Immunoglobulin A Vasculitis After Initiation of Treatment for Tuberculous Pleurisy: A Case Report and Literature Review.

Immunoglobulin A vasculitis (IgAV), also known as Henoch-Schönlein purpura (HSP), is a disease that causes inflammation and bleeding in small blood vessels in the skin, joints, intestines, and kidneys. Although various infections and chemicals are known to be triggers, the underlying cause of IgAV remains unknown. Here, we describe a case of an 86-year-old male patient with IgAV that developed after anti-tuberculosis treatment for tuberculous pleurisy. There have been several case reports implicating Mycobacterium tuberculosis and other acid-fast bacterium in the development of IgAV, but only a few case reports implicating anti-tuberculous drugs. This case highlights the importance of recognizing that IgAV can be caused by anti-tuberculous drugs.

Assessment of memory recognition using a smartphone-based test system: A pilot study.

BACKGROUND: Elucidation of the detailed nature of age-related memory decline requires analysis of memory performance in large populations of various ages. To promote large-scale studies, we developed a smartphone-based self-test for memory recognition. We examined whether this test could detect age-related memory decline and the effects of aerobic exercise on memory. METHODS: Seventy-eight younger and 42 older participants were randomly divided into active and passive groups. Both groups took a memory recognition test (consisting of 2 sessions separated by a 48-hour interval) conducted on smartphones. The participants answered the positive and negative affect schedule questionnaire at the beginning and end of each session. In the first session, the participants performed cognitive tasks on 90 photographs displayed on a smartphone screen. Immediately after the cognitive tasks, the active group performed a bout of light aerobic exercise for 10 minutes, while the passive group remained calm for 10 minutes. In the second session, the participants were tested on the recognition of 90 previously observed photographs and 90 distractor photographs. RESULTS: Passive older participants had ~40% to ~50% lower recognition scores (RSs) than passive younger participants did. Moreover, the aerobic exercise used in this study improved the RSs of active younger participants by up to ~40% compared with those of passive younger participants, while such an improvement was not observed in older participants. The RS did not depend on the affect levels evaluated using positive and negative affect schedule questionnaire. CONCLUSIONS: These results demonstrated that the smartphone-based test could detect age-related decline and could promote behavior modification that may lead to memory enhancement, as reported in previous studies using conventional laboratory tests. The results of the smartphone-based test were not influenced by the subjects affect. This indicates the possibility of large-scale memory studies and healthcare for memory performance by using personal mobile devices.

Pancreatic glycoprotein 2 is a first line of defense for mucosal protection in intestinal inflammation.

Increases in adhesive and invasive commensal bacteria, such as Escherichia coli, and subsequent disruption of the epithelial barrier is implicated in the pathogenesis of inflammatory bowel disease (IBD). However, the protective systems against such barrier disruption are not fully understood. Here, we show that secretion of luminal glycoprotein 2 (GP2) from pancreatic acinar cells is induced in a TNF-dependent manner in mice with chemically induced colitis. Fecal GP2 concentration is also increased in Crohn's diease patients. Furthermore, pancreas-specific GP2-deficient colitis mice have more severe intestinal inflammation and a larger mucosal E. coli population than do intact mice, indicating that digestive-tract GP2 binds commensal E. coli, preventing epithelial attachment and penetration. Thus, the pancreas-intestinal barrier axis and pancreatic GP2 are important as a first line of defense against adhesive and invasive commensal bacteria during intestinal inflammation.

Orally desensitized mast cells form a regulatory network with Treg cells for the control of food allergy.

