Skin microbiota-associated inflammation precedes autoantibody induced tissue damage in experimental epidermolysis bullosa acquisita.
Epidermolysis bullosa acquisita (EBA) is a chronic autoimmune blistering skin disease characterized by autoantibodies against type VII collagen (COL7). Immunization of SJL/J mice with recombinant murine COL7 results in break of tolerance and skin blisters. Strikingly, despite circulating autoantibodies, the same genetic background and identical environmental conditions, 20% of mice remain healthy. To elucidate the regulation of the transition from the presence of autoantibodies to overt autoimmune disease, we characterized the innate and adaptive immune response of mice that remain healthy after immunization and compared it to mice that developed skin disease. Both clinically healthy and diseased SJL/J mice showed circulating autoantibodies and deposition of complement-ﬁxing IgG2c autoantibodies and C3 at the dermal-epidermal junction. However, only in diseased animals significant neutrophil infiltration and increase in FcgRIV expression were observed in the skin. In contrast, the expression of T cell signature cytokines in the T cell zone of the draining lymph node was comparable between clinically healthy and diseased animals after immunization. Surprisingly, health was associated with a decreased expression of CD11c, TNFA and KC (CXCL1) in the skin prior to immunization and could be predicted with a negative predictive value of >80%. Furthermore, mice that did not develop clinical disease showed a significantly higher richness and distinctly clustered diversity of their skin microbiota before immunization. Our data indicate that the decision whether blisters develop in the presence of autoantibodies is governed in the skin rather than in the lymph node, and that a greater richness of cutaneous bacterial species appears to be protective.
Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA; Institute of Anatomy, University of Lübeck, Ratzeburger Allee 162, 23562 Lübeck, Germany. Electronic address: chell@mail.med.upenn.edu.
Christoph T
CT
Ellebrecht
Max-Planck Institute for Evolutionary Biology, August-Thienemann-Straße 2, 24306 Plön, Germany.
Girish
G
Srinivas
Department of Dermatology, University of Lübeck, Ratzeburger Allee 162, 23562 Lübeck, Germany.
Katja
K
Bieber
Institute of Anatomy, University of Lübeck, Ratzeburger Allee 162, 23562 Lübeck, Germany.
David
D
Banczyk
Institute of Anatomy, University of Lübeck, Ratzeburger Allee 162, 23562 Lübeck, Germany.
Kathrin
K
Kalies
Max-Planck Institute for Evolutionary Biology, August-Thienemann-Straße 2, 24306 Plön, Germany.
Sven
S
Künzel
Department of Dermatology, University of Lübeck, Ratzeburger Allee 162, 23562 Lübeck, Germany.
Christoph M
CM
Hammers
Max-Planck Institute for Evolutionary Biology, August-Thienemann-Straße 2, 24306 Plön, Germany.
John F
JF
Baines
Department of Dermatology, University of Lübeck, Ratzeburger Allee 162, 23562 Lübeck, Germany.
Detlef
D
Zillikens
Department of Dermatology, University of Lübeck, Ratzeburger Allee 162, 23562 Lübeck, Germany.
Ralf J
RJ
Ludwig
Institute of Anatomy, University of Lübeck, Ratzeburger Allee 162, 23562 Lübeck, Germany.
Jürgen
J
Westermann
D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D016107:Epidermolysis Bullosa Acquisita / Q000209:etiology* / Q000473:pathology*; D005260:Female; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate; D007114:Immunization; D056186:Metagenomics; D051379:Mice; D064307:Microbiota; D012372:ROC Curve; D012867:Skin / Q000276:immunology / Q000382:microbiology / Q000473:pathology
D001323:Autoantibodies
Autoantibodies; Autoimmune bullous disease; Host-microbiome interaction