Indian Journal of Dental Research

REVIEW ARTICLE
Year
: 2015  |  Volume : 26  |  Issue : 4  |  Page : 340--344

Defensins in periodontal health


Taran Bedi, Jaideep Mahendra, N Ambalavanan 
 Department of Periodontics, Meenakshi Ammal Dental College, Maduravoyal, Chennai, Tamil Nadu, India

Correspondence Address:
Jaideep Mahendra
Department of Periodontics, Meenakshi Ammal Dental College, Maduravoyal, Chennai, Tamil Nadu
India

Abstract

Defensins are abundant and widely distributed peptides in human and animal tissues that are involved in host defence. Defensins not only have the ability to strengthen the innate immune system but can also enhance the adaptive immune system by chemotaxis of monocytes, T-lymphocytes, dendritic cells and mast cells to the infection site. Defensins also improves the capacity of macrophage phagocytosis. A greater understanding of how these peptides act in the healthy, gingivitis and periodontitis conditions would definitely open new opportunities for identification, prevention and treatment of periodontal diseases. This discussion focuses on recent studies about biological function of defensins in human diseases and animal models.



How to cite this article:
Bedi T, Mahendra J, Ambalavanan N. Defensins in periodontal health.Indian J Dent Res 2015;26:340-344


How to cite this URL:
Bedi T, Mahendra J, Ambalavanan N. Defensins in periodontal health. Indian J Dent Res [serial online] 2015 [cited 2019 Sep 18 ];26:340-344
Available from: http://www.ijdr.in/text.asp?2015/26/4/340/167627


Full Text



Periodontitis is one of the most common causes of tooth loss in adults.[1] The etiology of this chronic infection can be considered to be the result of bacterial colonization by a variety of pathogenic microorganisms, including Porphyromonas gingivalis, and Aggregatibacter actinomycetemcomitans, which exist in the biofilm. The colonization and subsequent invasion of these Gram-positive and Gram-negative microorganisms into the gingival epithelium leads to an innate immune response, including the production of various mediators as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α).[2] This leads to inflammation, which ultimately results in the periodontal attachment loss and bone loss.[3] Once the innate response, that acts as the first line of defense has been breached the adaptive immune response acts as a coping mechanism. The adaptive response is activated all the time through a further diverse range of antimicrobial peptides, which directly kill a range of bacteria (both Gram-positive and Gram-negative species), fungi, and some viruses.

Antimicrobial peptide families are majorly defensins and cathelicidins. More than 800 antimicrobial peptides molecules have been identified; almost half are linear, and half have disulfide bridges, including over 200 defensins. Many are insect or plant derived, but almost 30 have been identified from mammals.[4]

The first defensins were isolated from rabbit lung macrophages,[5],[6] although the name defensin was coined 2 years later when three such molecules were extracted from human neutrophils.

Structurally similar peptides in human leukocytes 1, 2 were discovered and were named “defensins” based on their association with host defense settings. Defensins have been isolated from leukocytes and various types of epithelial cells 12, 13.

Defensins exhibit role in innate and adaptive immunity and remarkable antibacterial, antifungal and antiviral activities. The wide-spread occurrence of defensins has led to their identification, isolation, and characterization.

 Occurence and Distribution



Defensins are expressed in large numbers and various forms in normal human tissues, and in inflamed or infected human tissues. They are present in oral tissues,[7],[8] salivary glands,[9] salivary secretions,[10] and gingival crevicular fluid [11] and are ideally positioned to trigger adaptive immune responses in the oronasal cavity.

Both α- and β-defensin are localized in different parts of gingival epithelium. β-defensins such as DEFB1, DEFB2, DEFB3 are expressed in the oral and sulcular stratified epithelium of gingiva, but α-defensin are expressed in the junctional epithelium.

The genes, which are responsible for defensin production are highly polymorphic. α-defensin are expressed by polymorphonuclear leukocytes, and β-defensin are expressed by mucosal epithelial cells.[12]

The human neutrophil peptide (HNP1-4) present in neutrophils shows antimicrobial activity against Gram-positive, Gram-negative bacteria and fungi. Other human defensin (5, 6) are also seen in human intestinal paneth cells, but do not show any particular antimicrobial activity.

 Classification



Human defensins can be broadly classified into 2 types:

α-defensin β-defensin.

α-defensin

α-defensin are further subdivided into various types [Table 1].{Table 1}

β-defensin

The hallmarks of a β-defensin are its small size and high density of cationic charge [Table 2].{Table 2}

 Synthesis



α-defensin

The α-defensin are synthesized as preprodefensins in Paneth cells, they are further secreted into the lumen of the small intestine where they are proteolytically cleaved into active antimicrobial peptides.

β-defensin

β-defensin are synthesized in the epithelial compartment. In epithelial cells, it has been found that human β-defensin (hBD) genes are both constitutively expressed and inducible.

The two defensin families have various structural differences suggesting that they could be stored and packaged by distinct intracellular pathways and mobilized differently from the respective cells.

