Role of the NK Cell-Activating Receptor CRACC in Periodontitis

Periodontitis is a highly prevalent, biofilm-mediated chronic inflammatory disease that results in the loss of the tooth-supporting tissues. It features two major clinical entities: chronic periodontitis, which is more common, and aggressive periodontitis, which usually has an early onset and a rapid progression. Natural killer (NK) cells are a distinct subgroup of lymphocytes that play a major role in the ability of the innate immune system to steer immune responses. NK cells are abundant in periodontitis lesions, and NK cell activation has been causally linked to periodontal tissue destruction. However, the exact mechanisms of their activation and their role in the pathophysiology of periodontitis are elusive. Here, we show that the predominant NK cell-activating molecule in periodontitis is CD2-like receptor activating cytotoxic cells (CRACC). We show that CRACC induction was significantly more pronounced in aggressive than chronic periodontitis and correlated positively with periodontal disease severity, subgingival levels of specific periodontal pathogens, and NK cell activation in vivo. We delineate how Aggregatibacter actinomycetemcomitans, an oral pathogen that is causally associated with aggressive periodontitis, indirectly induces CRACC on NK cells via activation of dendritic cells and subsequent interleukin 12 (IL-12) signaling. In contrast, we demonstrate that fimbriae from Porphyromonas gingivalis, a principal pathogen in chronic periodontitis, actively attenuate CRACC induction on NK cells. Our data suggest an involvement of CRACC-mediated NK cell activation in periodontal tissue destruction and point to a plausible distinction in the pathobiology of aggressive and chronic periodontitis that may help explain the accelerated tissue destruction in aggressive periodontitis.     

The NADPH oxidase NOX2 plays a role in periodontal pathologies

Oxidative stress plays an important role in periodontal health and disease. The phagocyte nicotinamide adenine dinucleotide phosphate oxidase NOX2 is most likely one of the key sources of reactive oxygen species (ROS) in periodontal tissues. This review will discuss three clinical aspects of NOX2 function. We will first focus on oral pathology in NOX2 deficiency such as chronic granulomatous disease (CGD). CGD patients are thought to suffer from infections and sterile hyperinflammation in the oral cavity. Indeed, the periodontium appears to be the most common site of infection in CGD patients; however, as periodontitis is also common in the general population, it is not clear to which extent these infections can be attributed to the disease. Secondly, the role of oxidative stress in periodontal disease of diabetic patients will be reviewed. Diabetes is indeed a major risk factor to develop periodontal disease, and increased activity of leukocytes is commonly observed. Enhanced NOX2 activity is likely to be involved in the pathomechanism, but data remains somewhat preliminary. The strongest case for involvement of NOX2 in periodontal diseases is aggressive periodontitis. Increased ROS generation by leukocytes from patients with aggressive periodontitis has clearly been documented. This increased ROS generation is to be caused by two factors: (1) genetically enhanced ROS generation and (2) oral pathogens that enhance NOX function. NOX enzymes in the oral cavity have so far received little attention but are likely to be important players in this setting. New therapies could be derived from these new concepts.     

Oral manifestations of Langerhans cell histiocytosis with unusual histomorphologic features

Langerhans cell histiocytosis (LCH) is a bone marrow-derived immature myeloid dendritic cell proliferative disorder with diverse clinical manifestations commonly involves bone, skin, lymph node and lung. Oral involvement is uncommon. Intraoral lesions can be the first sign of either a localized LCH or clinically undiagnosed systemic LCH, predates systemic manifestations of LCH, or an early indicator of recurrence in known cases. Clinically, it can be mistaken for primary oral and dental inflammatory, infectious and neoplastic lesions. Histologically, diagnostic challenges may arise because of the nature of oral and dental specimens, different tissue reaction patterns and variations in histomorphology of LCH. We performed a retrospective review study over 10 years. We searched for diagnosed cases of LCH. We retrieved and reviewed cases of LCH with oral involvement. We found 54 cases of LCH, four (7.4%) with oral involvement. The age range was between 1 and 27 years with an average age of 13.7 years. They were males. They were clinically confused with abscess, cysts, infection, granulation tissue and other neoplastic lesions. Histologically, they showed different histopathologic features including different patterns of necrosis, granulomas, allergic-like inflammation, superimposed infection, stomatitis, cyst and sinus formation, foreign body giant cell reaction, and foci mimicking lymphomas and metastasis. Certain cytologic features were helpful hints. In doubtful cases, immunohistochemistry helped confirm the diagnosis. Because of the multiple fragmented nature of oral specimens with different tissue reaction patterns, the diagnostic Langerhans cells may be missed or misinterpreted. Oral LCH may be confused with infectious, inflammatory, benign and malignant neoplastic lesions because of its variable clinical presentations and its heterogeneous histomorphologic features. Pathologists have an important role in guiding clinicians to the correct diagnosis and patients' management. They should be familiar with the different histomorphologic patterns to avoid pitfalls. Attention to certain morphologic features and immunohistochemistry should help resolve challenging cases.     

