Neutrophil dysfunction : a keystone for periodontal infection ? (II)

Introduction

As regards periodontium, small numbers of neutrophils permanently transmigrate through junctional epithelium, even in clinically normal gingiva. When bacteria begin to accumulate in gingival sulcus, they increase in number (^{Attström, 1971}) and play a critical role in controlling spreading of bacteria by coming between the surface of bacterial plaque and sulcular or pocket epithelium (^{Garant, 1976}). As for macrophages, if they are infrequent in the conjonctive tissue of clinically normal gingiva, their numbers increases in severe (^{Jully et al., 1982}) and active (^{Davenport et al., 1982}) lesions.

These phagocytes that serve important effector functions in host defense against invading micro-organisms may unfortunately present functional abnormalities, most of which will result in an increased susceptibility to infections (^{Cottet, 1998}). Given that much of what is known about the pathogenesis of these congenital and acquired immunodeficiencies come from the study of the neutrophils, we will focus our attention on these cells and discuss the relationships between their dysfunction and periodontal susceptibility to infection.

Defects in neutrophil function

As neutrophils are the first cellular line of defense, defects that affect this cell line are very often symptomatic. These defects may arise from quantitative abnormalities, from abnormalities in adherence and locomotion, or from abnormalities in killing. They may be intrinsic or extrinsic, intrinsic defects being generally more severe than extrinsic defects. Most of the resulting diseases or syndromes involve abnormalities of other cell populations. Clinical manifestations mainly result from infections that predominate at epithelial surfaces. With increasing severity, these infections tend to extend locally or deeply in tissues. In this review, special emphasis will be put on neutrophil dysfunction associated with periodontal disease.

Neutropenias

Neutropenia is defined as a decrease in the absolute blood neutrophil count that is more than two standard deviation below the normal mean. The degree of neutropenia may be « mild » (1.0-1.5 x 10.⁹ neutrophils/L), « moderate » (0.5-1.0 x 10⁹ neutrophils/L), or « severe » (less than 0.5 x 10⁹ neutrophils/L). Neutropenia is the most common granulocyte defect, it occurs 1) if there is a reduced or ineffective production, or 2) if there is an accelerated removal of neutrophils from peripheral blood. Consequently, its etiology is classified as intrinsic to myelopoiesis or extrinsic to bone marrow. The term agranulocytosis is often used to indicate severe neutropenia. Incidence and severity of accompanying infectious problems is directly proportional to both magnitude and duration of neutropenia. The risk of infection is greater when neutrophils are less than 0.5 x 10⁹/L ; the severity of infections is aggravated by defects in other host defenses and inability of bone marrow to respond. These infections are usually due to micro-organisms normally found on skin, in nasopharynx, mouth and intestinal tract. They result in otitis media, cutaneous cellulitis, abscesses, furunculosis, stomatitis, gingivitis, periodontitis, pharyngitis, or perirectal inflammation. Septicemia or deep tissue infections may also occur (^{Sievers and Dale, 1996}).

Kostman syndrome. This syndrome is a rare disorder probably inherited as an autosomal recessive trait. Bone marrow smear shows an arrest in maturation of the neutrophilic series with block at the promyelocyte-myelocyte level. Eosinophilia and monocytosis may be present ; IgG and IgA levels are usually normal or increased (^{Kostmann, 1975}). Gingivitis usually appears with the eruption of deciduous teeth ; early onset periodontitis is a characteristic feature of this syndrome (^{Mishkin et al., 1976}). Patients occasionally survive into adolescence (^{Kostmann, 1975}).

Chronic idiopathic neutropenia. This group of disorders affect both children beyond the age of 2 years and adults. Neutropenia affecting children is probably inherited as an autosomal dominant trait. Neutrophil counts vary from 0.2 to 2.0 x 10⁹ cells/L whereas monocytes counts are normal or increased. Increased levels of immunoglobulins are also observed. In most cases, bone marrow examination indicate an ineffective granulocytopoiesis (^{Dale et al., 1979} ; ^{Sievers and Dale, 1996}). Patients may present with symptoms ranging from gingivitis to early onset periodontitis (^{Baehni et al., 1983} ; ^{Kirstilä et al., 1993} ; ^{Porter et al., 1994}).

