**8. Respiratory diseases associated with the expression of β-defensin-2**

The respiratory epithelium is the largest surface of the human body in contact with external medium, and it exposed to a large number of pathogens.

The respiratory epithelium counts upon many defense effectors and one of them is the production of defensins. They act as a first line of host defense against invading microorganism. The cells of respiratory epithelium produce four types of defensins (HBD1–4). HBD1 is expressed constitutively and HBD2–4 are expressed during infectious or inflammatory processes. HBD2 is the most expressed in all respiratory epithelium from the oral cavity, pharynx, larynx, trachea, serous cells and submucosal glands to the lung [1, 29, 97]. Several authors have reported expression of the HBD2 in these tissues and also detected the protein in healthy and diseased people in different secretions of the body such as bronchoalveolar fluid, saliva, blood, plasma, milk, sputum, nasal secretions, etc. [32, 98–102].

Several studies have suggested that there is a relationship between HBD2 and the pathogenesis of several respiratory diseases. The increase or decrease of its expression can result in the protection or amplification of the disease.

#### **8.1 Lung cancer**

This type of disease has a high mortality rate and the treatments are very expensive. It is difficult to detect early stages of the disease or if the tumor is benign or malignant, especially in the preliminary condition. The higher concentrations of HBD2 in the serum of patients did not show any relation with the histopathological classification [103].

#### **8.2 Pneumonia**

It is a disease of the lower respiratory system that mainly affects young children and older adults and has a high mortality rate and a great social and economic impact due to long periods of hospitalization and resistance to antibiotics. The alteration of the immune function of the mucosa of the respiratory system in these age groups constitutes a risk factor for contracting pneumonia. Bacterial infections are frequent, such infections lead to a serious deterioration of lung function, and are usually associated with persistent colonization by bacteria such as *Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumonia* and *Legionella pneumophila.* Patients with acute pneumonia caused by bacterial infections have shown that the HBD2 is expressed in lung tissue and the concentration of the protein increases in blood and alveolar fluid [98, 101]. When the HBD2 levels in plasma are below 12.5 mg/ml, the patients with pneumonia have a high possibility of needing mechanical ventilation and development of new complications or death [104].

In an in vitro model, *L. pneumophila* induces the release of hBD-2 in A549 cells in a manner dependent on TLR2 and TLR5. The activation of p38 MAPK and JNK, as well as NF-B and AP-1, is involved in the production of hBD-2 induced by *L. pneumophila*. Therefore, regulation of the release of hBD-2 by *L. pneumophila* in A549 cells appears to be determined by multiple signaling molecules and may contribute to host defense in Legionnaires disease. [57].

#### **8.3 Cystic fibrosis**

Cystic fibrosis is a chronic lung disease with high morbidity and mortality rates. It is caused by a recessive mutation in the transmembrane conductance regulator gene (CFTR), which is located on chromosome 7 on the apical surface of epithelial cells [19, 24, 105]. This mutation causes abnormal transport of chlorine ions, which induce an increase in the salinity of the alveolar fluid. The high salt concentration abrogates the antimicrobial activity of HBD2; this might explain the recurrent bacterial infections in the lungs of these patients [32, 105].

**63**

*Multifunctional Activity of the β-Defensin-2 during Respiratory Infections*

Bacterial infections in patients with cystic fibrosis are very common; in the acute phase, the patients are infected mainly with *Haemophilus influenzae* and *Staphylococcus aureus*. While in the chronic phase, the infection is always caused by *Pseudomonas aeruginosa*, a Gram-negative bacterium, opportunistic and resistant to

