Interleukin‐6 limits influenza‐induced inflammation and protects against fatal lung pathology

Balancing the generation of immune responses capable of controlling virus replication with those causing immunopathology is critical for the survival of the host and resolution of influenza‐induced inflammation. Based on the capacity of interleukin‐6 (IL‐6) to govern both optimal T‐cell responses and inflammatory resolution, we hypothesised that IL‐6 plays an important role in maintaining this balance. Comparison of innate and adaptive immune responses in influenza‐infected wild‐type control and IL‐6‐deficient mice revealed striking differences in virus clearance, lung immunopathology and generation of heterosubtypic immunity. Mice lacking IL?6 displayed a profound defect in their ability to mount an anti‐viral T‐cell response. Failure to adequately control virus was further associated with an enhanced infiltration of inflammatory monocytes into the lung and an elevated production of the pro‐inflammatory cytokines, IFN‐α and TNF‐α. These events were associated with severe lung damage, characterised by profound vascular leakage and death. Our data highlight an essential role for IL‐6 in orchestrating anti‐viral immunity through an ability to limit inflammation, promote protective adaptive immune responses and prevent fatal immunopathology.     

CD40 ligand and interferon‐γ induce an antimicrobial response against Mycobacterium tuberculosis in human monocytes

The ability of T cells to activate antimicrobial pathways in infected macrophages is essential to host defence against many intracellular pathogens. Here, we compared the ability of two T‐cell‐mediated mechanisms to trigger antimicrobial responses against Mycobacterium tuberculosis in humans, CD40 activation and the release of interferon‐γ (IFN‐γ). Given that IFN‐γ activates a vitamin D‐dependent antimicrobial response, we focused on induction of the key components of this pathway. We show that activation of human monocytes via CD40 ligand (CD40L) and IFN‐γ, alone, and in combination, induces the CYP27b1‐hydroxylase, responsible for the conversion of 25‐hydroxyvitamin D (25D) to the bioactive 1,25‐dihydroxyvitamin D (1,25D), and the vitamin D receptor (VDR). The activation of the vitamin D pathway by CD40L and IFN‐γ results in up‐regulated expression of the antimicrobial peptides, cathelicidin and DEFB4, as well as induction of autophagy. Finally, activation of monocytes via CD40L and IFN‐γ results in an antimicrobial activity against intracellular M. tuberculosis. Our data suggest that at least two parallel T‐cell‐mediated mechanisms, CD40L and IFN‐γ, activate the vitamin D‐dependent antimicrobial pathway and trigger antimicrobial activity against intracellular M. tuberculosis, thereby contributing to human host defence against intracellular infection.     

Comparative Study of IS6110 Restriction Fragment Length Polymorphism and Variable-Number Tandem-Repeat Typing of Mycobacterium tuberculosis Isolates in the Netherlands,Based on a 5-Year Nationwide Survey

In order to switch from IS6110 and polymorphic GC-rich repetitive sequence (PGRS) restriction fragment length polymorphism (RFLP) to 24-locus variable-number tandem-repeat (VNTR) typing of Mycobacterium tuberculosis complex isolates in the national tuberculosis control program in The Netherlands, a detailed evaluation on discriminatory power and agreement with findings in a cluster investigation was performed on 3,975 tuberculosis cases during the period of 2004 to 2008. The level of discrimination of the two typing methods did not differ substantially: RFLP typing yielded 2,733 distinct patterns compared to 2,607 in VNTR typing. The global concordance, defined as isolates labeled unique or identically distributed in clusters by both methods, amounted to 78.5% (n = 3,123). Of the remaining 855 cases, 12% (n = 479) of the cases were clustered only by VNTR, 7.7% (n = 305) only by RFLP typing, and 1.8% (n = 71) revealed different cluster compositions in the two approaches. A cluster investigation was performed for 87% (n = 1,462) of the cases clustered by RFLP. For the 740 cases with confirmed or presumed epidemiological links, 92% were concordant with VNTR typing. In contrast, only 64% of the 722 cases without an epidemiological link but clustered by RFLP typing were also clustered by VNTR typing. We conclude that VNTR typing has a discriminatory power equal to IS6110 RFLP typing but is in better agreement with findings in a cluster investigation performed on an RFLP-clustering-based cluster investigation. Both aspects make VNTR typing a suitable method for tuberculosis surveillance systems.     

