This document discusses neutrophil disorders and their relationship to periodontal diseases. It begins with an introduction on the role of neutrophils in the innate immune system and periodontal diseases. It then describes various quantitative and qualitative neutrophil disorders. Quantitative disorders discussed include chronic benign neutropenia, cyclic neutropenia, congenital neutropenia, agranulocytosis, and Felty's syndrome. Qualitative disorders result from defects in neutrophil functions like rolling, adhesion, chemotaxis, phagocytosis, and intracellular killing. The document examines the oral complications that can result from various neutrophil disorders like gingivitis, periodontitis, and bone loss.

1. PMN DISORDERS AND PERIODONTAL
DISEASES
BY
DR. ANTARLEENA SENGUPTA
I MDS, DEPTT. OF
PERIODONTOLOGY,
MCODS MANGALORE
2019

2. CONTENTS

3. - INTRODUCTION
- ROLE OF NEUTROPHILS
- CLASSIFN OF NEUTROPHIL DISORDERS
- QUANTITATIVE DISORDERS:
I. CHR. BENIGN NEUTROPENIA
II. CYCLIC NEUTROPENIA
III. CONGENITAL NEUTROPENIA/KOSTMANN’S
IV. NEUTROPHILIA AND PERIODONTITIS
V. AGRANULOCYTOSIS
VI. FELTY'S SYNDROME
- QUALITATIVE DISORDERS:
NEUTROPHIL DYSFUNCTION
I. DEFECT IN ROLLING-- LAD II
II. DEFECT IN ADHESION-- LAD I
III. DEFECT IN CHEMOTAXIS
IV. DEFECT IN PHAGOCYTOSIS
- PAPILLON-LEFEVRE
- DOWN'S
- LAZY LEUKOCYTE SYNDROME
- HYPER-IgE SYNDROME/ JOB'S
- DM
V. DEFECT IN INTRACELLULAR KILLING
- OXIDATIVE MECH: CHRONIC GRANULOMATOUS
DISEASES
- NON-OXIDATIVE MECH: SPECIFIC GRANULE DEFICIENCY,
CHEDIAK- HIGASHI SYNDROME
- IBS
- SLE
- MPO DEFICIENCY
- GLYCOGEN STORAGE DISEASE TYPE 1B
- ACATALASIA
- NETosis
- CONCLUSION
- REFERENCES

4. INTRODUCTION
• Periodontal diseases -- infectious diseases resulting from the interactions
of oral bacteria residing in dental plaque and the host
• Neutrophils form the first line of defence of the human innate immune
system. (Bender et al., 2006)
Myeloid-derived
Antimicrobial
Phagocytes
Can kill pathogens extracellularly
Links innate and adaptive arms of the immune response
Help to endorse the inflammatory resolution and tissue

5. ROLE OF NEUTROPHILS
• Since neutrophils are not concerned with their own survival, they are free to use delivery modes which
can be suicidal.
• Neutrophils deliver antimicrobial substances by different mechanisms
1. Adherence — When stimulated, the neutrophil interacts with, and sticks to, substrate (endothelial
cells) via specific molecules on the neutrophil and the endothelial cell.
2. Chemotaxis- Neutrophils migrate to sites of bacterial ingress or tissue damage through the process
of chemotaxis.
3. Opsonization & Phagocytosis-
- The neutrophil recognizes specific molecules on the bacterial surface called opsonins (IgG, C3b) and
engulfs the bacteria.
- Phagocytosis is the engulfment of particles within a membrane-bound structure called the
"phagosome."
- Fusion between the cytoplasmic granules (lysosomes) and the phagosome form the "phagolysosome,"
and represent a specialized form of secretion.
4. Bacterial Killing – The neutrophil is responsible for bacterial killing by 2 pathways for controlling
microorganisms- oxygen dependent and independent mechanisms

6. NEUTROPHIL DISORDERS
QUANTITATIVE QUALITATIVE
• Neutropenia– mild, moderate, severe
• Kostmann Syndrome (OMIM- Online
Mendelian Inheritance in Man 610738)
• Felty’s Syndrome
• Lazy leukocyte syndrome
• Neutrophilia
• Herman sky–Pudlak syndrome
• Shwachman–Diamond syndrome.
Defects in Adhesion
Defects in Chemotaxis &
Phagocytosis
Defects of killing
& degradation
• Leukocyte
adhesion
deficiency
• LAD I
• LAD II
• Papillion Lefevre
Syndrome
• Down’s Syndrome
• Lazy Leukocyte
Syndrome
• Hyper IgE Syndrome
• Diabetes mellitus
• Chediak Higashi
Syndrome
• Myeloperoxidase
Deficiency
• Specific Granule
Deficiency
• Chronic Granulomatous
Disease

7. Quantitative Disorders:
1. Chronic benign neutropenia
2. Cyclic Neutropenia
3. Congenital Neutropenia
4. Agranulocytosis
5. Felty’s Syndrome

8. • A relative deficiency in neutrophil no. can dramatically increase susceptibility to
infectious diseases.
• Neutropenia is considered clinically significant when the ABSOLUTE NEUTROPHIL
COUNT falls <1000 cells/ml (normal adult range: 1500-8000 cells/ml)
 When the absolute neutrophil count is <500 cells/ml, control of endogenous factors
is often impaired & the risk for serious infection increases.
 An absolute neutrophil count <200 cells/ml corresponds with an inability to mount
an inflammatory response.
• Defects in any of these functions or a marked decrease in the no. of neutrophils capable
of responding to the site of infection may result in varying degrees of susceptibility to
infection.
• These qualitative & quantitative defects may be:
1. Inherited
2. Acquired

9. Quantitative disorders include:
• Neutropenia can be an
• Inherited Disorder or
• Congenital Disorder or
• Acquired Secondary to
Infection or
Malignancy or
Certain Medications or
Autoimmune Disease or
Nutritional Deficiencies or
Hematopoietic Disease
The Pathophysiology of Neutropenia may
be classified as
• Abnormalities of Bone Marrow Stem
Cell Development
• Impaired Release of Neutrophils from
the Bone Marrow
• Abnormalities in Distribution of
Neutrophils b/w the Circulating &
Marginating Pool in the Blood
• Decreased Survival of Neutrophils in
the Blood
Diagnosis of Neutropenia is based on Clinical Signs & Symptoms as well as Absolute Neutrophil Counts

