We searched PubMed using the terms “pemphigoid”, “linear IgA”, “herpes gestationis”, and “epidermolysis bullosa acquisita”. Our search covered articles published in English between Jan 1, 2000, and May 31, 2012. We identified additional reports from the reference lists of selected articles. Some important older publications are cited either directly or indirectly through review articles.
SeminarPemphigoid diseases
Introduction
Pemphigoid diseases are characterised by the presence of autoantibodies against distinct structural components of the dermal–epidermal junction (figure 1). Junction proteins link the cytoskeleton of the basal keratinocytes to the extracellular matrix of the dermis. Binding of pemphigoid autoantibodies leads to the separation of the epidermis and dermis by a complex, yet fairly well understood process.
The pemphigoid diseases include eight disorders for which the molecular target antigens have been identified (table). In addition to the seven named diseases listed in the table, a few patients have a pemphigoid disease that is characterised by renal insufficiency and autoantibodies against the α5 chain of type IV collagen.1 IgG and IgA autoantibodies that target several not-fully-characterised antigens (including 105 kDa, 125 kDa, and 168 kDa proteins) have also been detected in serum samples from patients with pemphigoid disorders.2, 3 Dermatitis herpetiformis, another subepidermal immunobullous disease, is not regarded as a pemphigoid disorder since the autoantigen epidermal transglutaminase is not a structural component of the dermal–epidermal junction.
Pemphigoid diseases share some clinical characteristics, such as tense blisters and erosions and, by contrast with pemphigus, a negative Nikolsky sign—ie, friction of non-lesional skin does not lead to intraepidermal disruption and visible erosion. The disorders are, however, heterogeneous with respect to overall clinical presentation, target antigens, and autoantibody isotype. Importantly, prognosis and treatment can vary substantially, so exact diagnosis is necessary. However, the different diseases cannot usually be distinguished on clinical grounds alone, so an assessment of skin-bound or mucous membrane-bound autoantibodies and serum autoantibodies is needed.
In 1953, Lever4 differentiated pemphigoid diseases from pemphigus clinically and histopathologically. He described intraepidermal split formation and loss of cell adherence between keratinocytes (acantholysis) as hallmarks of pemphigus, and coined the term pemphigoid for disorders characterised by subepidermal splitting. About 10 years later, Jordon and colleagues5 (including Lever) first described serum and skin-bound autoantibodies in bullous pemphigoid. Since then, detection of skin-bound or epithelium-bound and serum autoantibodies have become diagnostic cornerstones for pemphigoid diseases, alongside clinical characteristics (table).
Section snippets
Incidence
In a prospective study of bullous pemphigoid that encompassed the entire Swiss population, the investigators calculated an incidence of 12·1 new cases per 1 million people per year.6 In Germany, Scotland, and France, incidences of 13·4, 14, and 21·7 per 1 million people per year, respectively, have been reported.7, 8, 9 A 2008 report10 from the UK calculated a higher incidence of 66 new cases per 1 million people per year, on the basis of a data registry established in general practice. In the
Mucous membrane pemphigoid
