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Taking our breath away: dendritic cells in the pathogenesis of asthma

Abstract

Dendritic cells (DCs) are mainly known for their capacity to induce primary immune responses. Here, we propose that DCs are similarly essential for controlling effector T-cell responses and, therefore, might have a role in T-cell-mediated diseases. In the case of asthma, airway DCs are essential for controlling T helper 2 (TH2)-dependent eosinophilic airway inflammation. Therefore, interfering with DC function could be of therapeutic benefit.

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Figure 1: Distribution of dendritic cells in the lungs.
Figure 2: An integrated overview of DCs and CD4+ T-cell migration during primary and secondary immune responses.
Figure 3: Koch's postulates applied to dendritic cells in experimental asthma.
Figure 4: Role of airway dendritic cells during ongoing inflammation.

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Acknowledgements

The research in our laboratory is supported by grants from the Dutch Asthma Foundation and the Netherlands Organization for Scientific Research. H.H. is a recipient of a European Union Marie Curie Foundation Fellowship. We greatly acknowledge the work of our students and colleagues, in particular L. van Rijt, H. Kuipers, H. de Heer, A. Kleinjan and H. Hoogsteden.

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Correspondence to Bart N. Lambrecht.

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DATABASES

LocusLink

CCL5

CCL17

CCL20

CCL22

CCR4

CD80

CD86

CXCL10

GM-CSF

ICOSL

IL-4

IL-5

IL-10

IL-12

IL-13

OX40

OX40L

TGF-β

Glossary

ATOPY

The propensity for developing allergic diseases, such as asthma, atopic dermatitis, food allergy or hay fever, defined operationally by increases in serum levels of IgE reactive with allergens or by skin-test reactivity to allergens.

BRONCHOALVEOLAR LAVAGE

A technique that is often used experimentally or in clinical practice to sample the cellular or biochemical components of the conducting airways and lung alveoli. It is carried out by placing a tube in the trachea or large conducting airways and rinsing the downstream compartment with saline.

CENTRAL MEMORY T CELLS

Memory T cells that home to secondary lymphoid organs. These cells are heterogeneous and do not have the full range of functions that are characteristic of effector T cells. They are responsible for secondary or chronic responses to antigen and might be involved in long-term maintenance of effector-memory cells.

DEFENSINS

These are natural, broad-spectrum antibiotic cysteine-rich peptides that kill bacteria and fungi. β-defensins are released by epithelial cells of the skin, gut and lung in response to inflammatory cytokines. α-defensins are found inside the granules of neutrophils.

GOBLET CELL

Specialized epithelial cell that secretes mucin, easily recognized by staining with periodic acid Schiff reagent. Goblet cells are found scattered among other cells in the epithelium of the intestine and respiratory tract. Goblet refers to the morphology, known to be an artefact of fixation in which mucus-laden granules in the apical portion of the cell expand, causing the cell to balloon.

HOUSE DUST MITE

The mite Dermatophagoides pteronyssinus is ubiquitously present in our homes, where it feeds on exfoliated human skin. It grows particularly well in moist environments. Its faecal pellets contain numerous allergens (Der p1–Der p9), many of which have enzyme activity.

HYGIENE HYPOTHESIS

First proposed by Strachan, it proposes that reduced microbial exposure, because of increased sanitation and cleaner lifestyles, has facilitated the rise in asthma and allergic disease in the Western world. The same theory could also explain the rise in some autoimmune diseases such as type 1 diabetes and multiple sclerosis.

INVARIANT NATURAL KILLER (NK) T CELLS

Lymphocytes that express Vα14 (mice) or Vα24 (humans) precisely rearranged to particular Jα gene segments to give T-cell receptor α-chains with an invariant sequence. Typically, they co-express cell-surface markers that are encoded in the NK locus and they are activated by recognition of CD1D, particularly when an α-galactosyl ceramide is bound in its groove.

PATTERN RECOGNITION RECEPTORS

(PRRs). Receptors that bind to molecular patterns found in pathogens, but not mammalian cells. Examples include the mannose receptor, which binds to terminally mannosylated and polymannosylated compounds, and Toll-like receptors, which are activated by various microbial products, such as bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA.

PLASMACYTOID DENDRITIC CELLS

A subset of dendritic cells (DCs) that were first described in humans and termed plasmacytoid because of their microscopic appearance, which is similar to plasmablasts. In humans, these DCs can be derived from lineage-negative stem cells in peripheral blood and are the main producers of type I interferons (IFNs) in response to infection with virus. Recent studies have identified a subset of type I IFN-producing DCs in mice, which are characterized by the expression of B220 and Ly6C/G.

T HELPER 2 CELL

(TH2 cell). A type of T cell that, through the production of interleukin-4 (IL-4), IL-13 and other cytokines, can help B cells to produce IgE and other antibodies and, through the secretion of IL-5, IL-3 and others, can promote increased numbers of eosinophilic granulocytes (eosinophils), basophils and mast cells.

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Lambrecht, B., Hammad, H. Taking our breath away: dendritic cells in the pathogenesis of asthma. Nat Rev Immunol 3, 994–1003 (2003). https://doi.org/10.1038/nri1249

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