Chronic cyclic neutropenia. This disorder, usually diagnosed during childhood, occurs in autosomal dominant, spontaneous, or acquired forms. It is characterized by regular periodic oscillations of blood neutrophil counts from normal to neutropenic values. The habitual cycle time is approximately 21 ± 3 days. In a given patient, this periodicity is constant (^{Lange, 1983} ; ^{Sievers and Dale, 1996}). The other hematopoietic lineages often cycle as well (^{Dale and Hammond IV, 1988} ; ^{Sievers and Dale, 1996}). The neutropenic episodes generally last 3 to 6 days, and for 1 to 3 days in these periods no mature neutrophils can be detected in blood (^{Lange, 1983} ; ^{Dale and Hammond IV, 1988} ; ^{Sievers and Dale, 1996}). Cycling is due to an unknown defect in regulation of hematopoiesis (^{Lange, 1983}). A monocytosis appears to compensate the drop in neutrophil numbers (^{Quie, 1975}). However, despite this compensation, most of the patients develop malaise, fever, oral ulcers, pharyngitis associated with cervical lymph node enlargement during neutropenic periods. Patients often present with periodontitis (^{Cohen and Morris, 1961} ; ^{Wade and Stafford, 1963} ; ^{Prichard et al., 1984}). As they become older, symptoms are often milder, cycling become less pronounced, and disease tend to resemble to chronic idiopathic (benign) neutropenia (^{Quie, 1975} ; ^{Dale and Hammond IV, 1988}).

Autoimmune neutropenia. This disorder, diagnosed during infancy, is hard to distinguish from chronic idiopathic neutropenia. Only demonstration of anti-neutrophil antibodies permits to differentiate these two conditions (^{Sievers and Dale, 1996}). The neutropenia is usually severe, but white blood cell counts are within normal limits and a monocytosis may be observed. Usually most of the patients present with recurrent otitis media, respiratory tract infections, gastroenteritis and gingivitis ; however infections may be more severe. Spontaneous remissions may occur early in childhood (^{Boxer and Blackwood, 1996}).

Drug-induced neutropenia. This neutropenia is due to idiosyncrastic drug reactions. These responses are unpredictable. A first type of idiosyncrastic reactions is due either to a direct toxicity of a drug (or chemical) or its intermediate metabolites, or to slower hepatic or renal clearance. The onset is insidious, delayed (weeks to months following the initial drug exposure), and a latency period following reexposure is observed. Usually, there is a complete recovery when the drug is discontinued but neutropenia may persist after its withdrawal (^{Quie, 1975} ; ^{Young, 1994} ; ^{Sievers and Dale, 1996}). A second type of idiosyncrastic reactions is due to hypersensitivity reactions. In this case, the drug acts as haptens and stimulates auto-antibody production resulting in destruction of neutrophils. The neutropenia begins 7 to 14 days following initial exposure to the drug, and there is no latency period following reexposure. The symptomatology usually last for several months after the drug is withdrawn (^{Young, 1994} ; ^{Sievers and Dale, 1996}). In both types of reactions, if neutropenia persists for a long time, patients may present with symptoms of chronic idiopathic neutropenia and periodontitis (^{Swenson et al., 1965} ; ^{Ohishi et al., 1988}).

Chemotherapy-induced neutropenia. Chemotherapy is the most common cause of neutropenia. Usually, this neutropenia occurs 7 to 10 days following start of cancer chemotherapy. Patients receiving antineoplastic drugs are more prone to develop serious infectious complications because of the induced bone marrow depression or suppression (^{Quie, 1975} ; ^{Boxer and Blackwood, 1996}).

