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1.  Death at the airway epithelium in asthma 
Cell Research  2013;23(5):588-589.
doi:10.1038/cr.2013.26
PMCID: PMC3641595  PMID: 23419513
2.  Osteopontin has a crucial role in allergic airway disease through regulation of dendritic cell subsets 
Nature medicine  2007;13(5):570-578.
Osteopontin (Opn) is important for T helper type 1 (TH1) immunity and autoimmunity. However, the role of this cytokine in TH2-mediated allergic disease as well as its effects on primary versus secondary antigenic encounters remain unclear. Here we demonstrate that OPN is expressed in the lungs of asthmatic individuals and that Opn-s, the secreted form of Opn, exerts opposing effects on mouse TH2 effector responses and subsequent allergic airway disease: pro-inflammatory at primary systemic sensitization, and anti-inflammatory during secondary pulmonary antigenic challenge. These effects of Opn-s are mainly mediated by the regulation of TH2-suppressing plasmacytoid dendritic cells (DCs) during primary sensitization and TH2-promoting conventional DCs during secondary antigenic challenge. Therapeutic administration of recombinant Opn during pulmonary secondary antigenic challenge decreased established TH2 responses and protected mice from allergic disease. These effects on TH2 allergic responses suggest that Opn-s is an important therapeutic target and provide new insight into its role in immunity.
doi:10.1038/nm1580
PMCID: PMC3384679  PMID: 17435770
3.  Evidence for local dendritic cell activation in pulmonary sarcoidosis 
Respiratory Research  2012;13(1):33.
Background
Sarcoidosis is a granulomatous disease characterized by a seemingly exaggerated immune response against a difficult to discern antigen. Dendritic cells (DCs) are pivotal antigen presenting cells thought to play an important role in the pathogenesis. Paradoxically, decreased DC immune reactivity was reported in blood samples from pulmonary sarcoidosis patients. However, functional data on lung DCs in sarcoidosis are lacking. We hypothesized that at the site of disease DCs are mature, immunocompetent and involved in granuloma formation.
Methods
We analyzed myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in broncho-alveolar lavage (BAL) and blood from newly diagnosed, untreated pulmonary sarcoidosis patients and healthy controls using 9-color flowcytometry. DCs, isolated from BAL using flowcytometric sorting (mDCs) or cultured from monocytes (mo-DCs), were functionally assessed in a mixed leukocyte reaction with naïve allogeneic CD4+ T cells. Using Immunohistochemistry, location and activation status of CD11c+DCs was assessed in mucosal airway biopsies.
Results
mDCs in BAL, but not in blood, from sarcoidosis patients were increased in number when compared with mDCs from healthy controls. mDCs purified from BAL of sarcoidosis patients induced T cell proliferation and differentiation and did not show diminished immune reactivity. Mo-DCs from patients induced increased TNFα release in co-cultures with naïve allogeneic CD4+ T cells. Finally, immunohistochemical analyses revealed increased numbers of mature CD86+ DCs in granuloma-containing airway mucosal biopsies from sarcoidosis patients.
Conclusion
Taken together, these finding implicate increased local DC activation in granuloma formation or maintenance in pulmonary sarcoidosis.
doi:10.1186/1465-9921-13-33
PMCID: PMC3352267  PMID: 22513006
Sarcoidosis; Dendritic cells; Bronchoalveolar lavage; Granuloma; TNFα
4.  TLR4 signalling in pulmonary stromal cells is critical for inflammation and immunity in the airways 
Respiratory Research  2011;12(1):125.
Inflammation of the airways, which is often associated with life-threatening infection by Gram-negative bacteria or presence of endotoxin in the bioaerosol, is still a major cause of severe airway diseases. Moreover, inhaled endotoxin may play an important role in the development and progression of airway inflammation in asthma. Pathologic changes induced by endotoxin inhalation include bronchospasm, airflow obstruction, recruitment of inflammatory cells, injury of the alveolar epithelium, and disruption of pulmonary capillary integrity leading to protein rich fluid leak in the alveolar space. Mammalian Toll-like receptors (TLRs) are important signalling receptors in innate host defense. Among these receptors, TLR4 plays a critical role in the response to endotoxin.
