NEUTROPHIL DYSFUNCTION IN PERIODONTAL DISEASES

NEUTROPHIL DYSFUNCTION IN PERIODONTAL DISEASES

Neutrophils are the most abundant type of leukocytes present in the peripheral bloods of humans, constituting approximately 40% to 70% of the total circulating leukocytes. As the primary circulating phagocytic cells, neutrophils play a key role in host defense against extra allular bacteria, especially phylogenic bacteria. They also play a role in the acute phase of inflammatory reactions.

Patients with neutrophil defects, which are either quantitative (neutroperia) or qualitative (adherence, chemotaxis, Microbiocidal activity), often suffer from oral mucosal ulcerations, gingivitis, and for periodontits. Severe oral disease occurs with both primary and secondary neutrophil abnormalities.

The primary neutrophil disorders characterized by severe periodontal disease include mutropenia (chronic or cyclic), leukocyte adhesion deficiency (LAD), chediak - Higashi syndrome, and drug induced agranulocytosis.

Neutrophil abnormalities that occur secondary to underlying systemic disease and that are also associated with severe periodontal disease included insulin dependent (type I) and non-Insulin dependent (type II) diabeter, papillon Lefevre syndrome. Downs syndrome, hyperimmunoglobuliremia E-recurrent infection syndrome (HIE or Jobs syndrome), inflammatory bowel disease (crotins disease), prelenkemic syndrome, acquired immuno deficiency syndrome (AIDS) and acute mycloid denkemia.

The importance of the neutrophil in the defense against periodontal infections has also been strongly supported by studies of LJP (Van dyke et al., 1985; Genco et al., 1986) Neutrophil abnormalities have been demonstrated in patients with LJP as well as in those with rapidly progressing forms of periodontitis (Lavire et al., 1979).

Patients with LJP or rapidly progressing periodontitis are characterized by severe periodontitis but do not appear to be predisposed to extraoral infections (Van dyke 1985; Gerco et al., 1986; Gallin et al., 1988). There observations suggest that the periodontal tissues are one of the first organ systems to be compromised by reductions in neutropil protective functions.

Neutrophils function as a two-edged sword; although they are primarily protective, they also can act as prointammatory alls capable of causing significant tissue destruction. Since the neutrophil is a critical cell in periodontal intentions, a description of its development and function is necessary to gain appreciation for its role in disease.

NEUTROPIL DEVELOPMENT

In normal adults neutrophils are found in the bone marrow, blood and tissues.

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In the bone marrow, neutrophils undngo development and proliferation form blast alls through promydecyte to mydocytu. The finally it forms band alls (or) segmented alls that are no longer capable of mitosis, then there are release into the blood, they circulate for a bout 10 hours. They then migrate into the tissues where they survive for only 1 or 2 days. This migration is either rondom or in response to specific chemical signals callable chemo attractants.

NEUTROPHIL MIGRATION:

Egress from bone marrow, transit across vascular endothelial barriers (diapedesis), and migration to sites of infection or inflammation are critical steps in the expression of neutrophil function.

Infection, inflammation, and stress can lead to elevation in circulating neutrophil levels (neutrophilia) as a result of mobilization of bone marrow reserves. In healthy individual more than 100 billion neutriphils are in transit form the bone marrow daily; but this may increase almost tenfold in patients with a serious infection [normal count 3000-5000 alls /mm3 of peripheral blood].

The process by which neutrophils leave the blood vessels and then proceed to a site of infection has two stages:

1. Leukocyte adhesion to the endothelium:

Here there will be a interaction between surface adenines on the neutrophils and their corresponding Ligands, the cell attachment molecules, on endothelial cells. Modulation of neutrophil adhering and endothelial all attachment molecules by inflammatory mediators triggers neutrophil migration across blood vessel walls.

Maintenance of a constant number of neutrophils in the gingival crevice or periodontal pocket is critical for defense against periodontal pathogens.