The decrease in the expression and degradation of HBD2 plays an important role in the pathogenesis of pulmonary infection for *P. aeruginosa* in patients with cystic fibrosis [105]. They explain that in the chronic phase of infection, the phenotype of the bacteria changes and it loses the flagella. The flagella are composed of flagellin, which is a virulence factor that promotes mobility and adhesion. The flagellum is the ligand that triggers the signaling pathway for the expression of HBD2. When losing the flagella, the bacterium does not recognize the receptor (TLR5) of the epithelium and transcription of the gene is not executed through NF-kB. The bacterium causes damage to the epithelium of the lung producing a severe inflammatory process, with production of IL-8. IL-8 causes the accumulation of neutrophils; later, they enter apoptosis and phagocytosed by macrophages. Many macrophages accumulate in the lung and secrete cathepsin, a cysteine protease that remodels the extracellular matrix found in large quantities in bronchoalveolar lavage. This enzyme degrades the disulfide bonds of the defensins by inactivating them, thus losing their antimicrobial

The patients with cystic fibrosis and polyps showed high levels of HBD2 and TLR2 expression with an increase in IL-8 [106]. In nasal epithelium of patients with CF, HBD2 is not upregulated in response to inflammatory stimuli. The higher levels of inflammatory markers were seen but without any correlation with the expression of HBD2. They explain that the epithelium of patients with cystic fibrosis is chronically exposed to inflammatory stimuli and lost the capacity to upregulate defensin synthesis. The inflammatory stimuli may not be the sole inducers of defense expres-

COPD is an inflammatory disease of the respiratory tract that is characterized by recurrent infections, severe inflammation and is associated with a reduction of airflow and a decrease in lung function [108]. The main environmental risk factor is smoking; some authors suggest that tobacco smoke inhibits the activation of the host's innate immune system. The *in vitro* studies with respiratory epithelium exposed to tobacco smoke are reported to inhibit the expression of HBD2 when infected with bacterium [109]. COPD patients who smoke have lowered basal hBD-2 expression in the epithelial cells of the central airways, which correlates with the amount of cigarette pack years. The decreased HBD2 expression is associated with current or former smoking, which makes the population more susceptible

Moreover, genetic factors can contribute to the progression of the disease. The variation in the number of copies of HBD2 gene in epithelial cells is associated with the pathogenesis of the disease [110]. Moreover, genetic factors can contribute to the progression of the disease. The variation in the number of copies of HBD2 gene in epithelial cells is associated with the pathogenesis of COPD. In this study showed a significantly higher proportion of the patients with severe COPD had high diploid

In another study, the expression of HBD2 in peripheral lung tissue in patients with COPD is elevated and associated with the habit of smoking and with the high

β-defensin copy numbers (five or more) compared with the control sample.

**8.4 Chronic obstructive pulmonary disease (COPD)**

towards infections by microorganisms [108, 110].

levels of IL-8 as well as severity of the disease [111].

*DOI: http://dx.doi.org/10.5772/intechopen.80611*

antibiotics [32].

activity [9].

sion [107].

*Immune Response Activation and Immunomodulation*

plasma, milk, sputum, nasal secretions, etc. [32, 98–102].

**8.1 Lung cancer**

classification [103].

of new complications or death [104].

**8.3 Cystic fibrosis**

contribute to host defense in Legionnaires disease. [57].

bacterial infections in the lungs of these patients [32, 105].

**8.2 Pneumonia**

sion can result in the protection or amplification of the disease.

The respiratory epithelium counts upon many defense effectors and one of them is the production of defensins. They act as a first line of host defense against invading microorganism. The cells of respiratory epithelium produce four types of defensins (HBD1–4). HBD1 is expressed constitutively and HBD2–4 are expressed during infectious or inflammatory processes. HBD2 is the most expressed in all respiratory epithelium from the oral cavity, pharynx, larynx, trachea, serous cells and submucosal glands to the lung [1, 29, 97]. Several authors have reported expression of the HBD2 in these tissues and also detected the protein in healthy and diseased people in different secretions of the body such as bronchoalveolar fluid, saliva, blood,

Several studies have suggested that there is a relationship between HBD2 and the pathogenesis of several respiratory diseases. The increase or decrease of its expres-