Abnormalities in adherence and locomotion

Chédiak-Higashi syndrome (CHS). CHS is a rare disorder inherited as an autosomal recessive trait and characterized by the presence of abnormal giant granules in all granule-containing cells. In neutrophils, the giant granules result from fusion of primary granules with each other, with secondary granules or with cytoplasmic membrane components (^{White and Clawson, 1980}). The granule size may hamper the passage of neutrophils from bone marrow into medullar sinusoids alter cell motility, chemotaxis, and delay degranulation (^{Quie, 1975} ; ^{Clawson et al., 1978}). Altered cyclic adenosine monophosphate/cyclic guanosine monophosphate ratio has been reported (^{Arbiser, 1995}). Natural killer (NK) cell activity and antibody-dependent cellular cytotoxicity (ADCC) are also impaired (^{Boxer and Morganroth, 1987}). Patients present with partial oculocutaneous albinism, photophobia, rotatory nystagmus, recurrent infections involving skin, respiratory tract and mucous membrane, moderate neutropenia and prolonged bleeding time. Gingivitis and early-onset periodontitis are also reported (^{Charon et al., 1985} ; ^{Brown and Gallin, 1988}). In a number of patients, the disease will enter an accelerate phase characterized by diffuse lymphohistiocytic organ infiltration associated with pancytopenia and peripheral neuropathy. Death will occur from infection or hemorrage.

Leukocyte adhesion deficiency (LAD). Two types of LAD have been identified. LAD type 1 (LAD I) is a rare disorder inherited in an autosomal recessive manner. Its molecular basis is the presence of mutations affecting the gene encoding the β-chain of β₂-integrins. These mutations are responsible for an absence, insufficient quantity, or abnormal structure of the β₂-subunit precursor leading to a deficiency of the three β₂-integrins, LFA-1 (CD11a/CD18), CR3 (CD11b/CD18), and CR4 (CD11c/CD18) (^{Dimanche-Boitrel et al., 1988}). This deficiency results in a failure of phagocytes and lymphocytes to adhere to endothelium and to migrate to inflammatory foci. The first step of adherence which rely on L-selectin and sialyl Lewis^X antigen (sLe^X) is normal but there is no strengthening of adherence following stimulation. Neutrophils also fail to bind and ingest iC3b-opsonized particles, and, when these particles are bound, the accompanying degranulation and oxidative responses are diminished (^{Boxer and Morganroth, 1987}). Antibody-dependent cellular cytotoxicity (ADCC), T-lymphocyte-mediated killing, and natural killing are also impaired (^{Krensky et al., 1983} ; ^{Kohl et al., 1984}). Clinically, LAD I is characterized by delayed umbilical cord separation and wound healing, recurrent soft-tissue infections, and severely impaired pus formation despite blood neutrophilia (^{Boxer and Morganroth, 1987} ; ^{Rotrosen and Gallin, 1987}). Otitis and severe periodontal disease are present. The severity of the phenotype is correlated with the degree of β₂-integrin deficiency (^{Rotrosen and Gallin, 1987}). If the level of expression of the β₂-integrins is superior to approximately 3 % of normal, patients have a less severe form of disease and can survive infancy ; however, even in this case, severe gingivitis and periodontitis are present (^{Anderson et al., 1985}). LAD type 2 (LAD II) is an autosomal disorder described in two unrelated children who presented unusual facial appearance, severe mental retardation, Bombay blood phenotype, recurrent infections with neutrophilia, and periodontitis. The defect responsible for this disease is the absence of sLe^Xantigen on neutrophils. As a result, these cells are unable to bind to activated endothelial cells which express E-selectin and P-selectin (^{Etzioni et al., 1992} ; ^{Frydman et al., 1992}).