Lungs are a complex compartmentalized organ with separate barriers, namely the alveolar-capillary barrier, the microvascular endothelium, and the alveolar epithelium. An emerging theme in the field of lung immunology is that structural cells (SCs) of the airways such as epithelial cells (ECs), endothelial cells, fibroblasts and other stromal cells produce activating cytokines that determine the quantity and quality of the lung immune response. This review focuses on the role of TLR4 in the innate and adaptive immune functions of the pulmonary SCs.
doi:10.1186/1465-9921-12-125
PMCID: PMC3189122  PMID: 21943186
Airway diseases; dendritic cells; epithelial cell; pulmonary stromal cells; TLR4
5.  Disruption of the SapM locus in Mycobacterium bovis BCG improves its protective efficacy as a vaccine against M. tuberculosis 
EMBO Molecular Medicine  2011;3(4):222-234.
Mycobacterium bovis bacille Calmette-Guerin (BCG) provides only limited protection against pulmonary tuberculosis. We tested the hypothesis that BCG might have retained immunomodulatory properties from its pathogenic parent that limit its protective immunogenicity. Mutation of the molecules involved in immunomodulation might then improve its vaccine potential. We studied the vaccine potential of BCG mutants deficient in the secreted acid phosphatase, SapM, or in the capping of the immunomodulatory ManLAM cell wall component with α-1,2-oligomannoside. Both systemic and intratracheal challenge of mice with Mycobacterium tuberculosis following vaccination showed that the SapM mutant, compared to the parental BCG vaccine, provided better protection: it led to longer-term survival. Persistence of the SapM-mutated BCG in vivo resembled that of the parental BCG indicating that this mutation will likely not compromise the safety of the BCG vaccine. The SapM mutant BCG vaccine was more effective than the parental vaccine in inducing recruitment and activation of CD11c+MHC-IIintCD40int dendritic cells (DCs) to the draining lymph nodes. Thus, SapM acts by inhibiting recruitment of DCs and their activation at the site of vaccination.
doi:10.1002/emmm.201000125
PMCID: PMC3377067  PMID: 21328541
Mycobacterium; SapM; tuberculosis; vaccine; BCG
6.  High mobility group box-1 recognition: The beginning of a RAGEless era? 
EMBO Molecular Medicine  2010;2(6):193-195.
High mobility group box 1 (HMGB1) is a molecular alarm signal that triggers an immune response when released. It was assumed that the receptor for advanced glycation end-products (RAGE) would mediate the signal to the immune system. Recently pattern recognition receptors that are triggered by molecules of bacterial origin (the Toll-like receptor (TLR) family) were shown to also respond to HMGB1. Now two papers establish the TLR4–HMGB1 axis as proinflammatory, eventually leading to disparate conditions like seizures or skin cancer. These reports add a new twist to our understanding of the mode of action of the alarm signal HMGB1.
doi:10.1002/emmm.201000077
PMCID: PMC3377318  PMID: 20535746
HMGB1; inflammation; TLR4
7.  Ischemia of the lung causes extensive long-term pulmonary injury: an experimental study 
Respiratory Research  2008;9(1):28.
Background
Lung ischemia-reperfusion injury (LIRI) is suggested to be a major risk factor for development of primary acute graft failure (PAGF) following lung transplantation, although other factors have been found to interplay with LIRI. The question whether LIRI exclusively results in PAGF seems difficult to answer, which is partly due to the lack of a long-term experimental LIRI model, in which PAGF changes can be studied. In addition, the long-term effects of LIRI are unclear and a detailed description of the immunological changes over time after LIRI is missing. Therefore our purpose was to establish a long-term experimental model of LIRI, and to study the impact of LIRI on the development of PAGF, using a broad spectrum of LIRI parameters including leukocyte kinetics.
Methods
Male Sprague-Dawley rats (n = 135) were subjected to 120 minutes of left lung warm ischemia or were sham-operated. A third group served as healthy controls. Animals were sacrificed 1, 3, 7, 30 or 90 days after surgery. Blood gas values, lung compliance, surfactant conversion, capillary permeability, and the presence of MMP-2 and MMP-9 in broncho-alveolar-lavage fluid (BALf) were determined. Infiltration of granulocytes, macrophages and lymphocyte subsets (CD45RA+, CD5+CD4+, CD5+CD8+) was measured by flowcytometry in BALf, lung parenchyma, thoracic lymph nodes and spleen. Histological analysis was performed on HE sections.
