Oral Manifestations Associated with Neutrophil Deficiency and Neutrophil Disorders: a Review

Review Article

Oral manifestations associated with neutrophil deficiency and neutrophil disorders: A review

Archana Tangudu1*, B. Badari Ramakrishna2, K.V.S.P. Gupta3, M.V. Mrudula3, Rahul Marshal Vaddeswarapu3

1Reader, Department of Periodontics and Oral Implantology, Anil Neerukonda Institute of Dental Sciences, Visakhapatnam, Andhra Pradesh, India 2Reader, Department of Oral Medicine and Radiology, Anil Neerukonda Institute of Dental Sciences, Visakhapatnam, Andhra Pradesh, India 3Senior Lecturer, Department of Periodontics and Oral Implantology, Anil Neerukonda Institute of Dental Sciences, Visakhapatnam, Andhra Pradesh, India *Corresponding author email: [email protected]

International Archives of Integrated Medicine, Vol. 5, Issue 6, June, 2018. Copy right © 2018, IAIM, All Rights Reserved. Available online at http://iaimjournal.com/ ISSN: 2394-0026 (P) ISSN: 2394-0034 (O) Received on: 09-05-2018 Accepted on: 14-06-2018 Source of support: Nil Conflict of interest: None declared. How to cite this article: Archana Tangudu, B. Badari Ramakrishna, K.V.S.P. Gupta, M.V. Mrudula, Rahul Marshal Vaddeswarapu. Oral manifestations associated with neutrophil deficiency and neutrophil disorders: A review. IAIM, 2018; 5(6): 61-71.

Abstract

The immune system evolved to protect multicellular organisms from pathogens. It defends the body against invaders, and generates an enormous variety of cells and molecules capable of specifically recognizing and eliminating foreign invaders, all of which act together in a dynamic network. Neutrophils have been referred to as a first line of defense, meaning that they are first defensive cells to be recruited to a site of inflammation; however the resident leukocytes are cells which normally exist at the sites of inflammation. Neutrophils exhibit their antibacterial action with the help of granules or by virtue of its ability to reduce dioxygen to hydrogen peroxide. The primary mission of neutrophils is to find bacteria and neutralize them by phagocytosis.

Key words

Periodontitis, Neutrophils, Phagocytosis, Neutropenia, Gingiva.

Page 61

Introduction recruited which infiltrate the connective tissue, The strategy of host defense against periodontal develop into tissue macrophage and either digest infection may be viewed as similar to that used in the antigen completely (and signal repair combating any local infection. Initially, potential processes with cytokines such as transforming periodontal pathogens encounter plasma factors, growth factor β) or present partially digested such as complement, within the crevicular or antigen in association with Major extracellular fluids. The result of this encounter Histocompatibility Complex (MHC) encoded is the initiation of inflammatory processes, as class II molecules to lymphocytes [1]. evidenced by the recovery of complement activation products from the gingival crevice. If Perhaps to avoid systemic infections, chronic complement is not successful in controlling the periodontal inflammation may produce localized pathogen, the host defense turns to “Phagocytes” specific immune responses and a cytokine – [1]. orchestrated destruction of connective tissue which we call “Periodontal Disease”. Thus, Phagocytes are cells which ingest particles neutrophils are important because they control visible to light microscopy. The process of eating the periodontal micro-ecology prior to the particles is called “Phagocytosis”, a process involvement of chronic inflammatory cells. which is considered as one of the distinguishing According to the acute and chronic immune features of eukaryotic cells, found even in such elements, it may be proposed that specific primitive organisms as the amoeba, which hunt, periodontal disease can result from the failure of ingest and kill microbes for nutritional purposes. specific aspects of host immune system Many cells in our body are capable of (neutrophil in particular) in its interaction with phagocytosis, but only two are good enough to specific periodontal pathogens. Simplistically, be considered professional [2]. either hypofunction of neutrophils or 1. Neutrophilic polymorphonuclear hyperfunction of monocytes / lymphocytes may leukocytes ( PMNs) result in increased susceptibility to periodontal 2. Monocytes / Macrophages diseases [1, 2].

