Monopathogenic vs multipathogenic explanations of pemphigus pathophysiology.
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.
Department of Dermatology of Tufts University and Center for Blistering Diseases, Boston, MA, USA.
A Razzaque
AR
Ahmed
School of Dental Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.
Marco
M
Carrozzo
Department of Dermatology, University Paris 13, Avicenne Hospital, APHP, Bobigny, France.
Frédéric
F
Caux
Melbourne Dental School and Oral Health CRC, The University of Melbourne, Melbourne, Vic., Australia.
Nicola
N
Cirillo
Autoimmune Blistering Dermatoses Section, Department of Dermatology, Poznan University of Medical Sciences, Poznan, Poland.
Marian
M
Dmochowski
Department of Dermatology, School of Medicine, University Clinic of Navarra, University of Navarra, Navarra, Spain.
Agustín España
AE
Alonso
Division of Dermatology, University of Alberta, Edmonton, AB, Canada.
Robert
R
Gniadecki
Department of Dermatology and Allergology, Philipps University, Marburg, Germany.
Michael
M
Hertl
Department of Biochemistry and Genetics, University of Navarra, Navarra, Spain.
Maria J
MJ
López-Zabalza
Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy.
Roberta
R
Lotti
Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy.
Carlo
C
Pincelli
Department of Dermatology, Mayo Clinic, Scottsdale, AZ, USA.
Mark
M
Pittelkow
Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, Lübeck, Germany.
Enno
E
Schmidt
Department of Dermatology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
Animesh A
AA
Sinha
Department of Dermatology, Tel Aviv Medical Center, Tel Aviv, Israel.
Eli
E
Sprecher
Institute for Immunology and Departments of Dermatology and Biological Chemistry, University of California, Irvine, CA, USA. sgrando@uci.edu.
Sergei A
SA
Grando
D000818:Animals; D051182:Desmogleins / Q000276:immunology; D006801:Humans; D010392:Pemphigus / Q000209:etiology*
D051182:Desmogleins
FcRn; acantholysis; antimitochondrial antibody; autoantibody; autoantigen; autoimmunity; desmogleins 1 and 3; pemphigus vulgaris