Biology and Therapeutic Potential of the Interleukin-4/interleukin-13 Signaling Pathway in Asthma

American Journal of Respiratory Medicine : Drugs, Devices, and Other Interventions. 2002  |  Pubmed ID: 14720056

The future management of patients with allergic asthma is poised to change in the coming one to two decades. This prediction is based on fundamental new insights into the pathogenesis of disease, gained through the study of both humans and experimental models of asthma. These studies have revealed that allergic asthma is an immune-mediated disease which, despite the redundancy characteristic of all immune responses, may be induced through a single dominant signaling cascade called the interleukin (IL)-4/IL-13 signaling pathway. In addition to the cytokine IL-4, this pathway includes IL-13, the cytokine receptor subunit IL-4 receptor alpha (IL-4Ralpha), Janus-associated tyrosine kinases and the transcription factor, signal transducer and activator of transcription 6. The IL-4 signaling pathway controls the most important cellular developmental (afferent) events that underlie asthma. These include T helper (Th) type 2 cell activation, B cell activation and immunoglobulin (Ig) E secretion, mast cell development, and effector (efferent) events related exclusively to immune effects on the lung such as goblet cell metaplasia and airway hyperresponsiveness. Any of the IL-4 signaling molecules are potentially amenable to pharmacological intervention, but a detailed understanding of the entire pathway is required to appreciate their actual potential for drug development. For example, neutralization strategies that target only IL-4 are unlikely to succeed because they leave IL-13 free to continue the signaling cascade. In contrast, neutralization of IL-4Ralpha may represent a more feasible strategy, as it should prevent signaling by both IL-4 and IL-13. The therapeutic potential of targeting intracytoplasmic tyrosine kinases has already been achieved with the use of small molecules, suggesting that this approach may be realistically adopted for the treatment of asthma. However, well designed asthma clinical trials are warranted to determine with certainty, the efficacy of therapies based on IL-4/IL-13 blockade.

The Th2 Lymphocyte Products IL-4 and IL-13 Rapidly Induce Airway Hyperresponsiveness Through Direct Effects on Resident Airway Cells

American Journal of Respiratory Cell and Molecular Biology. Feb, 2002  |  Pubmed ID: 11804871

Airway inflammation and airway hyperresponsiveness (AHR) are hallmarks of asthma. Cytokines produced by T helper type 2 (Th2) lymphocytes have been implicated in both processes. There is strong support for the idea that Th2 cytokines can produce AHR indirectly by promoting the recruitment of inflammatory cells. Less attention has been given to the possibility that Th2 cytokines might induce AHR by acting directly on resident airway cells. To investigate this, we polarized and activated CD4(+) T cells in vitro and analyzed airway function after administration of lymphocyte-conditioned media to the airways of naive mice. Th2-lymphocyte-conditioned medium induced AHR within 6 h. This finding was reproduced in mast-cell-deficient and in T- and B-lymphocyte-deficient mice. AHR did not occur when Th2-lymphocyte-conditioned medium was administered to mice lacking the IL-4 receptor alpha subunit or Stat6, suggesting a critical role for interleukin (IL)-4 and/or IL-13. This was confirmed by the finding that recombinant IL-4 and IL-13 both induced AHR within 6 h. The induction of AHR occurred in the absence of inflammatory cell recruitment or mucus production. These results strongly suggest that products of activated Th2 lymphocytes can rapidly perturb airway function through direct effects on resident airway cells.

Decreased Allergic Lung Inflammatory Cell Egression and Increased Susceptibility to Asphyxiation in MMP2-deficiency

Nature Immunology. Apr, 2002  |  Pubmed ID: 11887181

Clearance of recruited immune cells is necessary to resolve inflammatory reactions. We show here that matrix metalloproteinase 2 (MMP2), as part of an interleukin 13 (IL-13)-dependent regulatory loop, dampens inflammation by promoting the egress of inflammatory cells into the airway lumen. MMP2-/- mice showed a robust asthma phenotype and increased susceptibility to asphyxiation induced by allergens. However, whereas the lack of MMP2 reduced the influx of cells into bronchoalveolar lavage (BAL), numerous inflammatory cells accumulated in the lung parenchyma. BAL of MMP2-/- mice lacked normal chemotactic activity, whereas lung inflammatory cells from the same mice showed appropriate chemotactic responses. Thus, MMP2 establishes the chemotactic gradient required for egression of lung inflammatory cells and prevention of lethal asphyxiation.

Interleukins-4, -5, and -13: Emerging Therapeutic Targets in Allergic Disease

Pharmacology & Therapeutics. Jun, 2002  |  Pubmed ID: 12113801

For the first time, allergic diseases have emerged as major public health concerns. Highly effective therapies for allergic disease now exist, but are plagued by serious side effects and the fact that a significant minority of patients remains unresponsive. Studies from many laboratories have established that T helper type 2 (T(H)2) cytokines contribute importantly to diseases such as asthma, and therapeutic strategies that target the key T(H)2 cytokines are of potential benefit in allergic disease. In this article, we will review the biology of the T(H)2 cytokines interleukin (IL)-4, IL-5, and IL-13 and their receptors, and will consider several novel strategies to neutralize these molecules in human and experimental asthma. While promising, newer therapies face a gauntlet of developmental challenges, but offer the hope of reducing allergic diseases once again to minor public health concerns.

Emerging Immune Targets for the Therapy of Allergic Asthma

Nature Reviews. Drug Discovery. Jan, 2002  |  Pubmed ID: 12119610

Recent discoveries on the molecular and cellular basis of asthma have markedly altered our understanding of this common respiratory disorder. These insights have come during an unexplained period of rising disease incidence and severity and are now being applied to develop improved therapies. This review explores the latest advances in our understanding of the pathogenesis of allergic asthma, and provides insight into the expanding collaborations between research scientists, clinicians and the pharmaceutical industry in the race to control the asthma epidemic.