Neutrophils, monocytes and other granulocytes As evidenced, individuals with defects in form the myeloid arm of the immune system. neutrophil function or biochemistry often exhibit The lymphoid arm includes T-Cells, B-Cells and severe forms of periodontal disease and large granular lymphocytes (Natural Killer cells). conversely, individuals with early onset or Bone marrow stem cells give rise to both cellular rapidly progressing forms of periodontal disease arms in a teeter – totter fashion [1]. often exhibit relatively subtle neutrophil defects. These defects can be primary or secondary in Neutrophils within the gingival crevice provide origin. Primary defects are actual defects of the first cellular host mechanism to control neutrophils namely Neutropenia, periodontal bacteria. They bring an astounding Agranulocytosis, Chediak – Higashi syndrome, arsenal of antimicrobial weaponry packed within Lazy Leukocyte syndrome. Secondary disorders almost all of their cellular compartments (like are seen in individuals with Down syndrome, calprotectin complex, lysozyme, defensins, Papillon – Lefevre syndrome and Inflammatory cofactor – binding proteins, neutral serine Bowel Disease etc. proteases, bactericidal/permeability increasing protein, myeloperoxidase and a NADPH oxidase This review would give an insight into system). If neutrophils are unsuccessful in neutrophils functions, their role in host defense controlling the pathogen (reducing bacterial mechanism, neutrophils disorders and their antigen levels sufficiently), monocytes are association with periodontal diseases.

Page 62

Neutrophils and The Periodontal health, when a constant bacterial burden is Inflammatory Lesion present [6]. The periodontal lesion is characterized by large proportions of inflammatory cells and the Neutrophil Disorders In Periodontitis vascular structures. Neutrophils predominate in pathogenesis In Otherwise Healthy Subjects the early periodontal lesion that characterizes Neutrophil dysfunctions have a strong effect on gingivitis. However, the relative proportion of the ability of the host to cope with infections, neutrophils in the inflammatory infiltrate including periodontal infection. However, the decreases during the transition to periodontitis in role of intrinsic or acquired neutrophil defects in which plasma cells and lymphocytes are the periodontal environment of otherwise healthy dominant. It was reported that plasma cells subjects is much less straight forward. Most of occupied 31% of the periodontitis lesion volume, the data on neutrophil disorders in otherwise while the proportion of lymphocytes varied healthy subjects were accumulated on young between 5% and 10%. Macrophages and patients with early onset forms of periodontitis neutrophils were found in densities of 1-2% and i.e., aggressive periodontitis. Early studies fibroblasts in 5% [3, 4]. demonstrated that peripheral neutrophils of patients with aggressive forms of periodontitis Neutrophils may be especially important during exhibited reduced chemotaxis in response to the transition from gingivitis to periodontitis. chemotactic signals in vitro and in vivo (Ryder Furthermore, they may play a role in the 2010) [2, 3, 6] pathogenesis of periodontitis in the gingival crevice and in the epithelium, where they are the The evidence that specific variants in neutrophil dominant inflammatory cells. The early, function contribute to periodontitis in otherwise nonspecific neutrophil response to dental plaque healthy individuals is low. Early studies had organisms (both the pathogenic and non demonstrated differences in chemotaxis and pathogenic) allows pathogenic bacteria to reactive oxygen species production (ROS) and proliferate and invade, setting the stage for the considered them as “Neutrophil Defects”. transition from gingivitis to periodontitis [2, 3]. However, today these results are interpreted as “neutrophil hyperresponsiveness”. It is possible Neutrophil Disorders Predispose To that in some cases genetic polymorphisms may Periodontitis contribute to pathogenesis in a minority of Disorders that affect neutrophil number or aggressive or chronic periodontitis cases [5]. function strongly predispose individuals to infection. Neutrophil disorders can be divided Chronic Benign Neutropenia into those that affect neutrophil number, Chronic benign neutropenia is characterized by a chemotaxis, and various physiological functions prolonged non cyclic neutropenia as the sole of the neutrophil once it has migrated to the site abnormality, with no underlying disease to which of inflammation [5]. Naturally occurring the neutropenia can be attributed. neutrophil disorders can relate biochemical  It is the most common form of pathways to the resulting clinical manifestations neutropenia of infants and children less of disease. Such functional disorders of than 4 years of age, with 90% of the neutrophils predispose to recurrent cutaneous, cases presenting before 14 months of respiratory and periodontal infections. The fact age. that quantitative or qualitative defects in  The incidence of chronic benign neutrophil function may lead to severe neutropenia is 3.9 per 1,00,000 births. periodontal breakdown supports the central role of these cells in protecting the periodontium in

