Risk factors that have been identified include family history, exposure to environmental tobacco smoke, indoor dampness, small family size and absence of early infection, absent or short breast feeding, early exposure to environmental aero allergen and perhaps pollution or dietary factors. Early manifestations are often those of food allergy or eczema in infancy.
Many of these infants go on to develop allergic respiratory disease, providing a rationale for intervention if these disorders are recognized early. In one study, for example, around 25 % of random infants in one study go on to develop rhinitis or asthma over a 5-year period, and the risk is approximately doubled if both parents are known to be atopic.
Antigen processing and the concept of Th1-Th2
responses
Intact allergen / antigen is processed
by antigen presenting cells (such as macrophages or dendritic
cells in the airway epithelium) into small amino acid peptides,
then presented on the surface of cells as a complex of MHC class
II and peptide. T cells are capable of recognizing this complex
if specific for this antigen, and become stimulated. The types
of cytokines secreted by these T cells is dependent on the initial
environment in which initial sensitization occurred.
"Uncommitted" T cells sensitized in an environment high in IL-4 or IL-10 tend to secrete IL-4, IL-5 or IL-10, thus promoting immunoglobulin class switching and the production of IgE by B cells, and the attraction of eosinophils into the tissue. These are known as "Th2 cells".
By contrast, T-cells initially sensitized in an environment high in TNF, interferon-gamma or IL-12 tend to produce similar cytokines, and promote delayed type hypersensitivity and destruction of intracellular organisms ("Th1 cells"). The cytokines secreted by Th1 and Th2 cells are mutually inhibitory, which means that once one response dominates, the other is often suppressed. This means that once a bias is established (as in allergic disease), it is often hard to alter, except with specific immunotherapy.
The intrauterine environment and allergen
sensitization
Pregnancy is a Th2-biased state. High
levels of Th-1 like cytokines are associated with fetal loss,
both in humans and animal models. The dendritic cell network (which
biases towards a Th1 response if presenting antigen) are poorly
developed in the fetus and young infants.
T cell responses to dietary and inhaled allergens
have been detected as early as 22 weeks gestation, with the implication
that allergens may be carried across the placenta to the fetus,
either as intact protein, peptides or allergen/maternal antibody
complexes. Cytokines are known to be present within the amniotic
fluid, which will come into direct contact with the developing
respiratory and gastrointestinal mucosa.
This means that the developing fetal immune response is potentially
developing in an environment favoring Th2-like responses. Levels
of amniotic fluid IL-4 and 10 are even higher in atopic mothers,
perhaps accounting for the greater risk of inheriting allergy
from one's mother than father. The ratio of IL-4 / interferon-gamma
by peripheral blood T cells is high in the neonate and even higher
is those with an atopic family background. The end result is a
bias in Th2 over Th1 responses in the neonate and infancy that
appears to be set early in infancy, and which may then be modified
by the environmental factors described above.
Alteration of the Th1/2 bias by specific
immunotherapy
One hypothesis to explain the efficacy
of immunotherapy (for which there is now strong experimental evidence
in both animals and humans) is that injection of allergen selectively
stimulates a Type I response, resulting in eventual inhibition
of the Type 2 response.
Not only would this result in the eventual
reduction in allergen specific IgE, but the alteration of cytokines
produced such as IL4 and IL5 would also alter the types of cells
which are recruited into the nose or respiratory tree which are
responsible for the late allergic response. This is because the
late allergic response is responsible for the chronic inflammation
observed in patients with chronic allergic rhinitis and asthma,
and therefore the nasal and bronchial hyperreactivity, respectively,
observed in both conditions.