Gamma-glutamyl Leukotrienase, a Novel Endothelial Membrane Protein, is Specifically Responsible for Leukotriene D(4) Formation in Vivo

The American Journal of Pathology. Aug, 2002  |  Pubmed ID: 12163373

The metabolism of cysteinyl leukotrienes in vivo and the pathophysiological effects of individual cysteinyl leukotrienes are primarily unknown. Recently we identified an additional member of the gamma-glutamyl transpeptidase (GGT) family, gamma-glutamyl leukotrienase (GGL), and developed mice deficient in this enzyme. Here we show that in vivo GGL, and not GGT as previously believed, is primarily responsible for conversion of leukotriene C(4) to leukotriene D(4), the most potent of the cysteinyl leukotrienes and the immediate precursor of leukotriene E(4). GGL is a glycoprotein consisting of two polypeptide chains encoded by one gene and is attached at the amino terminus of the heavy chain to endothelial cell membranes. In mice it localizes to capillaries and sinusoids in most organs and in lung to larger vessels as well. In contrast to wild-type and GGT-deficient mice, GGL-deficient mice do not form leukotriene D(4) in vivo either in blood when exogenous leukotriene C(4) is administered intravenously or in bronchoalveolar lavage fluid of Aspergillus fumigatus extract-induced experimental asthma. Further, GGL-deficient mice show leukotriene C(4) accumulation and significantly more airway hyperreponsiveness than wild-type mice in the experimental asthma, and induction of asthma results in increased GGL protein levels and enzymatic activity. Thus GGL plays an important role in leukotriene D(4) synthesis in vivo and in inflammatory processes.

Environmental Contributions to the Allergic Asthma Epidemic

Environmental Health Perspectives. Aug, 2002  |  Pubmed ID: 12194885

Current data overwhelmingly document the existence of a worldwide asthma epidemic, although individual studies remain controversial. The epidemic is thought to involve primarily persons with allergic asthma, and many diverse theories, based on an immunopathologic understanding of disease, have recently emerged to explain this involvement. In the context of recent insights into the immune basis of experimental asthma, we discuss in this review the leading asthma epidemic theories, including a new theory based on inhaled environmental proteases. Although no single theory may yet be fully embraced, there exists substantial hope that a unifying mechanism for the epidemic will be revealed through additional research.

A Protease-activated Pathway Underlying Th Cell Type 2 Activation and Allergic Lung Disease

Journal of Immunology (Baltimore, Md. : 1950). Nov, 2002  |  Pubmed ID: 12421974

The respiratory allergens that induce experimental Th cell type 2-dependent allergic lung inflammation may be grouped into two functional classes. One class of allergens, in this study termed type I, requires priming with adjuvants remote from the lung to overcome airway tolerogenic mechanisms that ordinarily preclude allergic responses to inhaled Ags. In contrast, the other, or type II, allergen class requires neither remote priming nor additional adjuvants to overcome airway tolerance and elicit robust allergic lung disease. In this study, we show in an experimental model that diverse type II allergens share in common proteolytic activity that is both necessary and sufficient for overcoming airway tolerance and induction of pulmonary allergic disease. Inactivated protease and protease-free Ag fragments showed no allergenic potency, demonstrating that only active protease acting on endogenous substrates was essential. Furthermore, induction of airway tolerance could be aborted and allergic lung disease established by simply adding purified protease to a type I allergen. Thus, exogenous proteases are common to type II allergens and may be generally required to overcome the innate resistance of the airway to Th cell type 2 activation and allergic inflammation, raising concern for their potential contribution to diseases such as asthma.

Absence of the Complement Anaphylatoxin C3a Receptor Suppresses Th2 Effector Functions in a Murine Model of Pulmonary Allergy

Journal of Immunology (Baltimore, Md. : 1950). Nov, 2002  |  Pubmed ID: 12421977

Asthma is a chronic inflammatory disease of the lung resulting in airway obstruction. The airway inflammation of asthma is strongly linked to Th2 lymphocytes and their cytokines, particularly IL-4, IL-5, and IL-13, which regulate airway hyperresponsiveness, eosinophil activation, mucus production, and IgE secretion. Historically, complement was not thought to contribute to the pathogenesis of asthma. However, our previous reports have demonstrated that complement contributes to bronchial hyperreactivity, recruitment of airway eosinophils, IL-4 production, and IgE responses in a mouse model of pulmonary allergy. To define the complement activation fragments that mediate these effects, we assessed the role of the complement anaphylatoxin C3a in a mouse model of pulmonary allergy by challenging C3aR-deficient mice intranasally with a mixed Ag preparation of Aspergillus fumigatus cell culture filtrate and OVA. Analysis by plethysmography after challenge revealed an attenuation in airway hyperresponsiveness in C3aR-deficient mice relative to wild-type mice. C3aR-deficient mice also had an 88% decrease in airway eosinophils and a 59% reduction in lung IL-4-producing cells. Consistent with the reduced numbers of IL-4-producing cells, C3aR-deficient mice had diminished bronchoalveolar lavage levels of the Th2 cytokines, IL-5 and IL-13. C3aR knockout mice also exhibited decreases in IgE titers as well as reduced mucus production. Collectively, these data highlight the importance of complement activation, the C3a anaphylatoxin, and its receptor during Th2 development in this experimental model and implicate these molecules as possible therapeutic targets in diseases such as asthma.

Frequency Dependence of Respiratory System Mechanics During Induced Constriction in a Murine Model of Asthma

Journal of Applied Physiology (Bethesda, Md. : 1985). Jan, 2003  |  Pubmed ID: 12486022

Airway dysfunction in asthma is characterized by hyperresponsiveness, heterogeneously narrowed airways, and closure of airways. To test the hypothesis that airway constriction in ovalbumin (OVA)-sensitized OVA-intranasally challenged (OVA/OVA) mice produces mechanical responses that are similar to those reported in asthmatic subjects, respiratory system resistance (Rrs) and elastance (Edyn,rs) spectra were obtained in OVA/OVA and control mice during intravenous methacholine (MCh) infusions. In control mice, MCh at 1,700 microg x kg(-1) x min(-1) produced 1) a 495 and 928% increase of Rrs at 0.5 Hz and 19.75 Hz, respectively, 2) a 33% rise in Edyn,rs at 0.5 Hz, and 3) a mild frequency (f)-dependent increase of Edyn,rs. The same MCh dose in OVA/OVA mice produced 1) elevations of Rrs at 0.5 Hz and 19.75 Hz of 1,792 and 774%, respectively, 2) a 390% rise in Edyn,rs at 0.5 Hz, and 3) marked f-dependent increases of Edyn,rs. During constriction, the f dependence of mechanics in control mice was consistent with homogeneous airway narrowing; however, in OVA/OVA mice, f dependence was characteristic of heterogeneously narrowed airways, closure of airways, and airway shunting. These mechanisms amplify the pulmonary mechanical responses to constrictor stimuli at physiological breathing rates and have important roles in the pathophysiology of human asthma.