Page 63

 It is usually not inherited; however the every 3 weeks. The interval between neutropenic familial form follows an autosomal episodes is not always obvious and may require dominant mode of inheritance [7, 8]. frequent laboratory tests. The disease tends to improve with age although death can occur in as Familial Chronic Benign Neutropenia many as 10 % of affected individuals as a result It was first reported by Glansslen in 1941, and of pneumonia, cellulitis, gangrene or peritonitis then by Bousser et al. in 1947. The clinical [7, 10]. presentation can be quite variable, from a benign condition discovered incidentally to an early life A recent description of 2 years old child threatening infection, but most patients with presented with recurrent gingivitis and apthous chronic benign neutropenia will live a normal life lesions. Clinically, no recession was noted and span. Individuals may suffer from increased probing depths were within normal limits. incidences of recurrent oral ulcerations, Analysis of microbial flora found P.intermedia, furuncles, upper respiratory tract infections, otitis Campylobacter rectus, Capnocytophaga media, cellulitis, lymphadenopathy, pneumonia gingivalis and C.sputigens. Inspite of treatment, and sepsis as a result of the limited neutrophil the child continued to experience gingivitis response to infection. As these individuals get during 2 years of follow-up. Numerous other older, the risk of infection appears to decrease case reports have been documented marked [8]. gingival inflammation, fever, oral ulcerations, otitis media, upper respiratory infections Oral manifestations of chronic benign associated with cyclic neutropenia. neutropenia include hyperplastic, edematous and Unfortunately, even with the best of professional fiery-red gingiva with areas of desquamation [7, care, teeth are often lost due to advancing 9]. periodontal disease [10].

Cyclic Neutropenia Congenital Neutropenia Cyclic neutropenia is a rare blood disease Congenital neutropenia is also called as characterized by periodic recurring symptoms of “Kostmann Syndrome” which was named for the fever, malaise, mucosal ulcers and possibly, life Sweedish pediatrician who first described the threatening infections related to the regular disease in 1950. It is an inherited hematologic cyclical fluctuations in the numbers of disorder manifesting in the first year of life and neutrophils. The disease is transmitted as characterized by severe bacterial infections. The autosomal dominant mode of inheritance. Its significant laboratory findings are an ANC incidence is 0.5 – 1 per million population. The <2,000 cells /µl and an arrest of neutrophil bone marrow may appear hypoplastic with pro- hematopoiesis at pro-myelocyte / myelocyte myelocytic arrest during periods of neutropenia. stage. The estimated frequency is 1 or 2 cases per Lots of promyelocytes and very few numbers of million in general populations with no sex mature cells are seen. Cyclic neutropenia has got predilection. Though the disease was originally both childhood and adult onset. Childhood onset described to be inherited as autosomal recessive is more common and appears in familial pattern trait, the diagnosis is now used for similar cases of inheritance whereas the adult onset is rare [7]. without a defined pattern of inheritance [7].

This condition was first reported by Leale in In most of the cases of congenital neutropenia, 1910, who described a persistent furunculosis in the underlying mechanism of the syndrome is an infant. Cyclic neutropenia usually presents unknown. Oral symptoms are universal in before the age of 10 years, with episodes of congenital neutropenia. In a recent report by fever, malaise, mood swings and oral ulcerations Carlsson & Farth, all the subjects that survived that can last 3-6 days and recur approximately infancy were affected by gingivitis and most

