Monocytes and macrophages comprise a variety of subsets with diverse functions. It is thought that these cells play a crucial role in homeostasis of peripheral organs, key immunological processes and ...development of various diseases. Among these diseases, fibrosis is a life-threatening disease of unknown aetiology. Its pathogenesis is poorly understood, and there are few effective therapies. The development of fibrosis is associated with activation of monocytes and macrophages. However, the specific subtypes of monocytes and macrophages that are involved in fibrosis have not yet been identified. Here we show that Ceacam1
Msr1
Ly6C
F4/80
Mac1
monocytes, which we term segregated-nucleus-containing atypical monocytes (SatM), share granulocyte characteristics, are regulated by CCAAT/enhancer binding protein β (C/EBPβ), and are critical for fibrosis. Cebpb deficiency results in a complete lack of SatM. Furthermore, the development of bleomycin-induced fibrosis, but not inflammation, was prevented in chimaeric mice with Cebpb
haematopoietic cells. Adoptive transfer of SatM into Cebpb
mice resulted in fibrosis. Notably, SatM are derived from Ly6C
FcεRI
granulocyte/macrophage progenitors, and a newly identified SatM progenitor downstream of Ly6C
FcεRI
granulocyte/macrophage progenitors, but not from macrophage/dendritic-cell progenitors. Our results show that SatM are critical for fibrosis and that C/EBPβ licenses differentiation of SatM from their committed progenitor.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
The aim of this study was to investigate the clinical impact of sarcopenia on the efficacy of programmed death (PD)-1 inhibitors. We retrospectively reviewed the medical records of all patients ...treated with nivolumab or pembrolizumab between January 2016 and September 2018 for previously treated advanced non-small cell lung cancer (NSCLC). The cross-sectional area of the psoas muscle at the level of the third lumbar vertebra on baseline computed tomography was assessed to calculate the psoas muscle index (PMI). Sarcopenia was defined based on PMI cut-off values for Asian adults (6.36 cm
/m
for males and 3.92 cm
/m
for females). A total of 42 patients were analysed. The prevalence of sarcopenia was 52.4%. Sarcopenia was significantly associated with poorer progression-free survival (PFS) (median, 2.1 vs. 6.8 months, p = 0.004). Compared to patients with sarcopenia, those without sarcopenia had a higher overall response rate (40.0% vs. 9.1%, p = 0.025) and 1-year PFS rate (38.1% vs. 10.1%). In conclusion, sarcopenia at baseline as determined using computed tomography is a significant predictor of worse outcome in patients with advanced NSCLC receiving PD-1 blockade. Screening for sarcopenia may help identify patients more likely to achieve a long-term response in routine clinical practice.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The combination of rifamycin (RFP), ethambutol (EB), and macrolides is currently the standard regimen for treatment of Mycobacterium avium complex pulmonary disease (MAC-PD). However, poor adherence ...to the standardized regimens recommended by current guidelines have been reported. We undertook a single-centred retrospective cohort study to evaluate the long-term outcomes in 295 patients with MAC-PD following first line treatment with standard (RFP, EB, clarithromycin CAM) or alternative (EB and CAM with or without fluoroquinolones (FQs) or RFP, CAM, and FQs) regimens. In this cohort, 80.7% were treated with standard regimens and 19.3% were treated with alternative regimens. After heterogeneity was statistically corrected using propensity scores, outcomes were superior in patients treated with standard regimens. Furthermore, alternative regimens were significantly and independently associated with sputum non-conversion, treatment failure and emergence of CAM resistance. Multivariate cox regression analysis revealed that older age, male, old tuberculosis, diabetes mellitus, higher C-reactive protein, and cavity were positively associated with mortality, while higher body mass index and M. avium infection were negatively associated with mortality. These data suggest that, although different combination regimens are not associated with mortality, first line administration of a standard RFP + EB + macrolide regimen offers the best chance of preventing disease progression in MAC-PD patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In autoantibody-mediated autoimmune diseases, pathogenic autoantibodies generated by a failure of central or peripheral tolerance, have different effects mediated by a variety of mechanisms. ...Interestingly, even non-autoimmune chronic diseases have a set of disease-specific natural autoantibodies that are maintained for a long time. Because most of these natural autoantibodies target intracellular proteins or long non-coding RNAs, they are speculated to be non-pathological and have some important as yet unrecognized physiological functions such as debris clearance. Recently, we revealed a set of disease-specific natural autoantibodies of chronic pulmonary diseases with unknown etiology by protein arrays that enable detection of specific autoantibodies against >8000 targets. Surprisingly, some of the targeted antigens of disease-specific autoantibodies were subsequently reported by other laboratories as strongly associated with the disease, suggesting that these antigens reflect the pathology of each disease. Furthermore, some of these autoantibodies that target extracellular antigens might modify the original course of each disease. Here, we review the disease-specific natural autoantibodies of chronic pulmonary diseases, including chronic fibrosing idiopathic interstitial pneumonias, sarcoidosis, and autoimmune pulmonary alveolar proteinosis, and discuss their utility and effects.