Sluggish neutrophil locomotion, resulting in a reduced rate of accumulation of there alls at the Gingival SUICUS, has been demonstrated in patients with LJP and refractory periodentitis. (Genco et al., 1986)

2. Directed migration towards areas of increased chemotaxin concentration:

Chemotaxis, defiend as directed movement of leukocytes along a concentration grapiest of substances called chemoattvactants (or) chemotaxins.

The chemotaxins may be derived from the tissue or form infecting organism.

Chemotaxins that are known to bind to neutrophil receptors include the N-formyl- methionyl peptides (eg, FMLP) complement treatment C5a, and lenkotriene B4 (LTB4).

The adhesion molecules on the leukocyte surface are termed CR3, LFA-1 and CR4 and together constitute one langer family of adhesion molecules called INTEGRINS.

Cell attachment molecules on endothelial cells include inter alulas adhesion molecules 1 and 2 (ICAM-1 and ICAM-2) and endothelial Leukocyte adhesion molecule 1 (ELAM-1).

NEUTROPHIL FUNCTION:

Once neutrophils have entered the circulation and migrated into infected or inflamed tissues, they are ready t perform this phagocytic function. The initial step is target recognition. This involves coating (opsonizing) the infecting organism or host tissue component with plasma proteins. Opsonizaiton facilitates adherence and subsequent phagocytosis of the infecting organism followed by intra allulen killing.

There are both heat stabile & heat labile opsonins in human sera

Heat stabile opsonins ( Antibodies of the IgG and IgG classes

Heat labile opsonins( complement system, of which the C3b and I C3b fragments of C3 are the most important.

The receptor for IgG ( FCY raptor

The receptor for C3b( CRI

Once the organism or particle is coated with opsonins such as immunoglobulin and / or complement components, binding to the neutrophil occurs and Ingestion follows. The particle is taken into the cell in an inside-out cell membrane celled the phogosome. The phagosome then fuses with neutrophil granules, forming a phagolysosome in which the bacteria are killed.

Intracellular killing of microbes by neutrophils:

Neutrophils will microorganisms by means of oxygen-dependent and Oxygen independent mechanisms.

Oxygen independent antimicrobial activity is carried out by a battery of substances, including catharsis L:actoferrin, lysozyme, deferesins, proteases and certain cationic proteins that increase bacterial permeability. Acidification of phagosome may result in either a bactericidal or bacteriostatic effect on many ingested organism.

Oxygen dependent killing mechanisms are linked to the production of toxic Oxygen metabolites such as supevoxide anion and hydreogen peroxide. The hydroxyl radical and signlet oxygen produced by this system are also thought to be toxic for many organism.

The substances involved in microbial killing by neutrophils are contained in to major types of granules:

1. Primary (or) Azurophile granules + 2) secondary (or) specific granules

Azurophilc granules ( contain microbicidal enzymes such as

mydoperoxidase + Lysozyme: neutral proteinares, including beta-giucuronidase; and the cationic proteins.

Specific granules

(Contain the microbicidal enzyme

lysozyme, a callagenare and lactoferrin

PERIDONTAL DISEASES ASSOCIATED WITH NEUTROPHIL ABNORMALITIES

Neutrophil exists when the periodpheral neutrophil count is less than 2000 alls/mm3. However neutrophil protective functions remain relatively intact if the neutrophil count is above 1000 alls/mm3. When the neutrophil count drops below 500 alls/mm3. The incidence of serious recurrent and recalcitrant infections rises markedly.

Oral monifestation:

Cyclic neutroperioa are always associated with severe pcriodontitis. (chen and morris, 1961).

Often the oral infections have been the first in a series of infections and have led to the parents seeking health serious for the child.

In children and young adults with congenital Neutrogena the mucosa may present with black or gray necrotic ulcerations that are sharply demarcated form the uninvolved areas. There may be hemorrhage and necrosis of the gingival margin, and the patients may exhibit increased salivation.

