Papers by Farrah Kheradmand
Environmental health perspectives, 2002
Current data overwhelmingly document the existence of a worldwide asthma epidemic, although indiv... more 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.
Background: Tobacco-related lung diseases, including chronic obstructive pulmonary disease (COPD)... more Background: 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. Objective: We sought to determine the mechanism underlying COPD exacerbation and host response to pathogen-derived factors. Methods: Over a 24-month period, we assessed the viral causes for upper and lower respiratory tract infections in patients with COPD (n 5 155) and control subjects (n 5 103). We collected nasal and bronchoalveolar lavage fluid and peripheral blood under baseline and exacerbated conditions. We determined the effect of human rhinovirus (HRV) proteinases on T-cell activation in human subjects and mice. Results: HRVs are isolated from nasal and lung fluid from subjects with AE-COPD. Bronchoalveolar lavage fluid and CD4 T cells from patients with COPD exhibited a T H 1 and T H 2 cell cytokine phenotype during acute infection. HRV-encoded proteinase 2A activated monocyte-derived dendritic cells in vitro and induced strong T H 1 and T H 2 immune responses from CD4 T cells. Intranasal administration of recombinant rhinovirus proteinase 2A in mice resulted in an increase in airway hyperreactivity, lung inflammation, and IL-4 and IFN-g production from CD4 T cells. Conclusion: Our findings suggest that patients with severe COPD show T H 1-and T H 2-biased responses during AE-COPD. HRV-encoded proteinase 2A, like other microbial proteinases, could provide a T H 1-and T H 2-biasing adjuvant factor during upper and lower respiratory tract infection in patients with severe COPD. Alteration of the immune response to secreted viral proteinases might contribute to worsening of dyspnea and respiratory failure in patients with COPD. (J Allergy Clin Immunol 2010;125:1369-78.)
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 2002
The respiratory allergens that induce experimental Th cell type 2-dependent allergic lung inflamm... more 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 ...
European Urology Supplements, 2011
Journal of Allergy and Clinical Immunology, 2014
Environmental fungi have been linked to TH2 cell-related airway inflammation and the TH2-associat... more Environmental fungi have been linked to TH2 cell-related airway inflammation and the TH2-associated chronic airway diseases asthma, chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), and allergic fungal rhinosinusitis (AFRS), but whether these organisms participate directly or indirectly in disease pathology remains unknown. To determine the frequency of fungus isolation and fungus-specific immunity in patients with TH2-associated and non-TH2-associated airway disease. Sinus lavage fluid and blood were collected from sinus surgery patients (n = 118) including patients with CRSwNP, patients with CRS without nasal polyps, patients with AFRS, and non-CRS/nonasthmatic control patients. Asthma status was determined from medical history. Sinus lavage fluids were cultured and directly examined for evidence of viable fungi. PBMCs were restimulated with fungal antigens in an enzyme-linked immunocell spot assay to determine total memory fungus-specific IL-4-secreting cells. These data were compared with fungus-specific IgE levels measured from plasma by ELISA. Filamentous fungi were significantly more commonly cultured in patients with TH2-associated airway disease (asthma, CRSwNP, or AFRS: n = 68) than in control patients with non-TH2-associated disease (n = 31): 74% vs 16%, respectively (P < .001). Both fungus-specific IL-4 enzyme-linked immunocell spot (n = 48) and specific IgE (n = 70) data correlated with TH2-associated diseases (sensitivity 73% and specificity 100% vs 50% and 77%, respectively). The frequent isolation of fungi growing directly within the airways accompanied by specific immunity to these organisms only in patients with TH2-associated chronic airway diseases suggests that fungi participate directly in the pathogenesis of these conditions. Efforts to eradicate airway fungi from the airways should be considered in selected patients.
Science Translational Medicine, 2009
Exposure to tobacco smoke activates innate and adaptive immune responses that in long-term smoker... more 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.