The emerging role of microRNAs in regulating immune and inflammatory responses in the lung

Chronic inflammatory diseases of the lung are leading causes of morbidity and mortality worldwide. Many of these disorders can be attributed to abnormal immune responses to environmental stimuli and infections. As such, understanding the innate host defense pathways and their regulatory systems will be critical to developing new approaches to treatment. In this regard, there is increasing interest in the role of microRNAs (miRNAs) in the regulation of pulmonary innate host defense responses and the inflammatory sequelae in respiratory disease. In this review, we discuss recent findings that indicate an important role for miRNAs in the regulation in mouse models of various respiratory diseases and in host defense against bacterial and viral infection. We also discuss the potential utility and limitations of targeting these molecules as anti-inflammatory strategies and also as a means to improve pathogen clearance from the lung.     

Lymphatic Vessel Memory Stimulated by Recurrent Inflammation

Inflammation stimulates new lymphatic vessel growth (inflammatory lymphangiogenesis). One key question is how recurrent inflammation, a common clinical condition, regulates lymphatic vessel remodeling. We show here that recurrent inflammation accelerated the development a functional lymphatic vessel network. This observation suggests a novel program of lymphangiogenesis and identifies a property of lymphatic vessel memory in response to recurrent inflammation. A brief episode of initial inflammation regressed lymphatic vessels, and a significant increase in CD11b⁺ macrophages were associated with the development of lymphatic vessel memory. These vessels had major differences in the structure and the spatial distribution of specialized lymphatic vessel features. Surprisingly, we found that the lymphatic vessel memory response did not depend on the vascular endothelial growth factor C or A pathway, indicating that different molecular pathways regulate inflammatory lymphangiogenesis and lymphatic vessel memory. These findings uncover a priming mechanism to facilitate a rapid lymphatic vessel memory response: a potential important component of peripheral host defense.The lymphatic vasculature is one component of the inflammatory response that is remarkably understudied. The lymphatic system can be broadly classified into the lymphoid tissue (tonsils, lymph nodes, and spleen) and the conduit system or lymphatic vasculature. The focus of these studies is the lymphatic capillaries which literally are the most peripheral extension of the immune system and reside intimately in the diseased tissue. Aside from the classic functions of the lymphatic vasculature described many years ago (transport of extracellular fluid, cells, antigens, and lipid), surprisingly little is known about the normal physiology of this system and how it regulates inflammation and wound recovery. Multiple lines of evidence have shown that the lymphatic vasculature proliferates in response to inflammatory conditions, suggesting an active, perhaps essential, role during the inflammatory response.^1–6 Inflammatory lymphangiogenesis is thought to be a physiological mechanism that develops to meet the increased demands of fluid, antigen, and cellular transport during an inflammatory response. New lymphatic vessel growth has been associated with beneficial effects in several different preclinical models of acute or chronic inflammatory disease.^3,7–9 It is well recognized that vascular endothelial growth factor (VEGF)-C-VEGF receptor (VEGFR)-3 and VEGF-A-VEGFR-2 pathways are important in inflammatory lymphangiogenesis.¹⁰ The most accepted model of inflammatory lymphangiogenesis is that vessels sprout and elongate from pre-existing lymphatic vessels. In contrast, is some evidence is available that circulating endothelial progenitors or macrophages differentiate into lymphatic endothelial cells to comprise newly synthesized lymphatic vessels.^11,12Clinically, two general outcomes occur after an initial episode of inflammatory disease: wound recovery or recurrent inflammation. We developed a mouse model of wound recovery and recurrent inflammation to simulate these clinical outcomes and to study the lymphatic vasculature during these conditions. We recently demonstrated that lymphatic vessel regression developed during wound recovery in the cornea.¹³ Fragmented lymphatic vessels that persisted over time were visualized in wound recovery conditions.In contrast to wound recovery, recurrent inflammation is a common clinical outcome after an initial episode of inflammation. We studied the effects of recurrent inflammation in corneal tissue recovered from an initial inflammatory response. This approach is different from earlier studies in that it features wound recovery followed by recurrent inflammation rather than an acute or chronic unrelenting pathogen or tumor-based inflammatory stimuli.^3,4,7,14 We induced recurrent inflammation in recovered corneal tissue by placing a subsequent suture in the cornea (re-suturing). Here, we show that one feature of recurrent inflammation was the accelerated localized development of a functional lymphatic vessel network. The rapid kinetics and memory response were reminiscent of an immunological memory response; for this reason we describe this process as lymphatic vessel memory. This response appeared to stimulate the anastomosis of fragmented lymphatic vessels. Unlike inflammatory lymphangiogenesis induced by initial inflammation, we showed that lymphatic vessel memory was independent of the VEGF-C and VEGF-A pathways. Thus, these studies reveal a novel program of lymphatic vessel memory.     

