The Journal of Experimental Medicine
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Published online 27 May 2003 doi:10.1084/jem.20022031
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© Rockefeller University Press, 0022-1007/2003/6/1501 $5.00
The Journal of Experimental Medicine, Volume 197, Number 11, 1501-1510

The Role of Intramolecular Epitope Spreading in the Pathogenesis of Endemic Pemphigus Foliaceus (Fogo Selvagem)

Ning Li1, Valeria Aoki2, Gunter Hans-Filho3, Evandro A. Rivitti2 and Luis A. Diaz1

1 Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
2 Departamento de Dermatologia, Caixa Postal 8091, Universidade de Sao Paulo, Sao Paulo 05409-000, Brazil
3 Departamento de Dermatologia, Caixa Postal 549, Universidade Federal de Mato Grosso do Sul, Campo Grande 79002-212, Brazil

Address correspondence to Ning Li, Department of Dermatology, University of North Carolina at Chapel Hill, 3100 Thurston Building, CB#7287 Chapel Hill, NC 27599. Phone: 919-843-7229; Fax: 919-843-5766; E-mail: lining{at}med.unc.edu

We report here a relationship between intramolecular epitope spreading and the clinical onset of the endemic form of pemphigus foliaceus in a Brazilian community with a high prevalence and incidence of the disease. Also known as Fogo Selvagem (FS), this disease is characterized by severe skin blistering and pathogenic anti–desmoglein-1 (Dsg1) autoantibodies. These autoantibodies bind the Dsg1 ectodomain and trigger keratinocyte cell detachment, the hallmark of FS. We show that (a) sera from FS patients in the preclinical stage recognized epitopes on the COOH-terminal EC5 domain of Dsg1, (b) disease onset was associated with the emergence of antibodies specific for epitopes on the NH2-terminal EC1 and EC2 domains, (c) all sera from FS patients with active disease recognized the EC1 and/or EC2 domains, and (d) sera from FS patients in remission showed reactivity restricted to EC5. These results suggest that anti-Dsg1 autoantibodies in FS are initially raised against the COOH-terminal EC5 domain of Dsg1 in individuals without skin disease; in genetically predisposed subjects the autoimmune response may then undergo intramolecular epitope spreading toward epitopes on the NH2-terminal EC1 and EC2 domains of Dsg1 leading to disease onset. Moreover, intramolecular epitope spreading may also modulate remissions and relapses of FS.

Key Words: autoimmunity • autoantibodies • desmogleins • epitope spreading • pemphigus


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