Isolated Langerhans cell histiocytosis of the sublingual gland in an adult

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by the proliferation of pathologic Langerhans cells. Its clinical presentation is highly variable, that range from single-system, limited disease to severe, multi-organ disease with high mortality. LCH usually affects children and young adults. The most frequent sites for LCH are the bone, skin, lung, pituitary gland, and lymph nodes. Salivary gland involvement by LCH is extremely rare, and only a few cases of LHC involving the parotid glands have been reported in the English literature. To our knowledge, the involvement of the sublingual gland as a part of single or multisystem LCH has not been previously described. Herein we reported the first case of primary LCH of the sublingual gland. A 40-year-old woman presented with a 2-month history of a painless mass on the right sublingual area. Excision of the lesion including the right sublingual gland was performed. Histopathological diagnosis of LCH was rendered. The patient remains free of symptoms 17 months after surgery.     

Immunocytochemical investigation of Langerin (CD207) is a valuable adjunct in the cytological diagnosis of Langerhans cell histiocytosis of the thyroid

Langerhans cell histiocytosis (LCH) is an uncommon disease encompassing three clinically different entities: eosinophilic granuloma, Hand-Schüller-Christian disease, and Abt-Letterer-Siewe disease. Despite usually being a multisystemic disease affecting numerous different organs, involvement of the thyroid gland is extremely rare, and only a few cases in adults have been described in the literature. Herein, we present the case of a 28-year-old male patient presenting with LCH involving the skin, the skeletal system, and the thyroid gland. Fine needle aspiration (FNA) of the thyroid was performed and showed the typical Langerhans cells (LC) with foamy cytoplasm and slender nuclei with longitudinal grooves against a background of inflammatory cells with only a few eosinophilic granulocytes. Immunocytochemically, the LC showed positive staining with antibodies against CD1a and Langerin, a recently detected glycoprotein exclusively expressed in LC. Langerin is the major protein that makes up the so-called Birbeck granules, the electronmicroscopical hallmark of LC. Since LCH involvement of the thyroid is occasionally mistaken for papillary thyroid carcinoma cells, we propose that application of Langerin in combination with CD1a is a helpful diagnostic adjunct for the correct assessment of LCH affecting the thyroid gland.     

Langerhans cell histiocytosis involving the thyroid and parathyroid glands.

Langerhans cell histiocytosis (LCH) is a rare illness, and the disease afflicting the thyroid gland is very uncommon, even in the presence of multisystem involvement. In this report, we document histologically, for the first time, concurrent involvement of the thyroid and parathyroid glands by LCH. A young Chinese woman with a history of diabetes insipidus and hypogonadism underwent a total thyroidectomy for enlarged thyroid gland secondary to LCH causing airway obstruction. Microscopic examination of the excised specimen disclosed CD1a- and S-100-positive LCH cells involving the thyroid and parathyroid glands. In a patient with LCH affecting the thyroid gland, parathyroid gland disease should be suspected when the serum calcium levels are depressed in association with an inappropriate serum parathyroid hormone level, such as a normal parathyroid hormone level in this case.     

The influence of clinical features mimicking primary immunodeficiency diseases (mPID) on children with Langerhans cell histiocytosis (LCH) — Four with mPID among 39 LCH children from one referral center during 18-year period