Oral immunotherapy (OIT) is an effective approach to controlling food allergy. Although the detailed molecular and cellular mechanisms of OIT are unknown currently, they must be understood to advance the treatment of allergic diseases in general. To elucidate the mechanisms of OIT, especially during the immunological transition from desensitization to allergy regulation, we generated a clinical OIT murine model and used it to examine immunological events of OIT. We found that in mice that completed OIT successfully, desensitized mast cells (MCs) showed functionally beneficial alterations, such as increased induction of regulatory cytokines and enhanced expansion of regulatory T cells. Importantly, these regulatory-T-cell-mediated inhibitions of allergic responses were dramatically decreased in mice lacking OIT-induced desensitized MC. Collectively, these findings show that the desensitization process modulates the activation of MCs, leading directly to enhanced induction of regulatory-T-cell expansion and promotion of clinical allergic unresponsiveness. Our results suggest that efficiently inducing regulatory MCs is a novel strategy for the treatment of allergic disease.

Stratified layer analysis reveals intrinsic leptin stimulates cryptal mesenchymal cells for controlling mucosal inflammation.

Mesenchymal cells in the crypt play indispensable roles in the maintenance of intestinal epithelial homeostasis through their contribution to the preservation of stem cells. However, the acquisition properties of the production of stem cell niche factors by the mesenchymal cells have not been well elucidated, due to technical limitations regarding the isolation and subsequent molecular and cellular analyses of cryptal mesenchymal cells. To evaluate the function of mesenchymal cells located at the large intestinal crypt, we established a novel method through which cells are harvested according to the histologic layers of mouse colon, and we compared cellular properties between microenvironmental niches, the luminal mucosa and crypts. The gene expression pattern in the cryptal mesenchymal cells showed that receptors of the hormone/cytokine leptin were highly expressed, and we found a decrease in Wnt2b expression under conditions of leptin receptor deficiency, which also induced a delay in cryptal epithelial proliferation. Our novel stratified layer isolation strategies thus revealed new microenvironmental characteristics of colonic mesenchymal cells, including the intrinsic involvement of leptin in the control of mucosal homeostasis.

Acorbine, a Corbicula japonica-derived tripeptide containing non-proteinogenic amino acids, suppresses ethanol-induced liver injury.

Since ancient times, Corbicula extract has been believed in Japan to have hepatoprotective effects, but it remains unclear whether these claims are true, and if so, which component is responsible for hepatoprotection. In this study, we showed that Corbicula extract exerted a protective effect against liver damage. Recent work identified acorbine (ß-alanyl-ornithyl-ornithine), a novel tripeptide containing non-proteinogenic amino acids, in the extract of Corbicula japonica. Synthesized acorbine cured alcohol-induced liver damage in mice. In addition, acorbine purified from Corbicula extract exerted a protective effect against alcohol-induced hepatotoxicity in a culture liver model derived from mouse ES/iPS cells. Thus, acorbine is one of the components of Corbicula extract that protects hepatocytes against ethanol-induced death.

AT-rich-interactive domain-containing protein 5A functions as a negative regulator of retinoic acid receptor-related orphan nuclear receptor γt-induced Th17 cell differentiation.

OBJECTIVE: The proinflammatory cytokines tumor necrosis factor α and interleukin-6 (IL-6) and the Th17 cell cytokine IL-17A are implicated in the pathogenesis of rheumatoid arthritis (RA), and the blockade of these cytokines by biologic agents provides clinical benefits for RA patients. We undertook this study to clarify the mechanisms underlying the efficacy of IL-6 blockade in RA and to find a novel target for treatment of RA. METHODS: We examined gene expression profiles of CD4+ T cells by DNA microarray analysis before and after treatment with an anti-IL-6 receptor antibody, tocilizumab (TCZ), in RA patients who exhibited good clinical responses to the treatment. Using murine CD4+ T cells, we then examined the roles of a newly identified molecule whose expression was significantly reduced in CD4+ T cells by TCZ therapy. We also examined the effect of the forced expression of the molecule on retinoic acid receptor-related orphan nuclear receptor γt (RORγt)-induced IL-17A production in CD4+ T cells and on RORγt-induced IL-17A promoter activation. RESULTS: We identified AT-rich-interactive domain- containing protein 5A (ARID-5A) as a new molecule down-regulated by IL-6 blockade in the form of TCZ therapy. IL-6 induced the expression of ARID-5A in CD4+ T cells during Th17 cell differentiation by a STAT-3-dependent mechanism, whereas IL-6-induced ARID-5A expression was not affected by the absence of RORγt, a lineage-specifying transcription factor of Th17 cells. Furthermore, ARID-5A physically associated with RORγt through its N-terminal region and inhibited RORγt-induced Th17 cell differentiation. CONCLUSION: ARID-5A is a lineage-specific attenuator of Th17 cell differentiation and may be involved in the pathogenesis of RA.