It is a disease of the lower respiratory system that mainly affects young children and older adults and has a high mortality rate and a great social and economic impact due to long periods of hospitalization and resistance to antibiotics. The alteration of the immune function of the mucosa of the respiratory system in these age groups constitutes a risk factor for contracting pneumonia. Bacterial infections are frequent, such infections lead to a serious deterioration of lung function, and are usually associated with persistent colonization by bacteria such as *Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumonia* and *Legionella pneumophila.* Patients with acute pneumonia caused by bacterial infections have shown that the HBD2 is expressed in lung tissue and the concentration of the protein increases in blood and alveolar fluid [98, 101]. When the HBD2 levels in plasma are below 12.5 mg/ml, the patients with pneumonia have a high possibility of needing mechanical ventilation and development

In an in vitro model, *L. pneumophila* induces the release of hBD-2 in A549 cells in a manner dependent on TLR2 and TLR5. The activation of p38 MAPK and JNK, as well as NF-B and AP-1, is involved in the production of hBD-2 induced by *L. pneumophila*. Therefore, regulation of the release of hBD-2 by *L. pneumophila* in A549 cells appears to be determined by multiple signaling molecules and may

Cystic fibrosis is a chronic lung disease with high morbidity and mortality rates. It is caused by a recessive mutation in the transmembrane conductance regulator gene (CFTR), which is located on chromosome 7 on the apical surface of epithelial cells [19, 24, 105]. This mutation causes abnormal transport of chlorine ions, which induce an increase in the salinity of the alveolar fluid. The high salt concentration abrogates the antimicrobial activity of HBD2; this might explain the recurrent

This type of disease has a high mortality rate and the treatments are very expensive. It is difficult to detect early stages of the disease or if the tumor is benign or malignant, especially in the preliminary condition. The higher concentrations of HBD2 in the serum of patients did not show any relation with the histopathological

**62**

Bacterial infections in patients with cystic fibrosis are very common; in the acute phase, the patients are infected mainly with *Haemophilus influenzae* and *Staphylococcus aureus*. While in the chronic phase, the infection is always caused by *Pseudomonas aeruginosa*, a Gram-negative bacterium, opportunistic and resistant to antibiotics [32].

The decrease in the expression and degradation of HBD2 plays an important role in the pathogenesis of pulmonary infection for *P. aeruginosa* in patients with cystic fibrosis [105]. They explain that in the chronic phase of infection, the phenotype of the bacteria changes and it loses the flagella. The flagella are composed of flagellin, which is a virulence factor that promotes mobility and adhesion. The flagellum is the ligand that triggers the signaling pathway for the expression of HBD2. When losing the flagella, the bacterium does not recognize the receptor (TLR5) of the epithelium and transcription of the gene is not executed through NF-kB. The bacterium causes damage to the epithelium of the lung producing a severe inflammatory process, with production of IL-8. IL-8 causes the accumulation of neutrophils; later, they enter apoptosis and phagocytosed by macrophages. Many macrophages accumulate in the lung and secrete cathepsin, a cysteine protease that remodels the extracellular matrix found in large quantities in bronchoalveolar lavage. This enzyme degrades the disulfide bonds of the defensins by inactivating them, thus losing their antimicrobial activity [9].

The patients with cystic fibrosis and polyps showed high levels of HBD2 and TLR2 expression with an increase in IL-8 [106]. In nasal epithelium of patients with CF, HBD2 is not upregulated in response to inflammatory stimuli. The higher levels of inflammatory markers were seen but without any correlation with the expression of HBD2. They explain that the epithelium of patients with cystic fibrosis is chronically exposed to inflammatory stimuli and lost the capacity to upregulate defensin synthesis. The inflammatory stimuli may not be the sole inducers of defense expression [107].