Page 64

Archana Tangudu, B. Badari Ramakrishna, K.V.S.P. Gupta, M.V. Mrudula, Rahul Marshal Vaddeswarapu. Oral manifestations associated with neutrophil deficiency and neutrophil disorders: A review. IAIM, 2018; 5(6): 61-71. were noted to have periodontitis with alveolar periodontitis is at least as great in Felty’s bone loss. Another case report demonstrated syndrome patients as in others with severe generalized severe periodontitis in an adolescent neutropenias [7]. patient with congenital neutropenia. In most of the cases even after the treatment there was Lazy leukocyte syndrome persistent gingivitis [5]. Lazy leukocyte syndrome is an extremely rare disorder that manifests in both quantitative and Agranulocytosis qualitative neutrophil defects. It is characterized Agranulocytosis is a blood dyscrasia by recurrent infection due to both a deficiency in characterized by a decrease in or even the neutrophil chemotaxis and a systemic disappearance of granular leukocytes (including neutropenia, while the phagocytic function neutrophils) in conjunction with peripheral remains intact. Within the bone marrow, the leukoplakia [11]. quantity and morphology of the neutrophils are normal. Peripherally, however, there exists not The decreased number of neutrophils can result only a severe neutropenia but also functional from either a decreased production of cells, or an defects of neutrophils with regard to chemotaxis increased peripheral destruction of cells. and random migration [2, 5, 7]. Decreased production is usually due to bone marrow hypoplasia, although drugs, chemicals, Oral manifestations -Very few case reports have ionizing radiation, infection, vitamin deficiencies been reported, but each has had oral and bone marrow tumors can cause similar manifestations. Constantopoulous et al. described effects. a 5 month old boy who presented with high fever, cough, bilateral pneumonia, oral stomatitis Oral manifestations -Generalized, painful and purulent skin abscesses. Laboratory tests stomatitis, spontaneous bleeding and necrotic revealed a peripheral neutropenia, and tissue. Radiographs generally reveal a impairment of both neutrophil chemotaxis and progressive pattern of bone loss at an early age. random motility. Another case report was of a 4 Depending on the cause and duration, severity year old child with Lazy leukocyte syndrome and varies [7]. followed over 7 years. The boy suffered from painful stomatitis, gingivitis and recurrent Felty’s syndrome ulcerations of the buccal mucosa and tongue. The leukoplakia noted in Felty’s syndrome is Periodontitis progressed to advanced alveolar primarily due to a lack of circulating neutrophils bone loss and tooth loss by the age of 7. The (neutropenia). This neutropenia may be due to prognosis for the dentition of patients with lazy insufficient formation of neutrophils, reduced leukocyte syndrome appears poor [7]. release from bone marrow, shortened neutrophil life span and excessive neutrophil margination. Leukocyte adhesion deficiency (LAD) Breedveld et al. monitored a variety of In 1979, a group of patients with similar hematologic parameters in a group of 15 patients symptoms of delayed umbilical cord separation at 3 months intervals for 3 years. The authors and persistent bacterial infections in the absence determined that the risk of infection was best of pus formation were found to share a common correlated with neutrophil cells [7]. neutrophil motility defect. The name leukocyte adhesion deficiency syndrome was given to this Oral ulceration and stomatitis are frequently condition by Anderson & Springer in 1986 [5]. occurring manifestations. Periodontitis has only rarely been reported. Even then, it is assumed Leukocytes are known to adhere to vessel wall that with the dramatic deficiency in circulating endothelium, other leukocytes and to neutrophils in some patients, the incidence of complement via cell surface integrins. These

Page 65

Archana Tangudu, B. Badari Ramakrishna, K.V.S.P. Gupta, M.V. Mrudula, Rahul Marshal Vaddeswarapu. Oral manifestations associated with neutrophil deficiency and neutrophil disorders: A review. IAIM, 2018; 5(6): 61-71. integrins are protein complexes that are stored contributor to GPP, which may not necessarily within neutrophil granules and when activated, be true and several congenital neutrophil defects are found on the surface of neutrophil cell have been associated with severe periodontitis membranes. The initial study on leukocyte [11, 13]. adhesion deficiency patients found a defect in the neutrophil integrins CD11 & CD18.Subsequent Type – II: investigations into this disorder have identified LAD-II was first described in 1992 by Etziomi, two types of leukocyte adhesion deficiency et al. Only 4 cases have been documented of this disorders [12]. type. Individuals with LAD-II are characterized by short stature, mental retardation and Type I: craniofacial abnormalities as well as recurrent It is an autosomal disorder (localized to infections. The neutrophil defect in LAD – II is chromosome 21q22.3) characterized by the of the Sialyl-Lewis X glycoprotein (CD 15s), inability of individuals to expressβ2 subunit which allows neutrophils to attach to selectins (CD18) common to the leukocyte integrins LFA- (CD62E) on the endothelial surface. The end 1, Mac-1 & GP 150/95. LAD-I is a disorder that result is similar to LAD-I and neutrophils are involves a deficiency in three membrane unable to migrate extravascularly in response to integrins as mentioned earlier. CD18/CD11a inflammation. Individuals with deficiency suffer (LFA-1) binds to leukocytes and to endothelium from neutrophilia (20,000 – 70,000 cells /mm3) via intercellular adhesion molecules (ICAM). and severe, early onset periodontitis [7, 11]. CD18/CD11b (Mac-1) binds to ICAM and complement facilitates complement mediated Oral Manifestations- Page et al studied 5 patients phagocytosis. The function of the third integrin with generalized prepubertal periodontitis and CD18/CD11c is not well understood. The found that all of these patients had abnormalities deficiency of these integrins prevents the of all three of the leukocyte receptors, LFA-1, neutrophil from adhering to the vessel wall at the GP 150/95 & Mac-1(CD-11). They stated that site of an infection. Therefore, in spite of this abnormality could account for the observed leukocytosis (20,000 – 80,000 cells /μl) defect in cell adherence, diminished neutrophil neutrophils are unable to migrate into the chemotactic response and the enhanced affected tissues[12]. susceptibility to generalized prepubertal periodontitis [5, 7]. There have been just over 600 cases described, each identified shortly after birth. More than Klaldrop, et al. characterized the periodontal 75% of children will die before the age of 5, if conditions of patients with a moderate phenotype they do not receive a bone marrow transplant. of Mac-1, LFA-1 deficiency through The severity of the disease is based on the examination and gingival biopsy. Their results relative expression of CD18. Less than 1% of indicated that these patients suffered from normal is described as severe, while 2.5 – 10% is generalized prepubertal periodontitis with an considered as moderate to mild. Periodontal onset during or following the eruption of the disease is related to whether one or two defective primary dentition, rapid horizontal and vertical alleles are present. Homozygotes exhibit bone loss, intense fiery red gingiva, marginal generalized pre pubertal periodontitis (GPP) gingival proliferation, recession, clefting, which effects both deciduous and permanent bleeding and significant plaque accumulation. dentition. Heterozygotes appear to have normal Gingival biopsies in these patients showed a pre pubertal periodontal status. However, “post- marked peripheral blood leukocytosis with LJP-like” lesions appear at some point post minimal or no infiltration of neutrophils into the pubertally. Few studies that associate GPP with inflamed extravascular periodontal areas. In LAD-1tend to suggest that LAD-a is the only contrast, in these heterozygotic patients, they

