Shintaro Okazaki

IL-17A/F Modulates Fibrocyte Functions in Cooperation with CD40-Mediated Signaling

T helper 17 (Th17) cells that produce interleukin (IL)-17A and IL-17F have been found to participate in the development of bronchial asthma and bleomycin-induced pulmonary fibrosis. However, whether they play a causative role in the airway remodeling observed in these respiratory diseases remains unclear. Because fibrocytes are involved in tissue repair and fibrosis and are presumably precursors of lung fibroblasts and myofibroblasts, we examined the effects of IL-17A/F on fibrocyte functions. Both IL-17A and IL-17F enhanced fibrocytes’ α-smooth muscle actin expression. Priming fibrocytes with IL-17A enhanced their CD40-mediated IL-6 production, whereas IL-17F-priming increased the CD40-mediated mRNA expression of collagen I, vascular endothelial growth factor, and angiogenin. CD4+ T cells co-cultured with fibrocytes produced IL-17A, which was inhibited by blocking CD40 and CD40 ligand interactions. These findings suggest that cooperative interactions between fibrocytes and Th17 cells play an important role via CD40- and IL-17A/F-mediated signaling for collagen and proangiogenic factor production, which may lead to the extracellular matrix deposition and neovascularization seen in airway remodeling.

Marked elevation of interleukin-6 in mild encephalopathy with a reversible splenial lesion (MERS) associated with acute focal bacterial nephritis caused by Enterococcus faecalis

This report describes two cases of mild encephalitis/encephalopathy with reversible splenial lesion (MERS) associated with acute focal bacterial nephritis (AFBN). The patients, who presented with fever and delirious behavior, exhibited hyponatremia and markedly elevated interleukin (IL)-6 in cerebrospinal fluid (CSF) and serum. Enterococcus faecalis was detected in the urine culture. After ampicillin treatment, their consciousness improved without neurological sequelae. Moreover, a diffusion-weighted MRI abnormality, i.e., intensified signals in splenium of the corpus callosum, disappeared. MERS is a possible complication of AFBN. Elevated CSF IL-6 levels suggest that remote activation of intracerebral immune response through the immune-neuroendocrine pathway might play an important role in the pathophysiology of MERS.

Biotin and carnitine profiles in preterm infants in Japan.

Biotin plays an important role as a covalently bound coenzyme for carboxylases. Carnitine is essential in β‐oxidation to transport long‐chain fatty acids across the inner mitochondrial membrane. The present study was conducted to assess the risk of biotin and carnitine deficiencies in preterm infants who received enteral feeding with maternal milk and/or standard infant formula made in Japan.

ACTN1 rod domain mutation associated with congenital macrothrombocytopenia.

Mutations in ACTN1, the gene encoding the actin-crosslinking protein α-actinin-1, cause autosomal dominant macrothrombocytopenia. α-Actinin-1 exists as antiparallel dimers, composed of an N-terminal actin-binding domain (ABD), four spectrin-like repeats (SLRs), which form the spacer rod, and a C-terminal calmodulin-like (CaM) domain. All of the previously reported ACTN1 mutations associated with macrothrombocytopenia reside within the ABD and the CaM domain and not within the SLR domain. In this report, we describe a mutation in SLR2 of α-actinin-1 (p.Leu395Gln) associated with familial macrothrombocytopenia. A 3-year-old boy and his mother both had this mutation. They showed a mild form of thrombocytopenia without severe bleeding, accompanied by an elevated mean platelet volume. Consistent with the previous reports of mutations that reside in the ABD or the CaM domain, immunofluorescence examination revealed disorganization of the actin cytoskeleton in Gln395 mutant-transduced Chinese hamster ovary cells. Our findings suggest a novel mechanism for the pathogenesis of ACTN1-related macrothrombocytopenia that does not involve functional domain mutations.

IL-33 enhanced the proliferation and constitutive production of IL-13 and IL-5 by fibrocytes.

Interleukin-33 appears to play important roles in the induction of allergic airway inflammation. However, whether IL-33 is involved in airway remodeling remains unclear. Because fibrocytes contribute to tissue remodeling in the setting of chronic inflammation, we examined the effects of IL-33 on fibrocyte functions. Fibrocytes were generated in vitro from peripheral blood mononuclear cells by culturing in the presence of platelet derived growth factors and the cells were stimulated with IL-33. IL-33 enhanced cell proliferation, α-SMA expression, and pro-MMP-9 activity by the fibrocytes without increasing endogenous transforming growth factor-β1 production. Fibrocytes constitutively expressed IL-13 and IL-5, and their production was augmented by stimulation with IL-33. Dexamethasone inhibited the functions of fibrocytes, but IL-33 made fibrocytes slightly refractory to the inhibitory effect of dexamethasone in terms of IL-13 production. Montelukast suppressed IL-13 production by nonstimulated fibrocytes but not those stimulated by IL-33. These findings suggest that IL-33 is involved in the airway remodeling process through its modulation of fibrocyte function independent of antigen stimulation. IL-33 might partially reduce the therapeutic effects of glucocorticoid and cysteinyl leukotriene receptor antagonist on fibrocyte-mediated Th2 responses.

