Endotoxins, asthma, and allergic immune responses

doi:10.1016/S0300-483X(00)00289-4

Toxicology

Volume 152, Issues 1–3, 2 November 2000, Pages 31-35

https://doi.org/10.1016/S0300-483X(00)00289-4 Get rights and content

Abstract

Asthma severity depends to a great extent on the levels of endotoxin present in the microenvironment. Although favouring a Th1 cytokine response that could be beneficial to the asthmatic, lipopolysaccharide (LPS) aggravates bronchopulmonary inflammation by several mechanisms. These include neutrophil and eosinophil recruitment, and release by activated macrophages of pro-inflammatory cytokines and nitric oxide. LPS exerts its biological actions through its interaction with CD14. The genetic locus of CD14 is close to the genomic region controlling levels of IgE. A polymorphism in the CD14 promoter region seems to favour high serum IgE levels. Genetic influences may thus control circulating levels of sCD14 and by this mechanism modulate Th1/Th2 balance and IgE synthesis. LPS exposure, although hazardous to the asthmatic, seems to exert a role in the maturation of the immune system in children towards a Th1-skewed pattern.

Introduction

The understanding of the interactions between environmental changes and individual predisposition to respiratory diseases is increasing, and this includes the relationship between microorganisms and allergy. The demonstration that endotoxin, and specifically its main constituent lipopolysaccharide (LPS), is present in indoor dust and that the severity of asthma is related to the amount of endotoxin present in house dust in a dose-dependent manner (Michel et al., 1996), opened new horizons for the study of the role of LPS in allergic inflammation. Interactions between inhaled endotoxins and allergens in the bronchoalveolar compartment of the lungs of asthmatic patients could amplify the local inflammatory response, rendering the clinical manifestations more severe and difficult to control. In other words, endotoxins present in the indoor environment could act as an adjuvant to allergens.

The possible mechanisms involved in these phenomena will be discussed here, including a broader approach to endotoxins as adjuvants in relation to the Th1/Th1 paradigm, so important to the understanding of asthma pathogenesis.

Section snippets

LPS as a pro-inflammatory agent

Endotoxins are a constituent of the outer layer of gram-negative bacteria and can be found in house dust, tap water, and in milk. LPS is the main component of endotoxin and it is formed by a phosphoglycolipid, called lipid A, that is covalently linked to a hydrophilic heteropolysaccharide (Rietschel et al., 1994). Lipid A connects the polysaccharide chains and it is responsible for the LPS toxicity. Five types of LPS receptors have been characterised. CD14 is a glycoprotein of 55 kD expressed

LPS and the Th1/Th2 balance in asthmatics

It seems clear that LPS in general shifts the cytokine response towards a Th1 balance. Mattern et al. (1994) demonstrated that LPS/lipid A induces T cell proliferation and production of IFN-γ but not of IL-4, IL-5, or IL-10. This T cell proliferation depends on the presence of LPS-activated monocytes and cell-to-cell contact, suggesting a role for CD40L or other co-stimulatory molecules. Other evidence indicates that the ligation of CD14 to LPS can induce production of IL-12 by macrophages.

Role of CD14 in T cell biology and allergy

The biological effects of LPS depend on its interaction with CD14, either soluble or fixed in cell membranes. CD14 itself has an important role in lymphocyte biology, as elucidated in recent work by Nores et al. (1999). They tested a possible direct effect of CD14 on the regulation of T cell activation and function by showing that sCD14 induces inhibition of T cell proliferation through a marked inhibition of IL-2 production by these cells and also inhibits the production of IFN-γ and IL-4.

Conclusion

LPS is an important adjuvant related to asthma severity through aggravation of bronchial inflammation but may re-equilibrate the Th1/Th2 balance to the Th1 side. Asthma and allergy are on the rise throughout the world, especially in the developed world, where cleaner, relatively aseptic microenvironments are frequently offered to affluent children, as part of the so-called Western style of life. The lack of exposure to LPS or to naturally occurring infections in children may delay maturation of

Acknowledgements

MDPS was supported by a scholarship by CAPES/Brazilian Ministry of Education. J.R. Lapa e Silva was Chercheur Etranger INSERM (Poste Orange).

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Endotoxins, asthma, and allergic immune responses

Abstract

Introduction

Section snippets

LPS as a pro-inflammatory agent

LPS and the Th1/Th2 balance in asthmatics

Role of CD14 in T cell biology and allergy

Conclusion

Acknowledgements

J. Allergy Clin. Immunol.

J. Allergy Clin. Immunol.

Immunity

Immunol. Lett.

Cytokine

A polymorphism in the 5′ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E

Am. J. Respir. Cell Mol. Biol.

Interleukin-4 and lipopolysaccharide synergise to induce vascular cell adhesion molecule-1 expression in human microvascular endothelial cells

Am. J. Respir. Cell Mol. Biol.

Asthma and endotoxin: lipopolysaccharide-binding protein and soluble CD14 in bronchoalveolar compartment

Am. J. Physiol.

Environmental factors and and primary T-cell sensitization to inhalant allergens in infancy: reappraisal of the role of infections and air pollution

Pediatr. Allergy Immunol.

Neutrophil inflammation in severe persistent asthma

Am. J. Respir. Crit. Care Med.

Systemic administration of endotoxin induces bronchopulmonary hyperreactivity dissociated from TNF-α formation and neutrophil sequestration into the murine lungs

J. Immunol.