*3.1.10 CC16 club cells/Clara cells*

Clara cells are non-ciliated, non-mucous, secretory cells in respiratory epithelium. These epithelial cells secrete several distinctive proteins, including Clara cell 10-kDa secretory protein (CCSP). Clara cells are most predominant in the terminal and respiratory bronchioles of humans.

Club cells, also known as bronchiolar exocrine cells and originally known as Clara cells, are dome-shaped cells with short microvilli, found in the small airways (bronchioles) of the lungs.

Of recent Clara cells (CC16) have re-emerged in the immune pathogenesis of Asthma [25].

### **3.2 The adaptive inflammatory cells**

T-cell responses to antigens consist of a combination of pro-inflammatory (effector) and anti-inflammatory (regulatory) cells.

• Lymphocytes differentiate into separate lineages. The B lymphocytes secrete antibodies.

The T lymphocytes operate in a supervising role to mediate cellular and humoral responses. Antigen presentation describes a vital immune process which is essential for T-cell immune response triggering immunity. B and T lymphocytes produce and express specific receptors for antigens. Collectively, the functions of the T and B cells encompass an entity called the adaptive immune system.

T-helper lymphocytes conventionally are TH1 and TH2 cells. TH1 cells produce cytokines that downregulate the atopic response. In those who are genetically susceptible to developing asthma, antigen presentation to T-helper cells leads to a

TH2 response, pro-inflammatory cytokines, and upregulation of airway inflammation of asthma by enhancing immunoglobulin E synthesis, eosinophils, and mast cell activation/function.

#### *3.2.1 TREG cells*

TREG cells, a type of T-helper lymphocytes, bind interleukins 2 via the CD25 and CD45RB receptors to signal suppression of the immune system. This is essential in arresting inflammatory allergic responses such as in asthma and allergic rhinitis. In addition, naive T lymphocytes are induced to synthesize FoxP3 which acts as a transcription factor for the cytokines involved in the TREG-mediated cascade. In particular, transforming growth factor-β (TGF-β) and interleukin-10 are the main cytokines implicated in the TREG-mediated suppression of inflammatory allergic responses [26, 27]. Thus, TREG cells are critical in the autoregulation of allergic inflammatory reactions by slowing the pathological effects of the Th2 type immune responses in bronchial hyper-reactivity and inflammation in asthma [26–28].

#### **3.3 The respiratory airway cells/mucosal immunology**

There are several cells in the epithelium of the lower respiratory tract. The upper part includes support cells (basement), mucous-secreting cells, and the cilia, to aid the expulsion of mucous. However, Clara cells and cilia dominate in the lower parts of the respiratory system [29, 30].

Some of these cells are involved in inflammatory allergic responses in asthma. For instance, in asthma the goblet cells, i.e., mucous-secreting cells, increased the number of goblet cells as part of airway remodeling. The mucus (i.e., a complex solution of lipids and proteins in the airways) aggravates the immunopathology of asthma. The function of mucous is to trap inhaled particles/allergen and the interaction with the tips of beating cilia and remove particles/allergen from the airways, a process termed mucociliary clearance [31]. Other cells such as the neuroendocrine cells are not directly involved in the immunopathogenesis of asthma. Neuroendocrine cells (i.e., small round cells with dark staining nucleus and clear cytoplasm) contain characteristic granules and secrete hormones and peptides such as serotonin.

In particular, lymphoid tissues are mainly found in the bronchial. Thus during an asthmatic attack, the airways are remodeled (i.e., bronchial thermoplasty), which is characterized by swelling, cellular infiltration, and hyperplasia of smooth muscles and goblet cells [7–9].

The adaptation (i.e., hypertrophy, metaplasia, fibrosis, and hyperplasia) of the epithelial airways and smooth muscle cells to allergic and/or noxious stimuli compromises the structure and function of the airways [31, 32].

Indeed, the epithelial cells are important in providing rapid response to counter allergens by secreting mucous and initiating the inflammation. This epithelium provides a barrier against the external environment and protects against infection from airborne pathogens. Defective barrier function or viral infection can lead to respiratory tract disease like asthma.

The first line of defense against invasion by potential pathogens is the thin layer of epithelium that covers mucosal surfaces including that of the upper and lower respiratory tract. The mucosal immune system has unique features including large size, uptake, and presentation of antigen and contains a large number of effector T lymphocytes. The circulation of lymphocytes within the mucosal immune system is controlled by tissue-specific adhesion molecules and chemokine receptors.

**125**

symptoms.

*3.3.2 Allergen exposure*

*The Immunology of Asthma and Allergic Rhinitis DOI: http://dx.doi.org/10.5772/intechopen.86964*

production.

well as measurement of therapeutic efficacy for asthma.

ders, including asthma, rhinosinusitis, and middle ear disease.

*3.3.1 Allergic rhinitis and mediators of the inflammatory response*

macrophages and other cells [32–34].