16. Immunologic Lung Disease

The Journal of Allergy and Clinical Immunology. Feb, 2003  |  Pubmed ID: 12592307

This review summarizes the recent advances regarding pathogenesis, diagnosis, and treatment of immunological diseases of the lung. Rather than attempt a comprehensive analysis, we have focused on selected diseases that are of particular relevance to the practicing physician, and the material has been organized according to the dominant immunologic mechanisms underlying the disease. Because of the redundancy that characterizes the mammalian immune repertoire, this system of classification inevitably produces overlap but facilitates acquisition of what is otherwise a disparate collection of facts. The principal lung immunologic mechanisms are most broadly classified as innate or adaptive immune processes. Innate immunity includes neutrophils and complement that are important in diseases, such as pneumonia and the acute respiratory distress syndrome. Adaptive immunity involves T and B cells capable of recognizing discrete antigens. T(H)1- and T(H)2-dependent adaptive immune responses underlie some of the most common and important of lung diseases, including tuberculosis and asthma, respectively. Other important immunopathologic processes include granulomatous inflammation that characterizes sarcoidosis and Churg-Strauss vasculitis, and autoimmunity, which is characteristic of antiglomerular basement membrane disease and others.

Differential Requirement for CD18 in T-helper Effector Homing

Nature Medicine. Oct, 2003  |  Pubmed ID: 14502280

To understand the integrin requirements of T-helper (T(H)) effector subsets, we investigated the contribution of CD18 (beta(2) integrin) to T(H)1 and T(H)2 function in vitro and in relevant disease models. CD18-deficient (Itgb2(-/-)) T cells showed largely normal in vitro function. Compared with wild-type mice, Itgb2(-/-) mice were better able to resolve Leishmania major infection and generated a superior T(H)1 immune response, as assessed from draining lymph nodes. In contrast, T(H)2-dependent allergic lung disease was markedly impaired in mutant mice. In both models, development of T(H)1 and T(H)2 cells in spleens was normal, but accumulation of T(H)2 (not T(H)1) cells at inflammatory sites was reduced. Thus, CD18 is selectively required for T(H)2, but not T(H)1, homing and has a minimal influence on T-effector development. These findings suggest a new integrin-based therapeutic approach in which the outcomes of diverse diseases may be favorably influenced by altering the homing of T(H)2 cells.

Mechanical Stretch Activates Nuclear Factor-kappaB, Activator Protein-1, and Mitogen-activated Protein Kinases in Lung Parenchyma: Implications in Asthma

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Oct, 2003  |  Pubmed ID: 14519659

We investigated the effects of mechanical stretch and induced stimulation of lung parenchyma on the activation of proinflammatory transcription factors in normal mice and in a mouse model of asthma. Mechanical stretching of lung parenchyma led to increased activation of NF-kappaB and AP-1 transcription factors. Incubation of lung parenchyma with methacholine increased the activation of NF-kappaB, which was further augmented by stretch. Activation of NF-kappaB in response to mechanical stretch was associated with the phosphorylation and degradation of IkappaBalpha and the activation of IkappaB kinase. Stretch-induced activation of NF-kappaB involves activation of stretch-activated (SA) channels and the production of free radicals. Mechanical stretch and/or treatment with methacholine resulted in an increased activation of ERK1/2 and p38 MAP kinase, and the inhibition of the activity of these kinases partially blocked the stretch-induced NF-kappaB and AP-1 activation. A greater level of NF-kappaB and ERK1/2 activity was observed in the asthmatic mice, which was further increased by mechanical stretching. The level of cyclooxygenase-2, an NF-kappaB-regulated enzyme, was also higher in lung parenchyma from asthmatic mice than in normal mice. Our data suggest that mechanical stretching of lung parenchyma activates NF-kappaB and AP-1, at least in part, through the activation of MAP kinase signaling pathways.

Airway Glycoprotein Secretion Parallels Production and Predicts Airway Obstruction in Pulmonary Allergy

The Journal of Allergy and Clinical Immunology. Jan, 2004  |  Pubmed ID: 14713910

Airway obstruction, perhaps the most relevant clinical feature of asthma, is typically assessed in allergic asthma models as airway hyperresponsiveness. Excess secretion of airway glycoproteins also contributes to airway obstruction in asthma but is not measured as part of most experimental models.

Overlapping and Independent Contributions of MMP2 and MMP9 to Lung Allergic Inflammatory Cell Egression Through Decreased CC Chemokines

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Jun, 2004  |  Pubmed ID: 15059974

The mechanisms that initiate allergic lung inflammation are relevant to expression of diseases such as asthma, but the factors underlying resolution of inflammation are equally important. Previously, we demonstrated the importance of matrix metalloproteinase 2 (MMP2) for airway egression of lung eosinophils, a critical anti-inflammatory mechanism without which mice are rendered highly susceptible to lethal asphyxiation. Here we show that leukocyte MMP9 is the dominant airway MMP controlling inflammatory cell egression. The allergic lung phenotype of MMP9-/- mice was similar to WT and was not altered by concomitant deletion of the MMP2 gene (double knockout; dko). However, inflammatory cells accumulated aberrantly in the lungs of allergen-challenged MMP9-/- and dko mice and fewer eosinophils and neutrophils were present in bronchoalveolar lavage. These aberrant cellular trafficking patterns were explained by disruption of transepithelial chemokine gradients, in MMP2-/- mice affecting only eotaxin (CCL11), but in MMP9-/- and dko mice involving eotaxin, MARC (CCL7), and TARC (CCL17). Thus, by establishing multiple transepithelial chemokine gradients, MMP9 is broadly implicated in the resolution of allergic inflammation, an essential protective mechanism that overlaps with a more limited role played by MMP2.

Homing Alone? CD18 in Infectious and Allergic Disease

Trends in Molecular Medicine. Jun, 2004  |  Pubmed ID: 15177189

Help for Interpretation of Cardiopulmonary Exercise Testing

Chest. Sep, 2004  |  Pubmed ID: 15364790

An Immune Basis for Lung Parenchymal Destruction in Chronic Obstructive Pulmonary Disease and Emphysema

PLoS Medicine. Oct, 2004  |  Pubmed ID: 15526056

Chronic obstructive pulmonary disease and emphysema are a frequent result of long-term smoking, but the exact mechanisms, specifically which types of cells are associated with the lung destruction, are unclear.

