Journal
EXPERIMENTAL DERMATOLOGY
Volume 25, Issue 11, Pages 839-846Publisher
WILEY-BLACKWELL
DOI: 10.1111/exd.13106
Keywords
acantholysis; antimitochondrial antibody; autoantibody; autoantigen; autoimmunity; desmogleins 1 and 3; FcRn; pemphigus vulgaris
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Funding
- International Pemphigus and Pemphigus Foundation
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This viewpoint highlights major, partly controversial concepts about the pathogenesis of pemphigus. The monopathogenic theory explains intra-epidermal blistering through the desmoglein (Dsg) compensation hypothesis, according to which an antibody-dependent disabling of Dsg 1- and/or Dsg 3-mediated cell-cell attachments of keratinocytes (KCs) is sufficient to disrupt epidermal integrity and cause blistering. The multipathogenic theory explains intra-epidermal blistering through the multiple hit hypothesis stating that a simultaneous and synchronized inactivation of the physiological mechanisms regulating and/or mediating intercellular adhesion of KCs is necessary to disrupt epidermal integrity. The major premise for a multipathogenic theory is that a single type of autoantibody induces only reversible changes, so that affected KCs can recover due to a self-repair. The damage, however, becomes irreversible when the salvage pathway and/or other cell functions are altered by a partnering autoantibody and/or other pathogenic factors. Future studies are needed to (i) corroborate these findings, (ii) characterize in detail patient populations with non-Dsg-specific autoantibodies, and (iii) determine the extent of the contribution of non-Dsg antibodies in disease pathophysiology.
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