Human Bullous Pemphigoid Antigen 2 Transgenic Skin Elicits Specific IgG in Wild-Type Mice

The Journal of Dermatology

et al. 2010

Self Cite

Bullous pemphigoid (BP) is the most common autoimmune blistering disease. BP patients have autoantibodies against type XVII collagen (COL17, also called BP180 or BPAG2), a type II transmembrane protein that spans the lamina lucida and projects into the lamina densa of the epidermal basement membrane. The non-collagenous 16A domain of COL17 is considered to contain pathogenic epitopes of BP. The transfer of immunoglobulin (Ig)G from BP patients fails to cause blisters on mouse skin probably due to differences between humans and mice in the amino acid sequence of NC16A pathogenic epitope of COL17. Passive transfer of rabbit IgG antibodies against the murine homolog of human COL17 NC16A triggers immune reactions to COL17 in mice, including complement activation, mast cell degranulation and neutrophilic infiltration, resulting in dermal-epidermal separation. Recent studies using COL17-humanized mice that express human COL17 but lack murine COL17 were the first to demonstrate the pathogenicity of anti-COL17 human BP IgG autoantibodies in vivo. These new findings provide a greater understanding of BP pathomechanisms and facilitate the development of novel specific and efficient therapeutic strategies for BP.

“…NC16A antibodies, Olasz et al 33 These studies strongly support the hypothesis that anti-COL17 NC16A IgG autoantibodies in BP patients have a pathogenic activity. However, this concept…”

supporting

confidence: 75%

What’s new in bullous pemphigoid

Ujiie

Shibaki

The Journal of Dermatology

et al. 2010

Self Cite

“…1). Wild-type mice can develop quite high titers of circulating anti-human COL17 IgG when grafted with human COL17 transgenic (Tg) mouse skin (19). We first immunized mCol17 ϩ/Ϫ mother mice with skin grafts obtained from human COL17 Tg mouse, and then we mated the immunized mCol17 ϩ/Ϫ mother mice with COL17-humanized (mCol17 Ϫ/Ϫ , hCOL17 ϩ/ϩ ) male mice.…”

Section: Gross Summary Of Strategymentioning

confidence: 99%

“…Interestingly, due to significant differences between humans and rodents in the amino acids sequence in the NC16A region, mice that have received human IgG from BP patients fail to show any clinical, histological, or immunological findings consistent with BP (13,14). We recently generated Col17a1 gene-targeted (mCol17 Ϫ/Ϫ ) mice as well as COL17-humanized mice by introducing human COL17A1cDNA (hCOL17 ϩ/ϩ ) transgene driven under keratin 14 promoter into mCol17 Ϫ/Ϫ mice (12,19). Importantly, the mCol17 Ϫ/Ϫ mice were too fragile to mate with male mice, but reproductive ability was restored in COL17-humanized (mCol17 Ϫ/Ϫ , hCOL17 ϩ/ϩ ) mice (12).…”

mentioning

confidence: 99%

A Novel Humanized Neonatal Autoimmune Blistering Skin Disease Model Induced by Maternally Transferred Antibodies

The Journal of Immunology

Sawamura

Natsuga

et al. 2009

Self Cite

All mammal neonates receive maternal Abs for protection against pathogenic organisms in the postnatal environment. However, neonates can experience serious adverse reactions if the Abs transferred from the mother recognize self-molecules as autoAgs. In this study, we describe a novel model for autoimmune disease induced by transferred maternal Abs in genetically transformed Ag-humanized mice progeny. Bullous pemphigoid is the most common life-threatening autoimmune blistering skin disease that affects the elderly, in which circulating IgG autoAbs are directed against epidermal type XVII collagen (COL17). We have established a genetically manipulated experimental mouse model in which maternal Abs against human COL17 are transferred to pups whose skin expresses only human and not mouse COL17, resulting in blistering similar to that seen in patients with bullous pemphigoid. Maternal transfer of pathogenic Abs to humanized neonatal mice is a unique and potential experimental system to establish a novel autoimmune disease model.

“…This active BP model was produced based on a previous study showing that the grafting of skin from hCOL17-expressing transgenic mice onto syngeneic wild-type mice induces potential immune reactions against hCOL17 in recipient mice. [59] By selectively transferring T-cell subtypes, CD4+ T cells but not CD8+ T cells play essential roles in the pathogenesis of the active adult BP model. [58] …”

Section: Immunization-induced Models Of Bpmentioning

confidence: 99%

In vitro and in vivo models to investigate the pathomechanisms and novel treatments for pemphigoid diseases

Bieber

Koga

Experimental Dermatology

2017

Pemphigoid diseases (PD) are a subgroup of rare acute or chronic autoimmune skin disorders characterized and caused by autoantibodies directed against distinct structural components of the dermal-epidermal junction. Binding of autoantibodies to their targets leads to the formation of blisters and erosions in patients. PDs comprise eight disorders for which the molecular target antigens have been identified. First, we review the available in vitro and ex vivo models for analysis of distinct aspects of the pathogenesis of PDs. This includes the binding of autoantibodies to skin sections, the analysis of blister formation capability and skin complement activation as well as investigation of neutrophil and keratinocyte activation. In addition to this, several animal models of PD have been developed during the last decades. These animal models have greatly contributed to our current understanding of the pathogenesis of PDs. We summarize spontaneously arising PD in animals and the induction of PD by transfer of (auto)antibodies, transfer of (auto)-antigen-specific lymphocytes and by immunization.In combined use, these models allow dissecting all aspects of PD pathogenesis, for example loss of tolerance, autoantibody production and inflammatory skin processes that lead to blister formation. Overall, we aimed to foster translational biomedical research, to deepen our understanding of PD pathogenesis and to develop novel treatments for patients suffering from these life-threatening and difficult-to-treat autoimmune diseases. K E Y W O R D Sanimal model, autoimmune bullous dermatoses, autoimmunity, bullous pemphigoid, epidermolysis bullosa acquisita, pemphigoid disease, skin