Endogenous Attenuation of Allergic Lung Inflammation by Syndecan-1

Journal of Immunology (Baltimore, Md. : 1950). May, 2005  |  Pubmed ID: 15843578

The airway plays a vital role in allergic lung diseases by responding to inhaled allergens and initiating allergic inflammation. Various proinflammatory functions of the airway epithelium have been identified, but, equally important, anti-inflammatory mechanisms must also exist. We show in this study that syndecan-1, the major heparan sulfate proteoglycan of epithelial cells, attenuates allergic lung inflammation. Our results show that syndecan-1-null mice instilled with allergens exhibit exaggerated airway hyperresponsiveness, glycoprotein hypersecretion, eosinophilia, and lung IL-4 responses. However, administration of purified syndecan-1 ectodomains, but not ectodomain core proteins devoid of heparan sulfate, significantly inhibits these inflammatory responses. Furthermore, syndecan-1 ectodomains are shed into the airway when wild-type mice are intranasally instilled with several biochemically distinct inducers of allergic lung inflammation. Our results also show that syndecan-1 ectodomains bind to the CC chemokines (CCL7, CCL11, and CCL17) implicated in allergic diseases, inhibit CC chemokine-mediated T cell migration, and suppress allergen-induced accumulation of Th2 cells in the lung through their heparan sulfate chains. Together, these findings uncover an endogenous anti-inflammatory mechanism of the airway epithelium where syndecan-1 ectodomains attenuate allergic lung inflammation via suppression of CC chemokine-mediated Th2 cell recruitment to the lung.

Resolving a Case of Split Personality

Nature Immunology. May, 2005  |  Pubmed ID: 15843797

The Future of Asthma Therapy: Integrating Clinical and Experimental Studies

Immunologic Research. 2005  |  Pubmed ID: 16120971

Asthma is one of the most common, and now most heavily investigated, of modern diseases. Research along two fronts, involving experimental models of asthma and human clinical trials, proceeds in parallel, often with investigators unaware of their counterpart's findings. Here, we review the unique immunological insights into asthma pathogenesis and therapy that may be gained from comparison of human clinical trial results and analogous experimental studies. The pitfalls and benefits of animal models of asthma are discussed, and we briefly review ongoing asthma clinical studies that are based on immunological principals. Finally, we use new insights from human and animal studies to construct a refined immunopathologic disease model that may be of use in designing future experimental and therapeutic studies.

Eotaxin and Obesity

The Journal of Clinical Endocrinology and Metabolism. Jan, 2006  |  Pubmed ID: 16263831

Asthma and obesity incidence is increasing worldwide, and asthma is often more severe in the obese. Eotaxin, a CC chemokine, is important in extrinsic asthma, an inflammatory disorder.

7. Control of Allergic Airway Inflammation Through Immunomodulation

The Journal of Allergy and Clinical Immunology. Feb, 2006  |  Pubmed ID: 16455347

Among the asthma clinical trials published over the last several years, a unique subset has focused on novel means for inhibiting the airway inflammation that is believed to cause airway obstruction in many patients. Such interventions, broadly considered here as immune-modifying or immunomodulatory therapies, include several new drugs (omalizumab, suplatast tosilate, anti-cytokine antibodies, soluble receptors, and recombinant cytokines) and bacterial extracts. In this chapter we review the major findings with these clinical trials and indicate which have changed the management of asthma, which have not, and those that deserve further study.

Interactions Between Leukotriene C4 and Interleukin 13 Signaling Pathways in a Mouse Model of Airway Disease

Archives of Pathology & Laboratory Medicine. Apr, 2006  |  Pubmed ID: 16594735

During an asthmatic episode, leukotriene C4 (LTC4) and interleukin 13 (IL-13) are released into the airways and are thought to be central mediators of the asthmatic response. However, little is known about how these molecules interact or affect each other's signaling pathway.

Asthma: Pathology and Pathophysiology

Archives of Pathology & Laboratory Medicine. Apr, 2006  |  Pubmed ID: 16594736

Asthma has been defined as a chronic inflammatory disorder of the airways that is associated with recruitment of inflammatory cells and the clinical development of wheezing, shortness of breath, chest tightness, and cough. Asthma is a major public health issue. It affects 5% of the United States population and accounts for 2 million emergency department visits, 470,000 hospitalizations, and 4500 deaths annually.

A General Method for Bead-enhanced Quantitation by Flow Cytometry

Journal of Immunological Methods. Dec, 2006  |  Pubmed ID: 17067632

Flow cytometry provides accurate relative cellular quantitation (percent abundance) of cells from diverse samples, but technical limitations of most flow cytometers preclude accurate absolute quantitation. Several quantitation standards are now commercially available which, when added to samples, permit absolute quantitation of CD4+ T cells. However, these reagents are limited by their cost, technical complexity, requirement for additional software and/or limited applicability. Moreover, few studies have validated the use of such reagents in complex biological samples, especially for quantitation of non-T cells. Here we show that addition to samples of known quantities of polystyrene fluorescence standardization beads permits accurate quantitation of CD4+ T cells from complex cell samples. This procedure, here termed single bead-enhanced cytofluorimetry (SBEC), was equally capable of enumerating eosinophils as well as subcellular fragments of apoptotic cells, moieties with very different optical and fluorescent characteristics. Relative to other proprietary products, SBEC is simple, inexpensive and requires no special software, suggesting that the method is suitable for the routine quantitation of most cells and other particles by flow cytometry.

Proteomic Identification of in Vivo Substrates for Matrix Metalloproteinases 2 and 9 Reveals a Mechanism for Resolution of Inflammation

Journal of Immunology (Baltimore, Md. : 1950). Nov, 2006  |  Pubmed ID: 17082650

Clearance of allergic inflammatory cells from the lung through matrix metalloproteinases (MMPs) is necessary to prevent lethal asphyxiation, but mechanistic insight into this essential homeostatic process is lacking. In this study, we have used a proteomics approach to determine how MMPs promote egression of lung inflammatory cells through the airway. MMP2- and MMP9-dependent cleavage of individual Th2 chemokines modulated their chemotactic activity; however, the net effect of complementing bronchoalveolar lavage fluid of allergen-challenged MMP2(-/-)/MMP9(-/-) mice with active MMP2 and MMP9 was to markedly enhance its overall chemotactic activity. In the bronchoalveolar fluid of MMP2(-/-)/MMP9(-/-) allergic mice, we identified several chemotactic molecules that possessed putative MMP2 and MMP9 cleavage sites and were present as higher molecular mass species. In vitro cleavage assays and mass spectroscopy confirmed that three of the identified proteins, Ym1, S100A8, and S100A9, were substrates of MMP2, MMP9, or both. Function-blocking Abs to S100 proteins significantly altered allergic inflammatory cell migration into the alveolar space. Thus, an important effect of MMPs is to differentially modify chemotactic bioactivity through proteolytic processing of proteins present in the airway. These findings provide a molecular mechanism to explain the enhanced clearance of lung inflammatory cells through the airway and reveal a novel approach to target new therapies for asthma.

