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.
*******************Fig*********
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 Nformyl- 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.