Page 66

Archana Tangudu, B. Badari Ramakrishna, K.V.S.P. Gupta, M.V. Mrudula, Rahul Marshal Vaddeswarapu. Oral manifestations associated with neutrophil deficiency and neutrophil disorders: A review. IAIM, 2018; 5(6): 61-71. found invitro, PMN and mono nuclear cell not established between myeloperoxidase functions that were essentially normal [7]. deficiency and periodontal disease [7].

Papillon – Lefevre syndrome (PLS) Chediak – Higashi syndrome The syndrome is named for the two authors who Dental case reports included signs such as dental first detected this condition in 1924. It is a rare pain, swollen gingiva with frank purulence, autosomal recessive condition with a prevalence severe horizontal bone loss and of one to three cases per million in the general lymphadenopathy. Delcourt – Debroyne, et al. population. Consanguinity between parents has examine a 14 year old Chediak – Higashi been reported in atleast one third of the reported syndrome patient with severe mobility of teeth, cases. It appears equally in males and females. suppuration, severe bone loss and generalized Most reported cases are in Caucasians [14]. recession with deep probing depths. DNA probe analysis of the bacteria within the periodontal The two essential features of PLS is pockets revealed a pathogenic flora consisting of hyperkeratosis of the palms and soles (either Actinobacillus actinomycetocomitans, diffused or localized) and generalized rapid P.gingivalis and P.intermedia [18, 19]. destruction of periodontal attachment apparatus, resulting in premature loss of both primary and Periodontal diseases associated with permanent teeth. Other findings such as ectopic neutrophil disorders calcifications of the falx cerebri and choroid Localized Juvenile Periodontitis (LJP) plexus, increased susceptibility to infection, Accumulation of neutrophils in connective mental retardation and endocrine disorders have tissues, junctional epithelium and gingival been reported [14,15]. crevice or periodontal pocket of the periodontium is a characteristic morphologic A particular form of PLS has been named the feature of chronic periodontal disease at all “Haim-Munk syndrome”. It is characterized by stages. When neutrophil function is impaired, palmoplantar keratosis and severe early onset there is an increase in periodontal disease as in periodontitis. This additionally presents digital conditions like Chediak – Higashi syndrome, abnormalities which include osteolysis of Localized juvenile periodontitis and other phalanges, abnormal length and slender nail of aggressive, early onset periodontal diseases [20]. the fingers and toes and a claw like hypertrophic deformity of the nails [15, 16]. Localized juvenile periodontitis, formerly termed “Periodontosis”, occurs in adolescents and Chronic granulomatous disease (CGD) teenagers. The prevalence of all forms of Patients with CGD have greater occurrence of juvenile periodontitis was reported to be 0.1%. oral ulcerations and gingival inflammation. LJP presents characteristic radiographic and Marginal erythema along with extensive clinical signs, including alveolar bone loss most attachment loss and gingival recession, often localized to permanent first molars and significant mobility and furcation involvement incisors, with occasional involvement of other has been seen. Bleeding on probing has been teeth. LJP patients often present with little reported in few cases. Limited mild periodontitis evidence of surface inflammation of the is consistent with the local factors present [17]. gingivae, although other gingival inflammation is sometimes seen, and histopathologic studies Myeloperoxidase deficiency showed marked inflammatory cell infiltration. Oral manifestations reported in few case reports Very little or no calculus is formed on the surface are deep mucocutaneous candidiasis, palatal associated with these lesions. Loe, et al. in a candidiasis, rare cases of periodontitis longitudinal study of the natural history of (Generalized Aggressive). But the link has been periodontal disease found that loss of periodontal

