"Oral Manifestations of Patients with Inherited Defect in Phagocyte Number or Function" a systematic review.

INTRODUCTION: Inherited phagocyte defects are one of the subgroups of primary immunodeficiency diseases (PIDs) with various clinical manifestations. As oral manifestations are common at the early ages, oral practitioners can have a special role in the early diagnosis. MATERIALS AND METHODS: A comprehensive search was conducted in this systematic review study and data of included studies were categorized into four subgroups of phagocyte defects, including congenital neutropenia, defects of motility, defects of respiratory burst, and other non-lymphoid defects. RESULTS: Among all phagocyte defects, 12 disorders had reported data for oral manifestations in published articles. A total of 987 cases were included in this study. Periodontitis is one of the most common oral manifestations. CONCLUSION: There is a need to organize better collaboration between medical doctors and dentists to diagnose and treat patients with phagocyte defects. Regular dental visits and professional oral health care are recommended from the time of the first primary teeth eruption in newborns.

Primary Immunodeficiencies With Defects in Innate Immunity: Focus on Orofacial Manifestations.

The field of primary immunodeficiencies (PIDs) is rapidly evolving. Indeed, the number of described diseases is constantly increasing thanks to the rapid identification of novel genetic defects by next-generation sequencing. PIDs are now rather referred to as "inborn errors of immunity" due to the association between a wide range of immune dysregulation-related clinical features and the "prototypic" increased infection susceptibility. The phenotypic spectrum of PIDs is therefore very large and includes several orofacial features. However, the latter are often overshadowed by severe systemic manifestations and remain underdiagnosed. Patients with impaired innate immunity are predisposed to a variety of oral manifestations including oral infections (e.g., candidiasis, herpes gingivostomatitis), aphthous ulcers, and severe periodontal diseases. Although less frequently, they can also show orofacial developmental abnormalities. Oral lesions can even represent the main clinical manifestation of some PIDs or be inaugural, being therefore one of the first features indicating the existence of an underlying immune defect. The aim of this review is to describe the orofacial features associated with the different PIDs of innate immunity based on the new 2019 classification from the International Union of Immunological Societies (IUIS) expert committee. This review highlights the important role played by the dentist, in close collaboration with the multidisciplinary medical team, in the management and the diagnostic of these conditions.

Characterization of neutrophil function in Papillon-Lefèvre syndrome.

Papillon-Lefévre syndrome is a rare, inherited, autosomal-recessive disease, characterized by palmoplantar keratosis and severe prepubertal periodontitis, leading to premature loss of all teeth. Papillon-Lefévre syndrome is caused by a mutation in the cathepsin C gene, resulting in complete loss of activity and subsequent failure to activate immune response proteins. Periodontitis in Papillon-Lefévre syndrome is thought to arise from failure to eliminate periodontal pathogens as a result of cathepsin C deficiency, although mechanistic pathways remain to be elucidated. The aim of this study was to characterize comprehensively neutrophil function in Papillon-Lefévre syndrome. Peripheral blood neutrophils were isolated from 5 patients with Papillon-Lefévre syndrome, alongside matched healthy control subjects. For directional chemotactic accuracy, neutrophils were exposed to the chemoattractants MIP-1α and fMLP and tracked by real-time videomicroscopy. Reactive oxygen species generation was measured by chemiluminescence. Neutrophil extracellular trap formation was assayed fluorometrically, and proinflammatory cytokine release was measured following overnight culture of neutrophils with relevant stimuli. Neutrophil serine protease deficiencies resulted in a reduced ability of neutrophils to chemotax efficiently and an inability to generate neutrophil extracellular traps. Neutrophil extracellular trap-bound proteins were also absent in Papillon-Lefévre syndrome, and Papillon-Lefévre syndrome neutrophils released higher levels of proinflammatory cytokines in unstimulated and stimulated conditions, and plasma cytokines were elevated. Notably, neutrophil chemoattractants MIP-1α and CXCL8 were elevated in Papillon-Lefévre syndrome neutrophils, as was reactive oxygen species formation. We propose that relentless recruitment and accumulation of hyperactive/reactive neutrophils (cytokines, reactive oxygen species) with increased tissue transit times into periodontal tissues, alongside a reduced antimicrobial capacity, create a locally destructive chronic inflammatory cycle in Papillon-Lefévre syndrome.

Cytokine production by leukocytes of Papillon-Lefèvre syndrome patients in whole blood cultures.