Results
LIRI resulted in hypoxemia, impaired left lung compliance, increased capillary permeability, surfactant conversion, and an increase in MMP-2 and MMP-9. In the BALf, most granulocytes were found on day 1 and CD5+CD4+ and CD5+CD8+-cells were elevated on day 3. Increased numbers of macrophages were found on days 1, 3, 7 and 90. Histology on day 1 showed diffuse alveolar damage, resulting in fibroproliferative changes up to 90 days after LIRI.
Conclusion
The short-, and long-term changes after LIRI in this model are similar to the changes found in both PAGF and ARDS after clinical lung transplantation. LIRI seems an independent risk factor for the development of PAGF and resulted in progressive deterioration of lung function and architecture, leading to extensive immunopathological and functional abnormalities up to 3 months after reperfusion.
doi:10.1186/1465-9921-9-28
PMCID: PMC2335107  PMID: 18366783
8.  GATA3-Driven Th2 Responses Inhibit TGF-β1–Induced FOXP3 Expression and the Formation of Regulatory T Cells 
PLoS Biology  2007;5(12):e329.
Transcription factors act in concert to induce lineage commitment towards Th1, Th2, or T regulatory (Treg) cells, and their counter-regulatory mechanisms were shown to be critical for polarization between Th1 and Th2 phenotypes. FOXP3 is an essential transcription factor for natural, thymus-derived (nTreg) and inducible Treg (iTreg) commitment; however, the mechanisms regulating its expression are as yet unknown. We describe a mechanism controlling iTreg polarization, which is overruled by the Th2 differentiation pathway. We demonstrated that interleukin 4 (IL-4) present at the time of T cell priming inhibits FOXP3. This inhibitory mechanism was also confirmed in Th2 cells and in T cells of transgenic mice overexpressing GATA-3 in T cells, which are shown to be deficient in transforming growth factor (TGF)-β–mediated FOXP3 induction. This inhibition is mediated by direct binding of GATA3 to the FOXP3 promoter, which represses its transactivation process. Therefore, this study provides a new understanding of tolerance development, controlled by a type 2 immune response. IL-4 treatment in mice reduces iTreg cell frequency, highlighting that therapeutic approaches that target IL-4 or GATA3 might provide new preventive strategies facilitating tolerance induction particularly in Th2-mediated diseases, such as allergy.
Author Summary
Specific immune responses against foreign or autologous antigens are driven by specialized epitope-specific T cells, whose numbers expand upon recognition of antigen found on professional antigen-presenting cells. The subsequent maturation process involves the differentiation of certain T cell phenotypes such as pro-inflammatory cells (Th1, Th2, Th17) or regulatory T (Treg) cells, which serve to keep the immune response in check. The current study focuses on the role of two key transcription factors—FOXP3 and GATA3—in controlling the commitment of these cells. We demonstrate that the Th2 cytokine IL-4 inhibits the induction of FOXP3 and thus inhibits the generation of inducible Treg cells. We show that IL-4–induced GATA3 mediates FOXP3 inhibition by directly binding to a GATA element in the FOXP3 promoter. We hypothesize that therapeutic agents aimed at neutralizing IL-4 could be a novel strategy to facilitate inducible Treg cell generation and thus promotion of tolerance in allergies and other Th2-dominated diseases.
It is shown that Th2 responses prevent the generation of inducible Tregs. This is mediated by IL-4 induction of GATA3, which binds directly to and represses the FOXP3 promoter. This mechanism is likely to be relevant in the induction of immunotolerance, particularly in allergic diseases.
doi:10.1371/journal.pbio.0050329
PMCID: PMC2222968  PMID: 18162042
9.  Immunologists getting nervous: neuropeptides, dendritic cells and T cell activation 
Respiratory Research  2001;2(3):133-138.
It is increasingly recognised that the immune and nervous systems are closely integrated to optimise defence systems within the lung. In this commentary, the contribution of various neuropeptides such as substance P, calcitonin gene-related peptide, vasoactive intestinal peptide and somatostatin to the regulation of T cell activation is discussed. These neuropeptides are released not only from nerve endings but also from inflammatory immune cells such as monocytes, dendritic cells, eosinophils and mast cells. On release they can exert both direct stimulatory and inhibitory effects on T cell activation and also indirect effects through their influence on the recruitment and activation of professional antigen-presenting dendritic cells. Neuropeptides should therefore be included in the conceptual framework of the immune regulation of T cell function by dendritic cells.
doi:10.1186/rr49
PMCID: PMC2002076  PMID: 11686876
calcitonin gene-related peptide; dendritic cells; substance P; T cells; vasoactive intestinal peptide

Results 1-9 (9)