Page 67

Archana Tangudu, B. Badari Ramakrishna, K.V.S.P. Gupta, M.V. Mrudula, Rahul Marshal Vaddeswarapu. Oral manifestations associated with neutrophil deficiency and neutrophil disorders: A review. IAIM, 2018; 5(6): 61-71. attachment occurred slowly in some individuals suggested that an abnormality of signal and rapidly in others [20]. transduction in LJP patients, presumably at the level of phospholipase, might be due to normal Considerable progress has been made in membrane calcium release [20, 21]. identifying the microorganisms associated with localized juvenile periodontitis, and much is LJP is known to appear in 2 forms, LJP-1 known about their virulence. Prominent (classic form) and LJP-2. LJP-1 is characterized organisms in the subgingival flora of the by a decrease in chemotactic responses to a periodontal lesions include Gram negative variety of chemotactic factors. This defect has facultative anaerobic rods, mainly been described as a “pain – receptor defect” Aggregatibacteractinomycetocomitans and because all chemotaxin receptors appear to be Capnocytophago species. Most evidence strongly decreased. The second form of LJP, clubbed incriminates A.actinomycetocomitans as the LJP-2, manifests as clinical lesions identical to cause of LJP [20, 21]. those seen in LJP -1, however neither decreased chemotaxis, FMLP or C5a receptors nor GP110 Studies reveal that Gram negative bacteria inhibit is observed in laboratory studies of patient neutrophil chemotaxis, suggesting virulence. The neutrophils [6]. mechanism of the chemotaxis defect is one that is intrinsic to the cell and is not reversible by The reason that LJP is limited to certain sites is treatment. Familial aggregation of individuals unknown. However, it has been proposed that the with the defect is seen. The functional site limitation is a result of a time – dependent suppression of chemotaxis associated with a “window of opportunity”. Antibody is absolutely decrease in the number of receptors for the required for the opsonization of chemotactic factors FMLP and C5a with no A.actinomycetocomitans. This indicates that change in receptor affinity monoclonal antibody responses must be initiated before antibodies to the glycoprotein GP110, were neutrophils can kill this microbe. The time found, which inhibits chemotaxis of normal cells required producing antibodies of the proper [20]. isotype, specificity and affinity may be prolonged by immunosuppressive factor Suzuki and co-workers, Kumar and co-workers elaborated by the microbe and represents a found that the bactericidal activity of LJP potential “window of opportunity” during which neutrophils was depressed. They found the time the organism may be able to considerable phagocytosis and intercellular killing of local tissue changes [21]. neutrophils to be abnormal. Singh reported a marked reduction in the number of neutrophils Rapidly Progressive Periodontitis (RPP) accumulating in the gingival sulcus in LJP. Other RPP is a severe form of periodontal disease functions including O2 consumption, superoxide affecting young adults and/or postpubescent release, ATP energy utilization, β-glucuronidase individuals. Individuals with RAP (Rapidly and lysozyme release have been found to be progressive Adult Periodontitis) have a mean age normal. Recent studies have focused on the of about 40 years (20-62). Generalized juvenile transduction mechanism of neutrophils. It was periodontitis has been associated with plaque and found that the intracellular transduction calculus, which suggests a somewhat different mechanisms that follow receptor ligand coupling microbial etiology than LJP [22]. on the neutrophil surface are not clearly established. The putative effectors for the Neutrophils from such individuals appear to chemotactic receptors of neutrophils are exhibit chemotaxis disorders and no alteration in phospholipase C, protein kinase C, methyl GP110. The chemotaxis disorders may result transferase or adenylatecyclase. Research has from some other phagocyte problem. Kishimoto