Papillon-Lefèvre syndrome (PLS) is characterised by aggressively progressive periodontitis combined with palmo-plantar hyperkeratosis. It is caused by "loss of function" mutations in the cathepsin C gene. The hypothesis behind this study is that PLS patients' polymorphonuclear leukocytes (PMNs) produce more proinflammatory cytokines to compensate for their reduced capacity to neutralize leukotoxin and to eliminate Aggregatibacter actinomycetemcomitans. Production of more interleukin (IL)-8 would result in the attraction of more PMNs. The aim of this study was to evaluate the cytokine profile in PLS patients' blood cultures. Blood was sampled from eight PLS patients (one female) from six families (antiinfective therapy completed: six; edentulous: two) with confirmed cathepsin C mutations and deficient enzyme activity. Nine healthy males served as controls. Whole blood cultures were stimulated with highly pure lipopolysaccharide (LPS) from Escherichia coli R515 and IL-1ß plus tumor necrosis factor (TNF)-α. Thereafter, release of IL-1ß (stimulation: LPS and LPS plus adenosine triphosphate), IL-6, IL-8, interferon-inducible protein (IP)-10, and interferon (IFN)-γ (stimulation: LPS, IL-1ß/TNFα) were detected by ELISA. Medians of cytokine release were, with the exception of IP-10, slightly higher for PLS than for controls' cultures. None of these differences reached statistical significance. Increased production of IL-1ß, IL-6, IL-8, IP-10, or IFNγ as a significant means to compensate for diminished activity and stability of polymorphonuclear leukocyte-derived proteases could not be confirmed in this study. Cytokine profiles in blood cultures may not be used to identify PLS patients.

Analysis of human leukocyte antigen class II gene polymorphism in Iranian patients with Papillon-Lefevre syndrome: a family study.

BACKGROUND: Papillon-Lefevre syndrome (PLS) is a rare autosomal recessive disorder characterized by palmoplantar hyperkeratosis and early development of aggressive periodontitis. Although cathepsin C (CTSC) gene mutations have been established in about 70-80% of PLS patients, it is assumed that the patients may have dysfunctioning of immune defense mechanisms. OBJECTIVE: To assess the association of HLA class II genes and PLS. METHODS: HLA class II genes were typed in nine Iranian PLS patients and their family members and the results were compared to 816 Iranian healthy subjects. RESULTS: The results of this study revealed that DRB1*0101 and DRB1*0301 alleles were more frequent in PLS patients than in normal controls. However, there was no significant difference between PLS patients and normal controls. Moreover, the same haplotypes and genotype combinations were also observed in some patients and their healthy siblings. CONCLUSION: The results of this study showed no strong association between HLA class II alleles and PLS.

Role of polymorphonuclear leukocyte-derived serine proteinases in defense against Actinobacillus actinomycetemcomitans.

Periodontitis is a chronic destructive infection of the tooth-supportive tissues, which is caused by pathogenic bacteria such as Actinobacillus actinomycetemcomitans. A severe form of periodontitis is found in Papillon-Lefèvre syndrome (PLS), an inheritable disease caused by loss-of-function mutations in the cathepsin C gene. Recently, we demonstrated that these patients lack the activity of the polymorphonuclear leukocyte (PMN)-derived serine proteinases elastase, cathepsin G, and proteinase 3. In the present study we identified possible pathways along which serine proteinases may be involved in the defense against A. actinomycetemcomitans. Serine proteinases are capable to convert the PMN-derived hCAP-18 into LL-37, an antimicrobial peptide with activity against A. actinomycetemcomitans. We found that the PMNs of PLS patients released lower levels of LL-37. Furthermore, because of their deficiency in serine proteases, the PMNs of PLS patients were incapable of neutralizing the leukotoxin produced by this pathogen, which resulted in increased cell damage. Finally, the capacity of PMNs from PLS patients to kill A. actinomycetemcomitans in an anaerobic environment, such as that found in the periodontal pocket, seemed to be reduced. Our report demonstrates a mechanism that suggests a direct link between an inheritable defect in PMN functioning and difficulty in coping with a periodontitis-associated pathogen.

A family with Papillon-Lefevre syndrome reveals a requirement for cathepsin C in granzyme B activation and NK cell cytolytic activity.

Activation of granzyme B, a key cytolytic effector molecule of natural killer (NK) cells, requires removal of an N-terminal pro-domain. In mice, cathepsin C is required for granzyme processing and normal NK cell cytolytic function, whereas in patients with Papillon-Lefèvre syndrome (PLS), loss-of-function mutations in cathepsin C do not affect lymphokine activated killer (LAK) cell function. Here we demonstrate that resting PLS NK cells do have a cytolytic defect and fail to induce the caspase cascade in target cells. NK cells from these patients contain inactive granzyme B, indicating that cathepsin C is required for granzyme B activation in unstimulated human NK cells. However, in vitro activation of PLS NK cells with interleukin-2 restores cytolytic function and granzyme B activity by a cathepsin C-independent mechanism. This is the first documented example of a human mutation affecting granzyme B activity and highlights the importance of cathepsin C in human NK cell function.

