Recently we demonstrated that a high percentage of atopic dermatitis (AD) patients displayed specific immunoglobulin E reactivity to human proteins. Here we show that IgE autoreactivity is found predominantly in AD patients with severe skin manifestations and reveal the molecular nature of four IgE autoantigens. An expression cDNA library constructed from a human epithelial cell line (A 431) was screened with serum IgE from two AD patients. DNA sequence analysis of three IgE-reactive clones identified the alpha-chain of the nascent polypeptide-associated complex, cytokeratin type II, and the BCL7B oncogen as atopy-related IgE autoantigens (ara). The fourth cDNA coded for an IgE autoantigen containing a typical calcium binding motif that occurred in histogenetically different cells and tissues (keratinocytes, muscle, brain). Recombinant Escherichia coli-expressed IgE autoantigens bound IgE from AD but not from patients with other immunologically mediated disorders (graft vs. host disease, systemic lupus erythematosus) and elicited immediate type skin reactions in AD patients. In serum samples collected from an AD patient over a period of 5 years, IgE anti-ara NAC antibody levels peaked during disease exacerbation. Our finding that ara BCL7B was detected in serum bound to IgE antibodies suggests that intracellular IgE autoantigens can become released after tissue damage and may occur as IgE immune complexes. Via binding to antigen presenting cells as well as to effector cells, IgE autoantigen immune complexes may contribute to exacerbation and/or perpetuation of severe atopic diseases even in the absence of exogenous allergens.