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Yvonne R Chan,
Kong Chen,
Steven R Duncan,
Kira L Lathrop,
Joseph D Latoche,
Alison J Logar,
Derek A Pociask,
Brendon J Wahlberg,
Prabir Ray,
Anuradha Ray,
Joseph M Pilewski,
Jay K Kolls
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ABSTRACT: BACKGROUND: IL-17 is an important cytokine signature of the T(H) differentiation pathway T(H)17. This T-cell subset is crucial in mediating autoimmune disease or antimicrobial immunity in animal models, but its presence and role in human disease remain to be completely characterized. OBJECTIVE: We set out to determine the frequency of T(H)17 cells in patients with cystic fibrosis (CF), a disease in which there is recurrent infection with known pathogens. METHODS: Explanted lungs from patients undergoing transplantation or organ donors (CF samples = 18; non-CF, nonbronchiectatic samples = 10) were collected. Hilar nodes and parenchymal lung tissue were processed and examined for T(H)17 signature by using immunofluorescence and quantitative real-time PCR. T cells were isolated and stimulated with antigens from Pseudomonas aeruginosa and Aspergillus species. Cytokine profiles and staining with flow cytometry were used to assess the reactivity of these cells to antigen stimulation. RESULTS: We found a strong IL-17 phenotype in patients with CF compared with that seen in control subjects without CF. Within this tissue, we found pathogenic antigen-responsive CD4(+)IL-17(+) cells. There were double-positive IL-17(+)IL-22(+) cells [T(H)17(22)], and the IL-22(+) population had a higher proportion of memory characteristics. Antigen-specific T(H)17 responses were stronger in the draining lymph nodes compared with those seen in matched parenchymal lungs. CONCLUSION: Inducible proliferation of T(H)17(22) with memory cell characteristics is seen in the lungs of patients with CF. The function of these individual subpopulations will require further study regarding their development. T cells are likely not the exclusive producers of IL-17 and IL-22, and this will require further characterization.
The Journal of allergy and clinical immunology 07/2012; · 9.17 Impact Factor
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Lokesh Guglani,
Radha Gopal,
Javier Rangel-Moreno,
Beth Fallert Junecko,
Yinyao Lin,
Thorsten Berger,
Tak W Mak,
John F Alcorn,
Troy D Randall,
Todd A Reinhart, Yvonne R Chan,
Shabaana A Khader
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ABSTRACT: Pulmonary tuberculosis (TB), caused by the intracellular bacteria Mycobacterium tuberculosis, is a worldwide disease that continues to kill more than 1.5 million people every year worldwide. The accumulation of lymphocytes mediates the formation of the tubercle granuloma in the lung and is crucial for host protection against M.tuberculosis infection. However, paradoxically the tubercle granuloma is also the basis for the immunopathology associated with the disease and very little is known about the regulatory mechanisms that constrain the inflammation associated with the granulomas. Lipocalin 2 (Lcn2) is a member of the lipocalin family of proteins and binds to bacterial siderophores thereby sequestering iron required for bacterial growth. Thus far, it is not known whether Lcn2 plays a role in the inflammatory response to mycobacterial pulmonary infections. In the present study, using models of acute and chronic mycobacterial pulmonary infections, we reveal a novel role for Lcn2 in constraining T cell lymphocytic accumulation and inflammation by inhibiting inflammatory chemokines, such as CXCL9. In contrast, Lcn2 promotes neutrophil recruitment during mycobacterial pulmonary infection, by inducing G-CSF and KC in alveolar macrophages. Importantly, despite a common role for Lcn2 in regulating chemokines during mycobacterial pulmonary infections, Lcn2 deficient mice are more susceptible to acute M.bovis BCG, but not low dose M.tuberculosis pulmonary infection.