10. CHRONIC NEUTROPENIAS:
The Risk of Infection due to Neutropenia is Typically Inversely Proportional to the Absolute Neutrophil
Count
Absolute Neutrophil Count Effect
<1000 cells/ml Risk of Stomatitis, Gingivitis, Cellulitis
<500 cells/ml Pneumonias, Peri-Rectal Abscesses, Sepsis etc.
• Low Absolute Neutrophil Count for >6 months.
While any episode can predispose a patient to recurring infections, the following neutropenic conditions have been
specifically identified in the dental literature as having oral complications:
• Chronic benign neutropenia
• Cyclic neutropenia
• Congenital neutropenia/Kostmann Syndrome
• Agranulocytosis
• Felty’s Syndrome

11. Chronic Benign Neutropenia:
• Characterized by a prolonged neutropenia as the sole abnormality, with no underlying
disease to which the neutropenia can be attributed
• It is the most common form of neutropenia of infants & children <4 years old, with 90%
of the cases presenting <14 months of age
• The incidence of chronic benign neutropenia is 3.9/100,000 births
• Chronic benign neutropenia is usually not inherited; however, the familial form follows
an autosomal dominant mode of inheritance

12. • Glanssen, 1941
• Bousser et al., 1947
• The clinical presentation can be quite variable, from a benign condition discovered
incidentally to an early life-threatening infection, but most patients with chronic benign
neutropenia will live a normal lifespan
• Individuals may suffer from increased incidences of
 Recurrent oral ulcerations
 Furuncles
 URTIs
 Otitis media
 Cellulitis
 Lymphadenopathy
 Pneumonia
 Sepsis
As a result of the limited neutrophil response to infection
• Fortunately, as these individuals get older, the risk of infection appears to decrease

13. •Oral complications:
• Include
 Hyperplastic, oedematous, & fiery-red gingiva
 Areas of desquamation
• Reichart et al (1978) reported on a 7 year old boy with chronic gingivitis,
periodontitis with 8 mm PPD, severe horizontal bone loss, & extreme
mobility of the deciduous teeth with chronic benign neutropenia
• Deasy (1980) described a 14 year old boy with chronic benign
neutropenia who was referred due to severe gingival inflammation,
hyperplastic papillae, isolated areas of gingival recession, & a molar
furcal lesion
Diagnosis:
• Persistent absolute neutrophil count <500 cells/ml with a normal TLC due to
elevated no. of lymphocytes & monocytes
• A possible causative agent for this condition is anti-neutrophil Ab, typically IgG

14. Cyclic Neutropenia:
• RARE blood disease characterized by:
• Periodic recurring symptoms of fever, malaise, mucosal ulcers.
• Life-threatening infections related to the regular cyclical fluctuations in the no. Of neutrophils.
• Autosomal dominant mode of inheritance.
• Incidence: 0.5-1 case/1000000.
• Cyclic neutropenia is caused by the periodic oscillations in both bone marrow production &
release of mature neutrophils, probably associated with the oscillation of other blood cells,
such as monocytes, eosinophils, lymphocytes, & platelets.
• Bone marrow progenitor cells are present in high conc.; However, these precursor cells seem
periodically unable to respond to granulocyte colony-stimulating factor.
(OLVERA et al., 2015)

15. Oral complications:
• Case reports by Okada et al. (2001) of a 2 year old that presented with
 Recurrent gingivitis & aphthous lesions.
 Clinically, no recession was noted & PPD were within normal limits.
 Analysis of the microbial flora found P. intermedia, C. rectus, Capnocytophaga gingivalis, &
Capnocytophaga sputigena
 In spite of treatment, the child continued to experience gingivitis during 2 years of follow-up.
• Numerous other case reports have documented patients with a history of marked gingival inflammation,
fever, oral ulcerations, otitis media, & URTIs associated with cyclic neutropenia.
Diagnosis:
• CBC count twice a week for 6 weeks in order to observe the fluctuation in neutrophil counts.
• For the majority of these patients, there is a 21 day cycle with severe neutropenia persisting for 3-10 days
Treatment:
• Rh-granulocyte colony-stimulating factor given 3x/week has been found successful in increasing the
neutrophil levels (Mannon, 2009)
• γ-globulin infusions have also been given to effect a short-lived increase in neutrophils in an URGENT
SITUATION (Guo, 2018)

16. Congenital Neutropenia/Kostmann Syndrome:
• Inherited hematologic disorder manifesting in the 1st year of life
• Characterized by the severe bacterial infections
• The estimated frequency of congenital neutropenia is 1-2 cases/1000000
population with no sex predilection
• Autosomal recessive trait
• Diagnosis:
The significant lab finding absolute neutrophil count of <2,000/ml & an arrest of neutrophil
hematopoiesis at the promyelocyte/myelocyte stage

17. ORAL COMPLICATIONS:
• Virtually universal in congenital neutropenia.
• Carlsson & Fasth (2001)-- all of the patients that survived
infancy were affected by gingivitis, & most were noted to
have periodontitis with alveolar bone loss.
• Another case report by Defraaia & Marinelli (2001)
demonstrated generalized severe periodontitis in an
adolescent patient with congenital neutropenia.
• Even with granulocyte colony-stimulating factor treatment,
most of these patients have persistent gingivitis, which tends
to wax & wane depending on their absolute neutrophil
counts

18. • In 1987, physicians began to treat congenital neutropenias with granulocyte colony-
stimulating factor, which is effective at increasing the absolute neutrophil count
>1,000/ml in most patients.
• Even though granulocyte colony-stimulating factor treatment results in an overall
improvement in symptoms, the therapy is not curative & most patients experience
cyclic improvements followed by relapses in neutrophil levels
• In most cases of congenital neutropenia, the underlying mechanism of the syndrome is
unknown.
• While most of the originally reported cases died in infancy only, aggressive treatment with
antibiotics has more recently prolonged the lifespan of children suffering from this disease

19. NEUTROPHIL COUNTS AND PERIODONTITIS
• Aggressive periodontitis ↔ congenital deficiencies in neutrophil numbers or
function (Hajishengallis et al., 2015)
• Inflammatory destruction of the periodontium -- collateral damage by hyperactive
neutrophils or neutrophils present in excessive numbers (Ryder, 2010)
• Local counts of neutrophils in the periodontal tissues correlate positively with
periodontal disease severity (Landzberg et al., 2014)
• Neutrophils can contribute to the pathogenesis of periodontitis, not only by
overexuberant activity but also by failing to perform regulatory functions.
(Moutsopoulos et al, 2014)