### **8.4 Chronic obstructive pulmonary disease (COPD)**

COPD is an inflammatory disease of the respiratory tract that is characterized by recurrent infections, severe inflammation and is associated with a reduction of airflow and a decrease in lung function [108]. The main environmental risk factor is smoking; some authors suggest that tobacco smoke inhibits the activation of the host's innate immune system. The *in vitro* studies with respiratory epithelium exposed to tobacco smoke are reported to inhibit the expression of HBD2 when infected with bacterium [109]. COPD patients who smoke have lowered basal hBD-2 expression in the epithelial cells of the central airways, which correlates with the amount of cigarette pack years. The decreased HBD2 expression is associated with current or former smoking, which makes the population more susceptible towards infections by microorganisms [108, 110].

Moreover, genetic factors can contribute to the progression of the disease. The variation in the number of copies of HBD2 gene in epithelial cells is associated with the pathogenesis of the disease [110]. Moreover, genetic factors can contribute to the progression of the disease. The variation in the number of copies of HBD2 gene in epithelial cells is associated with the pathogenesis of COPD. In this study showed a significantly higher proportion of the patients with severe COPD had high diploid β-defensin copy numbers (five or more) compared with the control sample.

In another study, the expression of HBD2 in peripheral lung tissue in patients with COPD is elevated and associated with the habit of smoking and with the high levels of IL-8 as well as severity of the disease [111].

#### **8.5 Allergic rhinitis (AR)**

AR is an inflammatory disorder that occurs in the nasal mucosa and triggered by the exposure to allergens (mites, pets, insects, pollen, latex items, tobacco particles, ozone, nitrogen oxide, sulfur dioxide, aspirin, etc.) producing inflammation mediated by IgE. Clinically, it is characterized by symptoms such as rhinorrhea, sneezing, nasal congestion and itching. These symptoms worsen a person's productivity and quality of life and cause sleep disturbances, fatigue or depression. Although it occurs more frequently in young children, adults are affected as well [18].

Studies with tonsil tissue (lymphocytes) and pharyngeal epithelial cells from patients with allergic rhinitis found a reduction in the expression of HBD2. When cells are exposed to Th2 cytokines (IL-4, IL-5 and IL-13) and histamine *in vitro*, they also cause a decrease in the expression of HBD2. Therefore, patients with allergic rhinitis are more susceptible to respiratory infections and severe exacerbations [112–114].

#### **8.6 Rhinosinusitis**

Rhinosinusitis is characterized by the presence of at least two respiratory symptoms, nasal obstruction and nasal discharge, wherein the presence or absence of nasal polyps is seen. In one study, the sinonasal epithelial cells of patients with rhinosinusitis with nasal polyps showed a decrease in the expression of β-defensin-2 in response to the presence of IL-4 and IL-13 [114–116].

#### **8.7 Otitis media**

It is a very common disease mainly affecting the young children under 3 years of age having episode of otitis media. The pathogenesis of the disease is multifactorial, and among the most important factors are viral infections (respiratory syncytial virus, rhinovirus, influenza A, adenovirus) and bacterial infections (Streptococcus pneumoniae, nontypeable *Haemophilus influenzae* (NTHI), and Moraxella catarrhalis). The acute illness resolves quickly but the chronic or recurrent disease can cause hearing loss [39, 117].

The epithelial cells of the middle ear express HBD2, and two signaling pathways have been described. HBD2 expression is induced by pro-inflammatory stimuli such as interleukin 1 alpha (IL-1a), tumor necrosis factor alpha (TNF-a), and lipopolysaccharide (LPS). Their transcriptional activation is mediated through an Src-dependent Raf-MEK1/2-ERK signaling pathway [119]. The other known route is when the bacterium is recognized by the TLR2 of epithelial cells through the MyD88-IRAKI-TRAF6-MKK3/6-p38 MAP kinase signal transduction pathway [117, 118].

#### **8.8 Asthma**

It is a common chronic obstructive disease characterized by obstruction, hyperreactivity and inflammation. It affects all age groups throughout the world and has high morbidity and mortality rates [119]. Epidemiological studies indicate that the pathogenesis of asthma is multifactorial. The viral respiratory infections are the main cause of exacerbations or asthma attacks; influenza viruses, parainfluenza, rhinovirus and respiratory syncytial are those that have been identified more frequently [120, 121].