Nature Medicine, 2014
Vaccination has been the most widely used strategy to protect against viral infections for centur... more Vaccination has been the most widely used strategy to protect against viral infections for centuries. However, the molecular mechanisms governing the long-term persistence of immunological memory in response to vaccines remain unclear. Here we show that autophagy has a critical role in the maintenance of memory B cells that protect against influenza virus infection. Memory B cells displayed elevated levels of basal autophagy with increased expression of genes that regulate autophagy initiation or autophagosome maturation. Mice with B cell-specific deletion of Atg7 (B/Atg7(-/-) mice) showed normal primary antibody responses after immunization against influenza but failed to generate protective secondary antibody responses when challenged with influenza viruses, resulting in high viral loads, widespread lung destruction and increased fatality. Our results suggest that autophagy is essential for the survival of virus-specific memory B cells in mice and the maintenance of protective antibody responses required to combat infections.
Nature Medicine, 2007
The factors that regulate airway goblet cell metaplasia and mucus secretion are essential to unde... more The factors that regulate airway goblet cell metaplasia and mucus secretion are essential to understanding how airway obstruction occurs in asthma. In this issue, Xiang et al. demonstrate the existence of an airway epithelial, extraneuronal GABAergic signaling system that promotes mucus overproduction during allergic airway inflammation (pages 862-867).
Nature Immunology, 2009
The innate immune response of airway epithelial cells to airborne allergens initiates the develop... more 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.
Nature, 1999
... Induction and regulation of the IgE response. David B. Corry & Farrah Kheradm... more ... Induction and regulation of the IgE response. David B. Corry & Farrah Kheradmand. Top of page Abstract. Immunoglobulin E (IgE) is believed to be one of the major mediators of immediate hypersensitivity reactions that underlie ...
Mucosal Immunology, 2009
Active fungal proteinases are powerful allergens that induce experimental allergic lung disease s... more Active fungal proteinases are powerful allergens that induce experimental allergic lung disease strongly resembling atopic asthma, but the precise relationship between proteinases and asthma remains unknown. Here, we analyzed dust collected from the homes of asthmatic children for the presence and sources of active proteinases to further explore the relationship between active proteinases, atopy, and asthma. Active proteinases were present in all houses and many were derived from fungi, especially Aspergillus niger. Proteinase-active dust extracts were alone insufficient to initiate asthma-like disease in mice, but conidia of A. niger readily established a contained airway mucosal infection, allergic lung disease, and atopy to an innocuous bystander antigen. Proteinase produced by A. niger enhanced fungal clearance from lung and was required for robust allergic disease. Interleukin 13 (IL-13) and IL-5 were required for optimal clearance of lung fungal infection and eosinophils showed potent anti-fungal activity in vitro . Thus, asthma and atopy may both represent a protective response against contained airway infection due to ubiquitous proteinase-producing fungi.
Mucosal Immunology, 2011
All commercial influenza vaccines elicit antibody responses that protect against seasonal infecti... more All commercial influenza vaccines elicit antibody responses that protect against seasonal infection, but this approach is limited by the need for annual vaccine reformulation that precludes efficient responses against epidemic and pandemic disease. In this study we describe a novel vaccination approach in which a nanoparticulate, liposome-based agent containing short, highly conserved influenza-derived peptides is delivered to the respiratory tract to elicit potent innate and selective T cell-based adaptive immune responses. Prepared without virus-specific peptides, mucosal immunostimulatory therapeutic (MIT) provided robust, but short-lived, protection against multiple, highly lethal strains of influenza in mice of diverse genetic backgrounds. MIT prepared with three highly conserved epitopes that elicited virus-specific memory T-cell responses but not neutralizing antibodies, termed MITpep, provided equivalent, but more durable, protection relative to MIT. Alveolar macrophages were more important than dendritic cells in determining the protective efficacy of MIT, which induced both canonical and non-canonical antiviral immune pathways. Through activation of airway mucosal innate and highly specific T-cell responses, MIT and MITpep represent novel approaches to antiviral protection that offer the possibility of universal protection against epidemic and pandemic influenza.