Cytokine Storm and an Anti-CD28 Monoclonal Antibody

The New England Journal of Medicine. Dec, 2006  |  Pubmed ID: 17171820

Promise and Pitfalls in Animal-based Asthma Research: Building a Better Mousetrap

Immunologic Research. 2006  |  Pubmed ID: 17172652

Asthma is one of the leading chronic diseases in the world today. An essential component of the asthma research endeavor is the animal-based experimental disease system, which provides knowledge that is not attainable through study of patients alone. Animal research is especially valuable for elucidating pathophysiology, drug testing, and as an adjunct for interpreting the results of human clinical trials. However, controversies surrounding animal systems data and at the interface between animal and human studies raise questions regarding the true utility of experimental asthma research. We consider here the considerable promise and important limitations of animal-based systems and their prospects for the future study asthma.

Antielastin Autoimmunity in Tobacco Smoking-induced Emphysema

Nature Medicine. May, 2007  |  Pubmed ID: 17450149

Chronic obstructive pulmonary disease and emphysema are common destructive inflammatory diseases that are leading causes of death worldwide. Here we show that emphysema is an autoimmune disease characterized by the presence of antielastin antibody and T-helper type 1 (T(H)1) responses, which correlate with emphysema severity. These findings link emphysema to adaptive immunity against a specific lung antigen and suggest the potential for autoimmune pathology of other elastin-rich tissues such as the arteries and skin of smokers.

A New Mechanism Regulating the Initiation of Allergic Airway Inflammation

The Journal of Allergy and Clinical Immunology. Aug, 2007  |  Pubmed ID: 17544098

The earliest immune events induced by allergens are poorly understood, yet are likely essential to understanding how allergic inflammation is established.

Interleukin 25 Promotes the Initiation of Proallergic Type 2 Responses

The Journal of Experimental Medicine. Jul, 2007  |  Pubmed ID: 17562814

The molecular mechanisms underlying the initiation of innate and adaptive proallergic type 2 responses are not understood. Interleukin (IL) 25, a member of the IL-17 cytokine family, was recently reported (Owyang, A.M., C. Zaph, E.H. Wilson, K.J. Guild, T. McClanahan, H.R. Miller, D.J. Cua, M. Goldschmidt, C.A. Hunter, R.A. Kastelein, and D. Artis. 2006. J. Exp. Med. 203:843-849; Fallon, P.G., S.J. Ballantyne, N.E. Mangan, J.L. Barlow, A. Dasvarma, D.R. Hewett, A. McIlgorm, H.E. Jolin, and A.N. McKenzie. 2006. J. Exp. Med. 203:1105-1116) to be important in Th2 cell-mediated immunity to parasitic infection. However, the cellular source and targets of IL-25 are not well understood. We show that mouse IL-25 is expressed by lung epithelial cells as a result of innate immune responses to allergens. Transgenic overexpression of IL-25 by these cells leads to mucus production and airway infiltration of macrophages and eosinophils, whereas blockade of IL-25 conversely reduces the airway inflammation and Th2 cytokine production in an allergen-induced asthma model. In addition, IL-25, with a receptor more highly expressed in Th2 than other effector T cells, promotes Th2 cell differentiation in an IL-4- and signal transducer and activator of transcription 6-dependent manner. During early T cell activation, IL-25 potentiates expression of the nuclear factor of activated T cells c1 and JunB transcription factors, which possibly results in increased levels of initial IL-4 production, up-regulation of GATA-3 expression, and enhanced Th2 cell differentiation. Thus, IL-25 is a critical factor regulating the initiation of innate and adaptive proallergic responses.

A New Link to Airway Obstruction in Asthma

Nature Medicine. Jul, 2007  |  Pubmed ID: 17618262

Software for Interpreting Cardiopulmonary Exercise Tests

BMC Pulmonary Medicine. 2007  |  Pubmed ID: 17953776

Cardiopulmonary exercise testing (CPET) has become an important modality for the evaluation and management of patients with a diverse array of medical problems. However, interpreting these tests is often difficult and time consuming, requiring significant expertise.

Discovery of Novel Markers in Allergic Lung Inflammation Through Proteomic-based Technologies

Expert Review of Proteomics. Feb, 2008  |  Pubmed ID: 18282117

Developmental Control of Integrin Expression Regulates Th2 Effector Homing

Journal of Immunology (Baltimore, Md. : 1950). Apr, 2008  |  Pubmed ID: 18354189

Integrin CD18, a component of the LFA-1 complex that also includes CD11a, is essential for Th2, but not Th1, cell homing, but the explanation for this phenomenon remains obscure. In this study, we investigate the mechanism by which Th2 effector responses require the LFA-1 complex. CD11a-deficient T cells showed normal in vitro differentiation and function. However, Th2 cell-dependent allergic lung disease was markedly reduced in CD11a null mice and wild-type mice given LFA-1 inhibitors, whereas control of infection with Leishmania major, a Th1-dependent response, was enhanced. In both disease models, recruitment of IL-4-, but not IFN-gamma-secreting cells to relevant organs was impaired, as was adhesion of Th2 cells in vitro. These diverse findings were explained by the markedly reduced expression of CD29, an alternate homing integrin, on Th2, but not Th1, cells, which precludes Th2 homing in the absence of CD11a. Thus, murine Th1 and Th2 cells use distinct integrins for homing, suggesting novel opportunities for integrin-based therapeutic intervention in diverse human ailments influenced by Th2 cells.

Mouse Let-7 MiRNA Populations Exhibit RNA Editing That is Constrained in the 5'-seed/ Cleavage/anchor Regions and Stabilize Predicted Mmu-let-7a:mRNA Duplexes

Genome Research. Oct, 2008  |  Pubmed ID: 18614752

Massively parallel sequencing of millions of < 30-nt RNAs expressed in mouse ovary, embryonic pancreas (E14.5), and insulin-secreting beta-cells (betaTC-3) reveals that approximately 50% of the mature miRNAs representing mostly the mmu-let-7 family display internal insertion/deletions and substitutions when compared to precursor miRNA and the mouse genome reference sequences. Approximately, 12%-20% of species associated with mmu-let-7 populations exhibit sequence discrepancies that are dramatically reduced in nucleotides 3-7 (5'-seed) and 10-15 (cleavage and anchor sites). This observation is inconsistent with sequencing error and leads us to propose that the changes arise predominantly from post-transcriptional RNA-editing activity operating on miRNA:target mRNA complexes. Internal nucleotide modifications are most enriched at the ninth nucleotide position. A common ninth base edit of U-to-G results in a significant increase in stability of down-regulated let-7a targets in inhibin-deficient mice (Inha-/-). An excess of U-insertions (14.8%) over U-deletions (1.5%) and the presence of cleaved intermediates suggest that a mammalian TUTase (terminal uridylyl transferase) mediated dUTP-dependent U-insertion/U-deletion cycle may be a possible mechanism. We speculate that mRNA target site-directed editing of mmu-let-7a duplex-bulges stabilizes "loose" miRNA:mRNA target associations and functions to expand the target repertoire and/or enhance mRNA decay over translational repression. Our results also demonstrate that the systematic study of sequence variation within specific RNA classes in a given cell type from millions of sequences generated by next-generation sequencing (NGS) technologies ("intranomics") can be used broadly to infer functional constraints on specific parts of completely uncharacterized RNAs.

