Page 1003 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Immunological Lung Diseases

Joyce S. Lee, Andrew P. Fontenot

The lung serves as an interface between the environment and Macrophages and lymphocytes have also been localized to
the sanctuary of the body. The defense systems of the upper areas of pulmonary fibrosis in patients with immunological lung
airways clear the majority of inhaled particulates. Those that diseases, including idiopathic pulmonary fibrosis (IPF), systemic
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evade the upper airway defenses are combated by the innate and sclerosis, and rheumatoid arthritis (RA). In the lung, macrophages
acquired immune responses. Essentially all autoimmune diseases can be divided, according to their location, into alveolar or
are dependent on the inappropriate activation of autoreactive CD4 interstitial macrophages. Resident alveolar macrophages are
T cells as well as autoreactive B cells responsible for pathogenic yolk-sac–derived cells that are dependent on interleukin-34
autoantibodies. Immunological lung diseases develop when the (IL-34), colony-stimulating factor 1 (CSF-1), and the transcription
2-4
normal mechanisms of immune self-tolerance fail. This chapter factor PU.1 for their development. These yolk-sac–derived
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deals with the pulmonary manifestations of these disorders. macrophages are self-renewing, maintained at a stable number
throughout life, and are localized on epithelial surfaces and lining
INFLAMMATION IN THE PATHOGENESIS OF fluid of the alveoli and airways. With relatively poor antigen-
INTERSTITIAL LUNG DISEASE presenting ability, they function to remove inhaled particles and
bacteria. Conversely, interstitial macrophages are derived from
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In the normal host, the resident alveolar macrophage is the hematopoietic stem cells (HSCs) and are located in the tissue
predominant cell type in fluid from bronchoalveolar lavage (BAL). spaces between the alveoli. In the context of lung injury, interstitial
Resident alveolar macrophages function to ingest and degrade macrophages greatly increase in number. Although interstitial
the inhaled antigenic load, to clear pulmonary surfactant, and macrophages have less phagocytic activity than alveolar macro-
to tonically suppress the development of inappropriate immune phages, they have increased ability to present antigens to T cells.
responses. Relatively few lymphocytes are present in the normal Upon activation, these macrophages express a variety of cytokines,
lung parenchyma. However, after stimulation by the relevant including tumor necrosis factor-α (TNF-α) and monocyte
antigen in the lung-draining lymph nodes, antigen-specific chemotactic protein-1 (MCP-1). In addition to antigen presenta-
lymphocytes migrate to the lung and participate in the inflam- tion to T cells, macrophages are important for lung fibrosis and
matory response. In addition to lymphocytes, other inflammatory tissue remodeling in immunological lung diseases through
and immune cells, including neutrophils, eosinophils, and other secretion of specific growth factors, such as transforming growth
mononuclear cells, accumulate in the lung of patients with factor-β (TGF-β), insulin-like growth factor-1 (IGF-I), platelet-
immunological lung disease, depending on the underlying disease. derived growth factor (PDGF), and fibroblast growth factor
Within the normal alveolus, the major cellular constituents are (FGF).
alveolar macrophages and epithelial cells. Resident dendritic cells T cells are also associated with lung fibrosis. For example,
(DCs) also project dendrites through the tight junctions of the T cells have been located in areas of interstitial fibrosis and
alveolar epithelium to sample the alveolar space. An initial insult honeycombing with relatively fewer in areas of normal lung
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typically involves the alveolar epithelial cell. Damage to type I in patients with IPF. In connective tissue disease–associated
alveolar epithelial cells results in release of chemokines that recruit interstitial lung disease (ILD), T cells are diffusely distributed
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and activate inflammatory cells, allowing for resolution of throughout the lung and within focal lymphoid aggregates.
inflammation and repair of injured tissue (Fig. 72.1). With either In animal models, depending on their phenotype, T cells can
prolonged exposure or failure to adequately clear an inhaled be either profibrotic or antifibrotic. γδ T cells decrease lung
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antigen, persistent inflammation results in extracellular matrix inflammation and fibrosis in multiple mouse models. CD8 T
(ECM) deposition, culminating in tissue remodeling, progressive cells have been found in high proportion in BAL and surgical
collagen deposition, and pulmonary fibrosis. Impaired ventilation lung biopsy samples from patients with IPF, as well as patients
and gas exchange occur as a consequence of lung fibrosis, resulting with systemic sclerosis, but their role in these immunological
in patient morbidity and mortality. With destruction of type I lung diseases is not well understood.
alveolar epithelial cells, exposure of the underlying basement Different subsets of CD4 T cells (Chapter 16) have been
membrane can cause further inflammation. Proper restoration implicated in the pathogenesis of immunological lung diseases.
of the epithelial barrier is critical for resolution of lung inflam- T-helper type 1 (Th1) cells express interferon-γ (IFN-γ). Although
mation. Type II alveolar epithelial cells can serve as progenitor IFN-γ is a potent proinflammatory cytokine, it has antifibrotic
cells that migrate and differentiate into type I alveolar epithelial effects through inhibiting fibroblast proliferation and collagen
cells to reestablish an intact lung epithelium. expression. Th2 cells are defined by expression of IL-4, IL-5, and

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