Reproducibility of quantitative plaque measurement in advanced coronary artery disease

BackgroundThe ability to characterize and to quantify the extent of coronary artery disease has the potential to improve the prognostic capability of coronary computed tomography angiography. Although reproducible techniques have been described in those with mild coronary disease, this has yet to be assessed in patients with advanced disease.MethodsTwenty patients with known multivessel disease underwent repeated computed tomography coronary angiography, 2 weeks apart. Coronary artery segments were analysed using semi-automated software by two trained observers to determine intraobserver, interobserver and interscan reproducibility.ResultsOverall, 149 coronary arterial segments were analysed. There was excellent intraobserver and interobserver agreement for all plaque volume measurements (Lin’s coefficient 0.95 to 1.0). There were no substantial interscan differences (P ?> ?0.05 for all) for total (2063 ?± ?1246 ?mm³, mean of differences ?35.6 ?mm³), non-calcified (1795 ?± ?910 ?mm³, mean of differences ?4.3 ?mm³), calcified (298 ?± ?425 ?mm³, mean of differences ?31.3 ?mm³) and low-attenuation (13 ?± ?13 ?mm³, mean of differences ?2.6 ?mm³) plaque volumes. Interscan agreement was highest for total and noncalcified plaque volumes. Calcified and low-attenuation plaque (?236.6 to 174 ?mm³ and -15.8 to 10.5 ?mm³ respectively) had relatively wider 95% limits of agreement reflecting the lower absolute plaque volumes.ConclusionIn the presence of advanced coronary disease, semi-automated plaque quantification provides excellent reproducibility, particularly for total and non-calcified plaque volumes. This approach has major potential to assess change in disease over time and optimize risk stratification in patients with established coronary artery disease.     

Genetic and Environmental Factors in Parkinson's Disease Converge on Immune Function and Inflammation

Idiopathic Parkinson's disease (iPD) is a movement disorder characterized by the degeneration of dopaminergic neurons and aggregation of the protein α-synuclein. Patients with iPD vary in age of symptom onset, rate of progression, severity of motor and non-motor symptoms, and extent of central and peripheral inflammation. Genetic and environmental factors are believed to act synergistically in iPD pathogenesis. We propose that environmental factors (pesticides and infections) increase the risk for iPD via the immune system and that the role of PD risk genes in immune cells is worthy of investigation. This review highlights the major PD-relevant genes expressed in immune cells and key environmental factors that activate immune cells and, alone or in combination with other factors, may contribute to iPD pathogenesis. By reviewing these interactions, we seek to enable the future development of immunomodulatory approaches to prevent or delay onset of iPD. © 2020 International Parkinson and Movement Disorder Society