Specific granule deficiency (SGD). SGD is a rare, heterogeneous disorder probably inherited as an autosomal recessive trait (^{Breton-Gorius et al., 1980} ; ^{Ganz et al., 1988}). Neutrophils are characterized by abnormal nuclear segmentation (^{Breton-Gorius et al., 1980} ; ^{Parmley et al., 1983}), presence of empty specific granules (^{Parmley et al., 1983}), lack of defensins (^{Ganz et al., 1988} ; ^{Parmley et al., 1989}) and gelatinase (^{Parmley et al., 1989}). The lack of lactoferrin, stored in specific granules, seems to be relatively tissue specific since this protein is present in secretions (^{Vildé et al., 1982} ; ^{Raphael et al., 1989}). As a result of these abnormalities, neutrophils demonstrate impaired chemotaxis (^{Gallin et al., 1982}) and decreased respiratory burst (^{Breton-Gorius et al., 1980} ; ^{Gallin et al., 1982} ; ^{Vildé et al., 1982}) ; however, their bactericidal activity is normal (^{Breton-Gorius et al., 1980} ; ^{Vildé et al., 1982}). Given that specific granules are a source of substances which modulate monocyte infiltration to inflammatory foci, the chemotaxis of these latter cells is defective in vivo but normal in vitro (^{Gallin et al., 1982}). Eosinophils are also affected (^{Rosenberg and Gallin, 1993}). Clinically, patients suffer from recurrent bacterial infections (^{Breton-Gorius et al., 1980} ; ^{Vildé et al., 1982} ; ^{Raphael et al., 1989}). A case of specific granule deficiency with severe gingivitis has been reported (^{Charon et al., 1985}) but there is no indication of accompanying alveolar bone loss.

Hyperimmunoglobulin E syndrome (Job's syndrome, Buckley's syndrome) (HIES). HIES is a rare autosomal disorder with incomplete penetrance characterized by elevated serum IgE levels (> 2 000 IU/ml), chronic eczema resembling atopic dermatitis, recurrent cutaneous and sinopulmonary bacterial infections, and frequent mucocutaneous candidiasis. Laboratory abnormalities include high levels of anti-Staphilococcus aureus, and anti-Candida albicans IgE, mild to moderate eosinophilia, and an impaired neutrophil chemotaxis without defect in phagocytic function (^{Rebora et al., 1978} ; ^{Stanley et al., 1978} ; ^{Roth et al., 1992}). The abnormal IgE synthesis might result from an imbalance between T helper 1 and T helper 2 cell populations (^{Dreskin et al., 1985} ; ^{Cohen-Solal et al., 1995}). The severity of the chemotactic abnormality, apparently extrinsic to neutrophils, varies from patient to patient and, in the same patient, with time. A deficiency of anti-Staphylococcus aureus IgA and total salivary IgA is also reported (^{Dreskin et al., 1985}). Apart from immunological abnormalities, many patients present with coarse facial feature and bony defects that may lead to osteoporosis (^{Cohen-Solal et al., 1995}). The observed increased cortical bone loss might be due to the presence of a bone resorbing activity secreted by IgE-activated mononuclear cells (^{Cohen-Solal et al., 1995}). Patients also present with gingivitis and sometimes with periodontitis (^{Charon et al., 1985} ; ^{Van Dyke, 1985}).

Others. The R131 allotype of FcgRIIa which bind IgG2 with low affinity (^{Parren et al., 1992}) may predispose to infections by Neisseria meningitidis (^{Bredius et al., 1994}) and Actinobacillus actinomycetemcomitans (^{Wilson and Kalmar, 1996}).