The mechanisms that explain how viruses cause or exacerbate asthma are diverse and some are not yet fully characterized. Recent studies indicate that HBD2 may

**65**

**8.11 Tuberculosis**

*Multifunctional Activity of the β-Defensin-2 during Respiratory Infections*

play an important role in the pathogenesis of asthma. Some mechanisms have been suggested to explain the exacerbations of asthma such as (a) patients with asthma develop a TH2 type response; it induced the production of cytokines (IL-4, IL-5, IL-13) that inhibit the production of HBD2, causing susceptibility to infections [122]. (b) HBD2 induces the activation and degranulation of mastoid cells that release histamine and prostaglandins, substances that increase asthma exacerba-

It is a disease in the respiratory tract caused by infection with human papilloma virus. The papilloma virus belongs to the Papovaviridae family. It is a circular double-stranded DNA virus and has no envelope, and its genome is 7200–8000 bp. There are more than 100 serotypes, which due to their oncogenic capacity are

The disease characterized by abnormal proliferation of epithelial keratinocytes forming a papilloma. It occurs more frequently in the larynx but might spread to the trachea or even lungs. It is common in children 2–4 years of age and in children over 12 years of age and in young adults. The first symptom is progressive dysphonia, with symptoms of variable respiratory obstruction, dyspnea and stridor. Some patients have spontaneous remission and others may have a very rapid growth that may require multiple surgical procedures or cause obstruction resulting in death. Papilloma viruses have a high morbidity rate because of its recurrence, and there are

The serotypes of papilloma that have been found with higher frequency are the serotypes of low risk 6 and 11; nevertheless, a 2% can be infected with other subtypes like the 16 and 18 of high risk, but these are associated with transformation of

The expression of HBD2 in samples of papillomavirus induced lesions in patients with recurrent respiratory papillomatosis, and its association with IL-8 [126] was studied. The lesions showed high levels of HBD2 expression, and the inflammatory process was not significant. Despite the higher expression of HBD2 in the deepseated tissues, the persistence of the virus leads to the disease progression. They suggest that HBD2 can serve as a signaling molecule to induce the adaptive immune

DP is a disease with chronic inflammation in the bronchioles of respiratory system. The immune cells are activated, and neutrophils are found in large quantities and activate T lymphocytes. There are often bacterial infections (*P. aeruginosa* and *H influenzae*). The pathogenesis of this disease is not clear; but recently, HBD2 has been implicated. In a study with patients with DP, high levels of HBD2 in bronchoalveolar fluid and plasma were found, suggesting that it could play an important role in the defense against infections. The levels of HBD2 in BAL fluid may be a useful

Tuberculosis is one of the most frequent infectious diseases that cause more deaths; its incidence is still a global health problem. *Mycobacterium tuberculosis* is the causative agent of tuberculosis, and it can cause a progressive disease or a latent infection. It has been reported that a third part of the population is latently infected

response against viral infection with acceptable inflammatory events.

marker of airway inflammation in patients with DPB [127].

*DOI: http://dx.doi.org/10.5772/intechopen.80611*

**8.9 Recurrent respiratory papillomatosis**

divided into high risk and low risk [123].

no satisfactory treatments [124, 125].

**8.10 Diffuse panbronchiolitis (DP)**

cells causing carcinoma [123].

tions [26].

*Multifunctional Activity of the β-Defensin-2 during Respiratory Infections DOI: http://dx.doi.org/10.5772/intechopen.80611*

play an important role in the pathogenesis of asthma. Some mechanisms have been suggested to explain the exacerbations of asthma such as (a) patients with asthma develop a TH2 type response; it induced the production of cytokines (IL-4, IL-5, IL-13) that inhibit the production of HBD2, causing susceptibility to infections [122]. (b) HBD2 induces the activation and degranulation of mastoid cells that release histamine and prostaglandins, substances that increase asthma exacerbations [26].

