Kozo Yasui

Thalidomide dramatically improves the symptoms of early‐onset Sarcoidosis/Blau syndrome: Its possible action and mechanism

OBJECTIVE Early-onset sarcoidosis (EOS), which occurs in children younger than 5 years of age, is associated with granulomatous lesions and a sporadic genetic mutation of the nucleotide-binding oligomerization domain 2 that causes constitutive NF-kappaB activation. The symptoms of EOS can be uncontrollable, progressive, and associated with profound complications. However, appropriate therapy is still under investigation. The aim of this study was to assess the efficacy of thalidomide in patients with severe EOS, based on etiology supporting an initial role of NF-kappaB in activation of this disease. METHODS Thalidomide was given to 2 patients with EOS (a 16-year-old girl and an 8-year-old boy) at an initial dosage of 2 mg/kg/day, and the dosage was increased if necessary. To elucidate the mechanism of the drug, peripheral blood monocytes were isolated from the patients and stimulated with cytokines (macrophage colony-stimulating factor, tumor necrosis factor alpha, and interleukin-4), and their ability to form multinucleated giant cells (MGCs) and osteoclasts was measured. RESULTS Both patients showed dramatic improvement of their clinical symptoms (alleviation of fever and optic nerve papillitis, achievement of a response according to the American College of Rheumatology Pediatric 50 and Pediatric 70 criteria) and laboratory findings. Monocytes from patients with EOS had a greater ability to survive and induce MGCs and osteoclasts than those from healthy control subjects. The formation of MGCs and osteoclasts was inhibited by the presence of thalidomide. CONCLUSION The ability of thalidomide to improve clinical symptoms and laboratory findings in patients with EOS indicates a central role for NF-kappaB activity in this disorder. Inhibition of IKK might be a pharmacologic action by which thalidomide down-regulates NF-kappaB signaling. Thalidomide may be an effective medication in patients with severe complications of EOS, including ocular involvement.

Increase of tumor necrosis factor-α in the blood induces early activation of matrix metalloproteinase-9 in the brain

Increases of cytokine in the blood play important roles in the pathogenesis of influenza‐associated encephalopathy. TNF‐α was administered intravenously to wild‐type mice, after which blood, CSF and brain tissue were obtained, and changes in BBB permeability, the amounts of MMP‐9 and TIMP‐1, and the localization of activated MMP were assessed. There was a significant increase in BBB permeability after 6 and 12 hr. MMP‐9 was increased after 3 hr in the brain and cerebrospinal fluid, which was earlier than in the serum. TIMP‐1 protein in the brain increased significantly after MMP‐9 had increased. Activation of MMP‐9 was observed in neurons in the cerebral cortex and hippocampus, and in vascular endothelial cells. These findings suggest that an increase in blood TNF‐α promotes activation of MMP‐9 in the brain, and may also induce an increase in permeability of the BBB. Early activation of MMP‐9 in the brain may contribute to an early onset of neurological disorders and brain edema prior to multiple organ failure in those inflammatory diseases associated with highly increased concentrations of TNF‐α in the blood, such as sepsis, burns, trauma and influenza‐associated encephalopathy.

The effect of ascorbate on minor recurrent aphthous stomatitis.

Aim:  Minor recurrent aphthous stomatitis (MRAS) is a common, painful and inflammatory ailment of the oral cavity with juvenile onset and unknown aetiology. The purpose of this study was to evaluate the potential of ascorbate (vitamin C) to reduce the frequency of MRAS and severity of pain.

Multi-nucleated giant cell formation from human cord blood monocytes in vitro, in comparison with adult peripheral blood monocytes

Multi‐nucleated giant cells (MGCs; Langhans‐type cell), formed from macrophage fusion, are recognized as a hallmark histological feature in chronic inflammation. However, their precise pathological role is still poorly understood, especially for microorganism pathogens in the neonatal immune system, which are capable of surviving intracellularly in phagocytes. To conduct a partial evaluation of the monocyte function of neonates, we investigated the ability of human cord blood monocytes to form MGCs in vitro by stimulating various cytokines and comparing them with adult peripheral blood monocytes. Monocytes from cord blood and adult peripheral blood were isolated and cultured for 14 days with cytokines known to induce MGC in vitro. The fusion index in experiments with a combination of interleukin (IL)‐4 and macrophage colony‐stimulating factor (M‐CSF) and a combination of IL‐4 and granulocyte–macrophage colony‐stimulating factor (GM‐CSF) was significantly lower in cord blood than in adult blood monocytes (P = 0·0018 and P = 0·0141, respectively). The number of nuclei per MGC was significantly lower in cord blood than in adult blood monocytes in experiments with IL‐4 alone, the combination of IL‐4 and M‐CSF, and the combination of IL‐4 and GM‐CSF (P < 0·0001). These results suggest the possibility that the susceptibility of newborns to mycobacterium infection is due partly to impaired MGC formation.

Theophylline inhibits the differentiation of human monocyte into dendritic cell potentially via adenosine receptor antagonism

Background Theophylline has an anti‐inflammatory action that may account for its clinical effectiveness in the reduction of inflammatory cells in the airways. Dendritic cells (DCs) are professional antigen‐presenting cells, capable of priming naïve T cells, and play key roles in the activation of immune responses in asthma.

Tumor necrosis factor-α can induce Langhans-type multinucleated giant cell formation derived from myeloid dendritic cells

The formation of the rich cellular features of MGCs, where the nuclei are arranged circularly at the periphery of the cell (morphologically epithelioid; Langhans‐type), is assumed to be associated with any granulomatous disease. The mechanism by which TNF controls the formation of human MGCs in vitro was investigated, focusing on the effect of the TNF‐neutralizing antibody.