Histopathologically, Bauer (1946) described hemorrhage into the periodontal ligament with destruction of the principle fibres and osteoporosis of the cancellous bone with osteoclastic resorption.

Often the periodontal ulcrations in patients with neutroperia have a Punched-out appearance and may proceed to a progressive periodontitis with sharply demarcated hyperemic zones along the marginal gingival.

Treatment of periodontal disease in cyclic neutroperia requires meticulous attention debridement, plague control and the use of antibiotics. Treatment of periodontal disease in chronic neutropenia is les successful, often resulting in loss of teeth despite aggressive therapy. However symptomatic relief can often be obtained with thorough subgingival scaling and root planing, along with adjunctive topical antimicrobial agents, systemic antibiotics, and long term use of an antiplague agent such as chlorhexidine.

2. Leukocyte adhesion deficiency: (LAD)

Patients with a deficiency in expression of leukocyte adhesions suffer form recurrent infections with phylogenic bacteria, including severe periodontal disease. There patients mostly children, have multiple defects in neutrophil and mononuclear phagocyte adhesion dependent functions, including chemotaxis and CR3-mediated phagocytosis. They also have a persistent leukocytosis, delayed wound healing, and depressed leukocyte mobilization in vivo (Anderson et al., 1985); Anderson and springer, 1987).

Oral and periodontal manifestation:

Several children with LAD have been shown to have marked periodontal disease and severe gingivitis (Thompson et al., 1948). Periodontitis with attachment loss and severe alveolar bone loss is described in a series of children with LAD by woldrop et al., (1987).

Periodontal disease as a complication of systemic diseases in which neutrophil function is compromised.

In systemic disease exhibiting neutrophil abnormalities, oral manifertation, including periodontitis are common. This observation suggests that the common feature (ie. neutrophil defects) in there patients accounts I part for this increases susceptibility to periodontal disease.

Systemic disease with neutrophil abnormalities and severe periodontal disease include ctediak-Higshi syndrome, Diabetes mellitus, downs syndrome, Jobs syndrome, Papillion Lefivre syndrome, Crohns disease, acute monocytic leukemia and AIDS.

1. Chediak Higashi syndrome:

Its a rare autosomal recessive disorder characterized by neutropenia, gingivitis, periodontal disease, and ecurrent pyogenic infections. (Tempel et al., 1973).

This disease is also associated with partial oculocutaneous albinism, photophobia, nystagmus, and progressive peripheral neuropathy. Abnormal lysosomal granules are seen in many cells, resulting form the fusion of Azurophil and specific granules. Severe periodontal disease and gingivitis at on early age have been reported.

Impaired neutrophil and monocyte migration and defective degranulation are thought to be linked to the increased susceptibility to infection, including periodontal disease.

2. Diabetes:

Diabetes basically fall into two clinical types:

i) Type I (or) insulin dependent diabetes mellitus (IDDM)

ii) Type II (or) non-insulin dependent diabetes mellitus (NIDDM)

Each type has a different prognosis, treatment, and cause, although periodontal disease can be a complication for patients with either type.

i) Periodontal disease in IDDM:

Reant studies have shown that children with IDDM are clearly less resistant to periodontal infection. For example, Gislen et al., (1980) shoed that diabetic children who had poor metabolic control had more gingivitis than children who were not diabetic.

Many researchers also found that the greater prevalence of periodontal disease in diabetic patients could not be explained by plaque or calculus levels, since there irritants were at similar levels in diabetic as compared with non diabetic patients.

The subgingival microflora in IDDM patients with periodontitis was studied by msdhimo et al., (19830. It was found that the cultivable microflora predominantly capnocytophaga and anaesobic vibrios. In the majority of periodontitis patients, Actinobacillus actinomyletem comitans was also found. However, fow block-piqmented Bacteriodes, such as B. gingivalis (or) B. intermedius species, were found.

Some studies have shown that the floras in IDDM patients with periodontitis resemble that seen in other Jurenile forms of periodontal disease with A.A as a major candidate pathogen. Thus decreased host response most likely leads to an increased risk for periodontal disease in Juvenile diabetes that is probably directly related to the lack of diabetic control.