BackgroundRecurrent or refractory infections can be a warning sign of primary immunodeficiency diseases (PID). Such mimicking PID (mPID) can occur in patients with Langerhans cell histiocytosis (LCH). Because some cases with refractory molluscum contagiosum-like lesions and persistent otorrhea are finally diagnosed with LCH, we wondered whether such mPID can occur in LCH children and affect on their prognosis.MethodsWe retrospectively reviewed all children with LCH at our institute from 2001 to 2018. A complete medical review of sex, age, symptoms, treatment course, and outcome comparison was performed.ResultsOf 39 enrolled LCH patients, three had persistent otorrhea and one had refractory molluscum contagiosum-like lesions despite aggressive antibiotic therapy. These four cases with mPID had significantly higher rates of multi-system involvement, recurrence and 5-month more lag time, but no risk organ (liver, spleen and bone marrow) involvement compared to those without mPID, although bone and skin were the most involved in both groups. Overall, the lag-time in multi-system was longer than that in single-system involvement (median 2.5 vs. 1.0 months; p = 0.003). The diagnosis-age of risk organ involvement was younger than those without (median 8 vs. 43 months; p = 0.004). There were no significant differences in diagnosis-age, single/multi-system and risk organ involvement between remission and recurrence groups. All were alive excluding four who were lost to follow-up.ConclusionsThe LCH children with mPID had greater lag time, multi-system involvement, recurrence and more refractory treatment including transplantation despite the ratio of bone and skin lesions equal to those without mPID.     

Diacerein: a potential therapeutic drug for periodontal disease

Periodontal diseases are chronic inflammatory diseases characterized by the destruction of the tooth-supporting structures. They are the most prevalent form of bone pathology in humans and act as a modifying factor of the systemic health of patients. Accumulating evidence has provided insight into mechanisms of periodontal inflammation revealing that oral pathogens induce inflammatory cascades, including a variety of cytokines produced by different cell types, which promotes host-mediated tissue destruction. Cytokine networks established in diseased periodontal tissues are extremely complex, and substances regulating immuno-inflammatory reactions and signaling pathways, in addition to traditional periodontal treatment, could potentially be targeted as an approach for prevention and treatment of periodontal diseases. Diacerein, a purified anthraquinone derivative, was derived originally from plants with profound anti-inflammatory and analgesic activities. Its wide range of biological activities have been applied and discussed for several decades; however, studies of diacerein have mainly concentrated on effects on joint-derived tissues/cells, which suggest a beneficial role in osteoarthritis treatment. Diacerein reduces association of the IL-1 receptor to form heterodimer complexes, repressing IL-1 and its related downstream events and impairing active IL-1 release due to the inhibition of the IL-1-converting enzyme (ICE). To date, there are no reports describing the therapeutic effect of diacerein for treatment of periodontitis. Given the involvement of inflammation and occurrence of tissue destruction in periodontal disease, we propose that diacerein might be a promising biological drug for periodontal disease due to its therapeutic advantages. In addition, we hypothesize that the underlying mechanisms might involve the capacity of diacerein to selectively inhibit signal transduction to affect the cytokine profiles and, consequently, produce the outcome of ameliorating disease breakdown.     

Langerhans cell histiocytosis infiltration in cerebrospinal fluid: a case report

Langerhans cell histiocytosis (LCH) is a disease of unknown etiology characterized by a proliferation of histiocytic cells resembling the integumentary cells bearing the name of Langerhans cells. LCH can be unifocal or multifocal, with one- or many-organ involvement. We present a case of LCH diagnosed in the cerebrospinal fluid of a patient with generalized lymphadenopathy and central nervous system involvement.     

局限型和广泛型侵袭性牙周炎的临床特点及预后研究

目的：观察局限型和广泛型侵袭性牙周炎患者的临床特点和治疗效果。方法：选取2014年5月至2015年5月在我科接受治疗的80例牙周炎患者为研究对象,其中局限型和广泛型侵袭性牙周炎患者各40例。观察不同类型牙周炎患者的临床特点及治疗效果,分析影响侵袭性牙周炎治疗效果的因素。结果：广泛型侵袭性牙周炎患者的菌斑百分率、出血指数和牙周袋深度明显高于局限型患者,差别具有统计学意义;广泛型侵袭性牙周炎患者的WBC、NEU%和炎症细胞因子(PCT、IL-6、hs-CRP和TNF-α)水平均明显高于局限型侵袭性牙周炎(P<0.05);局限型侵袭性牙周炎患者治疗的有效例数明显多于广泛型侵袭性牙周炎患者,无效例数明显少于广泛型侵袭性牙周炎患者;多因素Logistic回归分析结果显示,牙周炎类型、治疗前牙周状况、是否吸烟以及是否采用全身治疗是影响侵袭性牙周炎患者治疗的危险因素,其OR值分别为4.435、7.952、3.281、5.283。结论：广泛型侵袭性牙周炎患者的牙周状况和炎症相关实验室指标均较局限型侵袭性牙周炎差,且牙周炎类型、治疗前牙周状况、是否吸烟以及是否采用全身治疗是影响侵袭性牙周炎患者治疗效果的重要因素。     