At Last, an Immune Organ We Can Call Our Own?

American Journal of Respiratory and Critical Care Medicine. Apr, 2009  |  Pubmed ID: 19326572

Divergent Functions for Airway Epithelial Matrix Metalloproteinase 7 and Retinoic Acid in Experimental Asthma

Nature Immunology. May, 2009  |  Pubmed ID: 19329997

The innate immune response of airway epithelial cells to airborne allergens initiates the development of T cell responses that are central to allergic inflammation. Although proteinase allergens induce the expression of interleukin 25, we show here that epithelial matrix metalloproteinase 7 (MMP7) was expressed during asthma and was required for the maximum activity of interleukin 25 in promoting the differentiation of T helper type 2 cells. Allergen-challenged Mmp7(-/-) mice had less airway hyper-reactivity and production of allergic inflammatory cytokines and higher expression of retinal dehydrogenase 1. Inhibition of retinal dehydrogenase 1 restored the asthma phenotype of Mmp7(-/-) mice and inhibited the responses of lung regulatory T cells, whereas exogenous administration of retinoic acid attenuated the asthma phenotype. Thus, MMP7 coordinates allergic lung inflammation by activating interleukin 25 while simultaneously inhibiting retinoid-dependent development of regulatory T cells.

Distinct Roles for MyD88 and Toll-like Receptor 2 During Leishmania Braziliensis Infection in Mice

Infection and Immunity. Jul, 2009  |  Pubmed ID: 19364834

We have previously reported that Leishmania braziliensis infection can activate murine dendritic cells (DCs) and upregulate signaling pathways that are essential for the initiation of innate immunity. However, it remains unclear whether Toll-like receptors (TLRs) are involved in L. braziliensis-mediated DC activation. To address this issue, we generated bone marrow-derived DCs from MyD88(-/-) and TLR2(-/-) mice and examined their responsiveness to parasite infection. While wild-type DCs were efficiently activated to produce cytokines and prime naïve CD4(+) T cells, L. braziliensis-infected MyD88(-/-) DCs exhibited less activation and decreased production of interleukin-12 (IL-12) p40. Furthermore, MyD88(-/-) mice were more susceptible to infection in that they developed larger and prolonged lesions compared to those in control mice. In sharp contrast, the lack of TLR2 resulted in an enhanced DC activation and increased IL-12 p40 production after infection. As such, L. braziliensis-infected TLR2(-/-) DCs were more competent in priming naïve CD4(+) T cells in vitro than were their controls, findings which correlated with an increased gamma interferon production in vivo and enhanced resistance to infection. Our results suggest that while MyD88 is indispensable for the generation of protective immunity to L. braziliensis, TLR2 seems to have a regulatory role during infection.

Extravascular Inflammation Does Not Increase Atherosclerosis in ApoE-deficient Mice

Biochemical and Biophysical Research Communications. Jun, 2009  |  Pubmed ID: 19393222

There is much speculation whether extravascular inflammation accelerates atherosclerosis. We tested this hypothesis in apoE(-/-) mice using three well-characterized models of non-autoimmune chronic inflammation: croton oil-induced skin inflammation, Aspergillus fumigatus antigen-induced allergic lung disease, and A. fumigatus antigen-induced peritonitis. The croton oil model produced recurrent inflammatory skin ulceration, and marked increases in plasma levels of IL-6 and serum amyloid A (SAA). The allergic lung disease model showed strong local inflammation with eosinophilic infiltration and serum IgE induction. The recurrent peritonitis model was accompanied by mild elevation in plasma SAA levels. Aortic atherosclerosis was quantified by computer-assisted morphometry of en face arteries in apoE(-/-) mice at 34 weeks for the croton oil model, 26 and 42 weeks for the allergic lung disease model, and 26 weeks for the peritonitis model. We found that all three forms of chronic extravascular inflammation had no effect on the rate of atherosclerosis development.

Toward a Comprehensive Understanding of Allergic Lung Disease

Transactions of the American Clinical and Climatological Association. 2009  |  Pubmed ID: 19768161

Allergic asthma is a respiratory disease induced by exposure to environmental agents that elicit allergic inflammation and transient airway obstruction and which produce the characteristic symptoms of cough and dyspnea. Prior to the advent of experimental models, asthma was believed to be caused primarily by the degranulation of mast cells and eosinophils primed by antigen-specific immunoglobulin E (IgE). More recent studies in mice have shown that T cells primarily mediate antigen-dependent airway obstruction and allergic inflammation through secretion of the cytokines interleukin 4 (IL- 4) and IL-13. Our additional studies indicate that a major environmental link to asthma may be through exposure to environmental proteinases and especially airway infection by proteinase-producing organisms such as fungi. Pending verification in humans, these findings suggest entirely new therapeutic interventions in asthma that include the restricted use of anti-inflammatory therapy and universal application of anti-fungal agents.

Smoking Gun: Mature Dendritic Cells in Human Lung Provide Clues to Chronic Obstructive Pulmonary Disease

American Journal of Respiratory and Critical Care Medicine. Dec, 2009  |  Pubmed ID: 19949238

Lung Myeloid Dendritic Cells Coordinately Induce TH1 and TH17 Responses in Human Emphysema

Science Translational Medicine. Oct, 2009  |  Pubmed ID: 20368170

Exposure to tobacco smoke activates innate and adaptive immune responses that in long-term smokers have been linked to diseases of the lungs, cardiovascular system, joints, and other organs. The destruction of lung tissue that underlies smoking-induced emphysema has been associated with T helper 1 cells that recognize the matrix protein elastin. Factors that result in the development of such autoreactive T cells in smokers remain unknown but are crucial for further understanding the pathogenesis of systemic inflammatory diseases in smokers. Here, we show that lung myeloid dendritic cells were sufficient to induce T helper 1 and T helper 17 responses in CD4 T cells. T helper 1 and 17 cells are invariably present in lungs from patients with emphysema but not in lungs from normal individuals. Interleukin-17A, a canonical T helper 17 cytokine, enhanced secretion of CCL20, a chemoattractant for dendritic cells, and matrix metalloproteinase 12, a potent elastolytic proteinase, from lung macrophages. Thus, although diverse lung factors potentially contribute to T helper effector differentiation in vivo, lung myeloid dendritic cells direct the generation of pathogenic T cells and support a feedback mechanism that sustains both inflammatory cell recruitment and lung destruction. This mechanism may underlie disease in other elastin-rich organs and tissues.