Prediction of therapeutic responses to tocilizumab in patients with rheumatoid arthritis: biomarkers identified by analysis of gene expression in peripheral blood mononuclear cells using genome-wide DNA microarray.

OBJECTIVE: The aim of this prospective multicenter study was to identify biomarkers that can be used to predict therapeutic responses to tocilizumab in patients with rheumatoid arthritis (RA). METHODS: We recruited patients with RA who were treated with tocilizumab for the first time, and determined therapeutic responses at 6 months. In the training cohort (n = 40), gene expression in peripheral blood mononuclear cells (PBMCs) at baseline was analyzed using genome-wide DNA microarray, with 41,000 probes derived from 19,416 genes. In the validation cohort (n = 20), expression levels of the candidate genes in PBMCs at baseline were determined using real-time quantitative polymerase chain reaction (qPCR) analysis. RESULTS: We identified 68 DNA microarray probes that showed significant differences in signal intensity between nonresponders and responders in the training cohort. Nineteen putative genes were selected, and a significant correlation between the DNA microarray signal intensity and the qPCR relative expression was confirmed in 15 genes. In the validation cohort, a significant difference in relative expression between nonresponders and responders was reproduced for 3 type I interferon response genes (IFI6, MX2, and OASL) and MT1G. Receiver operating characteristic curve analysis of models incorporating these genes showed that the maximum area under the curve was 0.947 in predicting a moderate or good response to tocilizumab in the validation cohort. CONCLUSION: Using genome-wide DNA microarray analyses, we identified candidate biomarkers that can be used to predict therapeutic responses to tocilizumab in patients with RA. These findings suggest that type I interferon signaling and metallothioneins are involved in the pathophysiology of RA.

B and T lymphocyte attenuator inhibits LPS-induced endotoxic shock by suppressing Toll-like receptor 4 signaling in innate immune cells.

Although innate immune responses are necessary for the initiation of acquired immune responses and the subsequent successful elimination of pathogens, excessive responses occasionally result in lethal endotoxic shock accompanied by a cytokine storm. B and T lymphocyte attenuator (BTLA), a coinhibitory receptor with similarities to cytotoxic T-lymphocyte antigen (CTLA)-4 and programmed death (PD)-1, is expressed in not only B and T cells but also dendritic cells (DCs) and macrophages (Mϕs). Recently, several studies have reported that BTLA-deficient (BTLA(-/-)) mice show enhanced pathogen clearance compared with WT mice in early phase of infections. However, the roles of BTLA expressed on innate cells in overwhelming and uncontrolled immune responses remain unclear. Here, we found that BTLA(-/-) mice were highly susceptible to LPS-induced endotoxic shock. LPS-induced TNF-α and IL-12 production in DCs and Mϕs was significantly enhanced in BTLA(-/-) mice. BTLA(-/-) DCs also produced high levels of TNF-α on stimulation with Pam3CSK4 but not poly(I:C) or CpG, suggesting that BTLA functions as an inhibitory molecule on Toll-like receptor signaling at cell surface but not endosome. Moreover, BTLA(-/-) DCs showed enhanced MyD88- and toll/IL-1R domain-containing adaptor inducing IFN (TRIF)-dependent signaling on LPS stimulation, which is associated with impaired accumulation of Src homology 2-containing protein tyrosine phosphatase in lipid rafts. Finally, we found that an agonistic anti-BTLA antibody rescued mice from LPS-induced endotoxic shock, even if the antibody was given to mice that had developed a sign of endotoxic shock. These results suggest that BTLA directly inhibits LPS responses in DCs and Mϕs and that agonistic agents for BTLA might have therapeutic potential for LPS-induced endotoxic shock.

