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.

FIGURE 5.1

Proposed scheme for how viruses might trigger chronic inflammatory disease. In a susceptible genetic background, two broad issues must be defined: (A) an altered immune program with the development of a chronic immune response involving APCs, memory cells, and effector cells; and (B) end-organ dysfunction with a transition from epithelial precursor cells (such as Clara cells and ciliated cells) to mucous cells. The present review is focused on alterations in the immune program.

FIGURE 5.2

Cellular and molecular scheme for an adaptive immune axis leading to acute lung disease after viral infection. Viral infection activates two major immune pathways. (A) In one of these pathways, viruses cause AEC and pDC production of type-I IFN. Subsequent IFNAR signaling leads to upregulation of FcεRIα expression on resident lung cDCs. In turn, FcεRI activation by viral antigen and antiviral IgE leads to production of CCL28 and recruitment of CCR10-expressing IL-13-producing Th2 cells to the lung. Persistent IL-13 production drives differentiation of AEC precursors towards mucous cells (MCM) and airway smooth muscle cells to become more reactive to contractile agonists (AHR). (B) In another pathway, viral infection also leads to maturation of lung cDCs that use CCL5-CCR5 and CCL19/21-CCR7 interactions to migrate to regional lymph nodes. In the nodes, these cDCs regulate MHC Class I-dependent generation of CD8⁺ cytotoxic T cells as well as MHC Class II-dependent production of CD4⁺ Th cells and consequent B cell production of virus-specific IgE. This IgE is thereby available to participate in FcεRI signaling in the pathway described in (A). Modified from Grayson et al. (2007a).

FIGURE 5.3

Cellular and molecular scheme for an innate immune axis leading to chronic lung disease after viral infection. Virus may directly or indirectly activate an APC and thereby facilitate CD1d-dependent antigen presentation and consequent activation of invariant CD4⁻ NKT cells. NKT cells then interact directly with lung macrophages via IL-13 production and binding to the IL-13 receptor (IL-13R) as well as contact between invariant Vα14 TCR and glycolipid-loaded CD1d. This interaction leads to increased expression of IL-13R and production of IL-13 that drives a positive feedback loop to amplify IL-13 production and alternative activation of macrophages, including Chi3l3/4, Fizz1, Mmp12, Arg1, and Alox12e gene expression in mice and Chit3L1, Chit1, Arg1, and Alox15 in humans. Modified from Kim et al. (2008).

FIGURE 5.4

Time course for immune events in the development of acute and chronic lung disease after respiratory viral infection. Viral replication is maximal by postinoculation Days 3–5 in concert with immune-response gene expression and subsequent immune cell infiltration into the site of infection. The development of acute disease is characterized by acute AHR and MCM and is manifested at 3 weeks after viral inoculation; this disease is driven by a combined innate and adaptive immune response that includes type-I IFN production, high-affinity IgE receptor expression and CCL28 production by cDCs, and recruitment of IL-13-producing Th2 cells. The development of chronic disease is fully manifested at 7 weeks after viral inoculation and is regulated by APC-dependent activation of iNKT cells that drive the generation of alternatively activated macrophages (AAMacs). Modified from Holtzman et al. (2002).