20. Agranulocytosis:
• Agranulocytosis is a blood dyscrasia characterized by a decrease in or even the
disappearance of granulocytes (including neutrophils) in conjunction with peripheral
leukopenia.
• The decreased no. of granulocytes can result from either a decreased production or an
increased peripheral destruction of cells.
• Decreased production of granulocytes is usually due to
 Bone marrow hypoplasia
 Drugs e.g., antithyroid (carbimazole, methimazole), anti-inflammatory medications
(sulfasalazine, dipyrone) and NSAIDs, antipsychotics (Clozapine)
 Ionizing radiation
 Infection
 Vitamin deficiencies
 Bone marrow tumors

21. • Clinically, patients with agranulocytosis do not always present with the usual signs &
symptoms of infection.
• Patients often are febrile & may exhibit necrotizing, gangrenous lesions of mucous
membranes, to include oral, gastrointestinal, & vaginal membranes, but without
purulence.
• Oral complications:
• Include generalized, painful stomatitis, spontaneous bleeding & necrotic tissue.
• Radiographs generally reveal a progressive pattern of bone loss at an early age.
• Depending on the cause & duration of the agranulocytosis, severe periodontitis & tooth
loss can be expected

22. Felty’s Syndrome:
• Uncommon complication of rheumatoid arthritis, in which splenomegaly & leukopenia are the
major additional features.
• In addition to the distinguishing triad (complication of rheumatoid arthritis, splenomegaly,
leukopenia) of symptoms, various case reports have listed other recurring symptoms including
 Weight loss
 Progressive weakness
 Hyperpigmentation of the skin
 Generalized lymphadenopathy
 Hepatomegaly
 Increased susceptibility to infection
 A variety of abnormalities in WBC count & function (YAZICI, 2014; NEWSON, 2015; KAY, 2019)
• Incidence of Felty’s syndrome is in about 1% of all rheumatoid arthritis cases.

23. • The leukopenia noted in Felty’s syndrome is primarily due to lack of circulating neutrophils
(<1000cells/µl)
• Coakley et al. & Kumakara et al. listed the possible causes as
 Anti-Neutrophil Ab
 Serum Inhibitory Factors directed against Neutrophil Precursors
 Suppressor Action by Cytotoxic T-cells
 Phagocytosis of Neutrophils within the Bone Marrow
• Several Mechanisms have been suggested to explain this phenomenon, including
 Insufficient Formation of Neutrophils
 Reduced Release of Neutrophils from the Bone Marrow
 Shortened Neutrophil Life Span
 Excessive Neutrophil Margination

24. - Not all Felty’s Syndrome patients have the Extreme Neutropenia that predisposes them to infections
- For those who do, SPLENECTOMY has been successful at Increasing the Neutrophil Count & Relieving
Symptoms in up to 80% of patients.
- Drug Therapy has included
Li2CO3 (Mant, 1986)
γ-globulin (Breedveld, 1985; Kay, 2019)
Corticosteroids (Liatsos, 2018) – Prednisone 1 mg/kg I.V.
Cyclophosphamide (Wiesner, 1977; Kay, 2019)
• Successful outcomes have been noted with the use of Rh-Granulocyte Colony-stimulating Factor, although
significant side effects have been noted in some Felty’s syndrome patients. (SJ Stanworth, 1998)
•ORAL COMPLICATIONS:
• While Oral Ulceration & Stomatitis are frequently mentioned in reports of Felty’s syndrome,
Periodontitis has only rarely been implied.
• Even though, it can be assumed that with the Dramatic Deficiency in Circulating Neutrophils, the
Incidence of Periodontitis is as at least as great in Felty’s Syndrome patients as in others with
Severe Neutropenias.
TREATMENT OF THE NEUTROPENIA ASSOCIATED WITH FELTY’S SYNDROME:

25. QUALITATIVE DISORDERS

26. NEUTROPHIL DYSFUNCTION
The Neutrophil’s employment of specialized features enabling their Destruction of Invading
Organisms can be divided into 6 Stages or Functions:
• Rolling along Vascular Endothelium
• Adherence to the Endothelial Lining
• Migration (Chemotaxis) towards the Site of the Infection
• Adherence to Microorganisms
• Engulfment of Bacteria (Phagocytosis)
• Intracellular Killing

27. - Qualitative disorders of neutrophil function also increase the host’s susceptibility to infection.
- Classification of neutrophil disorders corresponds with the major neutrophil processes:
• Margination (rolling & adhesion)
• Chemotaxis & migration
• Phagocytosis, degranulation & killing
Defects in the process of margination can occur at 2 levels.
1. Defect in rolling:
• The 1st is a defect in a specific neutrophil ligand -- Sialy-Lewis x protein (cd15s)”. A defect in this glycoprotein
will result in the loss of the neutrophil’s ability to roll along the endothelial surface
• Alterations in the selectin-mediated rolling function prevent the neutrophil’s egress from the vessels
• This defect is detected through flow cytometry using a commercially available monoclonal Ab directed against
the membrane surface Ag associated with cd15s. The disease associated with this deficit is LAD-II

28. 2. DEFECT IN ADHESION:
• Defects in neutrophil surface integrins CD18/cd11a, CD18/cd11b, & CD18/cd11c prevent the neutrophil from
adhering to the endothelium. Inability to adhere to endothelial cells prevents the migration of neutrophils to
the site of infection.
• In addition, since these integrins are also responsible for neutrophil adhesion to opsonized bacteria, the
neutrophil’s ability to phagocytize bacteria is also compromised.
• Defects on cd18 & cd11 peptides are also identified by flow cytometry
• Deficiency of these integrins is seen in LAD-I

29. LAD (Leukocyte Adhesion Deficiency)
• 1979 -- Neutrophil Motility Defect.
• Anderson & Springer, 1986  “Leukocyte Adhesion Deficiency”
• Leukocytes adhere to endothelium surface, other leukocytes, & to complement via cell
surface integrins
• These integrins are protein complexes that are stored within neutrophil granules & when
activated, are found on the surface of the neutrophil cell membrane
• The Initial studies on LAD patients found a Defect in the Neutrophil Integrins CD11 & CD18
• Subsequent investigations into this disorder have identified 2 types of LAD i.e. LAD-I and
LAD-II

