title: Immune pathways for translating viral infection into chronic airway disease.
abstract: To better understand the immune basis for chronic inflammatory lung disease, we analyzed a mouse model of lung disease that develops after respiratory viral infection. The disease that develops in this model is similar to asthma and chronic obstructive pulmonary disease (COPD) in humans and is manifested after the inciting virus has been cleared to trace levels. The model thereby mimics the relationship of paramyxoviral infection to the development of childhood asthma in humans. When the acute lung disease appears in this model (at 3 weeks after viral inoculation), it depends on an immune axis that is initiated by expression and activation of the high-affinity IgE receptor (FcvarepsilonRI) on conventional lung dendritic cells (cDCs) to recruit interleukin (IL)-13-producing CD4(+) T cells to the lower airways. However, when the chronic lung disease develops fully (at 7 weeks after inoculation), it is driven instead by an innate immune axis that relies on invariant natural killer T (iNKT) cells that are programmed to activate macrophages to produce IL-13. The interaction between iNKT cells and macrophages depends on contact between the semi-invariant Valpha14Jalpha18-TCR on lung iNKT cells and the oligomorphic MHC-like protein CD1d on macrophages as well as NKT cell production of IL-13 that binds to the IL-13 receptor (IL-13R) on the macrophage. This innate immune axis is also activated in the lungs of humans with severe asthma or COPD based on detection of increased numbers of iNKT cells and alternatively activated IL-13-producing macrophages in the lung. Together, the findings identify an adaptive immune response that mediates acute disease and an innate immune response that drives chronic inflammatory lung disease in experimental and clinical settings.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Holtzman
authors.forename: Derek E
authors.initials: DE
authors.lastname: Byers
authors.forename: Loralyn A
authors.initials: LA
authors.lastname: Benoit
authors.forename: John T
authors.initials: JT
authors.lastname: Battaile
authors.forename: Yingjian
authors.initials: Y
authors.lastname: You
authors.forename: Eugene
authors.initials: E
authors.lastname: Agapov
authors.forename: Chaeho
authors.initials: C
authors.lastname: Park
authors.forename: Mitchell H
authors.initials: MH
authors.lastname: Grayson
authors.forename: Edy Y
authors.initials: EY
authors.lastname: Kim
authors.forename: Anand C
authors.initials: AC
authors.lastname: Patel
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019742:Chemokines, CC / Q000096:biosynthesis; D002908:Chronic Disease; D003170:Complement Pathway, Alternative; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D018793:Interleukin-13 / Q000502:physiology; D008171:Lung Diseases / Q000209:etiology*; D008264:Macrophages / Q000502:physiology; D055611:Natural Killer T-Cells / Q000276:immunology; D017455:Receptors, IgE / Q000032:analysis; D014777:Virus Diseases / Q000150:complications / Q000276:immunology*
chemical_list: C414047:CCL28 protein, human; D019742:Chemokines, CC; D018793:Interleukin-13; D017455:Receptors, IgE