Table 4: Mechanisms leading to autoantibody-induced tissue injury in EBA.

MechanismDemonstrated byReference

Anti-COL7 IgG/A bindingDetection of anti-COL7 antibodies in patients, vast in vitro and in vivo (animal models) evidence[125]
Genetic controlDiverse susceptibility of different inbred mouse lines[66]
NeutrophilsAnti-Gr1 treatment completely protects from antibody transfer-induced EBA[126]
Fc-fragment mediated effects(i) Anti-COL7 IgG, but not corresponding F(ab)2 fragments, induces EBA in vitro and in vivo
(ii) Anti-COL7 IgY fails to induce experimental EBA in mice
(iii) Enzymatic removal of terminal sugar residues has preventive and therapeutic effects in experimental EBA in mice
[44, 60, 64, 104, 113]

Cytokines
(a) CXCL1 and CXCL2Blockade of the receptors has preventive and therapeutic effects in experimental EBA in mice[127]
(b) GM-CSFGenetic and pharmacological GM-CSF inhibition has preventive and therapeutic effects in experimental EBA in mice[128]
(c) IL-6IL-6 has anti-inflammatory effects in antibody transfer-induced EBA; IL-6 induced IL-1ra, which in turn counteracts proinflammatory events triggered by IL-1[123]

Complement activationC5-deficient mice are completely protected from antibody transfer-induced EBA; partial protection is observed in C1q-, Factor B-, or C5aR-deficient mice[44, 129, 130]

Leukocyte extravasationCD18-deficient mice are completely protected from antibody transfer-induced EBA[126]

Fc gamma RIIBFc gamma RIIB-deficient mice show a significantly increased cutaneous blistering in antibody transfer-induced EBA[124]

Fc gamma RIVFc gamma RIV-deficient mice are completely protected from antibody transfer-induced EBA[124]

Neutrophil activation
(a) PI3K betaPI3K beta-deficient mice are partially protected from antibody transfer-induced EBA[61]
(b) AKTAKT impairs ROS released from immune omplex activated neutrophils[131]
(c) p38Pharmacologic inhibition of p38 phosphorylation partially protected from antibody transfer-induced EBA[131]
(d) ERK1/2Pharmacologic inhibition of ERK1/2 phosphorylation partially protected from antibody transfer-induced EBA[131]

ROSNeutrophil cytosolic factor 1-deficient mice are completely protected from antibody transfer-induced EBA[126]

Elastase/Gelatinase BBlockade of elastase or gelatinase B completely blocks dermal-epidermal separation[132]

FliiOverexpression of Flightless I (Flii) increases dermal-epidermal blistering in antibody transfer-induced EBA, and blockade of Flii improves blistering[133, 134]