30. LAD-I
• Deficiency in 3 Membrane Integrins.
• CD18/C11a (LFA-1) binds to leukocytes & to endothelium via Intercellular Adhesion Molecules
(ICAM)
• CD18/CD11b (Mac-1) binds to ICAM & complement & facilitates complement-mediated
phagocytosis
• The function of the 3rd Integrin, CD18/Cd11c is not well understood
• The deficiency of these integrins prevents the neutrophil from adhering to the vessel wall at the
site of an infection.
• Therefore, neutrophils are unable to migrate into the affected tissues.
• Clinical appearance:
• Ulceration & necrosis of tissue
• No signs of purulence

31. LAD-I
[HAJISHENGALLIS et al., 2015]

32. ORAL COMPLICATIONS:
• Waldrop TC et al.(1987) described the Oral
Conditions in a Family of 6 that suffered from LAD-I.
 The Father & 2 Children were Homozygous for
the Condition
 The Children presented with Acute Gingival
Inflammation of both Primary & Permanent
Dentitions, as well as Gingival Proliferations,
Recession, Tooth Mobility, & Pathologic
Migration
 The Primary Teeth were Lost by age 4 & Either
Partial or Total Loss of the Permanent Teeth
occurred by age 13
 Bone Loss was evident by age 3, & reached
60% by age 8
 Histology of the Gingival Tissue showed a
Dense Plasma Cell Infiltrate & the Marked
Absence of Extravascular Neutrophils

33. LAD-II
• Etziomi et al., 1992
• Individuals with LAD-II are characterized by
• Short Stature
• Mental Retardation
• Craniofacial Abnormalities
• Recurrent Infections
• The Neutrophil Defect in LAD-II is of the Sialy-Lewis x Glycoprotein (CD15s), which allows
neutrophils to attach to selectins (CD62E) on the endothelial surface
• The end result is similar to LAD-I, & neutrophils are unable to migrate extravascularly
• While the oral condition of these patients has not been reported, it can be assumed that the
neutrophil defect is such that severe periodontal disease & tooth loss is likely

34. • Deficits in neutrophil chemotaxis can be either “inherited, or secondary to a no. of other
neutrophil defects caused by a variety of diseases or medications”
 Any alteration in the neutrophil cytoskeleton or its ability to sense or respond to a
chemotactic gradient will interfere with the cell’s ability to reach the site of infection
• Neutrophil chemotactic deficits are diagnosed in-vivo through the use of the “Rebuck skin
window” or in the laboratory using a “Boyden chamber” or the “Agarose tech”
3. DEFECT IN CHEMOTAXIS:

35. • Impairment of phagocytic function is usually caused by deficiencies in certain
immunoglobulin isotypes & other opsonization factors rather than intrinsic defects in the
neutrophil.
• Assays of phagocytosis utilize either inert particles (stained oil-droplets, fluorescent
microspheres, latex beads) or radiolabeled microorganisms (bacteria, yeast) that are
detectable within the cell after phagocytosis
• Following incubation, the ingested particles are quantified to determine if phagocytosis is
impaired.
4. DEFECT IN PHAGOCYTOSIS :

36. PAPILLON-LEFEVRE SYNDROME:
• Diffuse Palmoplantar Keratosis associated with Aggressive
Periodontitis of both Primary & Permanent Dentitions
• Papillon & Lefévre, 1924
• RARE Autosomal Recessive Disorder
• Prevalence: of 1-3 cases/1000000
• No Gender & Racial Predilection
• PLS is caused by mutations in the Cathepsin C gene, located on
chromosome 11
• The 2 essential features of Papillon-Lefévre Syndrome are
 Hyperkeratosis of the palms & soles (either diffuse or
localized)
 Generalized rapid destruction of the periodontal attachment
apparatus resulting in premature loss of both primary &
permanent teeth
• “Palmoplantar keratoedema”
• Papillon-Lefévre syndrome is the only one associated with
aggressive periodontitis
• Haim-Munk syndrome-- particular form of Papillon-Lefévre
 While also characterized by palmoplantar keratosis & severe
early onset periodontitis, the Haim-Munk syndrome additionally
presents with digital abnormalities.
 These include osteolysis of the distal phalanges, abnormal
length & slenderness of the fingers & toes, & a claw-like
hypertrophic deformity of the nails
• Other findings:
 Ectopic calcifications of the falx cerebri & choroid plexus
 Increased susceptibility to infection
 Mental retardation
 Endocrine disorders

37. • Van dyke et al. described neutrophil chemotaxis defects in 2 patients with Papillon-Lefévre
syndrome & noted decrease in both random migration & directed migration toward a
chemotactic factor.
• This alteration of neutrophil function has not been observed in all cases. Both Lyberg &
Schroeder et al. reported normal neutrophil function including margination, chemotaxis,
phagocytosis, degranulation of lysosomes & intracellular destruction in several children
with Papillon-Lefévre syndrome who did not exhibit an increased susceptibility to
infection.
• It is possible that both the greater vulnerability to infection & neutrophil defects noted in
some patients may be a condition clinically distinct from Papillon-Lefévre syndrome, or
possibly secondary to an infection with a specific bacteria such as A.a.
• Preus has hypothesized that the hereditary defect in Papillon-Lefévre syndrome is located
in the epithelial barrier, which in the gingival sulcus may lead to a reduced host defense
against periodonto-pathogenic bacteria.

38. Down’s Syndrome:
• Down’s syndrome is one of the most common
causes of mental retardation in children
• The distinct similarities in the features &
conditions of the disease led early researchers
to suspect a chromosomal aberration, & in the
late 1950s Down’s syndrome was specifically
linked to trisomy of chromosome 21 (Down,
1866)
• Among the C/F of down’s syndrome there is the
high prevalence of periodontitis
• Cohen et al.( Periodontal Diseases in Mongolism, 1961) reported in their investigation of
100 young patients with Down’s Syndrome & found that virtually all had some degree of
periodontal disease, ranging from severe gingivitis in the youngest patients to periodontitis
with pocket formation & alveolar bone loss in the older patients.