Abnormalities in killing

Chronic granulomatous disease (CGD). CGD is a rare disease inherited either as an X-linked recessive trait, or as an autosomal recessive trait (^{table I}). The molecular basis for this disease is the presence of mutations in the genes encoding each of the four major components of NADPH oxidase. Biochemically, defective NADPH oxidase results in an inability to produce normal amounts of reactive oxygen intermediates. Consequently, phagocytes ingest but do not kill catalase-positive micro-organisms (^{Boxer and Morganroth, 1987}) which may survive and multiply in the cells where they are protected from antibodies, complement and most antibiotics. Catalase-negative micro-organisms are killed normally because the H₂O₂ they produce is used by the MPO system to form hypochlorous acid instead of being destroyed. However, in both cases, the micro-organisms are not properly digested since, in the absence of superoxide anion production, there is no initial rise but a rapid and extensive fall in vacuolar pH preventing the granule neutral proteases from acting (^{Segal et al., 1981}). The most commonly encountered pathogens are Staphylococcus aureus, Serratia marcescens, Escherichia coli, Klebsiella, Pseudomonas, Aspergillus sp and Candida albicans (^{Boxer and Morganroth, 1987} ; ^{Arbiser, 1995}). Clinically, CGD is characterized by recurrent bacterial and fungal infections complicated by micro-abscesses and granuloma formation (^{Boxer and Morganroth, 1987} ; ^{Arbiser, 1995}). Lung, skin, liver and lymph nodes are the most common sites of infection but any organ may be involved. Osteomyelitis may be observed at multiple sites (^{Boxer and Blackwood, 1996}). The onset may occur at any age (^{Boxer and Morganroth, 1987} ; ^{Schapiro et al., 1991}) and clinical presentation is variable. The X-linked form of CGD is more severe than the autosomally inherited one, and, in X-linked carriers, severity is related directly to the proportion of their neutrophils expressing the CGD phenotype (lyonisation). Gingivitis seems to be a feature of chronic granulomatous disease (^{Charon et al., 1985} ; ^{Cohen et al., 1985}) but there is no evidence for an increased susceptibility to early onset periodontitis (^{Cohen et al., 1985}).

Discussion

The affections, syndromes or diseases, reviewed clearly demonstrate that neutrophil dysfunction may result in periodontal disease the severity of which is linked to the nature of the dysfunction. Thus, the periodontal diseases are more severe when there is a quantitative abnormality (neutropenia) or when neutrophils are unable to migrate to infectious foci (leukocyte adhesion deficiency or LAD). As regards acquired neutropenias, the severity of the periodontal condition is directly proportional to the suddenness of the onset, the duration and the extent of the neutropenic episode.

The clinical presentation of patients with abnormalities in neutrophil chemotaxis is generally less severe, except for Chédiak-Higashi syndrome. In the latter case, presence of giant granules leads to intramedullary sequestration of the neutrophils and subsequently to neutropenia. In addition the presence of these granules is responsible for impaired motility and chemotaxis, delayed degranulation and intracellular killing. Consequently, all the functions of neutrophils are altered, which may explain the severity of clinical manifestations. In specific granule deficiency, the impaired chemotaxis is associated with a decrease in respiratory burst while the intracellular killing is normal. The absence of defect in intracellular killing is due to the fact that the bulk of bactericidal proteins is stored in azurophilic granules and is not affected, except for defensins. As for the hyperimmunoglobulin E syndrome, the impaired chemotaxis is variable and inconsistent ; this may explain why periodontitis is not a characteristic feature of this syndrome.

Isolated abnormality in intracellular killing does not seem to constitute a risk factor for severe periodontitis. The absence of a severe periodontal condition in chronic granulomatous disease may be explained by the efficiency of oxygen-independent bactericidal mechanisms, the anaerobic nature of the micro-organisms responsible for periodontal disease progression, and the continuous antibiotic prophylaxis administered to most of the patients. However this antibiotic prophylaxis is probably not a determining factor since it does not prevent the appearance of severe periodontitis in patients with LAD, for example.

These latter elements demonstrate that our understanding of the function of neutrophils in maintaining periodontal health is still superficial. Too few studies about neutrophil dysfunction include detailed informations on gingival and periodontal conditions of the affected patients. More research is therefore required to understand the mechanisms whereby neutrophils overpower periodontopathic bacteria preserving thus the periodontal health and so to determine the abnormalities that constitute a risk factor for destructive periodontitis.