Page 68

Archana Tangudu, B. Badari Ramakrishna, K.V.S.P. Gupta, M.V. Mrudula, Rahul Marshal Vaddeswarapu. Oral manifestations associated with neutrophil deficiency and neutrophil disorders: A review. IAIM, 2018; 5(6): 61-71. has reported that serum from non-diseased human leukocyte antigens (HLAS), which individuals did not support phagocytosis of regulate immune responses, have been evaluated A.actinomycetocomitans. RPP probably as candidate markers for aggressive periodontitis. represents a mixture of several diseases including HLA A9 and B15 antigens are constantly rapidly progressive adult periodontitis (RAP) associated with aggressive periodontitis [24, 25]. [23]. Several investigations have shown that patients In one of the studies it was found that in 3 of the with aggressive periodontitis display functional 19 cases studied (16%), intrinsic defects in defects of PMNs, monocytes or both. These leukotaxis could be observed. On the other hand, defects can impair either the chemotactic 6 of 19 cases (32%) exhibited factors in the attraction of PMNs to the site of infection or their serum that impaired leukocyte function. Some of ability to phagocytose and kill microorganisms. these factors were immunoglobulins that Current studies have also demonstrated a hyper functioned as cell directed inhibitors (CDIS) of responsiveness of monocytes from LAP patients chemotaxis rather than as autoantibodies. The involving their PGE2 in response to LPs. This difference between a CDI and an autosomal hyper responsiveness may lead to increased antibody is that CDI functions via its Fc region connective tissue or bone loss (caused by rather than its Fab region by an unexplained excessive production of catabolic factors). These mechanism. In one case an elevated factor in PMN and monocytes defects may be induced by serum led to inactivation of the chemotaxin the bacterial infection or may be genetic in origin known as chemotactic factor inactivator (CFI) is [24]. observed. Extrinsic and intrinsic defects in cell function were not observed in 53% of the cases Conclusion

[22]. In summary, it can be seen that neutrophil disorders that either primary or secondary to Aggressive Periodontitis systemic disease are often associated with severe A primary characteristic of aggressive periodontal disease. Hence neutrophil periodontitis that differentiates it from chronic dysfunction is a risk factor for periodontitis, most periodontitis is the rapid progression of likely lowering the host’s resistance to attachment and bone loss. Other consistent periodontal infection by periodontal organisms. features of patients with aggressive periodontitis are that they are otherwise healthy and that the disease demonstrates a familial pattern of Identifying and understanding the intricacies of occurrence. A number of features are generally the pathogenesis of periodontal diseases but not universally associated with aggressive associated with neutrophil disorders is highly periodontitis. These include inconsistencies essential to enable new treatment paradigms and between the amount of microbicidal deposits and prevention strategies to be developed. the severity of periodontal destruction, the presence of elevated levels of References A.actinomycetocomitans; and evidence of 1. Kenneth T. Miyasaki. The neutrophil: phagocyte abnormalities and hyper – responsive mechanisms of controlling periodontal monocytes/macrophages leading to elevations in bacteria. J Periodontol., 1991; Dec: 761-

PGE2 and 1α - 1β. Furthermore, the disease 774. process is self - limiting in some cases of 2. Daniel MA, Van Dyke TE. Alterations in aggressive periodontitis [23, 24]. phagocyte function and periodontal infection. J Periodontol., 1996; Some immune defects have been implicated in 67(Suppl.10): 1070-1075. the pathogenesis of aggressive periodontitis. The

