Vitamin D modulation of innate immune responses to respiratory viral infections.

Vitamin D, in addition to its classical functions in bone homeostasis, has a modulatory and regulatory role in multiple processes, including host defense, inflammation, immunity, and epithelial repair. Patients with respiratory disease are frequently deficient in vitamin D, implying that supplementation might provide significant benefit to these patients. Respiratory viral infections are common and are the main trigger of acute exacerbations and hospitalization in children and adults with asthma and other airways diseases. Respiratory monocytes/macrophages and epithelial cells constitutively express the vitamin D receptor. Vitamin D, acting through this receptor, may be important in protection against respiratory infections. Whether the in vitro findings can be translated into a substantial in vivo benefit still remains uncertain. Here we review the in vitro data on the role of vitamin D in antiviral innate immunity, the data concerning the deficient levels of vitamin D in lung diseases, and the in vivo role of supplementation as protection against respiratory viral infections in healthy individuals and in patients with chronic respiratory diseases. Finally, we suggest ways of improving the effectiveness of vitamin D as an adjuvant in the prevention and treatment of acute respiratory infections.

The role of macrophage IL-10/innate IFN interplay during virus-induced asthma.

Activation through different signaling pathways results in two functionally different types of macrophages, the pro-inflammatory (M1) and the anti-inflammatory (M2). The polarization of macrophages toward the pro-inflammatory M1 phenotype is considered to be critical for efficient antiviral immune responses in the lung. Among the various cell types that are present in the asthmatic airways, macrophages have emerged as significant participants in disease pathogenesis, because of their activation during both the inflammatory and resolution phases, with an impact on disease progression. Polarized M1 and M2 macrophages are able to reversibly undergo functional redifferentiation into anti-inflammatory or pro-inflammatory macrophages, respectively, and therefore, macrophages mediate both processes. Recent studies have indicated a predominance of M2 macrophages in asthmatic airways. During a virus infection, it is likely that M2 macrophages would secrete higher amounts of the suppressor cytokine IL-10, and less innate IFNs. However, the interactions between IL-10 and innate IFNs during virus-induced exacerbations of asthma have not been well studied. The possible role of IL-10 as a therapy in allergic asthma has already been suggested, but the divergent roles of this suppressor molecule in the antiviral immune response raise concerns. This review attempts to shed light on macrophage IL-10-IFNs interactions and discusses the role of IL-10 in virus-induced asthma exacerbations. Whereas IL-10 is important in terminating pro-inflammatory and antiviral immune responses, the presence of this immune regulatory cytokine at the beginning of virus infection could impair the response to viruses and play a role in virus-induced asthma exacerbations.

The role of IL-15 deficiency in the pathogenesis of virus-induced asthma exacerbations.

Rhinovirus infections are the major cause of asthma exacerbations. We hypothesised that IL-15, a cytokine implicated in innate and acquired antiviral immunity, may be deficient in asthma and important in the pathogenesis of asthma exacerbations. We investigated regulation of IL-15 induction by rhinovirus in human macrophages in vitro, IL-15 levels in bronchoalveolar lavage (BAL) fluid and IL-15 induction by rhinovirus in BAL macrophages from asthmatic and control subjects, and related these to outcomes of infection in vivo. Rhinovirus induced IL-15 in macrophages was replication-, NF-κB- and α/ß interferon-dependent. BAL macrophage IL-15 induction by rhinovirus was impaired in asthmatics and inversely related to lower respiratory symptom severity during experimental rhinovirus infection. IL-15 levels in BAL fluid were also decreased in asthmatics and inversely related with airway hyperresponsiveness and with virus load during in vivo rhinovirus infection. Deficient IL-15 production in asthma may be important in the pathogenesis of asthma exacerbations.

Immunological pathways in virus-induced COPD exacerbations: a role for IL-15.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by high levels of antiviral type 1 cytokine interferon-γ and activated CD8(+) T cells. COPD exacerbations are the major cause of morbidity and mortality, have a prolonged and intense effect on quality of life and may result in accelerated loss of lung function. Respiratory virus infections, frequently within a state of colonization by bacteria, are the major cause of COPD exacerbations, and there is also evidence of virus latency in 'stable' disease, suggesting that latent infection might be a cause of chronic inflammation in COPD. DESIGN: This is an update of current literature concerning the role of interleukin-15 and major histocompatibility complex class I-related chain A and B molecules in type 1 immune responses, particularly to respiratory virus infections, which are the main cause of COPD exacerbations. We also present data from our own group suggesting a role for interleukin-15 in virus-induced COPD exacerbations. RESULTS: Type 1 cytokine interleukin-15 is produced by resident airway cells (epithelial cells and macrophages) in response to virus infection and bacteria. Virus infections modulate major histocompatibility complex class I-related chain A and B molecules in respiratory epithelial cells. CONCLUSIONS: Interleukin-15 could play a major role in the airway inflammation in COPD directly, via its own receptors, by amplifying the type 1 immune responses and decreasing apoptosis or indirectly, via modulating molecules associated with cytotoxic activity of natural killer and CD8(+) T cells, such as major histocompatibility complex class I-related chain A and B.