#### **8.9 Recurrent respiratory papillomatosis**

*Immune Response Activation and Immunomodulation*

AR is an inflammatory disorder that occurs in the nasal mucosa and triggered by the exposure to allergens (mites, pets, insects, pollen, latex items, tobacco particles, ozone, nitrogen oxide, sulfur dioxide, aspirin, etc.) producing inflammation mediated by IgE. Clinically, it is characterized by symptoms such as rhinorrhea, sneezing, nasal congestion and itching. These symptoms worsen a person's productivity and quality of life and cause sleep disturbances, fatigue or depression. Although it

Studies with tonsil tissue (lymphocytes) and pharyngeal epithelial cells from patients with allergic rhinitis found a reduction in the expression of HBD2. When cells are exposed to Th2 cytokines (IL-4, IL-5 and IL-13) and histamine *in vitro*, they also cause a decrease in the expression of HBD2. Therefore, patients with allergic rhinitis are more susceptible to respiratory infections and severe exacerba-

Rhinosinusitis is characterized by the presence of at least two respiratory symptoms, nasal obstruction and nasal discharge, wherein the presence or absence of nasal polyps is seen. In one study, the sinonasal epithelial cells of patients with rhinosinusitis with nasal polyps showed a decrease in the expression of β-defensin-2 in

It is a very common disease mainly affecting the young children under 3 years of age having episode of otitis media. The pathogenesis of the disease is multifactorial, and among the most important factors are viral infections (respiratory syncytial virus, rhinovirus, influenza A, adenovirus) and bacterial infections (Streptococcus pneumoniae, nontypeable *Haemophilus influenzae* (NTHI), and Moraxella catarrhalis). The acute illness resolves quickly but the chronic or recurrent disease can cause hearing loss

The epithelial cells of the middle ear express HBD2, and two signaling pathways

It is a common chronic obstructive disease characterized by obstruction, hyperreactivity and inflammation. It affects all age groups throughout the world and has high morbidity and mortality rates [119]. Epidemiological studies indicate that the pathogenesis of asthma is multifactorial. The viral respiratory infections are the main cause of exacerbations or asthma attacks; influenza viruses, parainfluenza, rhinovirus and respiratory syncytial are those that have been identified more

The mechanisms that explain how viruses cause or exacerbate asthma are diverse and some are not yet fully characterized. Recent studies indicate that HBD2 may

have been described. HBD2 expression is induced by pro-inflammatory stimuli such as interleukin 1 alpha (IL-1a), tumor necrosis factor alpha (TNF-a), and lipopolysaccharide (LPS). Their transcriptional activation is mediated through an Src-dependent Raf-MEK1/2-ERK signaling pathway [119]. The other known route is when the bacterium is recognized by the TLR2 of epithelial cells through the MyD88-IRAKI-TRAF6-MKK3/6-p38 MAP kinase signal transduction pathway

occurs more frequently in young children, adults are affected as well [18].

response to the presence of IL-4 and IL-13 [114–116].

**8.5 Allergic rhinitis (AR)**

tions [112–114].

**8.6 Rhinosinusitis**

**8.7 Otitis media**

[39, 117].

[117, 118].

**8.8 Asthma**

frequently [120, 121].

**64**

It is a disease in the respiratory tract caused by infection with human papilloma virus. The papilloma virus belongs to the Papovaviridae family. It is a circular double-stranded DNA virus and has no envelope, and its genome is 7200–8000 bp. There are more than 100 serotypes, which due to their oncogenic capacity are divided into high risk and low risk [123].

The disease characterized by abnormal proliferation of epithelial keratinocytes forming a papilloma. It occurs more frequently in the larynx but might spread to the trachea or even lungs. It is common in children 2–4 years of age and in children over 12 years of age and in young adults. The first symptom is progressive dysphonia, with symptoms of variable respiratory obstruction, dyspnea and stridor. Some patients have spontaneous remission and others may have a very rapid growth that may require multiple surgical procedures or cause obstruction resulting in death. Papilloma viruses have a high morbidity rate because of its recurrence, and there are no satisfactory treatments [124, 125].

