Humoral and cell-mediated autoimmunity in allergy to Aspergillus fumigatus.

Abstract

SummaryA cDNA encoding an allergenic protein was isolated from an Aspergillusfumigatus (/1. fumigatus) cDNA library displayed on the surface of filamentous phage. Serum immunoglobulin E (IgE) from A. fumigatus--sensitized individuals was used to enrich phage-expressing gene products binding to IgE. One of the cDNAs encoded a 26.7-kD protein that was identified as a manganese superoxide dismutase (MnSOD) sharing 51.5% identity and 67.2% homology to the corresponding human enzyme. Both human and A. fumigatus MnSOD coding sequences were expressed in Escherichia coli as [His]6-tagged fusion proteins and purified by Ni2+-chelate affinity chromatography. The two recombinant MnSODs were both recognized by IgE antibodies from subjects allergic to the A. fumigatus MnSOD and elicited specific immediate type allergic skin reactions in these individuals. Moreover, both human and A. fumigatus MnSOD induced proliferation in peripheral blood monouuclear cells of A. fumigatus-allergic subjects who showed specific IgE responses and reacted in skin tests to MnSOD. These observations provide evidence for autoreactivity to the human MnSOD in allergic persons sensitized to an environmental allergen from A.fumigatus who share a high degree of sequence homology to the corresponding human enzyme.

Cross-Reactivity and 1.4-Å Crystal Structure ofMalassezia sympodialisThioredoxin (Mala s 13), a Member of a New Pan-Allergen Family

“…Perhaps the most interesting class of pan-allergens includes environmental allergens sharing structural homology to self-Ags. These structures, including manganese superoxide dismutase, acidic ribosomal P 2 proteins, cyclophilins, and profilins (9,11,12,20,38), have been implicated in exacerbation and/or perpetuation of severe atopic disorders. In contrast to allergenicity, which is an intrinsic property of many different molecular structures, Ab-mediated cross-reactivity among homologous proteins is largely determined by common structural features shared between protein families (13).…”

T Cell Vaccination in Mice with Invasive Pulmonary Aspergillosis

“…However, whether Th2 cells or some regulatory cells, known to mediate some forms of nasal tolerance (67), mediate the effects of Asp f 2 in IPA remains to be determined. The occurrence of autoreactivity in patients suffering from chronic A. fumigatus allergy (39,40) indicates the complexity of the allergic responses to Aspergillus. A number of studies indicate that lung DC play a primary role in surveillance of pathogenic Ags and initiation of a primary immune response in the lung (47,68,69).…”

Overview of Aspergillus Allergens

“…Interestingly some of these proteins show cross-reactivity also with their homologous human proteins at both, humoral and cellular level. The best investigated structures at this level are human MnSOD [57,58], cyclophilin [30,61] and thioredoxin [29], which were shown to bind to serum IgE from A. fumigatus sensitised patients in vitro, to elicit specific skin test reactions in vivo, and to be potentially involved in the pathogenesis of ABPA and atopic eczema [18,63]. Although the role played by IgE-mediated autoreactivity to self-antigens remains controversial, the fact that the application of human MnSOD in patch test on healthy skin areas of atopic eczema patients sensitised to fungal MnSOD is sufficient to induce an eczematous reaction [57,63] strongly indicates that autoreactivity could contribute to the exacerbation of the symptoms in the absence of external exposure to environmental allergens.…”

“…Basically cross-reactivity can be traced back to conserved proteins sharing common B and T cell epitopes as shown for many allergen structures [33]. Amongst these MnSOD (Asp f 6) [57,58], P 2 acidic ribosomal protein (Asp f 8) [59], cyclophilins (Asp f 11 and Asp f 27) [30,60,61] and thioredoxins (Asp f 28 and Asp f 29) [29] have been shown to belong to families of cross-reactive pan-allergens. Per definition pan-allergens share a high degree of sequence identity at primary structure level, thus belonging to protein families showing similar structural folding [33,62].…”