 Structure



The characteristic feature of all the defensins is their 3-disulfide bonds via pairs of cysteine residues. As shown in [Figure 1], the α-defensins are slightly smaller peptides in β-sheet arrangement of 29–35 residues, whereas the β-defensin are more basic and have 38–42 amino acids. Human α defensin, HNP-3 was determined by Hill et al.[21] Despite the great homology between members of the defensin families, small changes result in markedly different antibiocidal abilities.{Figure 1}

The backbone conformations of the three major classes of defensins are shown in [Figure 2]. Here, the tubes depict backbone conformation, and the disulfides are indicated as narrow rods. The structures have been arranged and hence that β hairpins have similar orientations:

Dimeric α-defensin Two monomeric α-defensin β defensin and insect defensin.{Figure 2}

 Role of Defensins in Immune Response



Role of defensins in innate immune response

The germ line-encoded receptors on epithelial cells and phagocytes act as sentinels of the host–environment boundary. The innate immune system relies on these receptors. These pattern-recognition receptors (PRRs) recognize conserved pathogen-associated molecular patterns such as lipopolysaccharide (LPS), peptidoglycan, zymosan and possibly isoleucine.[23] These PRRs initiate an appropriate antimicrobial response and try to contain the infection, which involves the up-regulation of specific antimicrobial peptides including defensins.

The second major task of innate immune system is to activate adaptive immune response against the invading organism.

Recent data suggests that defensins may play a key role in:

Recruitment Activation of the appropriate adaptive effector response.[24]

Role of defensins in adaptive immune response

Adaptive immune response comes into play in periodontitis after the first line of defense has been breached. Defensins are produced by the junctional and sulcular epithelium in the cells traversing the epithelium, as an important weapon of adaptive immune response. They directly kill a range of bacteria (both Gram-positive and Gram-negative species), fungi, and some viruses.

Defensins exihibit stimulatory effects on humoral and cell-mediated immune elements which illustrate their role in adaptive immune response.[23],[24]

Human α-defensin are chemotactic to monocytes, dendritic and T-cell at 10–10 M concentration, suggesting their importance in shaping the adaptive immune response.

A. Human β-defensins are chemotactic for dendritic and memory T-cell through the chemokine receptor CCR6.[25] In a murine model, human neutrophil defensins when delivered intra-nasally with ovalbumin, show enhanced systemic adaptive immune response by increasing antigen-specific IgG and IgM levels in serum.[26] β-defensin gene expression, and their up-regulation in the presence of bacterial LPS and TNF-α emphasize that these molecules function to protect the host against microbial pathogenesis at the critical confrontation sites.

 Gingival Defensins



Defensins have been associated with saliva.[4],[20] They are also present in the. The oral, sulcular/pocket, junctional epithelia, as well as dentogingival junction, are all associated with defensin expression. They are also associated with discrete areas of the underlying connective tissue in association with polymorphonuclear leukocytes.

More specifically,

The β-defensin hBDl, hBD2[27] and hBD3[28] are all found in the oral and sulcular/pocket epithelium but not in the junctional epithelium The mRNA is found principally in the suprabasal layers of the epithelium hBDl and hBD2 messages are most significantly expressed in the spinous layer Peptide is found primarily in the upper spinous and granular layers, with a tendency for hBD2 to be found slightly more suprabasally than the hBDl.

Dunsche et al.[28] reported a slight decrease in expression of these molecules in inflamed tissue in comparison to healthy, as detected with reverse transcriptase-polymerase chain reaction.

The absence of the β-defensin from the junctional epithelium and the tendency for expression to be concentrated in well-differentiated epithelium suggests that defensin production is linked to epithelial differentiation, to support this concept a study was done by Abiko et al.

In contrast to the epithelially expressed β-defensin, the α-defensin (HNP1-3) are found in the junctional epithelium, but always in close association with positively staining neutrophils, which pass through the tissue even in health.

 Periodontal Disease and Defensins



Periodontitis is a common chronic infectious disease associated with the formation of a predominantly Gram-negative anaerobic biofilm in the gingival crevice or periodontal pocket.

Defensins in the oral cavity inhibit IL-1β-induced secretion of IL-8 in both gingival epithelial cells (GECs) and THP-1 cells. This anti-inflammatory activity is associated with a reduction in activation of nuclear factor-κB, suggesting that they can act both as an anti-biofilm agent in an anaerobic environment and as an anti-inflammatory agent in infected tissues. They exert proinflammatory effects on various immune cells. hBDs induce cyclooxygenase-2 expression and prostaglandin E2 synthesis in human gingival fibroblasts.

In the environment of the periodontal pocket, bacterial tissue invasion and high levels of protease activity cause increased levels of activated α 2-macroglobulin, which is the major serum protease inhibitor and upon activation it binds to defensin peptide.[29] The defensin α 2-macroglobulin interaction may constitute an important mechanism in the host–pathogen interaction. This interaction leads to direct deactivation or clearance of defensins by dermatan sulfate and α 2-macroglobulin. Hence, defensin levels will be decreased by activated α 2-macroglobulin.

In addition to their direct antimicrobial activity, hBDs are constitutively expressed by GECs. hBDs directly stimulate antigen-presenting dendritic cells and memory T-cell, and thus can link innate and adaptive immune responses.[30],[31] They also provoke efficient epithelial barrier repair to limit entry of invading bacteria.[32] Antimicrobial peptides provide multiple benefits as frontline defense molecules, and are particularly important in the oral cavity in which the health of the tissue depends on the balance between commensal (nonpathogenic) and pathogenic microbes and host defenses [Table 3].{Table 3}

 Future Paradigms



Hence, the past research establishes the fact that defensins play a major role in adaptive and innate immunity. However, less research has been focused on the pharmaceutical application of defensins as an alternative to circumvent microbial adaptive resistance and toxicity associated with conventional antibiotics.

Defensins might serve as immuno-modulators to activate the immune system suppressed by infection and inflammation. The current knowledge of defensins envisages the possibility of their utilization as a new class of natural antibiotics to overcome microbial adaptive resistance to existing conventional antibiotics. In future studies, the role of defencins will be elucidated for the antimicrobial activity.[42]

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