BIBLIOGRAPHY

• ANDERSON DC, SCHMALSTIEG FC, FINEGOLD MJ, HUGHES BJ, ROTHLEIN R, MILLER LJ, KOHL S, TOSI MF, JACOBS RL, WALDROP TC. The severe and moderate phenotypes of heritable Mac-1, LFA-1 deficiency : their quantitative definition et relation to leucocyte dysfunction et clinical features. J Infect Dis 1985;152:668-689.
• ARBISER JL. Genetic immunodeficiencies : cutaneous manifestations and recent progress. J Am Acad Dermatol 1995;33:82-89.
• ATTSTRÖM R. Studies on neutrophil polymorphonuclear leukocytes at the dento-gingival junction in gingival health et disease. J Periodont Res 1971;8 (suppl):1-15.
• BAEHNI PC, PAYOT P, TSAI CC, CIMASONI G. Periodontal status associated with chronic neutropenia. J Clin Periodontol 1983;10:222-230.
• BOXER LA, BLACKWOOD RA. Leukocytes disorders : Quantitative et qualitative disorders of the neutrophil, Part 1. Pediatr Rev 1996;17:19-28.
• BOXER LA, BLACKWOOD RA. Leukocytes disorders : Quantitative et qualitative disorders of the neutrophil, Part 2. Pediatr Rev 1996;17:47-50.
• BOXER LA, MORGANROTH ML. Neutrophil function disorders. Dis Mon 1987;33:681-780.
• BREDIUS RG, DERKX BH, FIJEN CA, DE WIT TP, DE HAAS M, WEENING RS, VAN DE WINKEL JG, OUT TA. Fcg receptor IIa (CD32) polymorphism in fulminant meningococcal septic shock in children. J Infect Dis 1994;170:848-853.
• BRETON-GORIUS J, MASON DY, BURIOT D, VILDE JL, GRISCELLI C. Lactoferrin deficiency as a consequence of a lack of specific granules in neutrophils from a patient with recurrent infections. Am J Pathol 1980;99:413-428.
• BROWN CC, GALLIN JI. Chemotactic disorders. Hematol Oncol Clin North Am 1988;2:61-79.
• CHARON JA, MERGENHAGEN SE, GALLIN JI. Gingivitis et oral ulceration in patients with neutrophil dysfunction. J Oral Pathol 1985;14:150-155.
• CLAWSON CC, WHITE JG, REPINE JE.The Chédiak-Higashi syndrome. Am J Pathol 1978;92:745-754.
• COHEN DW, MORRIS AL. Periodontal manifestations of cyclic neutropenia. J Periodont 1961;32:159-168.
• COHEN MS, LEONG PA, SIMPSON DM. Phagocytic cells in periodontal defense. Periodontal status of patients with chronic granulomatous disease of childhood. J Periodontol 1985;56:611-617.
• COHEN-SOLAL M, PRIEUR AM, PRIN L, DENNE MA, LAUNAY JM, GRAULET AM, BRAZIER M, GRISCELLI C, DE VERNEJOUL MC. Cytokine-mediated bone resorption in patients with the hyperimmunoglobulin E syndrome. Clin Immunol Immunopathol 1995;76:75-81.
• COTTET MH. Dysfonctions des neutrophiles : pierre angulaire de l'infection parodontale ? (I) Fonctions des neutrophiles : aspects fondamentaux. J Parodont Implant Orale 1998;17:137-155.
• DALE DC, GUERRY IV D, WEWERKA JR, BULL JM, CHUSID MJ. Chronic neutropenia. Medicine 1979;58:128-144.
• DALE DC, HAMMOND IV WP. Cyclic neutropenia : a clinical review. Blood Rev 1988;2:178-185.
• DAVENPORT RH JR, SIMPSON DM, HASSEL TM. Histometric comparison of active an inactive lesions of advanced periodontitis. J Periodont 1982;53:285-295.