RSV-induced bronchial epithelial cell PD-L1 expression inhibits CD8+ T cell nonspecific antiviral activity.

Respiratory syncytial virus (RSV) is a major cause of bronchiolitis in infants. It is also responsible for high morbidity and mortality in the elderly. Programmed death ligands (PD-Ls) on antigen-presenting cells interact with receptors on T cells to regulate immune responses. The programmed death receptor-ligand 1/programmed death receptor 1 (PD-L1-PD-1) pathway is inhibitory in chronic viral infections, but its role in acute viral infections is unclear. We hypothesized that bronchial epithelial cell (BEC) expression of PD-Ls would inhibit local effector CD8(+) T cell function. We report that RSV infection of primary human BECs strongly induces PD-L1 expression. In a co-culture system of BECs with purified CD8(+) T cells, we demonstrated that RSV-infected BECs increased CD8(+) T cell activation, proliferation, and antiviral function. Blocking PD-L1 on RSV-infected BECs co-cultured with CD8(+) T cells enhanced CD8(+) T cell IFN-γ, IL-2, and granzyme B production. It also decreased the virus load of the BECs. Based on our findings, we believe therapeutic strategies that target the PD-L1-PD-1 pathway might increase antiviral immune responses to RSV and other acute virus infections.

Cardiotoxicity: A Major Setback in Childhood Leukemia Treatment.

Ongoing research in the field of pediatric oncology has led to an increased number of childhood cancer survivors reaching adulthood. Therefore, ensuring a good quality of life for these patients has become a rising priority. Considering this, the following review focuses on summarizing the most recent research in anthracycline-induced cardiac toxicity in children treated for leukemia. For pediatric cancers, anthracyclines are one of the most used anticancer drugs, with over half of the childhood cancer survivors believed to have been exposed to them. Anthracyclines cause irreversible cardiomyocyte loss, leading to chronic, progressive heart failure. The risk of developing cardiotoxicity has been known to increase with the treatment-free interval and total cumulative dose. However, because of individual variations in anthracycline metabolism, it has recently been shown that there is no risk-free dose. Moreover, studies have shown that diagnosing anthracycline-induced cardiomyopathy in the symptomatic phase is associated with poor treatment response and prognosis. Thus, early and systematic evaluation of these patients is crucial to allow optimal therapeutic intervention. Although currently echocardiographic assessment of left ventricle ejection fraction and cardiac biomarker evaluation are being used for cardiac function monitoring in oncologic patients, there is no established follow-up and treatment protocol for these patients, and these methods are neither specific nor sensitive for identifying early cardiac dysfunction. All things considered, the need for ongoing research in the field of pediatric cardiooncology is crucial to offer these patients a chance at a good quality of life as adults.

A Review of Macrophage MicroRNAs' Role in Human Asthma.

There is an imbalance in asthma between classically activated macrophages (M1 cells) and alternatively activated macrophages (M2 cells) in favor of the latter. MicroRNAs (miRNAs) play a critical role in regulating macrophage proliferation and differentiation and control the balance of M1 and M2 macrophage polarization, thereby controlling immune responses. Here we review the current published data concerning miRNAs with known correlation to a specific human macrophage phenotype and polarization, and their association with adult asthma. MiRNA-targeted therapy is still in the initial stages, but clinical trials are under recruitment or currently running for some miRNAs in other diseases. Regulating miRNA expression via their upregulation or downregulation could show potential as a novel therapy for improving treatment efficacy in asthma.

Vitamin D increases the antiviral activity of bronchial epithelial cells in vitro.

BACKGROUND: By modulating the antiviral immune response via vitamin D receptor, the active form of vitamin D (1,25-dihydroxyvitamin D, calcitriol) could play a central role in protection against respiratory virus infections. This in vitro study tested the hypothesis that respiratory viruses modulate vitamin D receptor expression in human bronchial epithelial cells and this modulation affects the antiviral response to exogenous vitamin D. METHODS: Human primary bronchial epithelial cells were infected with rhinoviruses and respiratory syncytial virus in the presence or absence of vitamin D. Expression of vitamin D receptor, 1α-hydroxylase (1α(OH)ase), 24-hydroxylase (24(OH)ase), innate interferons, interferon stimulated genes and cathelicidin were measured by quantitative polymerase chain reaction. The antiviral effect of vitamin D on rhinovirus replication was determined by measurement of virus load. A direct inactivation assay was used to determine the antiviral activity of cathelicidin. RESULTS: Both RV and RSV decreased vitamin D receptor and 24(OH)ase and, in addition, RSV increased 1α(OH)ase expression in epithelial cells. Vitamin D decreased rhinovirus replication and release, and increased rhinovirus-induced interferon stimulated genes and cathelicidin. Furthermore, cathelicidin had direct anti-rhinovirus activity. CONCLUSIONS: Despite lower vitamin D receptor levels in rhinovirus-infected epithelial cells, exogenous vitamin D increased antiviral defences most likely via cathelicidin and innate interferon pathways.