An international consensus conference87 has defined mucous membrane pemphigoid as immunobullous disease with autoantibodies against components of the dermal–epidermal junction and predominant mucosal involvement. Previously, the term cicatricial pemphigoid was used synonymously for mucous membrane pemphigoid. Now, cicatricial pemphigoid refers only to the rare clinical variant in which mucous membranes are not predominantly affected and skin lesions heal with scarring.87 Incidence of mucous
Pemphigoid gestationis
Pemphigoid gestationis, previously known as herpes gestationis, is a pregnancy-associated immunobullous disease with autoantibodies against BP180 NC16A. An annual incidence of between 0·5 and 2·0 cases per 1 million people has been reported in France, Germany, and Kuwait.7, 88, 114 A much higher incidence than in these countries was noted in two English tertiary referral centres, with the disease reportedly occurring in 4·2% of pregnancies.115 Pemphigoid gestationis usually occurs in the second
Linear IgA disease
Linear IgA disease is named for its main immunopathological feature, which is the linear binding of IgA at the dermal–epidermal junction. Some overlap is seen with bullous pemphigoid (patients with dual IgG and IgA deposition along the junction), with mucous membrane pemphigoid (patients with predominant mucosal involvement), and IgA epidermolysis bullosa acquisita. Incidences between 0·25 and 1·0 per 1 million people per year have been reported in central Europe, Singapore, and Kuwait.7, 88,
Epidermolysis bullosa acquisita
Epidermolysis bullosa acquisita is a clinically heterogeneous disease characterised by autoantibodies against type VII collagen. Incidence reportedly ranges between 0·2 and 0·5 new cases per 1 million people per year.7, 88, 123 The disease is associated with HLA-DR2—notably the DRB1*15:03 allele—and African descent.130 Clinically, epidermolysis bullosa acquisita can either be the classic form or an inflammatory variant.131, 132 The classic mechanobullous form presents with tense blisters and
Anti-p200/anti-laminin γ1 pemphigoid and lichen planus pemphigoides
Both anti-p200 pemphigoid and lichen planus pemphigoides are rare, with fewer than 100 reported cases of each worldwide. Anti-p200 pemphigoid clinically mimics bullous pemphigoid, although patients tend to be younger and concurrent psoriasis is seen in about a third of cases.146, 147 Serum samples from 90% of patients react with laminin γ1.148 Diagnosis is made by detection of autoantibodies against the 200 kDa protein of the dermal–epidermal junction by immunoblotting with extract of dermis or
Search strategy and selection criteria
References (150)
- et al.
The α5 chain of type IV collagen is the target of IgG autoantibodies in a novel autoimmune disease with subepidermal blisters and renal insufficiency
J Biol Chem
(2000) - et al.
Identification and partial characterization of a novel 105-kDalton lower lamina lucida autoantigen associated with a novel immune-mediated subepidermal blistering disease
J Invest Dermatol
(1993) Linear IgA disease: clinical presentation, diagnosis, and pathogenesis
Dermatol Clin
(2011)- et al.
Incidence and mortality of bullous pemphigoid in France
J Invest Dermatol
(2012) - et al.
Bullous pemphigoid in infancy: Clinical and epidemiologic characteristics
J Am Acad Dermatol
(2008) - et al.
Risk factors for bullous pemphigoid in the elderly: a prospective case-control study
J Invest Dermatol
(2011) - et al.
Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration
Cell
(1995) - et al.
Bullous pemphigoid and autoimmunity
J Am Acad Dermatol
(1993) - et al.
The incidence of internal malignancies in pemphigus and bullous pemphigoid in Japan
J Dermatol Sci
(1995) - et al.