Primary immunodeficiencies reveal the essential role of tissue neutrophils in periodontitis

Periodontitis is a common human inflammatory disease. In this condition, microbiota trigger excessive inflammation in oral mucosal tissues surrounding the dentition, resulting in destruction of tooth‐supporting structures (connective tissue and bone). While susceptibility factors for common forms of periodontitis are not clearly understood, studies in patients with single genetic defects reveal a critical role for tissue neutrophils in disease susceptibility. Indeed, various genetic defects in the development, egress from the bone marrow, chemotaxis, and extravasation are clearly linked to aggressive/severe periodontitis at an early age. Here, we provide an overview of genetic defects in neutrophil biology that are linked to periodontitis. In particular, we focus on the mechanisms underlying Leukocyte Adhesion Deficiency‐I, the prototypic Mendelian defect of impaired neutrophil extravasation and severe periodontitis.     

Identification of spirochetes related to Treponema pallidum in necrotizing ulcerative gingivitis and chronic periodontitis.

BACKGROUND. Spirochetes are commonly associated with periodontal disease, but it is not known whether these treponemes are pathogenic or merely opportunistic. We sought to determine whether spirochetes present in periodontal disease share antigens thought to be unique to spirochetes that are known pathogens. METHODS. We examined dental plaque from 24 healthy subjects, from ulcerative sites in 17 patients with ulcerative gingivitis, and from areas of involvement in 19 patients with chronic periodontitis, using an immunocyto-chemical technique with monoclonal antibodies against pathogen-specific determinants on 47-kd and 37-kd molecules from Treponema pallidum subspecies pallidum. Serum was tested against T. pallidum by immunoblotting and by serologic assays for syphilis. RESULTS. Spirochetes with a pathogen-specific epitope on a 47-kd molecule were not found in plaque samples from any of the 24 healthy subjects, but they were identified in plaque samples from 11 of 17 patients with ulcerative gingivitis (P less than 0.001) and from 10 of 19 patients with periodontitis (P less than 0.01). Monoclonal antibodies directed against a 37-kd molecule reacted with spirochetes in plaque samples from 1 of 14 controls, from all 11 patients with gingivitis from whom samples could be obtained (P less than 0.001), and from 14 of 19 patients with periodontitis (P less than 0.001). Five of 18 normal subjects had IgG against 47-kd and 37-kd molecules, but none had IgG against 14-kd or 12-kd molecules from T. pallidum subspecies pallidum. Among 19 patients with ulcerative gingivitis, IgG was identified against 47-kd molecules in 15, against 37-kd molecules in 12, against 14-kd molecules in 4, and against 12-kd molecules in 15. CONCLUSIONS. The spirochetes found in dental plaque from patients with ulcerative gingivitis or chronic periodontitis have antigens that are thought to be unique to pathogenic treponemes. This close antigenic relation suggests that T. pallidum or a closely related organism may be involved in the pathogenesis of periodontal disease.     

Erdheim‐Chester disease with prominent pericardial effusion

Erdheim‐Chester disease (ECD) is a rare, non‐Langerhans form of histiocytosis of unknown origin with distinct clinicopathologic and radiographic features. Reports detailing the cytology of ECD are rare. We describe a case of ECD with pericardial effusion. Cytologic examination revealed a hypercellular specimen composed of clusters and singly dispersed foamy macrophages with round nuclei and inconspicuous nucleoli, admixed with lymphocytes, eosinophils, and Touton‐type multinucleated giant cells. Immunostains for CD68 were strongly positive in the foamy macrophages while S100 and CD1a were negative. The presence of foamy histiocytes, multinucleated giant cells, lymphocytes and eosinophils are also features of other systemic histiocytic disorders, including Langerhans cell histiocytosis (LCH), Rosai‐Dorfman disease (RDD) and sarcoidosis. To the best of out knowledge, this is the first report describing the cytological features of ECD in a pericardial effusion. Diagn. Cytopathol. 2014;42:530–534. © 2013 Wiley Periodicals, Inc.     