• DIMANCHE-BOITREL MT, GUYOT A, DE SAINTE-BASILE G, FISCHER A, GRISCELLI C, LISOWSKA-GROSPIERRE B. Heterogeneity in the molecular defect leading to the leucocyte adhesion deficiency. Eur J Immunol 1988;18:1575-1579.
• DRESKIN SC, GOLDSMITH PK, GALLIN JI. Immunoglobulins in the hyperimmunoglobulin E et recurrent infection (Job's syndrome) : deficiency of anti-Staphylococcus aureus immunoglobulin A. J Clin Invest 1985;75:26-34.
• ETZIONI A, FRYDMAN M, POLLACK S, AVIDOR I, PHILLIPS ML, PAULSON JC, GERSHONI-BARUCH R. Brief report : recurrent severe infections caused by a novel leukocyte adhesion deficiency. N Engl J Med 1992;25:1789-1792.
• FRYDMAN M, ETZIONI A, EIDLITZ-MARKUS T, AVIDOR I, VARSANO I, SHECHTER Y, ORLIN JB, GERSHONI-BARUCH R. Rambam-Hasharon syndrome of psychomotor retardation, short stature, defective neutrophil motility, et Bombay phenotype. Am J Med Genet 1992;44:297-302.
• GALLIN JI, FLETCHER MP, SELIGMANN BE, HOFFSTEIN S, CEHRS K, MOUNESSA N. Human neutrophil-specific granule deficiency : a model to assess the role of neutrophil granules in the evolution of the inflammatory response. Blood 1982;59:1317-1329.
• GANZ T, METCALF JA, GALLIN JI, BOXER LA, LEHRER RI. Microbicidal/cytotoxic proteins of neutrophils are deficient in two disorders : Chédiak-Higashi syndrome and " specific " granule deficiency. J Clin Invest 1988;82:552-556.
• GARANT PR. Plaque neutrophil interaction in monoinfected rats as visualized by transmission electron microscopy. J Periodont 1976;47:132-138.
• JULLY JM, BENE MC, FAURE G, MARTIN G, DUHEILLE J. Identification et localisation des cellules infiltrant la gencive au cours des parodontopathies. I. Macrophages et lymphocytes T. J Parodontol 1982;1:157-171.
• KIRSTILÄ V, SEWON L, LAINE J. Periodontal disease in three siblings with familial neutropenia. J Periodontol 1993;64:566-570.
• KOHL S, SPRINGER TA, SCHMALSTIEG FC, LOO LS, ANDERSON DC. Defective natural killer cytotoxicity et polymorphonuclear leukocyte antibody-dependent cellular cytotoxicity in patients with LFA-1/OKM-1 deficiency. J Immunol 1984;133:2972-2978.
• KOSTMANN R. Infantile genetic agranulocytosis. Acta Pædiatr Scand 1975;64:362-368.
• KRENSKY AM, SANCHEZ-MADRID F, ROBBINS E, NAGY JA, SPRINGER TA, BURAKOFF SJ. The functional significance, distribution, et structure of LFA-1, LFA-2, LFA-3 : cell surface antigens associated with CTL-target interactions. J Immunol 1983;131:611-616.
• LANGE RD. Cyclic hematopoiesis : human cyclic neutropenia. Exp Hematol 1983;11:435-451.
• MISHKIN DJ, AKERS JO, DARBY CP. Congenital neutropenia. Oral Surg Oral Med Oral Pathol 1976;42:738-745.
• OHISHI M, OOBU K, MIYANOSHITA Y, YAMAGUCHI K. Acute gingival necrosis caused by drug-induced agranulocytosis. Oral Surg Oral Med Oral Pathol 1988;66:194-196.
• PARMLEY RT, GILBERT CS, BOXER LA. Abnormal peroxidase-positive granules in " specific granule " deficiency. Blood 1989;73:838-844.
• PARMLEY RT, TZENG DY, BAEHNER RL, BOXER LA. Abnormal distribution of complex carbohydrates in neutrophils of a patient with lactoferrin deficiency. Blood 1983;62:538-548.