Impaired cytotoxicity in Papillon-Lefèvre syndrome.

Papillon-Lefèvre syndrome (PLS), palmoplantar hyperkeratosis with periodontitis, has been genetically characterized. However, suspected associated immune dysfunctions remain elusive. The purpose of this study was to evaluate peripheral blood lymphocyte levels and natural killer (NK) cell cytotoxicity in PLS. Twenty patients and 20 healthy controls were examined. Peripheral blood lymphocytes were analyzed by flow cytometry for surface markers. NK cell cytotoxicity against K562 cells was determined by means of a 51Cr release assay. White blood cell differential and proportions of B-, T-, T-helper, T-suppressor, and NK cells revealed only sporadic borderline variations from control values. In contrast, NK cell cytotoxicity was consistently and severely depressed (32-53% of control values) in all patients. To the best of our knowledge, this newly described impairment of NK cell cytotoxic function is the first consistent immune dysfunction reported in PLS. This suggests that the impaired NK cell cytotoxicity might contribute to the pathogenesis of PLS-associated periodontitis.

Papillon-Lefèvre syndrome: correlating the molecular, cellular, and clinical consequences of cathepsin C/dipeptidyl peptidase I deficiency in humans.

A variety of neutral serine proteases are important for the effector functions of immune cells. The neutrophil-derived serine proteases cathepsin G and neutrophil elastase are implicated in the host defense against invading bacterial and fungal pathogens. Likewise, the cytotoxic lymphocyte and NK cell granule-associated granzymes A and B are important for the elimination of virus-infected cells. The activation of many of these serine proteases depends on the N-terminal processing activity of the lysosomal cysteine protease cathepsin C/dipeptidyl peptidase I (DPPI). Although mice deficient in DPPI have defects in serine protease activation in multiple cellular compartments, the role of DPPI for human serine protease activation is largely undefined. Papillon-Lefevre syndrome (PLS) is a rare autosomal recessive disease associated with loss-of-function mutations in the DPPI gene locus. In this study, we established that the loss of DPPI activity is associated with severe reduction in the activity and stability of neutrophil-derived serine proteases. Surprisingly, patients with PLS retain significant granzyme activities in a cytotoxic lymphocyte compartment (lymphokine-activated killer) and have normal lymphokine-activated killer-mediated cytotoxicity against K562 cells. Neutrophils from patients with PLS do not uniformly have a defect in their ability to kill Staphylococcus aureus and Escherichia coli, suggesting that serine proteases do not represent the major mechanism used by human neutrophils for killing common bacteria. Therefore, this study defines the consequences of DPPI deficiency for the activation of several immune cell serine proteases in humans, and provides a molecular explanation for the lack of a generalized T cell immunodeficiency phenotype in patients with PLS.

The presence of cytokine (IL-8, IL-1alpha, IL-1beta)-producing cells in inflamed gingival tissue from a patient manifesting Papillon-Lefevre syndrome(PLS).

The point of this study was to examine the presence or absence of cytokine-positive cells by means of immunohistochemical methods in the samples of inflamed gingival tissues obtained from an 11-year-old girl with Papillon-Lefevre syndrome (PLS). Interleukin-8 (IL-8)-positive cells were found to be present. In addition, IL-1alpha-and IL-1beta-positive cells were detected. No dysfunction in the phagocytosis and the bacterial killing of peripheral blood polymorphonuclear neutrophils (PMNs) was observed in this patient. Our findings suggest that these cytokines may be members responsible for modulating the process of rapidly progressive periodontitis for patient with PLS.

Papillon-Lefèvre syndrome: serum immunoglobulin G (IgG) subclass antibody response to periodontopathic bacteria. A case report.

BACKGROUND: Papillon-Lefevre syndrome (PLS) is a rare autosomal recessive disorder which is characterized by palmar-plantar hyperkeratosis and rapid periodontal destruction of both primary and permanent dentitions. In this case report, we present clinical features, and microbiological and immunological findings of 40 month-old Thai male PLS patient. METHODS: Microbiological examinations consisted of bacterial culture methods utilizing selective media, morphological identification, and biochemical tests. In addition, the specific serum IgG subclass antibody titers reactive with etiologic periodontal bacteria were determined by the dot-blot immunological analysis and enzyme linked immunosorbent assay (ELISA). RESULTS: The examinations revealed that the patient harbored 3 major suspected periodontopathic microorganisms, A. actinomycetemcomitans, P. gingivalis, and P. intermedia. The patient's serum IgG1, IgG2, and IgG3, but not IgG4, titers against A. actinomycetemcomitans were dramatically increased. The predominant IgG subclass was IgG1. In contrast, the IgG titers against other tested bacteria, P. gingivalis, P. intermedia, and F. nucleatum, appeared to be similar to those of a healthy control. CONCLUSIONS: A. actinomycetemcomitans seems to play a pivotal role in the bacteria-host interaction in PLS periodontal pathogenesis. Response of the specific serum IgG subclass antibody titers against the A. actinomycetemcomitans antigen has been demonstrated. This association warrants further investigation.