Langerhans Cell Histiocytosis of the Vulva: An Ultrastructural Study

Langerhans cells histiocytosis (LCH) is a proliferative disorder of Langerhans cells. The lesions are normally characterized by infiltration of eosinophils, neutrophils, lymphocytes, plasma cells, and Langerhans cells. The specific cells of LCH contain Birbeck granules, express the phenotype of Langerhans cells but with markers fixed at an early stage of activation, and are functionally defective in antigen-presenting ability. The disease most often affects children; when it occurs in older patients, anal and groin involvement is quite common and vulvar lesions can be found in older females. The authors report a case of a 64-year-old woman with LCH of the vulva and diabetes insipidus. An immunohistochemical and ultrastructural study of the vulvar lesions showed an infiltrate in which antigenically and morphologically mature Langerhans cells, monocytoid cells, and cells with an intermediate phenotype between monocytes and Langerhans cells were concurrently observed. Although the clinical and histological aspects of LCH are well established, the pathogenetic mechanism of lesions is not yet known. The finding of an infiltrate composed by Langerhans cells and many putative precursors of these cells suggests the hypothesis of an in situ differentiation of Langerhans cells from immature monocytoid precursors.     

Gastrointestinal involvement in Langerhans cell histiocytosis (histiocytosis X): diagnosis by rectal biopsy

We report two patients with biopsy-proven involvement of the gastrointestinal tract by Langerhans cell histiocytosis (LCH). The two patients were infants with congenital cutaneous lesions and bloody diarrhea beginning at 1 or 2 wk of age. Rectal biopsy specimens showed a mucosal infiltrate of typical Langerhans cells that focally invaded and destroyed the crypt epithelium. Gastrointestinal involvement by LCH is unusual and only rarely has represented a prominent clinical manifestation. In most cases, such involvement has been an indicator of widespread multisystemic disease. Its distinctive morphologic and immunohistochemical features allow LCH to be distinguished from other histiocytic infiltrations found in mucosal biopsy specimens.     

Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a rare disorder affecting predominantly children and manifesting as bone pains, bony swellings and lytic lesions. Involvement of vertebrae as presenting manifestation is unusual. Here we have presented three cases of LCH, two of multifocal eosinophilic granuloma (MEG) and one of Hand Schuller Christian disease (HSC). One of the patients with MEG; had vertebral involvement as the presenting manifestation.     

Role of complement in host–microbe homeostasis of the periodontium

Complement plays a key role in immunity and inflammation through direct effects on immune cells or via crosstalk and regulation of other host signaling pathways. Deregulation of these finely balanced complement activities can link infection to inflammatory tissue damage. Periodontitis is a polymicrobial community-induced chronic inflammatory disease that can destroy the tooth-supporting tissues. In this review, we summarize and discuss evidence that complement is involved in the dysbiotic transformation of the periodontal microbiota and in the inflammatory process that leads to the destruction of periodontal bone. Recent insights into the mechanisms of complement involvement in periodontitis have additionally provided likely targets for therapeutic intervention against this oral disease.     

Bacteria take control of tolls and T cells to destruct jaw bone

Bone undergoes a continuous cycle of remodeling for maintenance and healing. For almost a decade it has been appreciated that the immune system is intricately linked to bone homeostasis. Both acute and chronic inflammatory responses have been shown to impact bone health. A common form of inflammatory disease that causes bone destruction is the chronic infectious disease known as periodontitis (PD). PD is a bacteria-driven inflammation of the tooth-supporting apparatus that leads to resorption of the alveolar (jaw) bone, often leading to tooth loss. At the host-bacteria interface, Toll-like receptors (TLRs) play an instructive role in the development of innate and T cell adaptive responses to oral bacteria. Specifically, it is becoming apparent that TLR2-mediated inflammatory responses represent the major arm of the host immune response during periodontitis, and form an important link between periodontal infection and ensuing periodontal bone loss. This review summarizes the role of TLR2-mediated interplay between immune cells and bone cells in a periodontal disease setting.     

朗格汉斯组织细胞增生症的诊治进展

朗格汉斯组织细胞增生症（LCH）是一种少见的、病因尚不明确的单核-巨噬细胞异常增生性疾病,其临床表现具有多样性,累及多个系统,且发病机制复杂,目前主要认为是炎性髓样肿瘤,治疗上仍以联合化疗为主,随着靶向药物及骨髓移植应用逐渐增多,其并发症及不良反应需进一步解决。对于单系统受累LCH 患者预后较佳,临床报道治愈病例较多。而多系统受累LCH患者预后不佳,病死率高。本文就近年来有关LCH的发病机制、临床表现、诊断与治疗及预后进展进行综述。