Human Rhinovirus Proteinase 2A Induces TH1 and TH2 Immunity in Patients with Chronic Obstructive Pulmonary Disease

The Journal of Allergy and Clinical Immunology. Jun, 2010  |  Pubmed ID: 20430426

Tobacco-related lung diseases, including chronic obstructive pulmonary disease (COPD), are major causes of lung-related disability and death worldwide. Acute exacerbation of COPD (AE-COPD) is commonly associated with upper and lower respiratory tract viral infections and can result in respiratory failure in those with advanced lung disease.

Proinflammatory Role for Let-7 MicroRNAS in Experimental Asthma

The Journal of Biological Chemistry. Sep, 2010  |  Pubmed ID: 20630862

MicroRNAs (miRNAs) are short, non-coding RNAs that target and silence protein coding genes through 3'-UTR elements. Evidence increasingly assigns an immunosuppressive role for miRNAs in immunity, but relatively few miRNAs have been studied, and an overall understanding of the importance of these regulatory transcripts in complex in vivo systems is lacking. Here we have applied multiple technologies to globally analyze miRNA expression and function in allergic lung disease, an experimental model of asthma. Deep sequencing and microarray analyses of the mouse lung short RNAome revealed numerous extant and novel miRNAs and other transcript classes. Similar to mRNAs, lung miRNA expression changed dynamically during the transition from the naive to the allergic state, suggesting numerous functional relationships. A possible role for miRNA editing in altering the lung mRNA target repertoire was also identified. Multiple members of the highly conserved let-7 miRNA family were the most abundant lung miRNAs, and we confirmed in vitro that interleukin 13 (IL-13), a cytokine essential for expression for allergic lung disease, is regulated by mmu-let-7a. However, inhibition of let-7 miRNAs in vivo using a locked nucleic acid profoundly inhibited production of allergic cytokines and the disease phenotype. Our findings thus reveal unexpected complexity in the miRNAome underlying allergic lung disease and demonstrate a proinflammatory role for let-7 miRNAs.

Respiratory Tract Allergic Disease and Atopy: Experimental Evidence for a Fungal Infectious Etiology

Medical Mycology : Official Publication of the International Society for Human and Animal Mycology. Apr, 2011  |  Pubmed ID: 20807032

Allergic asthma is an obstructive lung disease linked to environmental exposures that elicit allergic airway inflammation and characteristic antigen-specific immunoglobulin reactions termed atopy. Analyses of asthma pathogenesis using experimental models have shown that T helper cells, especially T helper type 2 (Th2) cells and Th2 cytokines such as interleukin 4 (IL-4) and IL-13, are critical mediators of airway obstruction following allergen challenge, but the environmental initiators of lung Th2 responses are less defined. Our studies demonstrate that fungal-derived proteinases that are commonly found in home environments are requisite immune adjuvants capable of eliciting robust Th2 responses and allergic lung disease in mice. We have further shown that common household fungi readily infect the mouse respiratory tract and induce both asthma-like disease and atopy to otherwise innocuous bystander antigens through the secretion of proteinases. These findings support the possibility that asthma and atopy represent a reaction to respiratory tract fungal infection, suggesting novel means for diagnosis and therapy of diverse allergic disorders.

Seeking Common Pathophysiology in Asthma, Atopy and Sinusitis

Trends in Immunology. Feb, 2011  |  Pubmed ID: 21239229

Asthma and chronic sinusitis are inexplicably common airway diseases that are linked to atopy and allergic inflammation. T helper type 2 (Th2) cells and the associated cytokines are believed to play crucial pathogenic roles in asthma, but the environmental factors that instigate allergic airway disease remain poorly understood. Environmental proteinases are highly allergenic and are candidate inducers of airway Th2 responses. Determining the proteinases and their sources that are relevant to airway disease, however, remains challenging. In this Opinion, we summarize the evidence that implicates fungi as both a relevant source of allergenic proteinases and a potential cause of asthma, atopy and chronic sinusitis through airway infection. Clarification of the extrinsic causes of these processes will markedly improve diagnosis, prognosis and therapy.

Dual Protective Mechanisms of Matrix Metalloproteinases 2 and 9 in Immune Defense Against Streptococcus Pneumoniae

Journal of Immunology (Baltimore, Md. : 1950). Jun, 2011  |  Pubmed ID: 21508260

A localized and effective innate immune response to pathogenic bacterial invasion is central to host survival. Identification of the critical local innate mediators of lung defense against such pathogens is essential for a complete understanding of the mechanism(s) underlying effective host defense. In an acute model of Streptococcus pneumoniae lung infection, deficiency in matrix metalloproteinase (MMP)2 and MMP9 (Mmp2/9(-/-)) conferred a survival disadvantage relative to wild-type mice treated under the same conditions. S. pneumoniae-infected Mmp2/9(-/-) mice recruited more polymorphonuclear leukocytes to the lung but had higher bacterial burdens. Mmp2/9(-/-) mice showed significantly higher levels of IL-17A, IP-10, and RANTES in the lung. Although MMP2-dependent cleavage partially inactivated IL-17A, MMP9 was critical for effective bacterial phagocytosis and reactive oxygen species generation in polymorphonuclear neutrophils. These data demonstrate critical nonredundant and protective roles for MMP2 and MMP9 in the early host immune response against S. pneumoniae infection.

Cross-sectional Analysis of the Utility of Pulmonary Function Tests in Predicting Emphysema in Ever-smokers

International Journal of Environmental Research and Public Health. May, 2011  |  Pubmed ID: 21655122

Emphysema is largely an under-diagnosed medical condition that can exist in smokers in the absence of airway obstruction. We aimed to determine the sensitivity and specificity of pulmonary function tests (PFTs) in assessing emphysema using quantitative CT scans as the reference standard. We enrolled 224 ever-smokers (current or former) over the age of 40. CT of thorax was used to quantify the low attenuation area (% emphysema), and to measure the standardized airway wall thickness. PFTs were used individually and in combination to predict their ability to discriminate radiographic emphysema. Significant emphysema (>7%) was detected in 122 (54%) subjects. Twenty six (21%) emphysema subjects had no evidence of airflow obstruction (FEV(1)/FVC ratio <70%), while all subjects with >23% emphysema showed airflow obstruction. The sensitivity and specificity of spirometry for detecting radiographic emphysema were 79% and 75%, respectively. Standardized airway wall thickness was increased in subjects with airflow obstruction, but did not correlate with emphysema severity. In this cohort of lifetime ever-smokers, PFTs alone were inadequate for diagnosing emphysema. Airway wall thickness quantified by CT morphometry was associated with airflow limitation, but not with emphysema indicating that the heterogeneous nature of lung disease in smokers may represent distinct phenotypes.