Dentists seeing IDDM patients with severe periodontal disease should work with the patients and the primary physician top achieve control of the diabetes at the same time that they are treating the periodontal infection.

ii) Periodontal findings in NIDDM:

Early studies pointed to a greater rate of progression of periodontitis in NIDDM patients than in nondiabetic patients (Cohen et al., 1970).

Periodontal disease in diabetics is often characterized by multiple abscesses and granulation tissue. Rapid onset and severe bone loss was also observed in young individuals with NIDDM.

Periodontal disease severity is often correlated with diabetic control as indicated by the level of glycosylated lemoglobin. As diabetic control deteriorates, the glycosylated lemoglobin level increases.

It is clear, then, that diabetes is a major risk factor for periodontal disease. Patients with diabetes can be identified, and long term metabolic control of the diabetes, along with intensive periodontal preventive regimens, offers hope for preventing periodontal disease in diabetic patients.

4. Downs syndrome:

It is one of the best-known and most frequently occurring autosomal trisomic disorders. It is trisomy 21. This syndrome affects 1 in 700 live births.

The phenotype of Downs syndrome is characterized by an atypical facial appearance with epicanthic folds, a broad bridge of the nose, protruding tongue open mouth, square shaped cars, and a flattered facial profile.

Patient with downs syndrome are often susceptible to infections and about one half suffer from neutrophil functional defects.

Periodontal disease has also been associated with downs syndrome (saxen et al., 1977). The increased susceptibility of there patients to periodontitis has been associated with endogenous and exogenous factors (Renland Basma and Van Dijk 1986).

Abnormal neutrophil function like depressed bactericidal function, chemotaxis and respiratory burst activity ware also seen.

Phagocytic disorders

1) Jobs syndrome (hyerimmunoglobulinemia E-recurrent infection syndrome)

Jobs syndrome is associated with otitis, sinusitis, staphylococcal pneumonia, turunculosis and allulitis.

Patients with Jobs syndrome have extreme elevation of serum IgE levels, including IgE antibodies against S. aureus and candida albicans. They also have depressed acute inflammatory responses, as evidenced by cold abscesses.

Abnormal neutrophil and monocyte chemotaxis ahd been documented, for the depressed inflammation and recurrent infection

There have been reports of more severe periodontal disease inpatients with jobs syndrome.

2) Papillon lefivre syndrome

It is a rare, autonomal recessive disorder characterized by hyperkeratotic palms and soles.

Severe periodontal disease resulting in exfoliation of the primary and permanent dentition is one of the most constant features of papillon - lifevre syndrome and therefore is important in its diagnosis.

Periodontal lesions being shortly after eruption of both the primary and permanent dentitions. The periodontium is often affected in the order of tooth eruption; in addition, the teeth exhibit marked inflammation and suppuration, and there is bleeding of the gingiva, pocket formation, and loosening and spontaneous exfoliation, often without root resorption. After loss of the permanent dentition, healing is uneventful and tures are tolerated.

The immunologic status of patients their papillon-lefivre syndrome ahs been elucidated, and defects in cellules immunity (Djawari, 1978), neutrophil motility (Van dyse et al., 1984) are reduced neutrophil bactericidal activity. (Shasm Ei Duin et al., 1984) are found. The abnormality in neutrophil locomotion is associated with a decrease in reandom migration, which manifests itself as a decreasre inchemotaxis (Van Dyke et al., 1984).

The flora found in there patients is made up of A. Actions mycetemcomitans, B. Intermedius and capnocytophaga, which are typically foudninperiodotitis lesions of other Jurenile patients.

CONCLUSION

In summary, it can be seen that nentrophil disorders that either primary or secondary to systemic disease are often associated with severe periodontal disease. Hence neutrophil dysfunction is a risk factor periodontits, most likely lowering the hosts resistance to periodontal infection by periodontal organisms.