39. • Among the endogenous factors that may exacerbate the periodontitis in Down’s syndrome
are defects in neutrophils
• The 1st cellular anomaly:
Tendency of the nucleus in neutrophils of Down’s syndrome patients to be consistently less
segmented than in other patient groups.
While the absolute no. of neutrophils in Down’s syndrome patients are not significantly
different from healthy controls, some authors have reported a preponderance of younger
cell forms that is independent of both the TLC & the relative no. of neutrophils. (Noble,
1985; Izumi, 1989)
Others have suggested that this phenomenon is due to a tendency for the shortening of
the ½ -life of circulating neutrophils in patients with Down’s syndrome (Amano, 2008)

40. Finally, in addition to the well-studied Neutrophil Deficiencies in Down’s Syndrome
patients, still another line of research has investigated the Relationship b/w Neutrophil
Derived Cytokines & the Periodontitis Lesions of Down’s Syndrome patients.
• HALINEN ET AL.(1996) found Increased Levels of Neutrophil Collagenase (MMP-8) in the
Saliva & GCF of Down’s Syndrome patients
These findings suggest that the Active MMP-8 derived from triggered Neutrophils &/or
Cytokine Induced Periodontal Fibroblasts may reflect the Periodontal Destruction seen in
patients with Down’s Syndrome

41. Lazy-Leukocyte Syndrome:
• Extremely RARE disorder that manifests in both quantitative & qualitative neutrophil defects.
• Lazy-leukocyte syndrome is characterized by
• Recurrent infections due to both a deficiency in neutrophil chemotaxis & a systemic
neutropenia, while the phagocytic function of the neutrophil remains intact
• Neutrophils within the bone marrow – normal quantity + morphology.
• Peripheral neutrophils-- severe neutropenia, functional defects of neutrophils (chemotaxis &
random migration)
• Directional locomotion -- dependent on microtubule assembly within the neutrophil
 The abnormal function of these cytoskeletal components leads to a defect in cell
deformability, & this hinders the release of newly formed neutrophils from the bone
marrow
 Impaired random & directional motility leads to a diminished migration of neutrophils
into the tissue & to sites of inflammation
Oral complications:
• Constantopoulous et al.(1975) described a 5 month old boy that presented with a high fever, cough,
pneumonia, oral stomatitis & purulent skin abscesses.
 Laboratory tests revealed a peripheral neutropenia, & impairment of both neutrophil chemotaxis &
random motility
• A similar case report is that of a 4 year old diagnosed with lazy-leukocyte syndrome & followed over 7
years. (Rossi, 2012)
 The boy suffered from painful stomatitis, gingivitis & recurrent ulcerations of the buccal mucosa &
tongue
 Periodontitis progressed to the point of advanced bone loss & tooth loss by the age of 7

42. Hyperimmunoglobulin-E Syndrome/Job Syndrome
• Multisystem Disorder
• Inherited as an Autosomal Dominant Trait
• Affects Dentition, Skeleton, Connective
Tissues, & Immune System
• Classically, it has been characterized by a
TRIAD of Symptoms:
 Skin Abscesses
 Pneumonia
 Elevated Serum IgE Levels
• Eosinophilia, Candidiasis, Arthritis,
Chronic Eczematoid Dermatitis & Other
Recurrent Infections are also common.
Coarse facial skin with prominent pores
Facial asymmetry
Prominent forehead
Deep-set eyes
Broad nasal bridge
Mild prognathism
High incidence of long bone fractures.
Oral complications:
1. Ulceration & gingivitis
2. Increased susceptibility to
severe periodontitis.
3. Early loss of primary teeth

43. Recurrent Infection is one of the chief features of Hyperimmunoglobulin-E Syndrome.
• While patients may go years b/w Infections, a series of cases reviewed by the National
Institute of Health (2015) observed that Local Infections requiring Oral Antibiotics occurred on
Avg. Every 3.6 months & a Major Infection occurred Once/year.
• Hyperimmunoglobulin-E Syndrome is a Defect in Neutrophil Chemotaxis
• 3 Hypotheses exist for the Chemotactic Defect in the Neutrophils:
 A Specific IgE against an Infecting Bacterium (S. aureus) causes the Release of Histamine
that may Inhibit Neutrophil Chemotaxis
 Bacterial Ag cause Monocytes to Secrete Chemotaxis Inhibiting Mediators or IgG
 Mononuclear Cells may create a Specific Factor which Inhibits Neutrophil Chemotaxis
• Treatment OF HYPERIMMUNOGLOBULIN-E SYNDROME is dependent upon Antibiotics, Local
Debridement, & Surgical I&D .
 Improvement following T/t with Cimetidine or Ranitidine alone or in combination with
H1-Receptor Antagonists has also been reported (Shemer et al., 2001)

44. Diabetes Mellitus:
• In DM patients, alterations in host immuno-inflammatory response to the bacterial challenge
has been identified as a possible explanation for the increased prevalence & severity of
periodontitis often seen in the diabetics.
• The PMNs plays a major role in maintaining a healthy periodontium in the face of
periodontopathic microorganisms.
• In DM, numerous studies have shown a reduction in PMN function, including
 Chemotaxis
 Adherence
 Phagocytosis (Van dyke, 1985)
• Defects affecting PMNs, the 1st line of defense against subgingival microbial agents, may
result in significantly increased tissue destruction
• Chemotaxis may be improved in those with better glycemic control (Leeper et al., 1985)

45. Diabetes Mellitus:
PMN function has been demonstrated to be normal in many individuals with DM
• Oliver et al. (1993) suggested hyper-responsiveness or increased no. of PMN within the
gingival crevice of poorly controlled diabetics, as indicated by elevated levels of the PMN-
derived enzyme β-glucuronidase.
• In addition to the PMN, another critical cell line in the periodontal immuno-inflammatory
response to pathogens is the monocyte/Mφ line.
• Studies suggest that many diabetic patients possess a “hyper-responsive
monocyte/macrophage phenotype” in which stimulation by bacterial Ag (LPS) results in
dramatically increased pro-inflammatory cytokine, PGE2, MMP production.
(Offenbacher et al., 1997 )
• Salvi et al.(1997) have demonstrated Significantly Increased Production of Pro-
inflammatory Cytokines such as TNF-α by Monocytes derived from patients with DM.
• When challenged with LPS from P. gingivalis, Diabetic Monocytes showed a 24-32 fold
Increased Production of TNF-α compared to Non-diabetic Monocytes.
• In DM patients with Periodontitis, the GCF Levels of PGE2 & IL-1β were Significantly
Higher than in Non-DM Subjects with a similar Degree of Periodontal Destruction.

