ABSTRACT
BACKGROUND: Alarmins resulting from cell death or oxidative stress are involved in the development of Kawasaki disease (KD) vasculitis. In a previous study, we demonstrated the potential role of interleukin (IL)-33 as an alarmin in the development of KD vasculitis. Although edematous dissociation (necrotic change) of the tunica media is thought to be a major source of IL-33 in KD vasculitis, it has not yet been elucidated. METHODS AND RESULTS: We investigated the impact of IL-33 released from necrotic human coronary artery smooth muscle cells (HCASMCs) on human coronary artery endothelial cells (HCAECs) using a coculture assay. Subsequently, we evaluated the anti-inflammatory effects of anti-IL-33 and anti-suppression of tumorigenicity 2 (ST2) antibodies compared with conventional therapies of KD, such as high-dose IgG or anti-tumor necrosis factor (TNF)-α antibody. Primary necrosis of HCASMCs induced significant release of IL-33. In cocultures of necrotic HCASMCs with HCAECs, the necrotic HCASMCs significantly induced the production of various proinflammatory cytokines in the HCAECs. Anti-IL-33 and anti-ST2 antibodies exhibited unique inhibitory effects on the production of platelet-derived growth factor-BB or IL-12(p70) in HCAECs. CONCLUSIONS: There is potential involvement of edematous dissociation of the tunica media in the development of KD vasculitis. Furthermore, the distinctive anti-inflammatory effects of the anti-IL-33/ST2 axis drugs suggest novel therapeutic options for patients with refractory KD.
Subject(s)
Immune System Diseases , Nut Hypersensitivity , Humans , Macadamia , Legumins , Nut Hypersensitivity/diagnosis , NutsSubject(s)
Immune System Diseases , Nut Hypersensitivity , Humans , Child , Macadamia , Clinical Relevance , East Asian People , Nut Hypersensitivity/diagnosisABSTRACT
Kawasaki disease (KD) is an acute, self-limiting, febrile systemic vasculitis of unknown cause associated with the development of coronary artery lesions (CALs) during childhood. Damage-associated molecular patterns (DAMPs) from cell death and oxidative stress have been shown to be involved in the development of KD vasculitis. Interleukin (IL)-33 is released from damaged endothelial cells and acts as a DAMP. We studied whether IL-33 and its receptor (ST2) might be involved in KD pathogenesis. Serum levels of soluble ST2 (sST2) in KD patients were measured before their first therapy. Furthermore, we investigated the impact of IL-33 on human coronary artery endothelial cells (HCAECs). Serum levels of sST2 were significantly higher in KD patients with CALs than in those with normal coronary arteries. In vitro, IL-33 upregulated the expression of ST2L and increased production of sST2, IL-6, IL-8, and monocyte chemoattractant protein-1 in HCAECs in a time- and concentration-dependent manner. Moreover, IL-33 induced significantly greater production of IL-6 and IL-8 in HCAECs compared to the condition stimulated with isoconcentration of tumor necrosis factor-α. The results of the present study suggest that the IL-33/ST2 axis might be involved in the development of KD vasculitis. The IL-33/ST2 axis may be a therapeutic target for the treatment of KD.
Subject(s)
Mucocutaneous Lymph Node Syndrome , Humans , Mucocutaneous Lymph Node Syndrome/diagnosis , Mucocutaneous Lymph Node Syndrome/drug therapy , Mucocutaneous Lymph Node Syndrome/complications , Interleukin-33/metabolism , Interleukin-1 Receptor-Like 1 Protein/metabolism , Endothelial Cells/metabolism , Interleukin-6/metabolism , Interleukin-8/metabolism , Biomarkers/metabolismABSTRACT
Pandemic influenza virus A(H1N1)pdm09 infection occurred in healthy children and young adults, but asthmatic patients presented more rapid progression of respiratory distress and plastic bronchitis. To investigate the pathogenesis of worsening respiratory symptoms after A(H1N1)pdm09 infection, we focused on matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1). MMP-9 and TIMP-1 levels in bronchoalveolar lavage fluid and serum from mice with and without asthma were evaluated after A(H1N1)pdm09 or seasonal A(H1N1) infection. MMP-9 levels were more elevated in Asthma/A(H1N1)pdm09-infected mice than in non-Asthma/A(H1N1)pdm09-infected mice on both 3 and 7 days post-infection. Immunohistochemical findings in this pneumonia model showed that MMP-9 and TIMP-1 positive cells were observed in blood vessels and bronchus of lung tissue in severe pathological findings of pneumonia with asthma. Microscopically, shedding cells and secretions were conspicuous in the trachea on days 3 and 7 post-infection, in the A(H1N1)pdm09-infected mice with asthma. Our results suggest that MMP-9 and TIMP-1 expressions are related to severe pneumonia in the A(H1N1)pdm09 infection with asthma, leading to cause epithelial cell shedding.