PLoS ONE 01/2012; 7(11):e50052. · 4.09 Impact Factor
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Melissa A Gessner,
Jessica L Werner,
Lauren M Lilly,
Michael P Nelson,
Allison E Metz,
Chad W Dunaway, Yvonne R Chan,
Wenjun Ouyang,
Gordon D Brown,
Casey T Weaver,
Chad Steele
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ABSTRACT: We have previously reported that mice deficient in the beta-glucan receptor Dectin-1 displayed increased susceptibility to Aspergillus fumigatus lung infection in the presence of lower interleukin 23 (IL-23) and IL-17A production in the lungs and have reported a role for IL-17A in lung defense. As IL-23 is also thought to control the production of IL-22, we examined the role of Dectin-1 in IL-22 production, as well as the role of IL-22 in innate host defense against A. fumigatus. Here, we show that Dectin-1-deficient mice demonstrated significantly reduced levels of IL-22 in the lungs early after A. fumigatus challenge. Culturing cells from enzymatic lung digests ex vivo further demonstrated Dectin-1-dependent IL-22 production. IL-22 production was additionally found to be independent of IL-1β, IL-6, or IL-18 but required IL-23. The addition of recombinant IL-23 augmented IL-22 production in wild-type (WT) lung cells and rescued IL-22 production by lung cells from Dectin-1-deficient mice. In vivo neutralization of IL-22 in the lungs of WT mice resulted in impaired A. fumigatus lung clearance. Moreover, mice deficient in IL-22 also demonstrated a higher lung fungal burden after A. fumigatus challenge in the presence of impaired IL-1α, tumor necrosis factor alpha (TNF-α), CCL3/MIP-1α, and CCL4/MIP-1β production and lower neutrophil recruitment, yet intact IL-17A production. We further show that lung lavage fluid collected from both A. fumigatus-challenged Dectin-1-deficient and IL-22-deficient mice had compromised anti-fungal activity against A. fumigatus in vitro. Although lipocalin 2 production was observed to be Dectin-1 and IL-22 dependent, lipocalin 2-deficient mice did not demonstrate impaired A. fumigatus clearance. Moreover, lung S100a8, S100a9, and Reg3g mRNA expression was not lower in either Dectin-1-deficient or IL-22-deficient mice. Collectively, our results indicate that early innate lung defense against A. fumigatus is mediated by Dectin-1-dependent IL-22 production.
Infection and immunity 01/2012; 80(1):410-7. · 4.21 Impact Factor
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ABSTRACT: Lipocalin 2 is a protein that has garnered a great deal of interest in multidisciplinary fields over the last two decades since its discovery. However, its exact function in metabolic processes remains to be completely characterized. More recently, it has come to light as a highly upregulated protein in the setting of injury and infection. This review focuses on lipocalin 2 regulation and its relationship to cytokine and endocrine signaling pathways.
Cytokine 08/2011; 56(2):435-41. · 3.02 Impact Factor
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Kong Chen,
Derek A Pociask,
Jeremy P McAleer, Yvonne R Chan,
John F Alcorn,
James L Kreindler,
Matthew R Keyser,
Steven D Shapiro,
A McGarry Houghton,
Jay K Kolls,
Mingquan Zheng
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ABSTRACT: Chronic Obstructive Pulmonary Disease (COPD) is characterized by airspace enlargement and peribronchial lymphoid follicles; however, the immunological mechanisms leading to these pathologic changes remain undefined. Here we show that cigarette smoke is a selective adjuvant that augments in vitro and in vivo Th17, but not Th1, cell differentiation via the aryl hydrocarbon receptor. Smoke exposed IL-17RA(-/-) mice failed to induce CCL2 and MMP12 compared to WT mice. Remarkably, in contrast to WT mice, IL-17RA(-/-) mice failed to develop emphysema after 6 months of cigarette smoke exposure. Taken together, these data demonstrate that cigarette smoke is a potent Th17 adjuvant and that IL-17RA signaling is required for chemokine expression necessary for MMP12 induction and tissue emphysema.
PLoS ONE 01/2011; 6(5):e20333. · 4.09 Impact Factor
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James L Kreindler,
Chad Steele,
Nikki Nguyen, Yvonne R Chan,
Joseph M Pilewski,
John F Alcorn,
Yatin M Vyas,
Shean J Aujla,
Peter Finelli,
Megan Blanchard,
Steven F Zeigler,
Alison Logar,
Elizabeth Hartigan,
Marcia Kurs-Lasky,
Howard Rockette,
Anuradha Ray,
Jay K Kolls
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ABSTRACT: Allergic bronchopulmonary aspergillosis (ABPA) is caused by a dominant Th2 immune response to antigens derived from the opportunistic mold Aspergillus, most commonly Aspergillus fumigatus. It occurs in 4%-15% of patients with cystic fibrosis (CF); however, not all patients with CF infected with A. fumigatus develop ABPA. Therefore, we compared cohorts of A. fumigatus-colonized CF patients with and without ABPA to identify factors mediating tolerance versus sensitization. We found that the costimulatory molecule OX40 ligand (OX40L) was critical in driving Th2 responses to A. fumigatus in peripheral CD4+ T cells isolated from patients with ABPA. In contrast, CD4+ T cells from the non-ABPA cohort did not mount enhanced Th2 responses in vitro and contained a higher frequency of TGF-beta-expressing regulatory T cells. Heightened Th2 reactivity in the ABPA cohort correlated with lower mean serum vitamin D levels. Further, in vitro addition of 1,25 OH-vitamin D3 substantially reduced DC expression of OX40L and increased DC expression of TGF-beta. This in vitro treatment also resulted in increased Treg TGF-beta expression and reduced Th2 responses by CD4+ T cells from patients with ABPA. These data provide rationale for a therapeutic trial of vitamin D to prevent or treat ABPA in patients with CF.