46. • AGE formation plays an imp. Role in up-regulation of the monocyte/macrophage cell line.
• Accumulation of AGEs in the periodontium stimulates migration of
monocytes/macrophage to the site.
• Once in the tissue, AGEs interact with RAGE on the cell surfaces of
monocytes/macrophage
• This AGE-RAGE interaction results in
 “Immobilization of monocytes/macrophage at the local site”
 “Induces a change in monocyte/macrophage phenotype, upregulating the pro-
inflammatory cytokine & PGE2 production”
• This provides another explanation for increased GCF levels of TNF-α, IL-1β, PGE2 noted in
diabetic patients with periodontitis (Salvi et al.; Schmidt et al., 1997)
• This interaction also increases the oxidative stress within the tissues, resulting in tissue
destruction

47. 5. DEFECT IN INTRACELLULAR KILLING:
A) Defect in oxidative mech.:
• The neutrophil’s oxidative killing mech. involves
 defects in the 5 components of the complex enzyme NADPH oxidase.
 NADPH oxidase catalyzes the respiratory burst with the production of microbicidal
superoxide anion, hydrogen peroxide & hydroxyl radical
• Without this oxidative reaction, bacterial killing is greatly impaired. This neutrophil defect is
responsible for the life-threatening recurrent infections found in chronic granulomatous
diseases.
OXIDATIVE MECH.
NON- OXIDATIVE MECH.

48. B) DEFECT IN NON-OXIDATIVE MECHANISM:
• Degranulation of Neutrophils occurs in Non-oxidative Mechanism.
• There are 2 main conditions with Defects in Degranulation
 Specific Granule Deficiency
 Chédiak-Higashi Syndrome
• Specific granule deficiency
 Absence of or defective secondary or specific granules
 In this disease, there is decreased availability of specific enzymes & adhesion
molecules normally present in secondary granules
 Diagnosis of specific granule deficiency is through the use of Wright stain confirming
the absence of secondary granules
 Assays for constituent proteins of these granules should also demonstrate a reduction
or absence compared to normally functioning neutrophils

49. Chediak Higashi Syndrome:
• Rare Autosomal Recessive Disorder
• Primarily affects the Neutrophils
• It manifests Early in the Life in the form of
• Partial Oculo-cutaneous Albinism
• Photophobia
• Frequent Pyogenic Infections
• Lymphadenopathy
• Oral Findings
• Severe Gingivitis
• Ulcerations of the Tongue & Buccal Mucosa
• Early Onset Periodontitis leading to Premature
Loss of both Deciduous & Permanent Dentitions
Clinically, the syndrome may present as
- Abnormalities of Pigmentation
- Recurrent Infections
- Bleeding Tendencies
- Oculo-cutaneous albinism
- Nystagmus, photophobia, reduced
visual acuity

50.  The few individuals that do survive beyond the 1st Decade Often Progress to a “Lymphoma-like Disease” k/a
“ACCELERATED PHASE”
 This phase can include
 Fever
 Jaundice
 Hepatosplenomegaly
 Pancytopenia that leads to an Even Greater Susceptibility to Infection
• One of the Hallmarks of the Chédiak-Higashi Syndrome is Presence of Large Intracellular Azurophilic Inclusions
in the Cytoplasm of Neutrophils
 These large inclusions impair neutrophil migration, possibly by inhibiting cell deformability, & render
neutrophils unable to metabolize & digest microbes
• As a result, patients with Chédiak-Higashi Syndrome are prone to recurrent infections in early childhood
• Animal Research has led to the determination that a mutation in the “LYST” (Lysosome Trafficking Regulation)
Gene, the only known Chédiak-Higashi syndrome causing gene, may be responsible for this phenomenon
Oral Complications:
Delcourt-Debruyne et al (2000) reported a
14-yr old Chédiak-Higashi syndrome patient
with:
• Severe Mobility of the Teeth
• Suppuration
• Severe Bone Loss
• Gen. recession with deep PPD
• Lab reports confirmed the Presence
of Large Granules within the
Neutrophils.
 Shibutani et al (2000) presented a 12year
follow up of a 21yr old Woman with Chédiak-
Higashi syndrome.
 Age 9 --presented complaining of Gingival
Swelling & Mobility of Teeth
 Age 12, Severe Bone Loss was present
throughout both arches
 DNA-probe Analysis of the Bacteria within
the Periodontal Pockets revealed a
pathogenic flora consisting of A.a., P.
gingivalis & P. intermedia.
 In spite of Ongoing T/t, she experienced
Multiple Abscesses & Extractions of
Hopeless Teeth over the next 12yrs.

51. Chronic Granulomatous Disease:
• Extremely RARE Clinical Syndrome
• characterized by
• Life-Threatening Staphylococcus, Proteus or Pseudomonas spp. Infections
• Hypergammaglobulinemia
• Widespread Chronic Granulomatous Infiltrations
• Varied Incidences: 1 in 200000 to 1 in 1000000 births- Usually presents in the 1st year of life with recurrent bacterial & fungal infections including
 Pneumonia
 Lymphadenitis
 Liver abscess
 Osteomyelitis
 Septicemia
 Otitis media
The most common pathogens encountered are S. aureus, Aspergillus spp., enteric G- ve
bacteriae

52. Oral manifestations:
• Charon et al.(1985) reported on 9 patients from the national institute of allergy & infectious
diseases who were diagnosed with chronic granulomatous disease.
• Patients with chronic granulomatous disease had a significantly greater occurrence of
oral ulcerations & gingival inflammation compared to controls
• Budonelli et al.(2001) reported the case of a 5-year old Caucasian male diagnosed with
chronic granulomatous disease from the lab findings of “hypergammaglobulinemia” & a
low neutrophil burst test.
• Severe gingival inflammation & marginal erythema were noted, along with extensive
LOA & gingival recession that resulted in significant mobility & furcation involvement.