Subject(s)
Asthma , Matrix Metalloproteinase 9 , Orthomyxoviridae Infections , Pneumonia, Viral , Tissue Inhibitor of Metalloproteinase-1 , Animals , Asthma/metabolism , Disease Models, Animal , Influenza A Virus, H1N1 Subtype , Matrix Metalloproteinase 9/metabolism , Mice , Orthomyxoviridae Infections/metabolism , Plastics , Pneumonia, Viral/metabolism , Tissue Inhibitor of Metalloproteinase-1/metabolismABSTRACT
BACKGROUND: Kawasaki disease (KD) is an acute and febrile systemic vasculitis that occurs during childhood. Infliximab (IFX) is a chimeric monoclonal antibody that binds to tumor necrosis factor-α. Although IFX therapy is a useful option for refractory KD, vaccine-associated infections may develop after therapy. In Japan, IFX therapy is recommended after a duration of at least 3 months after live vaccinations or at least 6 months after Bacillus Calmette-Guérin (BCG) in children with KD. However, the appropriate duration between live vaccinations and IFX therapy is unclear. METHODS: We investigated children who developed KD within 3 months after live vaccinations or within 6 months after BCG. Clinical characteristics, side effects of therapies and efficacy of live vaccinations were retrospectively investigated. RESULTS: Forty-eight patients developed KD within 3 months of live vaccinations or within 6 months after BCG. Eight patients underwent IFX therapy. There were no apparent vaccine-associated infections. The patients who underwent IFX acquired protective IgG antibody titers in the 5 of 6 live vaccines. CONCLUSIONS: Safe and appropriate duration between live vaccinations and IFX therapy for KD patients could be shorter in the future, although more studies are warranted to establish the safe duration.
Subject(s)
Mucocutaneous Lymph Node Syndrome , BCG Vaccine , Child , Feasibility Studies , Humans , Infliximab/adverse effects , Mucocutaneous Lymph Node Syndrome/drug therapy , Retrospective Studies , Treatment Outcome , Vaccination , Vaccines, Attenuated/therapeutic useABSTRACT
The association between pollen food allergy syndrome (PFAS) and allergic march remains unclear. In this prospective cohort study of the general population in Tokyo (T-Child Study), we found that sensitization to Cry j 1 and Fel d 1 at ages 5 and 9 years was associated with an increased risk of PFAS at 13 years old (at 5 years, Cry j 1: adjusted odds ratio aOR, 2.74; 95% confidence interval CI, 1.53-4.91; Fel d 1: aOR, 2.61; 95% CI, 1.31-5.19; at 9 years, Cry j 1: adjusted odds ratio aOR, 4.28; 95% confidence interval CI, 1.98-9.25; Fel d 1: aOR, 2.40; 95% CI, 1.33-4.32). In particular, sensitization to Bet v 1 at ages 5 and 9 years was associated with a strong risk of PFAS at the age of 13 years (at 5 years: aOR, 10.6; 95% CI, 2.64-42.5; at 9 years: aOR, 9.1; 95% CI, 4.71-17.6). PFAS risk by age 13 years was increased by any allergic symptom at 5 or 9 years, a combination of wheezing, eczema, and rhinitis, and Bet v 1 sensitization. Our findings suggest that PFAS may be associated with allergic march.
Subject(s)
Fluorocarbons , Food Hypersensitivity , Adolescent , Allergens , Child , Child, Preschool , Food Hypersensitivity/diagnosis , Humans , Pollen , Prospective Studies , SyndromeABSTRACT
In October 2021, researchers from the German Society of Allergy and Clinical Immunology (DGAKI) and from the Japanese Society of Allergology (JSA) focused their attention on the pathological conditions and modifiers of various allergic diseases. Topics included 1) the pathophysiology of IgE/mast cell-mediated allergic diseases; 2) the diagnosis and prevention of IgE/mast cell-mediated diseases; 3) the pathophysiology, diagnosis, and treatment of eosinophilic airway diseases; and 4) host-pathogen interaction and allergic diseases. This report summarizes the panel discussions, which highlighted the importance of recognizing the diversity of genetics, immunological mechanisms, and modifying factors underlying allergic diseases.
Subject(s)
Hypersensitivity , Immunoglobulin E , Humans , Hypersensitivity/drug therapy , Hypersensitivity/therapyABSTRACT
Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobin E-mediated food hypersensitivity disorder. However, little is known about the clinical features of FPIES in patients with Down syndrome (DS). Medical records of children with DS diagnosed at our hospital between 2000 and 2019 were retrospectively reviewed. Among the 43 children with DS, five (11.6%) were diagnosed with FPIES; all cases were severe. In the FPIES group, the median age at onset and tolerance was 84 days and 37.5 months, respectively. Causative foods were cow's milk formula and wheat. The surgical history of colostomy was significantly higher in the FPIES group than in the non-FPIES group. A colostomy was performed in two children in the FPIES group, both of whom had the most severe symptoms of FPIES, including severe dehydration and metabolic acidosis. The surgical history of colostomy and postoperative nutrition of formula milk feeding may have led to the onset of FPIES. Therefore, an amino acid-based formula should be considered for children who undergo gastrointestinal surgeries, especially colostomy in neonates or early infants. When an acute gastrointestinal disease is suspected in children with DS, FPIES should be considered. This may prevent unnecessary tests and invasive treatments.
