Bullous Pemphigoid and Cicatricial Pemphigoid Autoantibodies React with Ultrastructurally Separable Epitopes on the BP180 Ectodomain: Evidence that BP180 Spans the Lamina Lucida

Bédane, C.; McMillan, James R.; Balding, Shawn D.; Bernard, Philippe; Prost, Cathérine; Bonnetblanc, J.M.; Díaz, Luis A.; Eady, R.A.J.; Giudice, George J.

doi:10.1111/1523-1747.ep12292701

Cited by 133 publications

(100 citation statements)

References 44 publications

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“…4). [10][11][12][13][14] The extracellular domain of COL17 has been proven to have at least one loop structure in the lamina densa in vivo (Fig. 4).…”

Section: Major Pathogenic Autoantigen: Type XVII Collagen (Col17)mentioning

confidence: 99%

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What’s new in bullous pemphigoid

Ujiie

Shibaki

Nishie

et al. 2010

The Journal of Dermatology

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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.

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“…4). [10][11][12][13][14] The extracellular domain of COL17 has been proven to have at least one loop structure in the lamina densa in vivo (Fig. 4).…”

Section: Major Pathogenic Autoantigen: Type XVII Collagen (Col17)mentioning

confidence: 99%

“…Autoantibodies bound to the C-terminal region of COL17 have been regarded as relating to the clinical features of cicatricial pemphigoid. 13 At the moment, the pathogenic role of autoantibodies against the C-terminal region of COL17 remains unclear.…”

Section: Major Pathogenic Autoantigen: Type XVII Collagen (Col17)mentioning

confidence: 99%

What’s new in bullous pemphigoid

Ujiie

Shibaki

Nishie

et al. 2010

The Journal of Dermatology

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“…The BP230 antigen is restricted to the cytoplasmic plaque of the hemidesmosome and appears to interact directly with the intermediate filament network (10,11). The BP180 antigen is a type II transmembrane protein with an aminoterminal endodomain and an extended carboxyterminal ectodomain that spans the lamina lucida, projecting into the lamina densa of the BMZ (12)(13)(14)(15)(16). The ectodomain of human BP180 contains a series of 15 interrupted collagen domains (complement components 1-15 [C1-C15]) with the typical Gly-X-Y repeat (14).…”

Section: Introductionmentioning

confidence: 99%

Role of different pathways of the complement cascade in experimental bullous pemphigoid

Nelson¹,

Zhao²,

Schroeder³

et al. 2006

J. Clin. Invest.

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102

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Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease associated with autoantibodies directed against the hemidesmosomal proteins BP180 and BP230 and inflammation. Passive transfer of antibodies to the murine BP180 (mBP180) induces a skin disease that closely resembles human BP. In the present study, we defined the roles of the different complement activation pathways in this model system. Mice deficient in the alternative pathway component factor B (Fb) and injected with pathogenic anti-mBP180 IgG developed delayed and less intense subepidermal blisters. Mice deficient in the classical pathway component complement component 4 (C4) and WT mice pretreated with neutralizing antibody against the first component of the classical pathway, C1q, were resistant to experimental BP. These mice exhibited a significantly reduced level of mast cell degranulation and polymorphonuclear neutrophil (PMN) infiltration in the skin. Intradermal administration of compound 48/80, a mast cell degranulating agent, restored BP disease in C4 -/-mice. Furthermore, C4 -/-mice became susceptible to experimental BP after local injection of PMN chemoattractant IL-8 or local reconstitution with PMNs. These findings provide the first direct evidence to our knowledge that complement activation via the classical and alternative pathways is crucial in subepidermal blister formation in experimental BP. IntroductionBullous pemphigoid (BP) is a subepidermal blistering skin disorder of the elderly (1). Lesional skin of BP patients is characterized by a detachment of the basal keratinocytes of the epidermis from the dermis, resulting in tense, fluid-filled vesicles. Similar skin lesions were noted in herpes gestationis (HG), a nonviral disease of pregnancy (2). Immunofluorescence (IF) studies demonstrated that these patients exhibit circulating and tissue-bound autoantibodies directed against antigens of the basement membrane zone (BMZ) (3-8).BP and HG autoantibodies recognize 2 antigens, BP230 and BP180, that are localized in the hemidesmosome, the main epidermal structure involved in dermal-epidermal adhesion (4-6, 9). The BP230 antigen is restricted to the cytoplasmic plaque of the hemidesmosome and appears to interact directly with the intermediate filament network (10, 11). The BP180 antigen is a type II transmembrane protein with an aminoterminal endodomain and an extended carboxyterminal ectodomain that spans the lamina lucida, projecting into the lamina densa of the BMZ (12-16). The ectodomain of human BP180 contains a series of 15 interrupted collagen domains (complement components 1-15 [C1-C15]) with the typical Gly-X-Y repeat (14). It has recently been shown that the BP180 extracellular domain forms a collagen triple helix (17, 18). The extracellular noncollagenous stretches are designated NC1 (located at the carboxyl terminus) through NC16A (adjacent to the membrane-spanning domain). The NC16A domain of human BP180 harbors major extracellular antigenic sites recognized by BP and HG sera (19,20).Complement can be activated...

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“…There is presently no firm correlation between specific clinical phenotypes and the target antigens in MMP patients (Carrozzo et al, 2004;Chan et al, 2002). To date, the most common target antigen associated with MMP is BP180 (Balding et al, 1996;Bedane et al, 1997;Calabresi et al, 2007). The extracellular domain of BP180 is considered to have a number of MMP-reactive antigenic sites of which at least two sites have been identified.…”

Section: Mucous Membrane Pemphigoidmentioning

confidence: 99%

“…The extracellular domain of BP180 is considered to have a number of MMP-reactive antigenic sites of which at least two sites have been identified. One is the non-collagenous 16 a (NC16a) domain located in the upper lamina lucida, and the other is the carboxy-terminus domain at the lamina lucida/lamina densa interface (Bagan et al, 2005;Balding et al, 1996;Bedane et al, 1997;Calabresi et al, 2007;Van den Bergh & Giudice, 2003). The authors evaluated circulating IgG autoantibody specific for BP180NC16a using enzyme-linked immunosorbent assay (ELISA) (Endo et al, 2006a).…”

Section: Mucous Membrane Pemphigoidmentioning

confidence: 99%