhat similar to cutaneous Langerhans cells and are involved in immune surveillance. In the lower airways and lung tissue, there are lung parenchymal dendritic cells (LPDCs) or interstitial DCs that are scattered in the alveolar epithelium and the alveolar space or the connective tissue between the epithelium and the arteries. LPDCs are often CD11b <sup>+</sup> and belong to the myeloid class.

DCs in the respiratory tract are considered strong cells in antigen uptake but have weak power in stimulating T lymphocytes. Airway DCs mainly direct the response to T2 and Treg, and by producing TGFβ lead to the switching of B cell class to IgAproducing plasma cells. In other words, airway dendritic cells regulate and modulate the immune response. Similar to MALT, dendritic cells meet and stimulate T cells by moving to the lymph nodes in the lungs. The lymph cells, then activated by lymph flow and then blood flow, return to the position of the lungs and participate in the immune response [4].

#### **9.4 Lymphocyte homing in the respiratory mucosa**

Integrins play an important role, especially α4 (α4: β7 and α4:β1) in the process of lymphocyte homing in the respiratory mucosa. E-cadherins are prominent in lung and intestinal cells and bind to αE:β7 integrins and are involved in the establishment of lymphocytes. Active T lymphocytes attach to CCL5 (RANTES) by expressing the CCR5 chemokine receptor at their surface and are located in the parenchyma of lung tissue. CCL5 is a chemotactic agent that is naturally secreted from lung tissue and increases during inflammation. In the airways, IgA-producing plasma blast implant by binding to the CCR10 chemokine receptor on its surface and the CCL28 chemokine secreted from the respiratory epithelium [1, 5].

#### **10. Mucosal vaccination**

By administering one or more oral doses of mucosal vaccine, in addition to producing sIgA on mucosal surfaces, it also stimulates cellular and systemic immune responses. With the entry of pathogens into O-MALT, the process of production and maintenance of memory lymphocyte population is established. In addition to the characteristics of injectable vaccines, oral vaccines must be able to pass through the stomach, intestines, and be resistant to bacterial enzymes and low pH.

Also, oral vaccines must be able to escape clearance mechanisms such as being trapped in mucus and be able to reach specific areas of the FAEcovered mucosa.

Furthermore, in addition, these vaccines need to compete by binding to the inner membrane to penetrate M cell vesicles. Immunological epitopes should be able to maintain their immunogenicity after crossing the epithelial barrier and penetrating the vesicles and be available to antigen-presenting cells for processing [2].

#### **10.1 How vaccines get access to O-MALT**

#### *10.1.1 Inert particulate carriers*

Vaccine access to Peyer's patches depends on the ability of M cells to transmit adherent multivalent macromolecules. One of the strongest products that have been

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

proven to be effective in the form of systemic vaccines is the Immune stimulating complex (ISCOM).

ISCOMs are particles 35 nm in diameter that are formed by the accumulation of protein antigens, such as the surface proteins of viruses, in a specific pattern. It should be noted that this form of immunogen was created for the proper and immunological present of viral surface proteins [70].

Immunization by ISCOMs leads to IgG production and cellular immune response against other viruses such as measles as well as inhibition of TH cells [70]. Intranasal immunization with ISCOM and influenza hemagglutinin leads to a local increase in anti-influenza cytotoxicity [71]. As a result, ISCOMs, as mucosal antigens, can be thought to produce IgA. In other words, ISCOMs are useful for mucosal use and are resistant to salt and bile acids.

Oral immunization in multiple doses with ISCOM containing ovalbumin or bacterial proteins results in the production of sIgA, systemic IgA, and cellular immunity [72].

They can also be used to immunize viral proteins that are naturally resistant to digestive proteases. Because they may not be resistant in the gut unless they are inside the capsule. Today, with the help of small hydroxyapatite crystals, effective solutions for particle penetration have been developed.

Crystals of 0.1 to 0.5 microns attach to M1 cells and are efficiently transported to intraepithelial envelopes. Because hydroxyapatite is a non-immunogenic and nontoxic component of bone structure, these antigen-coated crystals can be consumed in large quantities. These compounds should be used in capsule coatings [2].

#### *10.1.2 Live vaccine vectors*

The best way to stimulate mucosal immunity is to insert antigens into living microorganisms that can attach to M cells and settle and multiply in Peyer's patches and mucous membranes. Because living microorganisms elicit a strong and long-lasting immune response, a large number of viral and bacterial carriers are considered for this purpose. Given that living carriers can produce antigens for a long time and cause the production of antibodies as well as the development of cellular immune responses, the possibility of their use as a vaccine is being strongly considered.

The vaccinia virus recombinant has been tested as an oral vaccine [73]. But the mechanism of its absorption and transfer to Peyer's patches is still unknown. This method can probably be a safe and effective method of mucosal immunization. Because infection of mucosal cells with the recombinant virus can cause the presence of antigens on the cell surface. The vaccinia virus recombinant is used as a mucosal vaccine to enhance the capacity of bacterial carriers for foreign DNA [74]. Because viral carriers have limited replication and are unable to germinate the virus, the infection may be transient, with limited antigen present and the carrier cannot spread well in the mucosa of Peyer's patches.

Different species of bacteria can settle in Peyer's patches, including the live Attenuated strains of Salmonella and BCG [75, 76]. BCG is an effective adjuvant whose systemic immunization is safe. Once given at the time of birth, this vaccine provides long-term safety. BCG is also considered an oral vaccine [77] and is effective in transmitting O-MALT through M cells [78].

By orally administering recombinant Salmonella, laboratory animals have been vaccinated against a range of foreign antigens, including the heat-stable *E. Coli* enterotoxin [79], the streptococcal adhesin [80], and the malaria circumsporozoite protein [81]. In general, Salmonella is considered a strong mucosal immunogen. However, this limits the use of these carriers for repeated immunizations. Because

the anti-secretory immune response prevents re-absorption of oral doses of the carrier that deliver this antigen or other recombinant antigens.

IgA secretion of the superficial salmonella typhoid epitope of Morium can favorably prevent the penetration of these microorganisms into the mucosa [82].

However, applying effective methods to various events, such as immunogen retention in the gut, the ability of immunogen to bind to the surface of M cells, effective interaction with antigen-supplying cells, or facilitating its detection by M cells, can enhance mucosal immunity.
