Herpes gestationis autoantibodies recognize a 180-kD human epidermal antigen.

Morrison, Lynne; Labib, Ramzy S.; Zone, John J.; Díaz, Luis A.; Anhalt, Grant J.

doi:10.1172/jci113554

Cited by 159 publications

(64 citation statements)

References 15 publications

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“…for BP and HG and other subepidermal blistering diseases with an autoimmune response to BP180 such as mucous membrane pemphigoid, pemphigoid gestationis, and lichen planus pemphigoides (9,46,47). These findings may lead to more effective management of these human autoimmune blistering diseases.…”

Section: Figurementioning

confidence: 97%

“…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)(5)(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).…”

Section: Introductionmentioning

confidence: 99%

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

Nelson¹,

Zhao²,

Schroeder³

et al. 2006

J. Clin. Invest.

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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Section: Figurementioning

confidence: 97%

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.

102

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“…However, HDIG treatment led to a similar degree of reduction in circulating pathogenic antibodies in all 3 blistering disease models regardless of their disease mechanisms. These findings should be directly beneficial to other human blistering diseases in which IgG autoantibodies target Dsg3 and BP180, including paraneoplastic pemphigus (anti-Dsg3) (67), mucous membrane pemphigoid, pemphigoid gestationis, lichen planus pemphigoides (anti-BP180) (68)(69)(70).…”

Section: Figurementioning

confidence: 99%

Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases

Zhao²,

Hilario-Vargas³

et al. 2005

Journal of Clinical Investigation

229

189

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Numerous mechanisms of action have been proposed for intravenous Ig (IVIG). In this study, we used IgG passive transfer murine models of bullous pemphigoid (BP), pemphigus foliaceus (PF), and pemphigus vulgaris (PV) to test the hypothesis that the effect of IVIG in autoantibody-mediated cutaneous bullous diseases is to accelerate the degradation of pathogenic IgG by saturation of the MHC-like Fc receptor neonatal Fc receptor (FcRn). BP, PF, and PV are organ-specific antibody-mediated diseases in which autoantibodies target the hemidesmosomal antigen BP180 and desmosomal antigens Dsg1 and Dsg3, respectively. Antibodies against BP180, Dsg1, and Dsg3, when injected into neonatal mice, induce the BP, PF, and PV disease phenotypes, respectively. We found that FcRn-deficient mice were resistant to experimental BP, PF, and PV. Circulating levels of pathogenic IgG in FcRndeficient mice were significantly reduced compared with those in WT mice. Administration of high-dose human IgG (HDIG) to WT mice also drastically reduced circulating pathogenic IgG levels and prevented blistering. In FcRn-deficient mice, no additional protective effect with HDIG was realized. These data demonstrate that the therapeutic efficacy of HDIG treatment in the pemphigus and pemphigoid models is dependent on FcRn. Thus, FcRn is a promising therapeutic target for treating such IgG-mediated autoimmune diseases.

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“…The PG antigen in 180 kD antigen (BPAG2) is present in the hemidesmosomes of the basement membrane [9]. Antibasement membrane zone (BMZ) antibodies, mainly IgG1 are pathogenic [10].…”

Section: Discussionmentioning

confidence: 99%