53. Centers on control of infections:
• COTRIMOXAZOLE has a Broad Spectrum of Activity Against many of the causative
organisms & a Minimal Affect on the GI Flora.
• Antifungal Prophylaxis can be achieved with ITRACONAZOLE
• IF-γ has been shown to Partially Restore Oxidase Activity in Neutrophils & Monocytes
of some patients with X-linked Chronic Granulomatous Disease, & to Reduce
Infection Rates
• CORTICOSTEROIDS are Avoided in most instances, but they can be useful in Low
Doses to manage Symptomatic Complications of Granuloma Formation such as Colitis
& Hollow Organ Obstruction
• BONE MARROW TRANSPLANTATION, effective in treating some cases of Chronic
Granulomatous Disease, has become a More Predictable T/t during the past decade..
Treatment of Chronic Granulomatous Disease

54. Inflammatory Bowel Disease:
• Inflammatory bowel disease comprises 2 chronic clinical entities:
• Crohn’s disease
• Ulcerative colitis
• No gender predilection
• Inflammatory bowel disease is due to a complex combination of
 Genetic
 Environmental
 Bacterial triggering events
that activate both immune & non-immune systems within the intestine.
• Cell-mediated immune response induces effector t-cells & activates macrophages, neutrophils, &
eosinophils, while humoral response stimulates the production of Ab.
• Through secretion of soluble mediators & expression of cell adhesion molecules, immune &
non-immune cells exchange signals resulting in a further amplification of Ab, cytokines, growth
factors, PG, leukotrienes, reactive oxidative metabolites, nitric oxide, & proteolytic enzymes
that culminate in chronic inflammation & tissue damage
- Similar etiopathogenesis to periodontitis.
- Both involve
 Excessive exposure to Ag from the indigenous microflora
 Persistent stimulation of protective immune systems
 Modifying influence of environmental factors (smoking)
- Flemmig et al.(2005) performed I/O examinations on 107 inflammatory bowel disease
patients seeking T/t at a medical school clinic.
- although the prevalence of periodontal disease was slightly higher in patients with
inflammatory bowel disease, the severity of periodontal disease was less than the
general population.
- Concluded that severe periodontal disease & inflammatory bowel disease are 2
unrelated disease entities that can occur in the same individual.

55. Some studies have suggested a Depressed Neutrophil Chemotaxis.
• Van Dyke et al. (1986) performed both Microbiological Studies of Periodontal Pockets &
Laboratory Studies of Neutrophil Function in 20 Inflammatory Bowel Disease patients.
• The authors speculated that Neutrophil Chemotaxis Defects identified in some of the
Inflammatory Bowel Disease patients could be attributed in part to the Antigenic load of
Periodonto-pathogens known to Inhibit Neutrophil Chemotaxis.
• In 1978, Lamster et al. reported Enhanced Phagocytic Ability of Neutrophils from a patient
with Crohn’s Disease & Severe Periodontitis.
This seems to represent the most current line of research in Inflammatory Bowel Disease,
where interest in Neutrophil Function now seems to centre around the Neutrophil’s Role in
Amplifying the Inflammatory Response.

56. SLE (Systemic Lupus Erythematosus)
• SLE is a Chronic Autoimmune Disease that affects the
connective tissue & Multiple Organ Systems.
• More Common in Women (likely due to a Combination of
Genetic Factors & Environmental Triggering Events).
• SLE ranges in Severity from a Mild Disease, with Rash &
Arthritis, to a Serious Illness characterized by Renal Failure &
Significant Neurological Disturbances.
• The prevalence of SLE in North America & Northern Europe has
been estimated at about 40 cases/100,000 population
Oral and facial manifestations include
- Malar rash (buttefly-shaped)
- oral ulceration
- honeycomb plaque
- raised keratotic plaque
- nonspecific erythema, purpura, petechiae
- Cheilitis
Patients with SLE can exhibit
 Diminished neutrophil formation
 Anti-neutrophil Ab & enhanced
neutrophil apoptosis

57. • Infection is among the most cited reasons for hospital admission in SLE patient
• Among the Hematologic Disorders that may explain this Increased Incidence of Infection are
a tendency to NEUTROPENIA AND VARIOUS NEUTROPHIL ABNORMALITIES.
• Specific Neutrophil Defects have also been reported. Some reports suggest Neutrophil
Chemotaxis Defect, Most of the evidence suggests that Impaired Neutrophil Phagocytosis is
present in SLE patients
• In spite of the numerous reports of oral lesions, & the increased overall susceptibility to
infection, there is little information on the Periodontal Status of SLE patients.
• Mutlu et al.(1993) found that in a comparison of the Periodontal Status of SLE patients with
Age & Sex-matched Controls, the SLE patients had significantly shallower PPD than the
control group.

58. Myeloperoxidase Deficiency:
• Hemeprotein
• located in the azurophilic granules of neutrophils & monocytes
• Functional significance: ability to oxidize Cl-, which in the presence of H2O2 leads to the
production of the microbicidal HOCl
• Myeloperoxidase- H2O2-Cl System most efficient component of the oxygen-dependent
antimicrobial system of neutrophils
- Frequency: 1 in 4000 person
- It can be
- Congenital
- Acquired (due to Hematological Neoplasms, Fe Deficiency, Pb Intoxication, Renal
Transplants, Severe Infectious Diseases, DM)
- No Increased Risk for Infection or other C/F
- Alternative oxidative pathways exist that overcome the myeloperoxidase-dependent
mechanism-- less effective in eliminating certain fungi such as Candida or Aspergillus
spp.
- Rate of severe infections in myeloperoxide deficiency <5% - reports of severe visceral
candidal infections in people with myeloperoxidase deficiency & DM) (Klebanoff, 2013;
Petersen, 2016)

59. Oral Manifestations:
• There are limited case reports on the oral manifestations of Myeloperoxidase Deficiency
• Okuda et al.(1991) reported Deep Mucocutaneous Candidiasis with Oral Lesions in a 32 year
old Female with Myeloperoxidase Deficiency
• The only report of Periodontitis & Myeloperoxidase Deficiency was made by D’Angelo et
al.(1992) who described a case of AgP in a 3 year old girl with Myeloperoxidase deficiency &
Papillon-Lefévre Syndrome.
• This child, who had a H/O of recurrent infections, was also noted to have Defective Neutrophil
Chemotaxis.
• Based on these reports, especially considering that Myeloperoxidase Deficiency is not a rare
finding, it is not possible to establish a conclusive link b/w Myeloperoxidase Deficiency &
Periodontal Disease