Papillon-Lefèvre syndrome: analysis of HLA antigens.

OBJECTIVES: Papillon-Lefèvre syndrome (PLS) is a rare disease associated with prepubertal periodontitis. Our previous studies demonstrated that three unrelated patients with PLS showed the similar antigen-specific immune responses to Actinobacillus actinomycetemcomitans. The initiation of antigen-specific immune responses was involved with human leukocyte antigens (HLA) on antigen-presenting cells. The aim of this study was to examine HLA haplotypes in the three patients with PLS. SUBJECTS AND METHODS: The three PLS patients, their mothers and the father of one patient participated in this study. HLA class I and class II antigens were determined serologically and DNA typing for DRB1 and DQB1 was performed using the restriction fragment length polymorphism-polymerase chain reaction method. RESULTS: The distribution of serologic HLA haplotypes, in two of three patients, was found to be quite similar. The DNA typing revealed that DRB1*0406, DRB1*08032, DQB1*0302, DQB1*06011 genotypes were shared in the two patients. The probability of sharing these four DNA types in unrelated individuals was nearly 1:40,000 in the Japanese population. CONCLUSION: Our results suggest that HLA antigen may be included as a possible host factor in the pathogenesis of PLS and that a genetically controlled immune response may account for an increased susceptibility to periodontal infection.

Leukocyte functions in 2 cases of Papillon-Lefèvre syndrome.

AIM: To investigate the rôle of leukocytes in the pathogenesis of Papillon-Lefevre syndrome (PLS). METHODS: Peripheral blood polymorphonuclear neutrophils (PMNs), monocytes (MNs) and gingival crevicular fluid (GCF) were obtained from 2 cases of PLS with typical features. The chemotaxis of PMNs and MNs were evaluated using a modified Boyden chamber. The adherence of PMNs was determined by adherence of PMNs to petri dishes. Interleukin-8 (IL-8) in GCF was detected by sandwich ELISA. Elastase activity in GCF was measured with a low molecular weight substrate (S-2484) specific for granulocyte elastase. RESULTS: PMNs from both patients showed depressed chemotactic response to FMLP and IL-8. Total amounts of IL-8 in GCF from the 2 patients were much higher than those of the normal controls. Elastase activity was not significantly different from that of the controls. The adherence of PMN and the chemotaxis of MN in the 2 patients were normal. CONCLUSION: The depressed chemotactic response of PMN leads to decreased recruitment of PMN and/or release of lysozyme from PMN in the diseased gingival tissue, increasing the susceptibility of PLS patients to periodontal infection.

Papillon-Lefèvre syndrome: neutrophil function in 15 cases fron 4 families in Egypt.

OBJECTIVE: The primary purpose of this study was to investigate the periodontal pathologic cause of Papillon-Lefèvre syndrome by comparing, with respect to neutrophil function, probands with Papillon-Lefèvre syndrome from 4 families in Egypt, unaffected siblings of the probands, and age-matched and gender-matched control subjects. STUDY DESIGN: Family histories and clinical dermal and oral manifestations of Papillon-Lefèvre syndrome were evaluated for 15 affected members of 4 families with the syndrome, 10 siblings of the probands, and 7 age-matched and gender-matched controls. Phagocytic and intracellular killing (lytic activity) of polymorphonuclear neutrophils was evaluated for all subjects according to a modification of the method of Wilkinson; opsonization was evaluated according to a modification of the methods of Cutler et al. Data were analyzed by means of analysis of variance. RESULTS: Family pedigrees were plotted, and consanguinity was noted in 3 of the 4 families with Papillon-Lefèvre syndrome. The means and SDs for phagocytic killing, lytic activity, and opsonization indices were as follows: probands, 4.76+/-1.99, 0.42+/-0.20, and 0.84+/-0.07; unaffected siblings, 10.4+/-1.3, 3.3+/-0.3, and 0.84+/-0.07; controls, 10.8+/-0.8, 3.5+/-0.6, and 0.85+/-0.05. The phagocytic killing and lytic activity indices demonstrated significance between the probands and both siblings and controls (P<.0005), whereas the opsonization index did not demonstrate significance between groups. CONCLUSIONS: Significantly decreased neutrophil function in probands with Papillon-Lefèvre syndrome was demonstrated with respect to neutrophil phagocytotic and lytic activity but not with respect to opsonization. Therefore, specific neutrophil dysfunction appears to be etiologically involved in this disorder.