Lipopolysaccharide-enhanced, Toll-like Receptor 4–dependent T Helper Cell Type 2 Responses to Inhaled Antigen

By S. Eisenbarth, D. Piggott, J. Huleatt, I. Visintin, C. Herrick, K. Bottomly. Journal of Experimental Medicine, 2002

1,204 citations recorded by the source corpus.

Allergic asthma is an inflammatory lung disease initiated and directed by T helper cells type 2 (Th2). The mechanism involved in generation of Th2 responses to inert inhaled antigens, however, is unknown. Epidemiological evidence suggests that exposure to lipopolysaccharide (LPS) or other microbial products can influence the development and severity of asthma. However, the mechanism by which LPS influences asthma pathogenesis remains undefined. Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 (Th1) responses, it is unclear if TLRs are needed for Th2 priming. Here, we report that low level inhaled LPS signaling through TLR4 is necessary to induce Th2 responses to inhaled antigens in a mouse model of allergic sensitization. The mechanism by which LPS signaling results in Th2 sensitization involves the activation of antigen-containing dendritic cells. In contrast to low levels, inhalation of high levels of LPS with antigen results in Th1 responses. These studies suggest that the level of LPS exposure can determine the type of inflammatory response generated and provide a potential mechanistic explanation of epidemiological data on endotoxin exposure and asthma prevalence.

Subfields: Immunology, Physiology

View Paper: https://www.semanticscholar.org/paper/d1a056d9e46692e9ac500d2f5d56e94141100310

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In Immunology

1. Shizuo Akira
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4. T. Kaisho
5. B. Lambrecht
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In Physiology

1. H. Hammad
2. B. Lambrecht
3. Luke A. O'Neill

Citations in the corpus

• House dust mite allergen induces asthma via TLR4 triggering of airway structural cells (2009, background): “For comparison, some mice were also injected with a low (100 ng) and high (10 μg) dose of endotoxin, which has been previously shown to induce T H 2 and T H 1 immunity, respectivel”
• Essential Role of Lung Plasmacytoid Dendritic Cells in Preventing Asthmatic Reactions to Harmless Inhaled Antigen (2004, background): “Despite the occurrence of inhalational tolerance, some authors have witnessed sensitization to inhaled inert antigen, particularly when signals activating the innate immune system were coadministered (14, 22).”
• Negative regulation of Toll-like receptor-mediated immune responses (2005, background): “TLRs also play a crucial part in the induction and progress of chronic inflammatory disorders such as asthma, a T helper 2 (T H 2)-mediated chronic airway disorde”
• Inflammatory dendritic cells—not basophils—are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen (2010, background): “Yet our current work and many previously published studies have shown induction of Th2 immunity by DCs in vitro and in vivo (Lambrecht et al., 2000; Eisenbarth et al., 2002; MacDonald et al., 2002; van Rijt et al., 2005).”
• Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice (2004, background): “, but can also induce a T H 2 response in a mouse model of allergic sensitizatio”
• How are TH2-type immune responses initiated and amplified? (2010, background): “It has been shown that low levels of LPS enhance T H 2-type responses to inhaled antigens, whereas high levels of LPS result in T H 1 cell response”
• Toll-like receptor function and signaling. (2006, background): “Furthermore, LPS can induce TH2 responses at low doses or when inhaled.(12) Most TLR ligands, however, stimulate APCs to produce TH1-inducing cytokines, such as IL-12 and IL-18, and to support TH1-skewed immune responses.”