Clinical features and practical diagnosis of bullous pemphigoid
Dermatol Clin
(2011)
Characterization of bullous pemphigoid antigen: a unique basement membrane protein of stratified squamous epithelia
Cell
IgG autoantibodies from bullous pemphigoid (BP) patients bind antigenic sites on both the extracellular and the intracellular domains of the BP antigen 180
J Invest Dermatol
Severity and phenotype of bullous pemphigoid relate to autoantibody profile against the NH2- and COOH-terminal regions of the BP180 ectodomain
J Invest Dermatol
Multicenter prospective study of the humoral autoimmune response in bullous pemphigoid
Clin Immunol
Characterization of the anti-BP180 autoantibody reactivity profile and epitope mapping in bullous pemphigoid patients
J Invest Dermatol
Patients with bullous pemphigoid and linear IgA disease show a dual IgA and IgG autoimmune response to BP180
J Autoimmun
IgG4 and IgE are the major immunoglobulins targeting the NC16A domain of BP180 in Bullous pemphigoid: serum levels of these immunoglobulins reflect disease activity
J Am Acad Dermatol
IgG autoantibodies from bullous pemphigoid patients recognize multiple antigenic reactive sites located predominantly within the B and C subdomains of the COOH-terminus of BP230
J Invest Dermatol
Demonstration of epitope-spreading phenomena in bullous pemphigoid: results of a prospective multicenter study
J Invest Dermatol
BP180 ELISA using bacterial recombinant NC16a protein as a diagnostic and monitoring tool for bullous pemphigoid
J Dermatol Sci
IgG from patients with bullous pemphigoid depletes cultured keratinocytes of the 180-kDa bullous pemphigoid antigen (type XVII collagen) and weakens cell attachment
J Invest Dermatol
Autoantibodies to BP180 associated with bullous pemphigoid release interleukin-6 and interleukin-8 from cultured human keratinocytes
J Invest Dermatol
An in vitro model of immune complex-mediated basement membrane zone separation caused by pemphigoid antibodies, leukocytes, and complement
J Invest Dermatol
Autoantibodies to bullous pemphigoid antigen 180 induce dermal-epidermal separation in cryosections of human skin
J Invest Dermatol
Dual targets for mouse mast cell protease-4 in mediating tissue damage in experimental bullous pemphigoid
J Biol Chem
Human bullous pemphigoid antigen 2 transgenic skin elicits specific IgG in wild-type mice
J Invest Dermatol
Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model
J Autoimmun
Noncollagenous 16A domain of type XVII collagen-reactive CD4+ T cells play a pivotal role in the development of active disease in experimental bullous pemphigoid model
Clin Immunol
A pathogenic role for IgE in autoimmunity: bullous pemphigoid IgE reproduces the early phase of lesion development in human skin grafted to nu/nu mice
J Invest Dermatol
IgE basement membrane zone antibodies induce eosinophil infiltration and histological blisters in engrafted human skin on SCID mice
J Invest Dermatol
Pathogenicity of IgE in autoimmunity: successful treatment of bullous pemphigoid with omalizumab
J Allergy Clin Immunol
Experimental bullous pemphigoid generated in mice with an antigenic epitope of the human hemidesmosomal protein BP230
J Autoimmun
Enzyme-linked immunosorbent assay using bacterial recombinant proteins of human BP230 as a diagnostic tool for bullous pemphigoid
J Dermatol Sci
Histopathology of anti-laminin 5 mucous membrane pemphigoid
J Am Acad Dermatol
A comparison of two regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: a multicenter randomized study
J Invest Dermatol
Mucous membrane pemphigoid and pseudopemphigoid
Ophthalmology
Cicatricial pemphigoid
J Am Acad Dermatol
Ocular mucous membrane pemphigoid: diagnosis and management strategies
Ocul Surf
Anti-epiligrin cicatricial pemphigoid and relative risk for cancer
Lancet
Cicatricial pemphigoid autoantibodies react with multiple sites on the BP180 extracellular domain
J Invest Dermatol
Anti-basement membrane autoantibodies in patients with anti-epiligrin cicatricial pemphigoid bind the alpha subunit of laminin 5
J Invest Dermatol
Antigen specificity in subsets of mucous membrane pemphigoid
J Invest Dermatol
Pemphigus
Medicine (Baltimore)
Basement zone antibodies in bullous pemphigoid
JAMA
Incidence of bullous pemphigoid and pemphigus in Switzerland: a 2-year prospective study
Br J Dermatol
Prospective analysis of the incidence of autoimmune bullous disorders in Lower Franconia, Germany
J Dtsch Dermatol Ges
Annual incidence and mortality of bullous pemphigoid in the Grampian region of north-east Scotland
Br J Dermatol
Bullous pemphigoid and pemphigus vulgaris—incidence and mortality in the UK: population based cohort study
BMJ
Increased risk of bullous pemphigoid in male and very old patients: a population-based study on incidence
J Am Acad Dermatol
Mortality of bullous pemphigoid in Switzerland: a prospective study
Br J Dermatol
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