60. Glycogen Storage Disease Type- 1B
• The Glycogen Storage Diseases comprise a group of at least 18 Inherited Disorders
caused by Abnormalities of Enzymes Regulating the Synthesis & Degradation of Glycogen
• Autosomal Recessive Mode of Inheritance
• Most often diagnosed in Infancy or Early Childhood
• Defect in the Glucose-6-Phosphate Transporter Protein:
• As a result Glucose-6-Phosphate cannot be Transported across the ER of Hepatocytes,
Preventing the Glycogen from being Metabolized into Glucose.
• Glycogen is then Deposited in the Liver with a Uniform Distension of Hepatocytes
Among the Prominent C/F are :
 “Doll-like” Facial Appearance
 Stunted Growth
 Hypoglycemia
 Ketosis
 Lactic Acidosis
 Hyperlipidemia
 Gout
 Bleeding Episodes (brought on by
Impaired Platelet Function
Secondary to Metabolic
Disorders)
• Additional distinguishing features of Glycogen Storage Disease-
Type1b are
 Neutropenia
 Neutrophil Dysfunction
 Increased Susceptibility to Infection
• The Neutropenia, either Constant or Cyclic, is suspected to be a
Consequence of Altered Myeloid Maturation
• Neutrophil Abnormalities identified in this disease patients
include Defects in both Random & Directed PMN Migration
• Koven et al. studied laboratory findings on several patients with
Glycogen Storage Disease-Type1b, & found Defects in
 Neutrophil Motility, Chemotaxis, Nitroblue Tetrazolium Test
Reduction, & Bactericidal Activity.
 The authors speculated that these results, similar to findings
in other studies, suggest a Generalized Metabolic
Neutrophil Defect in Glycogen Storage Disease-Type1b
patients

61. ORAL COMPLICATIONS:
• Reports of Oral Disease in Glycogen Storage Disease-Type1b patients are common, & include
Oral Ulceration, Candidiasis, Gingivitis, & Periodontitis.
• Visser et al. noted “Peri-Oral Infections” in the records of 37 of 57 Glycogen Storage Disease-
Type1b patients reviewed, all of whom had Neutropenia & Defective Neutrophil Function.
Based on the available information, it can be determined that the Neutropenia & Neutrophil
Dysfunction noted in some patients with Glycogen Storage Disease-Type1b leave them at Risk for
Developing Periodontitis.
- It is possible that a Block in the Transport of Glucose-6 Phosphate into the ER of Neutrophils, may
Interrupt the Metabolic Pathways Necessary for Neutrophil Function.
- The Range of Susceptibility to Infection in these patients could then be explained by whether
the Defect in the Glucose-6-Phosphate System is either Partial or Complete

62. Acatalasia:
• RARE Autosomal Recessive Disorder
• Most of the cases have been reported from JAPAN
• Patients with Acatalasia have a Deficiency of Erythrocyte Catalase.
• If this enzyme is Deficient, H2O2 Accumulate in Cells & predispose for Tissue Damage.
• In mammals, High Catalase Levels are found in the Liver, Kidney, & Erythrocytes.
• In Erythrocytes, Most Catalase is Normally found in the Cytosol, with a Small Fraction
Incorporated into the Erythrocyte Membrane.

63. ORAL COMPLICATIONS:
• Acatalasia patients are not generally prone to infections, approx. 25-50% suffer an Oral
Condition c/a Takahara’s Disease, characterized by Painful Ulcerations of the Gingiva &
Tonsillar Lacunae.
• Interestingly, only one report of this condition exists in the Dental Literature. In 1979,
Delgado & Calderon described the Oral Condition of 2 Peruvian Siblings with Acatalasia to
consist of NUP-like Lesions with Ulcerations of the Papillary Gingiva & Advanced Bone
Loss.
 A predominance of Catalase-Negative Pneumococci (known to produce H2O2) cultured
from Necrotic Gingival Tissue led the authors to speculate on a possible role for
Increased Levels of H2O2 in causing the Tissue Damage

64. NEUTROPHIL EXTRACELLULAR TRAPS (NETs)
• Brinkmann et al., 2004.
• Extracellular web like fingers; generated by activated neutrophils and largely composed of nuclear constituents.
• Bind to both Gram(+)ve and Gram(-)ve organisms, immobilize them and thus prevent further colonization of new host
surfaces.
• Process of release of NET : NETosis or Neutrophilic extracellular trap-osis.
• Release of NET: 1. Suicidal NETosis : rupture of plasma membrane.
2. Vital NETosis: release of mitochondrial DNA; no cell death.
• STRUCTURE: Co-localization of granular proteins/enzymes/histones with DNA.
• Antimicrobial action: 1. Trapping & immobilizing of pathogens to prevent tissue and systemic spread.
2. Pathogen killing by neutrophil extracellular trap-- embedded cathelicidin antimicrobial peptides.

65. NEUTROPHIL EXTRACELLULAR TRAPS (NETs)
or Periodontitis

66. • Reduced prevalence/effectiveness of NETs in diseased periodontal tissue
• Hypoactive NET production or periodontal bacteria rendering the NETs ineffective.
• Increased bacterial infiltration in periodontal tissues
• Widespread inflammatory response culminating in neutrophil mediated tissue destruction e.g. ROS and protease
damage.
• DNase digestion of NETs may result in liberation of NET associated antimicrobial peptides, resulting in more
widespread tissue destruction.
• Conversely, it is conceivable that periodontal disease may be associated with an excessive production of NETs.
• In either scenario, the implication is that both the neutrophils and their associated degradative enzymes are
concentrated within the abundant NETs for an extended duration.
Role of NETs in pathogenesis of periodontal disease
Therefore, the factors determining whether one individual
develops inflammatory periodontitis whilst another doesn’t,
are:
1. Type of bacteria inhabiting gingival crevice.
2. Whether these bacteria possess virulence factors for NET
production.
3. The individual’s innate ability for NET production.

67. • Although rare in occurrence, an association b/w various systemic conditions characterized by neutrophil
dysfunction & periodontal disease does exist.
• While this association is clearly defined in most of the systemic disorders listed so far, but for some of them
the definitive evidence is lacking.
• The periodontal treatment for patients with periodontitis related to neutrophil disorders has been
empirical & without consistent success.
• Local debridement, local & systemic antibiotics, antimicrobial rinses, sub-gingival irrigation, selective
extraction & frequent periodontal maintenance have all been attempted.
• Unfortunately, for those systemic conditions most associated with neutrophil disorders & periodontitis, the
end result is usually tooth loss.
CONCLUSION

68. REFERENCES
• CARRANZA’S Clinical Periodontology 13th Edition
• RYDER, M.I., 2010. Comparison of neutrophil functions in aggressive
and chronic periodontitis. Periodontology 2000.
• HAJISHENGALLIS, G., CHAVAKIS, T., HAJISHENGALLIS, E. and LAMBRIS,
J.D., 2015. Neutrophil homeostasis and inflammation: novel
paradigms from studying periodontitis. Journal of leukocyte biology.
• HERRMANN, J.M. and MEYLE, J., 2015. Neutrophil activation and
periodontal tissue injury. Periodontology 2000.