Proteinases As Molecular Adjuvants in Allergic Airway Disease

Biochimica Et Biophysica Acta. Nov, 2011  |  Pubmed ID: 21712069

Asthma and related respiratory tract allergic diseases are among the most common chronic diseases of adults and children. Despite their importance, disease course cannot be predicted and treatment remains non-specific and potentially hazardous, with no means for cure. Improved clinical management of asthma will require an improved understanding of the fundamental factors that initiate allergic inflammation, especially T helper type 2 (T(H)2) cell induction.

Fungal Chitin from Asthma-associated Home Environments Induces Eosinophilic Lung Infiltration

Journal of Immunology (Baltimore, Md. : 1950). Sep, 2011  |  Pubmed ID: 21824866

Development of asthma and allergic inflammation involves innate immunity, but the environmental contributions remain incompletely defined. Analysis of dust collected from the homes of asthmatic individuals revealed that the polysaccharide chitin is environmentally widespread and associated with β-glucans, possibly from ubiquitous fungi. Cell wall preparations of Aspergillus isolated from house dust induced robust recruitment of eosinophils into mouse lung, an effect that was attenuated by enzymatic degradation of cell wall chitin and β-glucans. Mice expressing constitutively active acidic mammalian chitinase in the lungs demonstrated a significant reduction in eosinophil infiltration after fungal challenge. Conversely, chitinase inhibition prolonged the duration of tissue eosinophilia. Thus, fungal chitin derived from home environments associated with asthma induces eosinophilic allergic inflammation in the lung, and mammalian chitinases, including acidic mammalian chitinase, limit this process.

Necessary and Sufficient Role for T Helper Cells to Prevent Fungal Dissemination in Allergic Lung Disease

Infection and Immunity. Nov, 2011  |  Pubmed ID: 21875960

Mucosal immune responses to fungal infection range from T helper type 2 (Th2) cell-directed allergic inflammation to Th1-predominant neutrophilic inflammation, but the mechanisms directing these divergent mucosal immune outcomes and the role of T cells in host defense against mucosal fungal infections are not known. Here we examined the mouse mucosal immune responses to 12 filamentous environmental fungal species over a broad range of exposure doses and determined the requirement of T cells for host defense. For all tested fungi, low-grade conidium exposures induced Th2- and eosinophil-predominant allergic lung disease, whereas higher exposures led to rapid conversion to neutrophil- and Th1 cell-predominant inflammation, a phenomenon we term immune phenotype switching. All fungal exposure doses were further linked to the secretion of interleukin-17A (IL-17A). Fungal infections with Curvularia lunata and Aspergillus fumigatus were typically confined to the airway during allergic inflammation but became locally invasive and disseminated to the brain at higher conidium challenge doses, in association with predominant Th1 responses. Fungal dissemination occurred at relatively low challenge doses with the conidia of Aspergillus fumigatus administered to recombinase activating gene 1 (Rag-1)-deficient mice, which lack B and T cells, but B cell-deficient μMT mice and T helper cell-reconstituted Rag-1-deficient mice were comparable to wild-type mice in preventing fungal dissemination. Our findings demonstrate that Th2 cell-predominant allergic responses followed by immune phenotype switching and fungal dissemination are highly predictable outcomes with progressive fungal infectious burdens and that T helper cell responses are protective against lethal fungal dissemination.

Fungi Linking the Pathophysiology of Chronic Rhinosinusitis with Nasal Polyps and Allergic Asthma

Immunological Investigations. 2011  |  Pubmed ID: 21985305

The immunologic reaction to fungal stimuli has long been thought to be a contributor to the development of sinonasal disease. We aim to review the role of fungi in upper and lower airway inflammatory diseases. The immune response to fungi in the pathogenicity of specific respiratory inflammatory diseases such as allergic bronchopulmonary aspergillosis and a subtype of CRS known as allergic fungal rhinosinusitis has been relatively well described. Fungi are thought to serve both as immunogenic antigens and as adjuncts to inflammation through protease activity. Development of a recent murine mouse model of asthma bypassing the pre-sensitization of allergen further suggests a broader role for fungi in allergic asthma. The literature is lacking in defining a clear presence of fungi within the inflamed sinus cavity of CRS patients and its potential immunologic effects, as well as the utility of antifungal therapy for CRS management. We will review these data and potential common molecular mechanisms activated by fungi in the common pathway toward upper and lower airway inflammatory pathology.

Cigarette Smoke Induction of Osteopontin (SPP1) Mediates TH17 Inflammation in Human and Experimental Emphysema

Science Translational Medicine. Jan, 2012  |  Pubmed ID: 22261033

Smoking-related lung diseases are among the leading causes of death worldwide, underscoring the need to understand their pathogenesis and develop new effective therapies. We have shown that CD1a(+) antigen-presenting cells (APCs) from lungs of patients with emphysema can induce autoreactive T helper 1 (T(H)1) and T(H)17 cells. Similarly, the canonical cytokines interferon-γ (IFN-γ) and interleukin-17A (IL-17A) are specifically linked to lung destruction in smokers, but how smoke activates APCs to mediate emphysema remains unknown. Here, we show that, in addition to increasing IFN-γ expression, cigarette smoke increased the expression of IL-17A in both CD4(+) and γδ T cells from mouse lung. IL-17A deficiency resulted in attenuation of, whereas lack of γδ T cells exacerbated, smoke-induced emphysema in mice. Adoptive transfer of lung APCs isolated from mice with emphysema revealed that this cell population was capable of transferring disease even in the absence of active smoke exposure, a process that was dependent on IL-17A expression. Spp1 (the gene for osteopontin) was highly expressed in the pathogenic lung APCs of smoke-exposed mice and was required for the T(H)17 responses and emphysema in vivo, in part through its inhibition of the expression of the transcription factor Irf7. Thus, the Spp1-Irf7 axis is critical for induction of pathological T(H)17 responses, revealing a major mechanism by which smoke activates lung APCs to induce emphysema and identifying a pathway that could be targeted for therapeutic purposes.

High Prevalence of Asthma in HIV-infected Adults: New Insights

The Journal of Allergy and Clinical Immunology. Jan, 2012  |  Pubmed ID: 22296750