The analysis of molecular markers of airway inflammation has provided promising and noninvasive techniques that facilitate the detection of disease phenotypes as

Current treatments for severe forms of asthma have been extended to the use of biological modifiers for the classical asthma endotypes (i.e., Th2 high and Th2 low). Conventional immune modulators (omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab) used in the management of severe forms of asthma are for patients with asthma of the type Th2 high. The inflammatory in patients with TH2 high asthma is principally mediated by eosinophils reactions as well as type 2 cytokines (i.e., IL-4, IL-13, IL-5) produced by Th2 cells. The type 2 cytokines are in turn regulated by other interleukins, namely, IL-25 and IL-33, as well as TSLP [9, 10]. These mediators are upstream innate factors that drive IL-13 and IL-5

In contrast, TH2 low asthma is poorly described. Patients do not have eosinophilia and other markers but have neutrophilia inflammation. This is mainly due to the activation of TH1 or 17 cells that release IFN and IL-17. These cells are specifically produced at mucosal surfaces and thus are important in airway inflammation. The role of ILCs, more specifically type 2 ILCs, in the pathogenesis of allergic airway diseases has been extensively investigated over the last decade. Chronic nasal inflammation may aggravate or lead to the development of other significant disor-

Sensitization is initiated in nasal tissues when antigen that is deposited on the nasal mucosa is engulfed by antigen-presenting cells—macrophages, dendritic cells, Langerhans cells—and partially degraded within their phagolysosomes into antigenic peptides. These peptides are then externalized on the surfaces of APCs and are presented to naive CD4+ T lymphocytes. The interaction of T-helper lymphocytes is activated by presentation of an allergen via the MHC class II receptor on

In patients with allergic rhinitis, allergen-triggered early and late responses are mediated by a series of inflammatory cells. Within minutes of contact with allergen, IgE-sensitized mast cells degranulate, releasing both preformed and newly synthesized mediators. Immunologic processes in both nasal and bronchial tissues involve TH2 lymphocytes and eosinophils. Eosinophils are the predominant cell in the chronic inflammatory process characteristic of the late-phase allergic response. Eosinophils release an array of pro-inflammatory mediators, including cysteinyl leukotrienes, cationic proteins, eosinophil peroxidase, and major basic protein, and might serve as a major source of IL-3, IL-5, GM-CSF, and IL-13. Neuropeptides also appear to contribute to the pathophysiology of allergic rhinitis

The respiratory tract is an important route of allergen entry. Several people react to airborne allergens with an IgE-mediated reaction, resulting from the deposition of mucosal mast cells beneath the nasal epithelium by allergens such as pollen that when they contact the epithelium, they release their soluble protein content, which is rich in eosinophils and allergic rhinitis characterized by intense itching, sneezing,

In atopic-related allergic rhinitis, the hypersensitivity mediated via IgE, mast cells, and lymphocytes is inherited. The continued exposure of allergens initiates

nasal blockage, and irritation of the nasal mucosa due to histamine release.

*The Immunology of Asthma and Allergic Rhinitis DOI: http://dx.doi.org/10.5772/intechopen.86964*

*Rhinosinusitis*

cell activation/function.

*3.2.1 TREG cells*

asthma [26–28].

as serotonin.

of the respiratory system [29, 30].

muscles and goblet cells [7–9].

respiratory tract disease like asthma.

TH2 response, pro-inflammatory cytokines, and upregulation of airway inflammation of asthma by enhancing immunoglobulin E synthesis, eosinophils, and mast

TREG cells, a type of T-helper lymphocytes, bind interleukins 2 via the CD25 and CD45RB receptors to signal suppression of the immune system. This is essential in arresting inflammatory allergic responses such as in asthma and allergic rhinitis. In addition, naive T lymphocytes are induced to synthesize FoxP3 which acts as a transcription factor for the cytokines involved in the TREG-mediated cascade. In particular, transforming growth factor-β (TGF-β) and interleukin-10 are the main cytokines implicated in the TREG-mediated suppression of inflammatory allergic responses [26, 27]. Thus, TREG cells are critical in the autoregulation of allergic inflammatory reactions by slowing the pathological effects of the Th2 type immune responses in bronchial hyper-reactivity and inflammation in

There are several cells in the epithelium of the lower respiratory tract. The upper part includes support cells (basement), mucous-secreting cells, and the cilia, to aid the expulsion of mucous. However, Clara cells and cilia dominate in the lower parts

Some of these cells are involved in inflammatory allergic responses in asthma. For instance, in asthma the goblet cells, i.e., mucous-secreting cells, increased the number of goblet cells as part of airway remodeling. The mucus (i.e., a complex solution of lipids and proteins in the airways) aggravates the immunopathology of asthma. The function of mucous is to trap inhaled particles/allergen and the interaction with the tips of beating cilia and remove particles/allergen from the airways, a process termed mucociliary clearance [31]. Other cells such as the neuroendocrine cells are not directly involved in the immunopathogenesis of asthma. Neuroendocrine cells (i.e., small round cells with dark staining nucleus and clear cytoplasm) contain characteristic granules and secrete hormones and peptides such

