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  • Review Article
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The immunogenetics of asthma and eczema: a new focus on the epithelium

Nature Reviews Immunology volume 4, pages 978–988 (2004)Cite this article

Key Points

  • Asthma is an inflammatory disease of the small airways of the lung. It shares some immunological features with atopic dermatitis (AD), the most common skin disease of childhood. Asthma and AD have now reached epidemic proportions.

  • Immunoglobulin E (IgE)-mediated sensitivity to allergens and the maintenance of IgE responses through a T helper 2 (TH2)-cell bias is currently considered to be central to the initiation of asthma and AD. However, this view has several inconsistencies with epidemiological observations of the diseases.

  • Asthma prevalence has been linked to progressive westernization of lifestyle, and a protective effect against asthma of microbial exposure in early childhood has been observed in many studies. The challenge is to explain this protective effect at the molecular level and so prevent disease.

  • The basic causes of asthma and AD are still unclear and it is helpful to understand their genetic basis. This review describes what is known about the genetics of asthma and AD, and then suggests potential mechanisms to explain the interaction between genes and the environment in disease pathogenesis.

  • Genome screens for asthma and AD have shown that the two diseases show only partial genetic overlap. This indicates that susceptibility to asthma and AD are mediated through different genes, rather than through a common atopic background. The AD loci are however closely coincident with psoriasis susceptibility loci, suggesting that particular genes or families of genes have general effects on immune reactions in the skin.

  • Genetic mapping studies have now identified several genes underlying asthma and AD. Many of these are expressed in the terminally differentiating epithelium, as are genes for psoriasis and inflammatory bowel disease. The expression of these genes in the skin or mucosa indicates that understanding innate mechanisms of epithelial defence is essential to the treatment and prevention of asthma and AD.

  • Mechanisms of epithelial immunity include barrier defences, danger recognition and the call for help. These mechanisms are reviewed because of their impact on understanding asthma and AD.

  • A focus on the epithelium encourages investigation of the mechanisms by which allergens damage the epithelium, the danger signals and pattern-recognition receptors that they activate, and the early signalling pathways that are used to recruit specific components of the innate and adaptive immune systems.

  • Genetic studies indicate the occurrence of many previously unknown or ignored molecules, such as the S100 proteins from the epidermal differentiation complex, which might be novel targets for the control and suppression of epithelial inflammation.

  • A central mystery of asthma revolves around the protective effect of microbial exposures in childhood. This effect has mainly been investigated in the context of TH1- or TH2-type biased responses, but it might also be explicable by mechanisms confined to epithelial-cell surfaces. It is probable that a full understanding of asthma and AD will also depend on studies that include the commensal bacteria.

Abstract

Asthma and eczema (atopic dermatitis) are the most common chronic diseases of childhood. These diseases are characterized by the production of high levels of immunoglobulin E in response to common allergens. Their development depends on both genetic and environmental factors. Over the past few years, several genes and genetic loci that are associated with increased susceptibility to asthma and atopic dermatitis have been described. Many of these genes are expressed in the mucosa and epidermis, indicating that events at epithelial-cell surfaces might be driving disease processes. This review describes the mechanisms of innate epithelial immunity and the role of microbial factors in providing protection from disease development. Understanding events at the epithelial-cell surface might provide new insights for the development of new treatments for inflammatory epithelial disease.

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Figure 1: Classical mechanisms of atopy in asthma and atopic dermatitis.
Figure 2: Susceptibility loci identified by genome screens for asthma, atopic dermatitis and other immune disorders.
Figure 3: The distribution of genes causing susceptibility to asthma and atopic dermatitis.
Figure 4: Defence mechanisms in epithelial cells.

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Authors and Affiliations

  1. Human Genetics, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK

    William Cookson

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DATABASES

Entrez Gene

ADAM33

CD14

CLCA1

DLG5

DPP10

FCERI

IL-4

IL-5

IL-9

IL-13

NOD2

PHF11

PSORS1

S100A12

SLC12A8

SLC22A4

SLC22A5

SLC9A3R1

SPINK5

SPRR2C

TGFB

TIM1

TLR2

TLR10

OMIM

ankylosing spondylitis

multiple sclerosis

Netherton's disease

rheumatoid arthritis

type 1 diabetes

Glossary

ASTHMA

Intermittent inflammation of the airways of the lung and chronic disease can lead to airway scarring and irreversible limitation of airflow.

ATOPIC DERMATITIS

(eczema). A scaly, itchy rash that typically occurs in the flexures of the elbows and knees, but can also be found anywhere on the body.

ATOPY

(meaning 'strange disease'). A term invented to describe the familial syndrome of asthma and hay fever and their association with positive skin-prick tests.

ALLERGENS

Common inhaled proteins that induce allergic responses. Typical allergen sources include house-dust mite, grass pollens and animal danders (droppings from skin and fur).

WHEAL-AND-FLARE RESPONSE

The acute response of the skin to an allergen in a skin-prick test. The wheal is a swelling of the epidermis around the site of the prick (usually several millimetres in diameter). The flare is a reddening of the skin over a wider area that is induced by neuronal mechanisms.

SKIN-PRICK TEST

The introduction of minute amounts of allergen into the epidermis by a prick or scratch induces mast-cell degranulation if allergen-specific IgE is present. A wheal and flare is visible if degranulation takes place, and its size is used as a measure of an individual's allergen sensitivity.

ANAPHYLAXIS

The generalized release of histamine and other inflammatory mediators following systemic induction of mast-cell degranulation by allergen. Anaphylaxis can cause bronchospasm, cardiovascular collapse and death.

PSORIASIS

The most common skin disease of adults, typically affecting the extensor surfaces of elbows and knees but can also be generalized. It is not associated with atopy.

GENOME SCREEN

The systematic localization of chromosomal regions that are co-inherited with disease. Typically, a panel of markers covering all the chromosomes are genotyped in multiple families containing individuals with the disease.

GENETIC LINKAGE

The identification of a chromosomal region that is co-inherited with disease in families.

POSITIONAL CLONING

The process of systematically identifying disease genes from the study of families. Positional cloning begins with genetic linkage regions, which can cover 20–30 million base pairs of DNA and contain 300 genes. The region is refined to 5–10 genes by genetic 'fine mapping', and the remaining genes are studied individually to determine whether they contribute to disease.

CORNIFIED ENVELOPE

The cell walls of fully differentiated keratinocytes, which form the stratum corneum.

CANDIDATE GENES

Known genes that are investigated for a role in disease by the comparison of polymorphisms in patients and controls.

STRATUM CORNEUM

The mechanically and chemically resistant outermost layer of the skin, which is made up of a complex mixture of lipids and proteins.

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

A disease of irreversible airway constriction. It usually results from a combination of cigarette smoking and asthma.

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Cookson, W. The immunogenetics of asthma and eczema: a new focus on the epithelium. Nat Rev Immunol 4, 978–988 (2004). https://doi.org/10.1038/nri1500

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