Increased Eosinophilic Cationic Protein in Nasal Fluid in Hospitalized Wheezy Infants with RSV Infection

BACKGROUND Respiratory syncytial virus (RSV) is a major respiratory pathogen which causes bronchiolitis with dyspnea and wheezing in children less than 2 years old. RSV bronchiolitis in infancy severe enough to cause hospitalization might be a risk factor for allergic sensitization and bronchial asthma in future. However, the pathophysiology behind this development has not been clearly characterized. To evaluate the existence of airway inflammation and characteristic of RSV bronchiolitis, we analyzed and compared the concentrations of eosinophilic cationic protein (ECP) in nasal fluid and plasma. METHODS From 69 infants (aged <2 years) hospitalized for possible lower respiratory tract infections including RSV infection, we collected nasal fluid and plasma and determined the ECP concentrations. RESULTS ECP concentrations in nasal fluid were significantly higher in patients with wheezing and/or bronchial rales than in patients without them (1733 ± 660 ng/mL vs 680 ± 450 ng/mL, p = 0.018), and those of the respiratory syncitial virus-infected group were significantly higher than those of the uninfected group (p = 0.04). Meanwhile, there was no significant difference in plasma ECP levels between patients with wheezing and patients without wheezing, and no significant difference between RSV-infected and other pathogen-infected patients. There were significant correlations between nasal fluid ECP concentrations and both neutrophil and eosinophil counts in the peripheral blood. CONCLUSIONS Nasal fluid ECP concentrations are increased in infants with lower respiratory infections including RSV infection accompanied with wheezing. ECP probably originates from neutrophils as well as eosinophils migrated into airways. The monitoring of ECP concentration in nasal fluid may be useful for evaluating leukocyte (including eosinophils and neutrophils)-mediated airway inflammation during infancy and its severity.

Thalidomide prevents formation of multinucleated giant cells (Langhans-type cells) from cultured monocytes: possible pharmaceutical applications for granulomatous disorders.

Thalidomide is an effective drug for chronic inflammatory diseases, but the mechanism underlying its immunomodulatory action remains uncertain. Thalidomide has been reported to clinically improve chronic inflammatory granulomatous disorders. In such disorders, the granulomas consist of epithelioid cells, scattered lymphocytes and multinucleated giant cells (MNGC; Langhans-type cells). The present experimental approach permitted the reproduction of MNGC formation from peripheral blood monocytes and examination of thalidomides effect on it. MNGC can be effectively generated from monocytes cultured in the presence of interleukin-4 (IL-4) and macrophage colony-stimulating factor (M-CSF) for 14 days. Thalidomide can inhibit the formation of MNGC in a dose-dependent manner. MNGC formation was partly inhibited by the presence of neutralizing TNF-α antibody in the responses induced by IL-4 and M-CSF. Autocrinal TNF-α production and modulation of cadhelin expression to regulate cell adhesion might be involved in this inhibitory action of thalidomide. Our results support thalidomides clinical efficacy in the treatment of chronic granulomatous disorders (granulomatosis).

Recurrent Chronic Cough, Wheeze and their Control without Corticosteroids in 1 to 5 Year-old Children

Background: Recurrent persistent cough and wheezing often begin in early childhood; however, not all episodes of them are caused by asthma and/or an allergic reaction, they are exacerbated with several respiratory infections. Previous research suggests that the best treatment for toddlers and preschool-age children with persistent cough and/or wheeze is a difficult clinical challenge. Methods: In this single-center prospective clinical trial, HIROSIMA study, we observed the clinical effect of oral leukotriene receptor antagonists (LTRAs: montelukast, pranlukast) with carbocystein and lysozyme chloride or ambroxol for over a year and assessed the relationship between infantile wheeze, chronic cough and rhinosinusitis. The patients were allocated to the intervention with their consent. Results: Eighty patients, who were admitted to hospital for persistent cough and dyspnea episodes, completed the study for a year and showed significantly fewer asthma exacerbation episodes (clinical asthma scores/week; 16.1 ± 3.1 vs 7.9 ± 2.7) during the first eight weeks (p < 0.01), comparing to the use of LTRA alone (n = 40).; and the improvement of conditions persisted for over the twelve-month period. None of the subjects was admitted to the hospital for asthma exacerbation, and had any corticosteroid treatment during the study. Conclusion: Our strategy for chronic cough including the management of allergic rhinitis and sinusitis significantly evaded persistent cough and wheeze of children age from 1 to 5 years, and reduced the frequency of recurrent otitis media. Note: HIROSIMA study provides promising data for the control of persistent cough and wheeze of children age from 1 to 5 years without the use of corticosteroids for over a year with a good adherence to the treatment.

Onset of polyarticular juvenile idiopathic arthritis with both anti-cyclic citrullinated peptide antibodies and rheumatoid factor in a 3-year-old girl

This report describes 3 year old girl with the unusual presentation of polyarticular juvenile idiopathic arthritis (JIA) with anti-cyclic citrullinated peptide (anti-CCP) antibodies and a positive rheumatoid factor (RF). She was initially treated with a nonsteroidal anti-inflammatory drug (NSAID; ibuprofen) followed by methotrexate (MTX, 10 mg/m2/week) and prednisolone (0.25 mg/kg/day), but these treatments were ineffective. Administration of tocilizumab, a humanized antihuman interleukin-6 receptor monoclonal antibody, promptly improved her clinical manifestations, and she has been in complete remission (DAS28 <2.6) without bone erosion and/or destruction. Positivity for both antibodies (anti-CCP and RF) can forecast the severity of JIA (radiographic bone destruction). In such cases the administration of biologic remissive therapy may be prudent early in the disease course.