In particular, lymphoid tissues are mainly found in the bronchial. Thus during an asthmatic attack, the airways are remodeled (i.e., bronchial thermoplasty), which is characterized by swelling, cellular infiltration, and hyperplasia of smooth

The adaptation (i.e., hypertrophy, metaplasia, fibrosis, and hyperplasia) of the epithelial airways and smooth muscle cells to allergic and/or noxious stimuli

Indeed, the epithelial cells are important in providing rapid response to counter allergens by secreting mucous and initiating the inflammation. This epithelium provides a barrier against the external environment and protects against infection from airborne pathogens. Defective barrier function or viral infection can lead to

The first line of defense against invasion by potential pathogens is the thin layer of epithelium that covers mucosal surfaces including that of the upper and lower respiratory tract. The mucosal immune system has unique features including large size, uptake, and presentation of antigen and contains a large number of effector T lymphocytes. The circulation of lymphocytes within the mucosal immune system is controlled by tissue-specific adhesion molecules and chemokine receptors.

compromises the structure and function of the airways [31, 32].

**3.3 The respiratory airway cells/mucosal immunology**

**124**

The analysis of molecular markers of airway inflammation has provided promising and noninvasive techniques that facilitate the detection of disease phenotypes as well as measurement of therapeutic efficacy for asthma.

Current treatments for severe forms of asthma have been extended to the use of biological modifiers for the classical asthma endotypes (i.e., Th2 high and Th2 low). Conventional immune modulators (omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab) used in the management of severe forms of asthma are for patients with asthma of the type Th2 high. The inflammatory in patients with TH2 high asthma is principally mediated by eosinophils reactions as well as type 2 cytokines (i.e., IL-4, IL-13, IL-5) produced by Th2 cells. The type 2 cytokines are in turn regulated by other interleukins, namely, IL-25 and IL-33, as well as TSLP [9, 10]. These mediators are upstream innate factors that drive IL-13 and IL-5 production.

In contrast, TH2 low asthma is poorly described. Patients do not have eosinophilia and other markers but have neutrophilia inflammation. This is mainly due to the activation of TH1 or 17 cells that release IFN and IL-17. These cells are specifically produced at mucosal surfaces and thus are important in airway inflammation. The role of ILCs, more specifically type 2 ILCs, in the pathogenesis of allergic airway diseases has been extensively investigated over the last decade. Chronic nasal inflammation may aggravate or lead to the development of other significant disorders, including asthma, rhinosinusitis, and middle ear disease.

#### *3.3.1 Allergic rhinitis and mediators of the inflammatory response*

Sensitization is initiated in nasal tissues when antigen that is deposited on the nasal mucosa is engulfed by antigen-presenting cells—macrophages, dendritic cells, Langerhans cells—and partially degraded within their phagolysosomes into antigenic peptides. These peptides are then externalized on the surfaces of APCs and are presented to naive CD4+ T lymphocytes. The interaction of T-helper lymphocytes is activated by presentation of an allergen via the MHC class II receptor on macrophages and other cells [32–34].

In patients with allergic rhinitis, allergen-triggered early and late responses are mediated by a series of inflammatory cells. Within minutes of contact with allergen, IgE-sensitized mast cells degranulate, releasing both preformed and newly synthesized mediators. Immunologic processes in both nasal and bronchial tissues involve TH2 lymphocytes and eosinophils. Eosinophils are the predominant cell in the chronic inflammatory process characteristic of the late-phase allergic response. Eosinophils release an array of pro-inflammatory mediators, including cysteinyl leukotrienes, cationic proteins, eosinophil peroxidase, and major basic protein, and might serve as a major source of IL-3, IL-5, GM-CSF, and IL-13. Neuropeptides also appear to contribute to the pathophysiology of allergic rhinitis symptoms.

#### *3.3.2 Allergen exposure*

The respiratory tract is an important route of allergen entry. Several people react to airborne allergens with an IgE-mediated reaction, resulting from the deposition of mucosal mast cells beneath the nasal epithelium by allergens such as pollen that when they contact the epithelium, they release their soluble protein content, which is rich in eosinophils and allergic rhinitis characterized by intense itching, sneezing, nasal blockage, and irritation of the nasal mucosa due to histamine release.

In atopic-related allergic rhinitis, the hypersensitivity mediated via IgE, mast cells, and lymphocytes is inherited. The continued exposure of allergens initiates the inflammatory process via the APC, lymphocytes, and cytokine cascades (i.e., IL-3, IL-4, and IL-5). Until, then the immune system is not yet sensitized to the allergen. Following sensitization, further exposures initiate the inflammatory/allergic response and clinical presentation of allergic rhinitis.
