Upregulation of leukocyte immunoglobulin-like receptor B4 on interstitial macrophages in COPD; their possible protective role against emphysema formation.

BACKGROUND: Leukocyte immunoglobulin-like receptor B4 (LILRB4) is one of the inhibitory receptors in various types of immune cells including macrophages. Previous reports suggested that LILRB4 could be involved in a negative feedback system to prevent excessive inflammatory responses. However, its role has been unclear in chronic obstructive pulmonary disease (COPD), in which macrophages play a crucial role in the pathogenesis. In this study, we aimed to examine the changes of LILRB4 on macrophages both in the lung specimens of COPD patients and the lungs of a mouse emphysema model. We then tried to compare the differences in both inflammation and emphysematous changes of the model between wild-type and LILRB4-deficient mice in order to elucidate the role of LILRB4 in the pathogenesis of COPD. METHODS: We prepared single-cell suspensions of resected lung specimens of never-smokers (n = 21), non-COPD smokers (n = 16), and COPD patients (n = 14). The identification of LILRB4-expressing cells and the level of LILRB4 expression were evaluated by flow cytometry. We analyzed the relationships between the LILRB4 expression and clinical characteristics including respiratory function. In the experiments using an elastase-induced mouse model of emphysema, we also analyzed the LILRB4 expression on lung macrophages. We compared inflammatory cell accumulation and emphysematous changes induced by elastase instillation between wild-type and LILRB4-deficient mice. RESULTS: The levels of surface expression of LILRB4 are relatively high on monocyte linage cells including macrophages in the human lungs. The percentage of LILRB4+ cells in lung interstitial macrophages was increased in COPD patients compared to non-COPD smokers (p = 0.018) and correlated with the severity of emphysematous lesions detected by CT scan (rs = 0.559, p < 0.001), whereas the amount of smoking showed no correlation with LILRB4 expression. Increased LILRB4 on interstitial macrophages was also observed in elastase-treated mice (p = 0.008). LILRB4-deficient mice showed severer emphysematous lesions with increased MMP-12 expression in the model. CONCLUSIONS: LILRB4 on interstitial macrophages was upregulated both in human COPD lungs and in a mouse model of emphysema. This upregulated LILRB4 may have a protective effect against emphysema formation, possibly through decreasing MMP-12 expression in the lungs.

A case of localized tracheobronchial relapsing polychondritis with positive matrilin-1 staining.

BACKGROUND: Relapsing polychondritis (RPC) is a rare progressive autoimmune disease characterized by inflammation in the cartilage of multiple organs. Tracheobronchial involvement appears in nearly half of RPC patients during the course of their disease and represents the main cause of death. Localized tracheobronchial RPC is much rarer, and the pathogenesis remains unclear. Matrilin-1 is a non-collagenous cartilage matrix protein and has been suggested to be a potent autoantigen that induces the airway disease of RPC in animal models. However, the expression of matrilin-1 in tracheobronchial tissue in human remains unclear. Therefore, we examined the expression of matrilin-1 in the tracheal and auricular tissues in a localized tracheobronchial RPC patient. CASE PRESENTATION: A 62-year-old man with systemic sclerosis presented with cough and dyspnea on exertion. The lung function test showed an expiratory flow limitation and chest computed tomography showed diffuse thickness from the trachea to the bronchiole. No other tests showed abnormal findings. To evaluate further, bronchoscopy was performed and endobronchial ultrasonography showed thickness in the fourth-marginal echo layer suggesting inflammation of the cartilage. However, the tracheal biopsy showed no specific findings. The subsequent surgical tracheal biopsies showed inflammatory cell infiltration with destruction of the cartilage. Neither auricular nor nasal deformity, except for a tracheobronchial lesion, was detected. Biopsy from the left auricular cartilage also did not show any inflammatory changes. Finally, we diagnosed the patient with localized tracheobronchial RPC. To address the hypothesis that autoimmunity against matrilin-1 is involved in the pathogenesis of localized tracheobronchial RPC, we evaluated the expression level of matrilin-1 in a tracheal and auricular specimen from this patient. Immunohistochemical staining with anti-matrilin-1 antibody showed matrilin-1 in the tracheal but not in the auricular cartilage. CONCLUSIONS: We first demonstrated the expression of matrilin-1 in tracheal but not in auricular cartilage in a localized tracheobronchial RPC patient. This result supports the possibility that matrilin-1 is involved in the pathogenesis of localized tracheobronchial RPC. However, this is only one case report and further observations will be needed to confirm this result.

