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Figure 7.1 Latency of new, work-related symptoms or development of sensitization to rat urinary allergens. (Cullman, P., et al., Eur. Respir. J., 1999; 13:1139-1143. Reproduced with permission.) 25

As methods to measure aeroallergen exposure have been developed, studies are beginning to explain the relationship of measured allergen exposure with development of allergy, symptoms of allergy, and biological evidence of sensitization.18,20,25 The prevalence of LAA has been shown to be associated with length and intensity of exposure to aeroallergens.18,20 Similar findings were reported in the one study that has examined the relationship between exposure and incidence of LAA.25

Although an exposure-response relationship has now been demonstrated for animal allergens, the nature of this relationship is not fully understood. The total dose of allergens accumulated over a period of animal exposure is a function of exposure intensity and exposure duration. In the case of LAA, it has been suggested that intensity and duration are not equivalent and peaks of high-intensity exposure may be more important.25,31 Both studies of the exposure-prevalence relationship and the study of incidence are consistent with a key role for peaks of exposure. However, there appears to be an exposure-response plateau at high exposure, for which there may be other explanations than healthy worker selection. Some individuals may develop immunological tolerance during high or constant exposure, as has recently been observed in the development of allergy to cats;32 this hypothesis must be studied longitudinally regarding LAA, which has not yet been done.

Apart from inhalation, it is not known what other mechanisms of exposure (such as mucocutaneous contact) have in the development of LAA. Skin contact is certainly relevant in the development of skin symptoms, such as contact urticaria,33 and may have a role in respiratory tract symptoms. Respiratory sensitization following skin exposure to chemicals has been described,34 and percutaneous exposure to animal allergen has been associated with acute (anaphylactic) respiratory symptoms.2,35,36

These exposure-response observations have important implications for strategies to control allergen risks. Studies suggest that reducing total exposure to aeroallergen may prevent allergy.18,20,25 However, reductions in aeroallergen exposure alone are likely to be inadequate. Measures should also be taken to reduce the number and intensity of peaks of exposure and the possibility of exposure by and through skin contact and by ingestion.

Animal Allergens

Several sources of allergens have been found in rodents, such as urine, fur, saliva, skin, and serum.3 However, about 90% of those who are allergic to rats or mice react to the closely related allergens Rat n 1.01 (alpha2u-globulin) and Rat n 1.02 (prealbumin) from rat37 and Mus m 1 (or the MUP complex) from mouse.38 Sensitization to one of the species is often associated with sensitization to the other.22 Thus, developing allergy against, for instance, rat increases the risk of soon becoming allergic also to mouse. The proteins are mainly excreted in urine, but minor amounts are also excreted in saliva and by perianal and other glands.39 The excretion is sex-, age-, and diet-dependent, and post-pubertal male urinary levels may be more than a hundredfold higher than in mature females or pre-pubertal animals.38,40 These allergens are transport pheromones, which are important for sexual communication and will influence other males, pregnant and non-pregnant females and pre-pubertal animals in a range of ways.41 The allergens belong to a rapidly growing group of molecules called lipocalins. Many other major fur-animal allergens, such as Equ c 1 from horse and Can f 1 from dog, also belong to the lipocalin superfamily.42 The molecules are structurally similar and have the capacity to bind or transport hydrophobic molecules within a barrel-shaped pocket. Other allergens from rodents are, for instance, rat albumin (68 kD), to which about 30% of rat-allergic subjects react.43,44 Allergens of 10-40 kD in urine, saliva, fur, and dander from guinea pigs and rabbits also cause LAA symptoms.45-47

Pathogenesis

Subjects who are hypersensitive to animals usually have an immediate type, IgE-mediated allergic reaction. This reaction is preceded by a sensitization process. Upon exposure to allergens, local cells belonging to the immune system (antigen-presenting cells) internalize the allergens. The molecules are processed, and pieces of the antigens are presented to T-helper lymphocytes. The production of signalling molecules called cytokines, especially Interleukin-4 (IL-4), will induce B-lymphocytes to proliferate and produce immunoglobulin E (IgE) antibodies with specificity against these allergen epitopes. IgE antibodies are released and bound to IgE receptors on the surfaces of certain white blood cells, notably mast cells. Next, mast-cell contact with the relevant allergens initiates a series of events. The cross-linking of IgE receptors on the mast-cell surface through binding of allergen causes degranulation: the numerous granules within the mast cell rapidly eject their contents. The mast-cell granules contain several preformed molecules, such as histamine, tryptase, and cytokines, and new synthesis of, e.g., leukotrienes and prostaglandins is stimulated. Histamine and other released factors have immediate effects on local blood vessels, mucous membranes, and airway smooth-muscle tissue, causing leakage and swelling, bronchoconstriction, etc. In highly sensitive subjects, the allergic reaction can cause rapid systemic effects (anaphylactic shock). The released molecules also mobilize other types of white blood cells. A late-phase response may follow, peaking at 4 to 8 hours after exposure, and involve inflammatory cells, such as eosinophils, attracted to the target tissues. Immune cells are activated, which potentiates and prolongs the allergic inflammation.

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