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The incidence and prevalence of non-tuberculous mycobacteria (NTM) infections are steadily increasing worldwide, partially due to the increased incidence of immunocompromised conditions, such as the ...post-transplantation state. The importance of proper diagnosis and management of NTM infection has been recently recognized. Host immunological responses play integral roles in vulnerability to NTM infections, and may contribute to the onset of specific types of NTM infection. Furthermore, distinct NTM species are known to affect and attenuate these host immune responses in unique manners. Therefore, host immune responses must be understood with respect to each causative NTM species. Here, we review innate, cellular-mediated, and humoral immunity to NTM and provide perspectives on novel diagnostic approaches regarding each NTM species.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Fibrosis is an incurable disorder of unknown etiology. Segregated-nucleus-containing atypical monocytes (SatMs) are critical for the development of fibrosis. Here we examined the mechanisms that ...recruit SatMs to pre-fibrotic areas. A screen based on cytokine expression in the fibrotic lung revealed that the chemokine Cxcl12, which is produced by apoptotic nonhematopoietic cells, was essential for SatM recruitment. Analyses of lung tissues at fibrosis onset showed increased expression of Rbm7, a component of the nuclear exosome targeting complex. Rbm7 deletion suppressed bleomycin-induced fibrosis and at a cellular level, suppressed apoptosis of nonhematopoietic cells. Mechanistically, Rbm7 bound to noncoding (nc)RNAs that form subnuclear bodies, including Neat1 speckles. Dysregulated expression of Rbm7 resulted in the nuclear degradation of Neat1 speckles, the dispersion of the DNA repair protein BRCA1, and the triggering of apoptosis. Thus, Rbm7 in epithelial cells plays a critical role in the development of fibrosis by regulating ncRNA decay and thereby the production of chemokines that recruit SatMs.
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•Rbm7 expression is increased in the fibrotic phase in both murine and human tissues•Repression of Rbm7 in nonhematopoietic cells in the fibrotic phase suppresses fibrosis•RBM7 dysregulation promotes apoptosis via nuclear degradation of NEAT1•Apoptotic nonhematopoietic cells release Cxcl12 to recruit SatMs, initiating fibrosis
Fibrosis is an incurable disorder of unknown etiology. Fukushima, Satoh et al. examine the mechanisms that recruit segregated-nucleus-containing atypical monocytes (SatMs), which are critical for fibrosis onset. They find that dysregulated expression of Rbm7, a component of the nuclear exosome targeting complex, in nonhematopoietic cells triggers apoptosis and thereby the production of chemokines that recruit SatMs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Chronic pulmonary aspergillosis (CPA) has been reported to be associated with poor prognosis in non-tuberculous mycobacteria (NTM)-pulmonary disease (PD) patients. However, whether isolation of
...species is associated with poor outcome or mostly just the reflection of colonization is a widely debated issue and a yet unsolved question. We conducted this single-centered retrospective cohort study of 409 NTM-PD patients to assess the impacts and prevalence of
isolation and CPA development. The median observation time was 85 months.
species were isolated from 79 (19.3%) and 23 (5.6%) developed CPA. Isolation of
species was not associated with mortality in NTM-PD patients (
= 0.9016). Multivariate logistic regression analysis revealed that higher CRP (
= 0.0213) and AFB stain positivity (
= 0.0101) were independently associated with
isolation. Different mycobacterial species were not associated with
isolation. Survival curves for patients with CPA diagnosis were significantly and strikingly different from those without (
= 0.0064), suggesting that CPA development severely affects clinical outcome. Multivariate logistic regression analysis revealed that the use of systemic steroids (
= 0.0189) and cavity (
= 0.0207) were independent risk factors for the progression to CPA. Considering the high mortality rate of CPA in NTM-PD, early diagnosis and treatment are essential to improve outcomes for NTM-PD patients.
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