Subject(s)
Down Syndrome/immunology , Enterocolitis/immunology , Food Hypersensitivity/immunology , Allergens/immunology , Animals , Case-Control Studies , Cattle , Child, Preschool , Colostomy/adverse effects , Dietary Proteins/immunology , Enterocolitis/diagnosis , Enterocolitis/epidemiology , Humans , Immunoglobulin E/blood , Infant , Infant Formula/adverse effects , Milk/immunology , Postoperative Complications/immunology , Retrospective Studies , Syndrome , Wheat Hypersensitivity/immunologySubject(s)
Globulins , Nut Hypersensitivity , Humans , Immunoglobulin E , Japan , Macadamia , Nut Hypersensitivity/diagnosis , Nut Hypersensitivity/epidemiology , NutsSubject(s)
Methylprednisolone/administration & dosage , Mycophenolic Acid/administration & dosage , Scleroderma, Localized/drug therapy , Scleroderma, Systemic/drug therapy , Adolescent , Anti-Inflammatory Agents , Child, Preschool , Female , Follow-Up Studies , Humans , Male , Scleroderma, Localized/diagnosis , Scleroderma, Systemic/diagnosis , Treatment OutcomeSubject(s)
Hypersensitivity , Humans , Hypersensitivity/epidemiology , Infant , Infant, Newborn , Infant, PrematureSubject(s)
Cysteine Endopeptidases/metabolism , Dermatitis, Atopic/pathology , Epidermis/enzymology , Seasons , Adolescent , Case-Control Studies , Child , Child, Preschool , Cysteine Endopeptidases/analysis , Epidermis/pathology , Female , Healthy Volunteers , Humans , Japan , Male , Severity of Illness IndexSubject(s)
Interleukin-18 , Liver Cirrhosis , Liver Transplantation/methods , Liver , NLR Proteins/genetics , Papillon-Lefevre Disease , Adolescent , Autoimmunity/immunology , Female , Humans , Inflammasomes/genetics , Inflammasomes/metabolism , Interleukin-18/analysis , Interleukin-18/immunology , Liver/immunology , Liver/pathology , Liver Cirrhosis/diagnosis , Liver Cirrhosis/etiology , Liver Cirrhosis/surgery , Mutation , Papillon-Lefevre Disease/genetics , Papillon-Lefevre Disease/immunology , Papillon-Lefevre Disease/physiopathology , Papillon-Lefevre Disease/therapy , Treatment OutcomeABSTRACT
BACKGROUND: Early-onset sarcoidosis (EOS) and Blau syndrome (BS) are systemic inflammatory granulomatous diseases without visible pulmonary involvement, and are distinguishable from their sporadic and familial forms. The diseases are characterized by a triad of skin rashes, symmetrical polyarthritis, and recurrent uveitis. The most common morbidity is ocular involvement, which is usually refractory to conventional treatment. A gain-of-function mutation in the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene has been demonstrated in this disease; however, little is known about the relationship between the activation of NOD2 and the pathophysiology of EOS/BS. Here we describe EOS/BS with a novel mutation in the NOD2 gene, as well as detection of Propionibacterium acnes (P. acnes) in the granulomatous inflammation. CASE PRESENTATION: An 8-year-old Japanese girl presented with refractory bilateral granulomatous panuveitis. Although no joint involvement was evident, she exhibited skin lesions on her legs; a skin biopsy revealed granulomatous dermatitis, and P. acnes was detected within the sarcoid granulomas by immunohistochemistry with P. acnes-specific monoclonal (PAB) antibody. Genetic analyses revealed that the patient had a NOD2 heterozygous D512V mutation that was novel and not present in either of her parents. The mutant NOD2 showed a similar activation pattern to EOS/BS, thus confirming her diagnosis. After starting oral prednisolone treatment, she experienced an anterior vitreous opacity relapse despite gradual prednisolone tapering; oral methotrexate was subsequently administered, and the patient responded positively. CONCLUSIONS: We presented a case of EOS/BS with a novel D512V mutation in the NOD2 gene. In refractory granulomatous panuveitis cases without any joint involvement, EOS/BS should be considered as a differential diagnosis; genetic analyses would lead to a definite diagnosis. Moreover, this is the first report of P. acnes demonstrated in granulomas of EOS/BS. Since intracellular P. acnes activates nuclear factor-kappa B in a NOD2-dependent manner, we hypothesized that the mechanism of granuloma formation in EOS/BS may be the result of NOD2 activity in the presence of the ligand muramyl dipeptide, which is a component of P. acnes. These results indicate that recognition of P. acnes through mutant NOD2 is the etiology in this patient with EOS/BS.