IgE-mediated mechanisms in bullous pemphigoid and other autoimmune bullous diseases (1)
Autoimmune bullous diseases (AIBDs) comprise a heterogeneous group of about a dozen entities that can be divided in three subgroups, pemphigus diseases, pemphigoid diseases, and dermatitis herpetiformis. Pemphigus disorders are characterized by autoantibodies against desmosomal proteins, including desmoglein 1 (in pemphigus foliaceus and the mucocutaneous form of pemphigus vulgaris), desmoglein 3 (in pemphigus vulgaris), and envoplakin (in paraneoplastic pemphigus). The target antigens of pemphigoid diseases include BP180 (type XVII collagen) and, less frequently, the intracellular BP230 (in bullous pemphigoid, mucous membrane pemphigoid, pemphigoid gestationis, and linear IgA disease), laminin 332 and α6β4 integrin (in mucous membrane pemphigoid), laminin γ1 (in anti-p200 pemphigoid), and type VII collagen (in epidermolysis bullosa acquisita).
The most frequent AIBD is bullous pemphigoid (BP), with incidences ranging from 13.4 to 66 new cases per 1 million per year. Blister development is usually preceded by a prodromal phase of weeks or months with pruritus, excoriations, and eczematous lesions, and some patients never develop blisters. Blister formation is initiated by binding of autoantibodies against two hemidesmosomal proteins, BP180 and BP230. BP230 is an intracellular plakin-like protein of the hemidesmosomal plaque, while BP180 (type XVII collagen) is a transmembrane glycoprotein with an extracellular C-terminus. The extracellular portion of the 16th non-collagenous domain of BP180 (BP180 NC16A) has been identified as an immunodominant region. Most effects of anti-BP180 IgG are Fc receptor-mediated.
Elevated total serum IgE levels have been described in multiple reports in 70–85% of BP sera. Total IgE serum levels were found to decline after exacerbation of disease had resolved and correlate with disease activity as well as anti-BMZ antibodies. sCD23, the soluble form of a low-affinity FcγRII, serum levels correlated with both disease activity and total serum IgE levels in BP. Binding of anti-BP180 NC16A IgE on eosinophils might result in eosinophil degranulation or may trigger mast cell degranulation, which has been suggested to be in a piecemeal degranulation pattern.
Besides IgG autoantibodies, IgE anti-BP180 autoantibodies of the IgA and IgE isotypes are found. Like IgG, IgA and IgE autoantibodies target mainly the NC16A domain. Epitopes outside the NC16A domain have also been described to be recognized by IgE. Serum levels of anti-NC16A IgE significantly correlated with disease severity in individual BP patients. The stimulation of Th2 cells may be responsible for the production of IgG4 and IgE autoantibodies to BP180 and BP230. IgE anti-BP230 reactivity was associated with local eosinophil accumulation.