The serotypes of papilloma that have been found with higher frequency are the serotypes of low risk 6 and 11; nevertheless, a 2% can be infected with other subtypes like the 16 and 18 of high risk, but these are associated with transformation of cells causing carcinoma [123].

The expression of HBD2 in samples of papillomavirus induced lesions in patients with recurrent respiratory papillomatosis, and its association with IL-8 [126] was studied. The lesions showed high levels of HBD2 expression, and the inflammatory process was not significant. Despite the higher expression of HBD2 in the deepseated tissues, the persistence of the virus leads to the disease progression. They suggest that HBD2 can serve as a signaling molecule to induce the adaptive immune response against viral infection with acceptable inflammatory events.

#### **8.10 Diffuse panbronchiolitis (DP)**

DP is a disease with chronic inflammation in the bronchioles of respiratory system. The immune cells are activated, and neutrophils are found in large quantities and activate T lymphocytes. There are often bacterial infections (*P. aeruginosa* and *H influenzae*). The pathogenesis of this disease is not clear; but recently, HBD2 has been implicated. In a study with patients with DP, high levels of HBD2 in bronchoalveolar fluid and plasma were found, suggesting that it could play an important role in the defense against infections. The levels of HBD2 in BAL fluid may be a useful marker of airway inflammation in patients with DPB [127].

#### **8.11 Tuberculosis**

Tuberculosis is one of the most frequent infectious diseases that cause more deaths; its incidence is still a global health problem. *Mycobacterium tuberculosis* is the causative agent of tuberculosis, and it can cause a progressive disease or a latent infection. It has been reported that a third part of the population is latently infected and 10% have active disease. There are many difficulties due to highly resistant strains and fewer therapeutic agents [128].

However, HBD2 is suggested to play an important role in the control of the disease by direct inactivation of the bacteria or as an immunostimulant in vaccines. This bacterium mainly infects macrophages and lung epithelial cells. The *in vitro* studies have shown that *M. tuberculosis* induces the expression of HBD2 in human lung epithelial cells (A549) and is associated with the destruction of bacteria [129, 130].

The transfection of monocytes derived from macrophages with the HBD2 gene increases the ability to control the growth of *M tuberculosis* when compared with non-transfected cells [131]. Children infected with *M. tuberculosis* present high concentrations of HBD2 in bronchoalveolar lavage suggesting its involvement in the pathogenesis of disease.

Results are favorable in animal model studies in mice, mice were vaccinated with DNA vaccines (gene encoding β-defensin-2 and antigens of *M tuberculoisis*) and months later were challenged with *M tuberculoisis* strains. The level of protection was evaluated by survival, and tissue damage. DNA vaccines showed protection with significant higher survival and less tissue damage in the mice [132]. When a person is infected with *M. tuberculosis*, the microenvironment is reduced in oxygen; this triggers the expression of the vitamin D receptor and HBD2 inhibits the growth bacteria. The lack of local oxygen benefits the macrophage for its elimination.

Other signaling pathways that have been discovered are in monocytes through the CD40L and IFN receptors that converge in the activation of vitamin D. HBD2 is expressed and acts against the bacterium *M. tuberculosis* [134].

#### **8.12 Sepsis**

The infectious diseases can cause severe sepsis and the patient's immune system to suffer drastic changes. This study investigated the concentration and the expression of HBD2 in peripheral whole blood cells from patients with severe sepsis. They detected that the peripheral blood cells expressed a decrease in the expression of HBD2. The patient serum showed higher concentrations of HBD2. The patients with severe sepsis have severe inflammatory processes and the proinflammatory cytokines are at high concentrations (IL-1 and TNF); these cytokines also induce the expression of HBD2. It is suggested that these cytokines may be involved in the overproduction of HBD2 in the blood of patients with sepsis. The decreased HBD2 induced in peripheral blood cells was not associated with decreased plasma levels, suggesting that peripheral blood cells do not represent the exclusive source of released protein [135].