Dephosphorylation of endogenous GABA(B) receptor R2 subunit and AMPK α subunits which were measured by in vitro method using transfer membrane.

Protein phosphorylation can be regulated by changes in kinase activity, phosphatase activity, or both. GABA(B) receptor R2 subunit (GABA(B)R2) is phosphorylated at S783 by 5'-AMP-activated-protein kinase (AMPK), and this phosphorylation modulates GABA(B) receptor desensitization. Since the GABA(B) receptor is an integral membrane protein, solubilizing GABA(B)R2 is difficult. To circumvent this problem and to identify specific phosphatases that dephosphorylate S783, we employed an in vitro assay based on dephosphorylation of proteins on PVDF membranes by purified phosphatases. Our method allowed us to demonstrate that S783 in GABA(B)R2 is directly dephosphorylated by PP2A (but not by PP1, PP2B nor PP2C) in a dose-dependent and okadaic acid-sensitive manner. We also show that the level of phosphorylation of the catalytic subunit of AMPK at T172 is reduced by PP1, PP2A and PP2C. Our data indicate that PP2A dephosphorylates GABA(B)R2(S783) less efficiently than AMPK(T172), and that additional phosphatases might be involved in S783 dephosphorylation.

Roles of CRTH2+ CD4+ T cells in immunoglobulin G4-related lacrimal gland enlargement.

BACKGROUND: Lacrimal gland enlargement (LGE) is one of the characteristics of Mikulicz's disease (MD). Recently, marked serum immunoglobulin (Ig)G4 elevation and infiltration of IgG4-positive plasma cells in the enlarged exocrine glands have been reported in MD patients. Moreover, we have reported that in patients with LGE and elevated serum IgG4 levels (IgG4-related LGE), T helper type 2 (Th2) cell-mediated immune responses are enhanced. Although prostaglandin D2 (PGD2) and its receptor CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) have been shown to be involved in Th2 cell-related diseases such as bronchial asthma, their roles in IgG4-related diseases remain unknown. AIM: The aim of this study is to address the role of CD4+ T cells expressing CRTH2 (CRTH2+ CD4+ T cells) in IgG4-related LGE. METHODS: We examined the expression of CCR4, CXCR3 and CRTH2 on peripheral blood CD4+ T cells in patients with IgG4-related LGE, in patients with bronchial asthma and in healthy controls. RESULTS: The ratio of CCR4+ to CXCR3+ in CD45RO+ CD4+ T cells was increased in patients with IgG4-related LGE when compared to that in healthy controls, confirming that Th2 cells are predominant in patients with IgG4-related LGE. In addition, the frequency of CRTH2+ cells in CD4+ T cells was significantly increased in these patients, compared to healthy controls. Furthermore, although not statistically significant, the frequency of CRTH2+ cells in CD4+ T cells tended to correlate with the levels of serum IgE and the number of blood eosinophils in patients with IgG4-related LGE. CONCLUSION: CRTH2+ CD4+ T cells may be involved in the pathogenesis of IgG4-related LGE.

Efficient in vivo delivery of siRNA into brain capillary endothelial cells along with endogenous lipoprotein.