Soluble major histocompatibility complex class I-related chain B molecules are increased and correlate with clinical outcomes during rhinovirus infection in healthy subjects.

BACKGROUND: Surface major histocompatibility complex class I-related chain (MIC) A and B molecules are increased by IL-15 and have a role in the activation of natural killer group 2 member D-positive natural killer and CD8 T cells. MICA and MICB also exist in soluble forms (sMICA and sMICB). Rhinoviruses (RVs) are the major cause of asthma exacerbations, and IL-15 levels are decreased in the airways of subjects with asthma. The role of MIC molecules in immune responses in the lung has not been studied. Here, we determine the relationship between MICA and MICB and RV infection in vitro in respiratory epithelial cells and in vivo in healthy subjects and subjects with asthma. METHODS: Surface MICA and MICB, as well as sMICA and sMICB, in respiratory epithelial cells were measured in vitro in response to RV infection and exposure to IL-15. Levels of sMICA and sMICB in serum, sputum, and BAL were measured and correlated with blood and bronchoalveolar immune cells in healthy subjects and subjects with asthma before and during RV infection. RESULTS: RV increased MICA and MICB in vitro in epithelial cells. Exogenous IL-15 upregulated sMICB levels in RV-infected epithelial cells. Levels of sMICB molecules in serum were increased in healthy subjects compared with subjects with stable asthma. Following RV infection, airway levels of sMIC are upregulated, and there are positive correlations between sputum MICB levels and the percentage of bronchoalveolar natural killer cells in healthy subjects but not subjects with asthma. CONCLUSIONS: RV infection induces MIC molecules in respiratory epithelial cells in vitro and in vivo. Induction of MICB molecules is impaired in subjects with asthma, suggesting these molecules may have a role in the antiviral immune response to RV infections.

Could interleukin-15 potentiate histone deacetylase inhibitor effects in haematological malignancy?

Despite significant progress in cancer therapy, prognosis in acute leukaemia remains dismal, and the development of new therapies is urgently warranted: in acute myeloid leukaemia, the current cure rate is of 30-40% in younger and much less in older patients. Chromatin remodeling through histone acetylation is one of the major mechanisms of transcriptional control of genes, and is involved in 'gene silencing' of antioncogenes in various tumour cells. Chromatin remodeling is also involved in transcriptional control of other genes, such as NKG2D ligand genes. Histone deacetylases and acetyltransferases are involved in the epigenetic regulation of gene expression, and increased/decreased activity of histone deacetylases has been reported in several cancer types. Histone deacetylase inhibitors were reportedly active in many cancers including hematological malignancies, and have been shown in numerous experiments to reduce cancer cell growth and enhance cell differentiation, growth arrest and apoptosis. In acute myeloid leukaemia, histone deacetylase inhibitors alone had limited efficacy, but their combination with other anticancer agents yielded promising results. Interleukin (IL)-15 is regarded with great hope in the immunotherapy of cancer, and IL-15-activated cytokine-induced killer cells showed potent antileukemic activity both in vitro and in vivo. IL-15 increases expression of NKG2D and its ligands and can increase natural killer cell mediated cytotoxicity against tumour cells. The administration of IL-15 was recently shown to be safe in preclinical models, and there are ongoing clinical trials of IL-15 in patients with cancer and HIV infection. We hypothesise that IL-15 will synergise with histone deacetylase inhibitors in increasing the levels of activatory NKG2D receptors on natural killer and CD8(+) T cells and of their ligands, the MHC class I related molecule A and B, on tumor cells, and will enhance innate immune antitumour responses in acute myeloid leukaemia and other haematological malignancies. Up-regulation of NKG2D-NKG2D-ligand antitumour immune response by combining histone deacetylase inhibitors with IL-15 has the potential to improve the efficacy of acute myeloid leukaemia treatment.

Systemic sclerosis-polymyositis overlap syndrome associated with autoimmune hepatitis and cerebral vasculitis.

Autoimmune hepatitis (AIH) is a chronic disorder characterized by persistent hepatocellular inflammation and necrosis. AIH overlap syndromes with other autoimmune diseases have been reported, including connective tissue diseases (CTD). Reports of AIH in systemic sclerosis (SSc), however, are scarce and have been particularly described in the limited SSc subtype. We report a case of systemic sclerosis-polymyositis overlap syndrome that developed AIH and subsequently, cerebral vasculitis. To our knowledge, this is the first report of such a complex mosaic of autoimmunity. We also review the literature regarding scleroderma-related AIH.