Atopic Dermatitis, Patch Testing, and House Dust Mites: A Brief Review

Alde Carlo P. Gavino; Glen R. Needham; Whitney A. High

Disclosures

Dermatitis. 2008;19(3):121-128. 

In This Article

HDMs and Their Mechanistic Role in AD

The European HDM, Dermatophagoides pteronyssinus (Der p), and the American HDM, Dermatophagoides farinae (Der f allergen) (fig1), are the most common mites that thrive in household dust[16] one of the major environmental aeroallergens to which AD patients are hypersensitive. According to the official list of allergens maintained and updated (March 7, 2007) by the Allergen Nomenclature Sub-Committee of the International Union of Immunological Societies, 14 Der p and 14 Der f allergen groups have been identified thus far ( Table 1 ).[17] Of these allergens, group 1 (Der p 1 and Der f 1) and group 2 (Der p 2 and Der f 2) are most allergenic[18,19]; specifically, they bind IgE in 80 to 100% of tested sera obtained from patients allergic to HDM.[20] Moreover, several studies have consistently shown a high rate of positivity for specific IgE antibodies to group 1 and 2 allergens in HDM-sensitized patients.[21–25]

Figure 1.

Scanning electron micrograph of a Dermatophagoides farinae mite. (×1300 original magnification).

The group 1 allergens Der p 1[26] and Der f 1[27] are 25 kD cysteine proteases that have 30% sequence homology with papain.[28] They have an amino acid sequence homology of 81%[27] and incite both cross-reacting and species-specific antibodies.[29] The group 1 cysteine proteases are believed to be secreted into the mite's gut[30] probably as digestive enzymes, and accumulate in mite cultures mostly in association with fecal balls (the remainder is associated with whole mites and cuticles).[31] Fecal particles from mite cultures have been found to contain as much as 10 mg/mL of Der p 1.[31] It has been suggested that as little as 2 μg of group 1 allergens per gram of dust is needed to sensitize an individual to HDMs.[32]

Der p 2[33] and Der f 2[34] on the other hand, are 14kD proteins that have a very high sequence homology (88%)[34] with each other, accounting for the almost completely cross-reactive antibody responses they elicit.[35] In the past, the group 2 allergens were believed to be lysozymes[36] but this hypothesis has been disproven.[37] Although the exact nature and function of these proteins has remained elusive, there is mounting evidence that the group 2 allergens may be involved in the recognition and binding of lipids.[38] Der p 2 and Der f 2 are currently classified under the Niemann-Pick type C2 (NPC2) family of proteins (see Table 1 ).[17] NPC2, a distant homologue of the group 2 allergens[39] is a soluble lysosomal glycoprotein that binds cholesterol.[40] Furthermore, recent studies have shown that the group 2 allergens have structural characteristics that are very similar to those of MD-2[39,41] a protein that recognizes bacterial lipopolysaccharides (by forming a complex with Toll-like receptor 4 and CD14 on the cell surface) and initiates an immune response against them.[42]

Although definite causality has yet to be determined, it has been alleged that HDMs play a role in the immunopathogenesis of AD. Not only do AD patients have elevated levels of serum IgE antibodies specific to HDM allergens, biopsy specimens of AD lesional skin have also been shown to be infiltrated with T lymphocytes that recognize Der p.[43] Through cysteine protease activity, group 1 allergens mediate several mechanisms by which HDMs might promote AD. For example, it has been shown that Der f 1 may facilitate its entry into AD skin by enzymatically breaking down the epidermal barrier[44] in much the same way that Der p 1 is able to increase the permeability of bronchial epithelium to serum albumin in vitro.[45] This protease-mediated epithelial disruption, coupled with a genetically determined barrier defect recently found in AD patients[46] provides for the easy entry of various allergens that may promote and perpetuate the disease.

Another proposed mechanism by which HDMs may promote AD is through their potent immunomodulatory effects. Mite allergens are able to activate keratinocytes and induce them to produce and secrete proinflammatory cytokines.[47] Moreover, Der p 1 is able to polarize immunity toward a Th2 type by (1) cleaving the low-affinity IgE receptor (CD23) on B cells, resulting in up-regulation of IgE synthesis[48]; (2) cleaving the alpha subunit (CD25) of the interleukin (IL)-2 receptor on T cells, causing inhibition of T-cell proliferation and reduced production of interferon (IFN)-γ, a Th1 cytokine[49]; and (3) cleaving CD40 on DCs, leading to decreased production of IL-12, another Th1 cytokine.[50] Recently, it was demonstrated that Der p 1 also has the ability to cleave DC-SIGN and DC-SIGNR, C type lectin receptors expressed by DCs that interact with T cells to promote Th1 immunity.[51] Cleavage of these receptors abrogates Th1 immune responses, giving way to the uninhibited propagation of Th2 immunity.[51]

Additionally, it is believed that delayed-type hypersensitivity (DTH) reactions characteristic of eczematous AD skin lesions may result from potentiated ability of LCs and DCs to process allergens. IgE-bearing LCs, as opposed to those lacking surface IgE, present HDM allergens to T cells with greater efficiency.[52] Also, DCs of atopic patients that are sensitized to HDMs express increased levels of mannose receptors, compared to those of nonatopic subjects, and more efficiently capture Der p 1 by a mannose receptor–dependent mechanism.[53] The independent role that LCs and DCs play in the pathogenesis of AD is supported by the fact that not all AD patients with elevated serum mite-specific IgE antibodies (an indicator of immediate-type hypersensitivity) show a positive response to patch testing (a model for DTH) with mite allergens.[54,55]

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