Medical Mycology, 2011
Allergic asthma is an obstructive lung disease linked to environmental exposures that elicit alle... more Allergic asthma is an obstructive lung disease linked to environmental exposures that elicit allergic airway infl ammation and characteristic antigen-specifi c 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 defi ned. 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 fi ndings 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.
The Journal of Immunology, 2005
The airway plays a vital role in allergic lung diseases by responding to inhaled allergens and in... more 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.
Journal of Allergy and Clinical Immunology, 2004
Background: Airway obstruction, perhaps the most relevant clinical feature of asthma, is typicall... more Background: 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. Objective: The purposes of this study were to develop a reliable, quantitative assay for detecting secreted airway glycoproteins and to assess the secretion of airway glycoproteins in comparison with other markers of airway obstruction resulting from allergic lung inflammation. Methods: Two microtiter plate-based glycoprotein-detecting methods were developed, one using an antiglycoprotein antibody and the other using the glycoprotein-binding plant lectin, jacalin. Both methods were used to assess airway glycoprotein secretion in response to 2 defined agonists given intranasally, IL-13 and an allergen derived from Aspergillus fumigatus. Glycoprotein secretion was assessed concomitant with another measure of airway obstruction, airway hyperresponsiveness provoked by acetylcholine challenge, and a histologic method for quantitating glycoprotein production. Results: Both assays were sufficient for quantitating airway glycoproteins over the full range of values encountered from murine bronchoalveolar lavage and yielded highly reproducible data. Secretion of airway glycoproteins increased commensurate with the detection of both airway hyperresponsiveness and airway glycoprotein production induced by IL-13 and allergen. Conclusion: Airway glycoprotein secretion is a consistent feature of the allergic lung phenotype and likely contributes to airway obstruction induced by allergen in both humans and rodents. (J Allergy Clin Immunol 2004;113:72-8.)
Journal of Allergy and Clinical Immunology, 2007
Background: The earliest immune events induced by allergens are poorly understood, yet are likely... more Background: The earliest immune events induced by allergens are poorly understood, yet are likely essential to understanding how allergic inflammation is established. Objective: We sought to describe the earliest signaling events activated by allergen and determine their significance to allergic inflammation. Methods: A fungal-associated allergenic proteinase (FAP) or ovalbumin was administered once intranasally to wild-type mice to determine their ability to induce allergy-associated genes and initiate allergic lung inflammation. Mice deficient in recombinase activating gene 1, C3a, the C3a anaphylatoxin receptor, and MyD88 were challenged similarly to understand the requirement of these molecules and T and B cells for allergic inflammation. Adoptive T-cell transfer experiments were further performed to determine whether signal transducer and activator of transcription 6 (STAT6) was required for cell recruitment and allergic inflammation. Results: FAP, but not ovalbumin, induced eosinophilic airway inflammation and lung IL-4 production in the absence of adaptive immune cells after the transcriptional induction of allergy-specific airway chemokines. Allergen-mediated chemokine secretion and innate allergic lung inflammation occurred in the absence of STAT6, recombinase activating gene 1, C3a, C3a anaphylatoxin receptor, Toll-like receptor 4, and MyD88 but required intact proteinase activity. Furthermore, FAP induced recruitment of T H 2 cells and eosinophils to lungs independently of STAT6, which was previously thought to be required for T H 2 cell homing. Conclusion: FAP induces allergic lung inflammation through a previously unrecognized innate immune signaling mechanism. Clinical implications: These findings reveal a new paradigm for understanding how allergic inflammation begins and suggest novel possibilities for the prevention and treatment of allergic diseases, such as asthma. (J Allergy Clin Immunol 2007;120:334-42.)
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Papers by Farrah Kheradmand