Emerging treatments for pemphigoid diseases

Ludwig, Ralf J.; Kalies, Kathrin; Köhl, Jörg; Zillikens, Detlef; Schmidt, Enno

doi:10.1016/j.molmed.2013.06.003

Cited by 47 publications

(51 citation statements)

References 110 publications

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“…In EBA, blister formation depends on and is initiated by the binding of autoantibodies to COL7, located at the dermal-epidermal junction (29,30). Subsequently, Fc-dependent mechanisms result in the formation of a proinflammatory milieu in the skin (31).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, these extravasated cells are indispensable for blister formation by the release of reactive oxygen species and proteolytic enzymes (30), and they express IL-1R after migration. This increased IL-1R expression is functionally relevant because the stimulation of neutrophils with IL-1 resulted in the transcription of NF-kB and the release of a number of downstream chemokines (39).…”

Section: Discussionmentioning

confidence: 99%

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Caspase-1–Independent IL-1 Release Mediates Blister Formation in Autoantibody-Induced Tissue Injury through Modulation of Endothelial Adhesion Molecules

Sadeghi

Lockmann

Hund

et al. 2015

The Journal of Immunology

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Although reports documented aberrant cytokine expression in autoimmune bullous dermatoses (AIBDs), cytokine-targeting therapies have not been established in these disorders. We showed previously that IL-6 treatment protected against tissue destruction in experimental epidermolysis bullosa acquisita (EBA), an AIBD caused by autoantibodies to type VII collagen (COL7). The anti-inflammatory effects of IL-6 were mediated by induction of IL-1ra, and prophylactic IL-1ra administration prevented blistering. In this article, we demonstrate elevated serum concentrations of IL-1β in both mice with experimental EBA induced by injection of anti-COL7 IgG and in EBA patients. Increased IL-1α and IL-1β expression also was observed in the skin of anti-COL7 IgG-injected wild-type mice compared with the significantly less diseased IL-1R–deficient or wild-type mice treated with the IL-1R antagonist anakinra or anti–IL-1β. These findings suggested that IL-1 contributed to recruitment of inflammatory cells into the skin. Accordingly, the expression of ICAM-1 was decreased in IL-1R–deficient and anakinra-treated mice injected with anti-COL7. This effect appeared to be specifically attributable to IL-1 because anakinra blocked the upregulation of different endothelial adhesion molecules on IL-1–stimulated, but not on TNF-α–stimulated, cultured endothelial cells. Interestingly, injection of caspase-1/11–deficient mice with anti-COL7 IgG led to the same extent of skin lesions as in wild-type mice. Collectively, our data suggest that IL-1, independently of caspase-1, contributes to the pathogenesis of EBA. Because anti–IL-1β in a prophylactic setting and anakinra in a quasi-therapeutic setting (i.e., when skin lesions had already developed) improved experimental EBA, IL-1 appears to be a potential therapeutic target for EBA and related AIBDs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Caspase-1–Independent IL-1 Release Mediates Blister Formation in Autoantibody-Induced Tissue Injury through Modulation of Endothelial Adhesion Molecules

Sadeghi

Lockmann

Hund

et al. 2015

The Journal of Immunology

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“…Clinically, EBA is characterized by chronic mucocutaneous subepidermal blistering (24). The autoimmune response is directed against a 290-kDa protein located at the dermal-epidermal junction (DEJ) (25), which has been identified as type VII collagen (COL7), a major component of anchoring fibrils (26).…”

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confidence: 99%

B Cells, Dendritic Cells, and Macrophages Are Required To Induce an Autoreactive CD4 Helper T Cell Response in Experimental Epidermolysis Bullosa Acquisita

Iwata

Bieber

Tiburzy

et al. 2013

The Journal of Immunology

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In autoimmune bullous dermatoses (AIBD), autoantibodies induce blisters on skin or mucous membranes, or both. Mechanisms of continued autoantibody production and blistering have been well characterized using AIBD animal models. Mechanisms leading to the initial autoantibody production, however, have not been investigated in detail. Epidermolysis bullosa acquisita (EBA) is an AIBD associated with autoantibodies to type VII collagen (COL7). The majority of EBA patients’ sera recognize the noncollagenous domain 1, including the von Willebrand factor A–like domain 2 (vWFA2). In experimental EBA induced by immunization with GST-COL7, disease manifestation depended on the genetic background, a Th1 polarization, and the GST-tag. In this model, nude mice neither produced autoantibodies nor blisters. It has remained uncertain which APC and T cell subsets are required for EBA induction. We established a novel EBA model by immunization with vWFA2 fused to intein (lacking the GST-tag). All tested mouse strains developed autoantibodies, but blisters were exclusively observed in mice carrying H2s. In immunized mice, CD4 T cells specific for vWFA2 were detected, and their induction required presence of B cells, dendritic cells, and macrophages. Anti-vWFA2 autoantibodies located at the lamina densa bound to the dermal side of salt-split skin and induced blisters when transferred into healthy mice. Absence of CD8 T cells at time of immunization had no effect, whereas depletion of CD4 T cells during the same time period delayed autoantibody production and blisters. Collectively, we demonstrate the pathogenic relevance of Abs targeting the vWFA2 domain of COL7 and show the requirement of APC-induced CD4 T cells to induce experimental EBA.