Cytokine profiles in Mycoplasma pneumoniae infection-associated hemophagocytic lymphohistiocytosis

A 3-year-old boy with Mycoplasma pneumoniae infection associated with hemophagocytic lymphohistiocytosis (MP-HLH) presented with an elevated level of serum interleukin-12 (IL-12) and lower levels of interferon-γ and IL-10 compared to patients with Epstein-Barr virus infection associated with HLH (EBV-HLH). Unlike the patients with EBV-HLH, CD8+ CD5low HLA-DR++ T cells were not detected in our pediatric patient. Thus, the pathophysiology of MP-HLH may differ from that of EBV-HLH.

Alternaria extract activates autophagy that induces IL-18 release from airway epithelial cells

Alternaria alternata is a major outdoor allergen that causes allergic airway diseases. Alternaria extract (ALT-E) has been shown to induce airway epithelial cells to release IL-18 and thereby initiate Th2-type responses. We investigated the underlying mechanisms involved in IL-18 release from ALT-E-stimulated airway epithelial cells. Normal human bronchial epithelial cells and A549 human lung adenocarcinoma cells were stimulated with ALT-E in the presence of different inhibitors of autophagy or caspases. IL-18 levels in culture supernatants were measured by ELISA. The numbers of autophagosomes, an LC3-I to LC3-II conversion, and p62 degradation were determined by immunofluorescence staining and immunoblotting. 3-methyladenine and bafilomycin, which inhibit the formation of preautophagosomal structures and autolysosomes, respectively, suppressed ALT-E-induced IL-18 release by cells, whereas caspase 1 and 8 inhibitors did not. ALT-E-stimulation increased autophagosome formation, LC-3 conversion, and p62 degradation in airway epithelial cells. LPS-stimulation induced the LC3 conversion in A549 cells, but did not induce IL-18 release or p62 degradation. Unlike LPS, ALT-E induced airway epithelial cells to release IL-18 via an autophagy dependent, caspase 1 and 8 independent pathway. Although autophagy has been shown to negatively regulate canonical inflammasome activity in TLR-stimulated macrophages, our data indicates that this process is an unconventional mechanism of IL-18 secretion by airway epithelial cells.

The Biomarker Salivary SP-D May Indicate Small Airway Inflammation and Asthma Exacerbation

BACKGROUND Noninvasive and child-friendly biomarkers are important tools for understanding the various phenotypes of childhood asthma. Objective: The aim of this study was to examine the usefulness of salivary surfactant protein (SP) D in assessing the pathophysiology of childhood asthma. METHODS We measured salivary concentrations of SP-D and forced oscillation technique (FOT) indexes in 19 healthy controls and 21 asthmatic children. Regression equations for the predictive values of FOT indexes were generated from healthy controls. We analyzed the correlations between salivary SP-D concentration and percentages of the predictive values of FOT indexes, as well as the severity of exacerbation. RESULTS We found that salivary SP-D levels were higher in asthmatic children than in healthy controls. In the asthmatic children, salivary SP-D levels correlated with the percentages of predicted differences in resistance between 5 Hz and 20 Hz (%R5-R20), which represented the resistance of peripheral airways, and with the severity of asthma exacerbation. CONCLUSIONS Salivary SP-D may reflect asthmatic inflammation in peripheral small airways and may be a useful marker for monitoring the degree of exacerbation in childhood asthma.

Rice protein-induced enterocolitis syndrome with transient specific IgE to boiled rice but not to retort-processed rice.

Described herein is the case of an 8‐month‐old girl with atypical food protein‐induced enterocolitis syndrome due to rice. She presented with vomiting and poor general activity 2 h after ingestion of boiled rice. Oral food challenge test using high‐pressure retort‐processed rice was negative, but re‐exposure to boiled rice elicited gastrointestinal symptoms. On western blot analysis the patients serum was found to contain IgE bound to crude protein extracts from rice seed or boiled rice, but not from retort‐processed rice. The major protein bands were not detected in the electrophoresed gel of retort‐processed rice extracts, suggesting decomposition by high‐temperature and high‐pressure processing. Oral food challenge for diagnosing rice allergy should be performed with boiled rice to avoid a false negative. Additionally, some patients with rice allergy might be able to ingest retort‐processed rice as a substitute for boiled rice.