• PARREN PWHI, WARMERDAM PAM, BOEIJE LC, ARTS J, WESTERDAAL NAC, VLUG A, CAPEL PJA, AARDEN L, VAN DE WINKEL JGJ. On the interaction of IgG subclasses with the low affinity FcγRIIa (CD32) on human monocytes, neutrophils, and platelets. Analysis of a functional polymorphism to human Ig. J Clin Invest 1992;90:1537-1546.
• PORTER SR, LUKER J, SCULLY C, OAKHILL A. Oral features of a family with benign familial neutropenia. J Am Acad Dermatol 1994;30:877-880.
• PRICHARD JF, FERGUSON DM, WINDMILLER J, HURT WC. Prepubertal periodontitis affecting the deciduous et permanent dentition in a patient with cyclic neutropenia. J Periodontol 1984;55:114-122.
• QUIE PG. Pathology of bactericidal power of neutrophils. Semin Hematol 1975;12:143-160.
• RAPHAEL GD, DAVIS JL, FOX PC, MALECH HL, GALLIN JI, BARANIUK JN, KALINER MA. Glandular secretion of lactoferrin in a patient with neutrophil lactoferrin deficiency. J Allergy Clin Immunol 1989;84:914-919.
• REBORA A, NUNZI E, PEZZUOLO M, PATRONE F, DALLEGRI F, SACCHETTI C. Buckley's syndrome. Br J Dermatol 1978;99:569-572.
• ROSENBERG HF, GALLIN JI. Neutrophil-specific granule deficiency includes eosinophils. Blood 1993;82:268-273.
• ROTH JG, PARKER TL, ESTERLY NB. What syndrome is this ? The hyperimmunoglobulin E syndrome. Pediatr Dermatol 1992;9:410-413.
• ROTROSEN D, GALLIN JI. Disorders of phagocyte function. Ann Rev Immunol 1987;5:127-150.
• SCHAPIRO BL, NEWBURGER PE, KLEMPNER MS, DINAUER MC. Chronic granulomatous disease presenting in a 69-year-old man. N Engl J Med 1991;325:1786-1790.
• SEGAL AW, GEISOW M, GARCIA R, HARPER A, MILLER R. The respiratory burst of phagocytic cells is associated with a rise in vacuolar pH. Nature 1981;290:406-409.
• SIEVERS EL, DALE DC. Non-malignant neutropenia. Blood Rev 1996;10:95-100.
• STANLEY J, PEREZ D, GIGLI I, GOLDTSEIN I, BAER RL. Hyperimmunoglobulin E syndrome. Arch Dermatol 1978;114:765-767.
• SWENSON HM, REDISH CH, MANNE MAgranulocytosis : two case reports. J Periodontol 1965;36:466-470.
• VAN DYKE TE. Role of the neutrophil in oral disease : receptor deficiency in leukocytes from patients with juvenile periodontitis. Rev Infect Dis 1985;7:419-425.
• VILDE JL, BRETON-GORIUS J, HAKIM J, BURIOT D, GRISCELLI C. Congenital et acquired lactoferrin deficiency in neutrophils. Adv Exp Med Biol 1982;141:611-620.
• WADE AB, STAFFORD JL. Cyclical neutropenia. Oral Surg Oral Med Oral Pathol 1963;16:1443-1448.
• WHITE JG, CLAWSON CC. The Chédiak-Higashi syndrome : the nature of the giant neutrophil granules et their interactions with cytoplasm et foreign particulates. I. Progressive enlargement of the massive inclusions in mature neutrophils. II. Manifestations of cytoplasmic injury et sequestration. III. Interactions between giant organelles et foreign particulates. Am J Pathol 1980;98:151-196.
• WILSON ME, KALMAR JR. FcgRIIa (CD32) : a potential marker defining susceptibility to localized juvenile periodontitis. J Periodontol 1996;67:323-331.
• YOUNG NS. Agranulocytosis. J Amer Med Assoc 1994;271:935-938.