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“…Abs in EBA has been well documented, both in vitro and in vivo [3]. Studies in men and mice revealed that the deposition of anti-COL7 IgG at the dermal-epidermal junction results in complement activation predominantly via the alternative pathway and subsequent neutrophil infiltration into the dermis of the skin.…”

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Conditional depletion of mast cells has no impact on the severity of experimental epidermolysis bullosa acquisita

Kasprick

Scholten³

et al. 2015

Eur J Immunol

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The role of mast cells (MCs) in autoimmunity is the matter of an intensive scientific debate. Based on observations in different MC-deficient mouse strains, MCs are considered as fundamental players in autoimmune diseases. However, most recent data suggest that the outcome of such diseases is strongly affected by the individual mouse strain used. By the use of two c-Kit mutant MC-deficient mouse strains and one c-Kit-independent strain, we here investigated the role of MCs in a systemic Ab transfer model of epidermolysis bullosa acquisita, a subepidermal autoimmune blistering skin disease characterized by autoantibodies against type VII collagen. While C57BL/6J-Kit W-sh/W-sh mice developed an unexpected increased blistering phenotype, no significant differences to WT controls were seen in WBB6F 1 -Kit W/W-v or the novel Mcpt5-Cre iDTR animals. Interestingly, in a local Ab transfer model, which induces a localized disease, we showed that application of high concentrations of anti-COL7 (where COL7 is type VII collagen) Abs induced MC activation and MC-dependent edema formation that did, however, not contribute to blister induction. Our results indicate that in the autoimmune disorder epidermolysis bullosa acquisita MCs do not contribute to the immune-mediated tissue injury. Modern c-Kit mutant-independent MC-deficient mouse strains will help to further redefine the role of MCs in autoimmunity.Keywords: Animal models r autoimmunity r conditional depletion r epidermolysis bullosa acquisita r mast cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAutoimmune bullous dermatoses represent a group of organspecific autoimmune diseases with autoantibodies targeting Correspondence: Prof. Frank Petersen e-mail: fpetersen@fz-borstel.de desmosomal and hemidesmosomal structural proteins of skin and mucous membranes. Within this group, epidermolysis bullosa acquisita (EBA) represents a subepidermal blistering disorder characterized by circulating and tissue-bound autoantibodies (mostly of the IgG subclass) against type VII collagen (COL7), a major component of anchoring fibrils essential for the attachment of epidermis and dermis [1,2]. The pathogenicity of anti-COL7C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1462-1470 Innate immunity 1463Abs in EBA has been well documented, both in vitro and in vivo [3]. Studies in men and mice revealed that the deposition of anti-COL7 IgG at the dermal-epidermal junction results in complement activation predominantly via the alternative pathway and subsequent neutrophil infiltration into the dermis of the skin. By releasing ROS and proteases, activated neutrophils are thought to destroy the basement membrane zone and mediate dermal-epidermal separation and blister formation [4,5]. Thus, patients with EBA mainly suffer from fragile skin, blistering, and scarring with milia formation [6]. Although therapeutic approaches include systemic corticosteroids, immunosuppre...

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Emerging treatments for pemphigoid diseases

Cited by 47 publications

References 110 publications

Caspase-1–Independent IL-1 Release Mediates Blister Formation in Autoantibody-Induced Tissue Injury through Modulation of Endothelial Adhesion Molecules

Caspase-1–Independent IL-1 Release Mediates Blister Formation in Autoantibody-Induced Tissue Injury through Modulation of Endothelial Adhesion Molecules

B Cells, Dendritic Cells, and Macrophages Are Required To Induce an Autoreactive CD4 Helper T Cell Response in Experimental Epidermolysis Bullosa Acquisita

Conditional depletion of mast cells has no impact on the severity of experimental epidermolysis bullosa acquisita

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