There are two major classes of food allergic reactions: IgE-mediated and non-IgE-mediated. IgE-mediated allergies usually present soon after ingestion, and thus the causative antigen is often readily identifiable. In addition, there are usually supportive diagnostic tests such as skin prick tests. These reactions are those of type I hypersensitivity (Table 22.2).12,13 They can be very severe, and may cause death through anaphylaxis in severe cases. Non-IgE-mediated allergies usually present later after ingestion, and the causative antigen may be more difficult to detect, particularly as tests for immediate allergies are often negative. These may include type IV hypersensitivity (Table 22.2), or may be caused by local eosinophil recruitment. They can be an important cause of morbidity, which may go unrecognized. The immunological basis of such reactions is discussed later.
Food allergic reactions may also be divided clinically into quick-onset reactions, occurring within an hour of food ingestion, and slow-onset reac tions, taking hours or days. In general, quick onset symptoms are IgE-mediated and slow-onset symptoms are non-IgE-mediated. However, this is by no means invariable, and many children with clear quick-onset responses to foods have a low or even undetectable serum total IgE level and absent food-specific IgE level.14 It is also notable that mice totally deficient in IgE owing to gene knockout may still suffer anaphylaxis, as IgG1 bound to FCyRIII on mast cells may induce antigen-specific degranulation.15,16 Such a phenomenon may explain why investigations such as skin prick tests may be positive in children despite undetectable specific IgE for that antigen.
Differentiation between IgE-mediated and non-IgE-mediated reactions may therefore be difficult. The Melbourne Milk Allergy Study, conducted by Hill and colleagues,17 identified three types of reaction in sensitized children - immediate reactions (rapid skin reactions with perioral erythema, facial angioedema and urticaria, some developing anaphylaxis), intermediate reactions (gastrointestinal symptoms such as vomiting or diarrhea occurring 1-24 h after ingestion) and delayed reactions (eczema flares or respiratory symptoms such as cough and wheeze, occurring between 1 and 5 days after challenge). The volume of milk required
Table 22.2 The classical forms of hypersensitivity (after reference 12)
Type I: anaphylactic or immediate hypersensitivity
This occurs within minutes of exposure, as seen in quick-onset food allergy. The allergen binds to, and cross-links IgE (occasionally IgG1) on the mast cell surface, inducing its degranulation and release of vasoactive agents (histamine, tryptase, etc.) and cytokines (tumor necrosis factor-a). Responses to some antigens (classically peanut) are usually of this kind.
Type II: cytotoxic hypersensitivity
This reaction occurs when antibody binds to an epitope on the cell surface, then fixes complement, causing complement-mediated cell death. This is not a reaction usually described for food allergy, but complement activation can be detected in celiac disease.
Type III: immune complex hypersensitivity
In this type of reaction, antigen complexes with antibody (IgG or IgM) in the presence of antigen excess, to induce complement fixation and a consequent local inflammatory response, several hours after exposure to the antigen. The expression of Fc receptors for immunoglobulin appears to determine tissue damage.13
Type IV: delayed hypersensitivity or cell-mediated immunity
This reaction is essentially mediated by T lymphocytes, with tissue damage also caused by macrophages responding to T-cell cytokines. The pattern of T-cell responses (Th1 or Th2) may determine overall immunopathology. The classic type IV reaction is a Th1 response, as in Crohn's disease, while both Th1 and Th2 reactions occur in food allergy.
to elicit these symptoms increased between groups, and classic allergy tests such as skin prick tests were helpful only for the first group of early reactors. Knowledge of the time course and likely immunopathogenesis indicates that the early reactions are due to IgE responses and mast cell degranulation, the intermediate reactions follow eosinophil recruitment and the delayed responses are likely to relate to T-cell responses.18 These concepts will be discussed later, in the sections on immunopathogenesis. The Melbourne group have also played an important role in the recognition of the increasing incidence of multiple food allergies, and of the role of food allergy in inducing a spectrum of symptoms not previously associated with allergy.5 The role of food allergy in inducing visceral dysmotility syndromes such as infant colic, gastroesophageal reflux and recurrent abdominal pain will be discussed later.
In a recent study of 121 children with allergy to two or more foods, including both those with IgE-mediated and those with non-IgE-mediated aller-gies,14 children with early-onset symptoms had a significant overall increase in serum IgE compared to those with late-onset symptoms. However, 30% of those with early-onset symptoms had no elevation of IgE concentration above the normal range, while 10% of those with only delayed symptoms did have an elevated IgE concentration. Over 90% of those with early-onset symptoms additionally demonstrated late-onset symptoms. Although the groups differed in IgE responses, they shared, regardless of speed of reaction, a pattern of immune deviation, with increased serum IgG1 and circulating B cells, but reduced IgG2 and IgG4, CD8 cells and natural killer cells. IgA concentrations were at the low end of the normal range or below. This raises the question of whether the propensity to sensitize to food antigens is associated with minor immunodeficiency, a concept first suggested by Soothill,19 who postulated that demonstrated maturational delay in IgA responses predisposed to food allergic sensitization. Further data in support of a link with a developmental delay in IgA maturation was provided by a population survey from Iceland, in which an IgA level at the lower end of the normal range was more predictive of allergic sensitization than was elevated IgE concentration,20 and from other studies of food allergic infants, in which increased B cells and decreased CD8 cells and decreased IgA,
IgG2 and IgG4 were associated with milk allergies and food-sensitive colitis.21,22 These data suggest that there may be a consistent pattern of minor immunodeficiency associated with the process of sensitization in early life, and that the manifestation of that sensitization (quick- or slow-onset) may depend on whether the child has inherited a tendency to high IgE production. Thus, a high IgE level may not cause food allergy per se, but may determine how that allergy is expressed. Most of the early literature on food allergy, however, understandably focuses on IgE and quick-onset responses.
Later in the chapter, the role of infectious exposures in maturation of mucosal immune responses and immune tolerance will be explored. Whether food allergy can be fully explained by the Clean Child Hypothesis7 remains uncertain, but there is substantial circumstantial evidence that these infectious exposures are probably an important contributory factor in the pathogenesis of allergies. Recent recognition of the role of infectious exposures in the generation of cells producing the regulatory cytokine transforming growth factor (TGF)-P, and of the central requirement for TGF-P in both IgA responses and oral tolerance, may provide some explanation for the consistent links with slow IgA maturation.8,19,23
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