The brain capillary endothelial cell (BCEC) is a major functional component of the blood-brain barrier and is an underlying factor in the pathophysiology of various diseases, including brain ischemia, multiple sclerosis, and neurodegenerative disorders. We examined gene silencing in BCECs by using endogenous lipoprotein to introduce short-interfering RNA (siRNA) in vivo. A cholesterol-conjugated 21/23-mer siRNA targeting organic anion transporter 3 (OAT3) mRNA (Chol-siOAT3) was intravenously injected into mice after its incorporation into extracted endogenous lipoproteins. Chol-siOAT3 was not delivered to neurons or glia, but was successfully delivered into BCECs and resulted in a significant reduction of OAT3 mRNA levels when injected after its incorporation into high-density lipoprotein (HDL). Efficient delivery was not achieved, however, when Chol-siOAT3 was injected without any lipoproteins, or after its incorporation into low-density lipoprotein (LDL). Investigations in apolipoprotein E (ApoE)-deficient and LDL receptor (LDLR)-deficient mice revealed that the uptake of HDL-containing Chol-siOAT3 was mainly mediated by ApoE and LDLR in mice. These findings indicate that siRNA can be delivered into BCECs in vivo by using endogenous lipoprotein, which could make this strategy useful as a new gene silencing therapy for diseases involving BCECs.

Protein geranylgeranylation regulates the balance between Th17 cells and Foxp3+ regulatory T cells.

Recent studies have suggested that statins, the inhibitors for 3-hydroxy-3-methyglutaryl (HMG)-CoA reductase in the mevalonate pathway, exhibit anti-inflammatory effects. However, the immune modulatory effects of statins on the differentiation of CD4(+) T cells and their underlying mechanisms are still largely unknown. To address these issues, we examined the effect of simvastatin and inhibitors for protein farnesylation and geranylgeranylation on the differentiation of IL-17-producing T cells (T(h)17 cells) and Foxp3(+) CD4(+) T cells. Simvastatin inhibited the differentiation of T(h)17 cells through the inhibition of HMG-CoA reductase activity but enhanced the differentiation of Foxp3(+) CD4(+) T cells. Geranylgeranyltransferase I inhibitor, GGTI-298, but not farnesyltransferase inhibitor, FTI-277, mimicked the effects of simvastatin, indicating that the inhibition of protein geranylgeranylation is responsible for the effects. Moreover, Foxp3(+) CD4(+) T cells developed in the presence of transforming growth factor-beta and GGTI-298 functioned as regulatory T cells (Tregs) in in vitro T cell proliferation assay as well as in an autoimmune colitis model. Finally, GGTI-298 induced SOCS3 expression and inhibited IL-6-induced signal transducers and activators of transcription3 phosphorylation in CD4(+) T cells. Taken together, these results indicate that protein geranylgeranylation enhances the differentiation of T(h)17 cells and inhibits the differentiation of Foxp3(+) Tregs partly via the inhibition of SOCS3 expression.

Altricial development in subsocial wood-feeding cockroaches.

Species in the wood-feeding genus Salganea within the cockroach subfamily Panesthiinae (Blaberidae) typically live in biparental families; their first instars suffer high mortality when removed from adults, and in at least one species, adults are known to feed neonates on oral liquids. In the closely related gregarious wood-feeding genus Panesthia , no parental interaction with offspring is known. We compared the external morphology of first instars of these two genera and found that eye development and cuticular pigmentation at hatching are correlated with social structure. First instars of Panesthia have a dark cuticle and well-developed eyes. First instars of Salganea have a pale, transparent cuticle, and eyes significantly smaller than those of Panesthia relative to adult eye size. The body size of the first-instar of Salganea esakii is significantly smaller than that of Panesthia angustipennis spadica , relative to adult body size (24.0 and 27.4% of adult head-capsule width, respectively), but a more general survey suggests that, overall, neonate size may be similar in the two genera. We compared the first instars of these two taxa of Panesthiinae to those in the biparental, wood-feeding cockroach Cryptocercus (Cryptocercidae) and discuss how decreased investment in both integumentary and ocular development in subsocial cockroaches parallels that seen in altricial vertebrates.

Quiescent string dominance parameter F and classification of one-dimensional cellular automata.

The classification of rules may be one of the most fundamental targets in the study of cellular automata. In this paper, we propose a method for achieving such a classification, in which a new quiescent string dominance parameter F, which is orthogonal to lambda, is introduced. For N -neighbor and K -state cellular automata, in the region 1/K