Clinical Presentation, Pathogenesis, Diagnosis, and Treatment of Epidermolysis Bullosa Acquisita

Table 4

Mechanisms leading to autoantibody-induced tissue injury in EBA.

Mechanism	Demonstrated by	Reference
Anti-COL7 IgG/A binding	Detection of anti-COL7 antibodies in patients, vast in vitro and in vivo (animal models) evidence	[125]
Genetic control	Diverse susceptibility of different inbred mouse lines	[66]
Neutrophils	Anti-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 CXCL2	Blockade of the receptors has preventive and therapeutic effects in experimental EBA in mice	[127]
(b) GM-CSF	Genetic and pharmacological GM-CSF inhibition has preventive and therapeutic effects in experimental EBA in mice	[128]
(c) IL-6	IL-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 activation	C5-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 extravasation	CD18-deficient mice are completely protected from antibody transfer-induced EBA	[126]
Fc gamma RIIB	Fc gamma RIIB-deficient mice show a significantly increased cutaneous blistering in antibody transfer-induced EBA	[124]
Fc gamma RIV	Fc gamma RIV-deficient mice are completely protected from antibody transfer-induced EBA	[124]
Neutrophil activation
(a) PI3K beta	PI3K beta-deficient mice are partially protected from antibody transfer-induced EBA	[61]
(b) AKT	AKT impairs ROS released from immune omplex activated neutrophils	[131]
(c) p38	Pharmacologic inhibition of p38 phosphorylation partially protected from antibody transfer-induced EBA	[131]
(d) ERK1/2	Pharmacologic inhibition of ERK1/2 phosphorylation partially protected from antibody transfer-induced EBA	[131]
ROS	Neutrophil cytosolic factor 1-deficient mice are completely protected from antibody transfer-induced EBA	[126]
Elastase/Gelatinase B	Blockade of elastase or gelatinase B completely blocks dermal-epidermal separation	[132]
Flii	Overexpression of Flightless I (Flii) increases dermal-epidermal blistering in antibody transfer-induced EBA, and blockade of Flii improves blistering	[133, 134]