Page 69

3. Nussbaum G, Shapira L. How has LFA-1, deficiency syndrome. Clinical, neutrophil research improved our histopathologic and molecular understanding of periodontal characteristics. J Periodontol., 1987; Jun: pathogenesis? J Clin Periodontol., 2011; 400-416. 38 (Suppl. 11): 49–59. 14. Thomas C. Hart, Lior Shapira. Papillon - 4. Thomas C. Hart, Lior Shapira, Thomas Lefevre syndrome. Periodontology 2000, E. Van Dyke. Neutrophil defects as risk 1994; 6: 88-100. factors for periodontal disease. J 15. Faiez N. Hattab, Maamon A. Periodontol., 1994; May Supp.: 521-529. Rawashdeh, Othman M. Yassin, Aref S. 5. Joerg Meyle, Jose R. Gonza Les. Al-Momani, Mustafa M. Papillon - Influences of systemic diseases on lefevre syndrome: A review of the periodontitis in children and adolescents. literature and report of 4 cases. J Periodontology 2000, 2001; 26: 92–112. Periodontol., 1995; May: 413-420. 6. Thomas E. Van Dyke, George A, Hoop. 16. Rongkun Liu, Caifang Cao, Huanxing Neutrophil function and oral disease. Meng, Zhihui Tang. Leukocyte functions Crit. Rev. Oral Biol Med., 1990; 1: 117. in 2 cases of Papillon-Lefevre syndrome. 7. David E. Deas, Scott A. Mackey, J Clin Periodontol., 2000; 27(1): 69-73. Howard T. McDonnell. Systemic disease 17. Buduneli N, Baylas H, Aksu G, and periodontitis: manifestations of Kutukculer N. Prepubertal periodontitis neutrophil dysfunction. Periodontology associated with chronic granulomatous 2000, 2003; 32: 82 –104. disease. J Clin Periodontol., 2001; 28: 8. Antonio Carrassi, Silvio Bati, Giorgio 589–593. Santarelli, Giorgio Vogel. Periodontitis 18. Toshiaki Shibutani, Keika Gen, Maki in a patient with chronic neutropenia. J Shibata, Yumi Horiguchi, Naomi Kondo, Periodontol., 1989; Jun: 352-357. Yukio Iwayama. Long-term follow-up of 9. Allison Zaromb, Darren Chamberlain, periodontitis in a patient with Chediak- Robert Schoor, Khalid Almas, Francine Higashi syndrome. A case report. J Blei. Periodontitis as a manifestation of Periodontol., 2000; 71: 1024-1028. chronic benign neutropenia. J 19. Elisabeth M.C. Delcourt-Debruyne, Periodontol., 2006; 77(suppl.11): 1921- Herve Ra. Boutigny. Features of severe 1926. periodontal disease in a teenager with 10. D. Walter Cohen, Alvin L. Morris. Chediak-Higashi syndrome. J Periodontal manifestations of cyclic Periodontol., 2000; 71: 816-824. neutropenia. J Periodontol., 1991; April: 20. R.J. Genco, T.E. Van Dyke, M.J. Levine, 159-168. R.D. Nelson, M.E. Wilson. 1985 11. Carranza, Newman, Takei. Carranza’s Kreshover lecture. Molecular factors Clinical Periodontology. 8th edition, influencing neutrophil defects in Philadelphia: W.B. Saunders; 1996. periodontal disease. J Dent Res., 1986; 12. Reem Dababneh, Adel M. Al-Wahadneh, 65: 1379. Shamekh Hamadneh, Antwan Khouri, 21. Jon B. Suzuki, B. Christine Collison, Nabil F. Bissada. Periodontal William A. Falkler Jr., Robert K. manifestation of Leukocyte adhesion Nauman. Immunologic profile of deficiency type 1. J Periodontol., 2008; juvenile periodontitis. Neutrophil 79: 764-768. chemotaxis, phagocytosis and spore 13. Thomas C.Waldrop, Donald C. germination. J Periodont Res., 1984; Anderson, William W.Hallmon, Frank 55(8): 461-467. C. Schmalstieg. Periodontal 22. Di Murro C, Nisini R, Cattabriga M, manifestations of the heritable Mac-1, Simonetti-Darca A, Le Moli S,

Page 70

Paolantonio M, Sebastiani L, D'Amelio 24. Huanxin Meng, Li Xu, Qiyan Li, Jie R. Rapidly progressive periodontitis. Han, Yibing Zhao. Determinants of host Neutrophil chemotaxis inhibitory factors susceptibility in aggressive periodontitis. associated with the presence of Periodontology 2000, 2007; 43: 133– Bacteroides gingivalis in crevicular fluid. 159. J Periodontol., 1987; 58(12): 868-72. 25. Robert A. Clark, Roy C. Page, Gregory 23. Carranza, Newman, Takei. Carranza’s Wilde. Defective neutrophil chemotaxis Clinical Periodontology, 10th edition, in juvenile periodontitis. Infection and Philadelphia: W. B. Saunders; 2006. Immunity, 1977; Dec: 694-700.

Page 71