Invasive pulmonary mucormycosis: rare presentation with pulmonary eosinophilia.

BACKGROUND: Fungi can cause a variety of infectious diseases, including invasive mycosis and non-invasive mycosis, as well as allergic diseases. The different forms of mycosis usually have been described as mutually exclusive, independent entities, with few descriptions of overlapping cases. Here, we describe the first reported case of a patient with the complication of pulmonary eosinophilia in the course of invasive mucormycosis. CASE PRESENTATION: A 74-year-old Japanese man with asthma-COPD overlap underwent emergency surgery for a ruptured abdominal aortic aneurysm. The surgery was successful, but fever and worsening dyspnea appeared and continued from postoperative day (POD) 10. A complete blood count showed leukocytosis with neutrophilia and eosinophilia, and the chest X-ray showed consolidation of the left upper lung at POD 15. We suspected nosocomial pneumonia together with an exacerbation of the asthma-COPD overlap, and both antibiotics and bronchodilator therapy were initiated. However, the symptoms, eosinophilia and imaging findings deteriorated. We then performed a bronchoscopy, and bronchoalveolar lavage (BAL) fluid analysis revealed an increased percentage of eosinophils (82% of whole cells) as well as filamentous fungi. We first suspected that this was a case of allergic bronchopulmonary mycosis (ABPM) caused by Aspergillus infection and began corticosteroid therapy with an intravenous administration of voriconazole at POD 27. However, the fungal culture examination of the BAL fluid revealed mucormycetes, which were later identified as Cunninghamella bertholletiae by PCR and DNA sequencing. We then switched the antifungal agent to liposomal amphotericin B for the treatment of the pulmonary mucormycosis at POD 29. Despite replacing voriconazole with liposomal amphotericin B, the patient developed septic shock and died at POD 39. The autopsy revealed that filamentous fungi had invaded the lung, heart, thyroid glands, kidneys, and spleen, suggesting that disseminated mucormycosis had occurred. CONCLUSIONS: We describe the first reported case of pulmonary mucormycosis with pulmonary eosinophilia caused by Cunninghamella bertholletiae, which resulted in disseminated mucormycosis. Although it is a rather rare case, two important conclusions can be drawn: i) mycosis can simultaneously cause both invasive infection and a host allergic reaction, and ii) Cunninghamella bertholletiae rarely infects immunocompetent patients.

OX40 ligand newly expressed on bronchiolar progenitors mediates influenza infection and further exacerbates pneumonia.

Influenza virus epidemics potentially cause pneumonia, which is responsible for much of the mortality due to the excessive immune responses. The role of costimulatory OX40-OX40 ligand (OX40L) interactions has been explored in the non-infectious pathology of influenza pneumonia. Here, we describe a critical contribution of OX40L to infectious pathology, with OX40L deficiency, but not OX40 deficiency, resulting in decreased susceptibility to influenza viral infection. Upon infection, bronchiolar progenitors increase in number for repairing the influenza-damaged epithelia. The OX40L expression is induced on the progenitors for the antiviral immunity during the infectious process. However, these defense-like host responses lead to more extensive infection owing to the induced OX40L with α-2,6 sialic acid modification, which augments the interaction with the viral hemagglutinin. In fact, the specific antibody against the sialylated site of OX40L exhibited therapeutic potency in mitigating the OX40L-mediated susceptibility to influenza. Our data illustrate that the influenza-induced expression of OX40L on bronchiolar progenitors has pathogenic value to develop a novel therapeutic approach against influenza.

Regulation of plasmacytoid dendritic cell responses by PIR-B.

Plasmacytoid dendritic cells (PDCs) produce type I interferons (IFNs) in response to viral nucleic acids to exert antiviral immunity. However, PDCs are related to the progress and severity of autoimmune diseases, such as systemic lupus erythematosus, because they respond to host DNA. Therefore, the regulation of PDC activation is critical for maintaining adequate immune responses. Here we show that an inhibitory major histocompatibility complex class I receptor, paired immunoglobulin-like receptor B (PIR-B), suppressed Fms-like tyrosine kinase 3 ligand-induced PDC differentiation in BM cells, as well as Toll-like receptor 9-mediated IFN-α production by PDCs, through the dephosphorylation of STAT1/STAT2. In particular, PIR-B inhibited IFN-α-mediated STAT phosphorylation, suggesting that PIR-B negatively regulates the positive feedback mechanism of IFN-α secretion triggered by Toll-like receptor 9. These results demonstrate a novel regulatory role for PIR-B in PDCs.