The Journal of clinical investigation 09/2010; 120(9):3242-54. · 15.39 Impact Factor
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Yvonne R Chan,
Jessica S Liu,
Derek A Pociask,
Mingquan Zheng,
Timothy A Mietzner,
Thorsten Berger,
Tak W Mak,
Matthew C Clifton,
Roland K Strong,
Prabir Ray,
Jay K Kolls
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ABSTRACT: Antimicrobial proteins comprise a significant component of the acute innate immune response to infection. They are induced by pattern recognition receptors as well as by cytokines of the innate and adaptive immune pathways and play important roles in infection control and immunomodulatory homeostasis. Lipocalin 2 (siderocalin, NGAL, 24p3), a siderophore-binding antimicrobial protein, is critical for control of systemic infection with Escherichia coli; however, its role in mucosal immunity in the respiratory tract is unknown. In this study, we found that lipocalin 2 is rapidly and robustly induced by Klebsiella pneumoniae infection and is TLR4 dependent. IL-1beta and IL-17 also individually induce lipocalin 2. Mucosal administration of IL-1beta alone could reconstitute the lipocalin 2 deficiency in TLR4 knockout animals and rescue them from infection. Lipocalin 2-deficient animals have impaired lung bacterial clearance in this model and mucosal reconstitution of lipocalin 2 protein in these animals resulted in rescue of this phenotype. We conclude that lipocalin 2 is a crucial component of mucosal immune defense against pulmonary infection with K. pneumoniae.
The Journal of Immunology 05/2009; 182(8):4947-56. · 5.79 Impact Factor
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ABSTRACT: Antimicrobial proteins constitute a phylogenetically ancient form of innate immunity that provides host defence at skin and mucosal surfaces. Although some components of this system are constitutively expressed, new evidence reviewed in this Progress article shows that the production of certain antimicrobial proteins by epithelial cells can also be regulated by cytokines of the innate and adaptive immune systems. In particular, the effector cytokines interleukin-17 and interleukin-22, which are produced by the T-helper-17-cell subset, are emerging as crucial regulators of antimicrobial-peptide production in the gut and the lungs. This suggests that this T-cell lineage and its cytokines have important roles in skin and mucosal immunity.
Nature Reviews Immunology 12/2008; 8(11):829-35. · 32.25 Impact Factor
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Shean J Aujla, Yvonne R Chan,
Mingquan Zheng,
Mingjian Fei,
David J Askew,
Derek A Pociask,
Todd A Reinhart,
Florencia McAllister,
Jennifer Edeal,
Kristi Gaus,
Shahid Husain,
James L Kreindler,
Patricia J Dubin,
Joseph M Pilewski,
Mike M Myerburg,
Carol A Mason,
Yoichiro Iwakura,
Jay K Kolls
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ABSTRACT: Emerging evidence supports the concept that T helper type 17 (T(H)17) cells, in addition to mediating autoimmunity, have key roles in mucosal immunity against extracellular pathogens. Interleukin-22 (IL-22) and IL-17A are both effector cytokines produced by the T(H)17 lineage, and both were crucial for maintaining local control of the Gram-negative pulmonary pathogen, Klebsiella pneumoniae. Although both cytokines regulated CXC chemokines and granulocyte colony-stimulating factor production in the lung, only IL-22 increased lung epithelial cell proliferation and increased transepithelial resistance to injury. These data support the concept that the T(H)17 cell lineage and its effector molecules have evolved to effect host defense against extracellular pathogens at mucosal sites.
Nature medicine 04/2008; 14(3):275-81. · 27.14 Impact Factor
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ABSTRACT: Molecular techniques offer the promise of improving diagnosis of lower respiratory tract infections. This review focuses on currently used molecular diagnostic techniques for various types of pneumonia and highlights potential future applications of this technology.
Lower respiratory tract infections result in a high degree of morbidity and mortality, but a definitive microbiologic diagnosis is often not obtained by traditional culture or serologic methods. In addition, culture of certain organisms may be difficult or require extended periods of time. Molecular techniques have the potential to improve diagnostic yield and decrease time to pathogen identification. These techniques are also helpful in the determination of drug sensitivity and the understanding of transmission and outbreaks. Most currently used techniques employ some variation of the polymerase chain reaction. Limitations include high costs, the need for specialized equipment, and problems with false-positive and -negative results.
Molecular diagnosis of pneumonia has the potential to improve identification of pathogens in patients with suspected lower respiratory tract infection. Limitations of molecular techniques currently prevent their widespread use, but future developments will likely lead to inclusion of these tests in routine diagnostic evaluations.
Current Opinion in Infectious Diseases 05/2007; 20(2):157-64. · 4.93 Impact Factor
