The pathogeneses of pemphigus and pemphigoid diseases.

Autoimmune bullous diseases (AIBDs) are skin disorders which are mainly induced by autoantibodies against desmosomal or hemidesmosomal structural proteins. Previous studies using patients' samples and animal disease models identified target antigens and elucidated the mechanisms of blister formation. Pemphigus has been the subject of more active clinical and basic research than any other AIBD. These efforts have revealed the pathogenesis of pemphigus, which in turn has led to optimal diagnostic methods and novel therapies, such as rituximab. In bullous pemphigoid (BP), studies with passive-transfer mouse models using rabbit anti-mouse BP180 antibodies and studies with passive-transfer or active mouse models using autoantigen-humanized mice elucidated the immune reactions to BP180 in vivo. Recently, dipeptidyl peptidase-4 inhibitors have attracted attention as a trigger for BP. For epidermolysis bullosa acquisita (EBA), investigations using mouse models are actively under way and several molecules have been identified as targets for novel therapies. In this review, we give an overview and discussion of the recent progress in our understanding of the pathogenesis of pemphigus, BP, and EBA. Further studies on the breakdown of self-tolerance and on the identification of key molecules that are relevant to blister formation may expand our understanding of the etiology of AIBDs and lead to the development of novel therapeutic strategies.

Ujiie H ，Yamagami J ，Takahashi H ，Izumi K ，Iwata H ，Wang G ，Sawamura D ，Amagai M ，Zillikens D ... -  《-》

Retrospective analysis of autoimmune bullous diseases in Middle Franconia.

Sollfrank L ，Schönfelder V ，Sticherling M 《Frontiers in Immunology》

Autoimmune bullous dermatoses.

Autoimmune bullous dermatoses (AIBD) are a heterogeneous group of about a dozen diseases characterized clinically by erosions and blisters and immunopathologically by autoantibodies against structural proteins of the skin or transglutaminase 2/3. The diagnosis of AIBD has made tremendous progress in the last decade due to the availability of standardized serological assays that, knowing the clinical picture, allow the diagnosis in the vast majority of patients. The development of various in vitro and in vivo models of the most common AIBD, namely, bullous pemphigoid, pemphigus vulgaris, mucous membrane pemphigoid, and the rare epidermolysis bullosa acquisita, allows identification of key molecules and inflammatory pathways as well as preclinical evaluation of the effect of new anti-inflammatory agents. The approval of rituximab for moderate and severe pemphigus vulgaris and the development of national and international guidelines for the most common AIBD have considerably advanced the care of these patients. Nevertheless, the limited therapeutic armamentarium is the main challenge for the management of AIBD. Several phase II and III randomized controlled clinical trials provide hope for new, effective, and safe therapeutic options in the coming years. This review summarizes the epidemiology, clinic, diagnosis, pathophysiology, and therapy of AIBD and gives an outlook on both current diagnostic and therapeutic needs as well as future developments.

Holtsche MM ，Boch K ，Schmidt E 《-》

Pathogenesis of epidermolysis bullosa acquisita, an autoimmune subepidermal bullous disease.

Autoimmune bullous diseases (ABDs) are organ-specific autoimmune diseases, in which blisters on the skin and mucous membranes develop through binding of pathogenic autoantibodies to target antigens. There are two major ABD groups: the pemphigus group, showing autoantibodies to desmosomal components; and the subepidermal ABD group, showing autoantibodies to hemidesmosomal components in the epidermal basement membrane zone. Recent immunological, biochemical and molecular biological studies revealed many new autoantigens, including desmocollins, various plakin family proteins and integrins. A revised ABD classification includes new disease entities such as paraneoplastic pemphigus, IgA pemphigus and anti-laminin γ1 pemphigoid. In addition to systemic corticosteroids and various immunosuppressive agents, various adjuvant therapies for ABDs have developed. Among them, intravenous immunoglobulin (IVIG) is a promising therapy, although the therapeutic mechanisms are still unknown. Various disease models for ABDs have developed, particularly for pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa acquisita (EBA), and these have provided insights into the pathogenesis of various ADBs that suggest possible new treatment strategies. However, the fundamental mechanisms in disruption of immune-tolerance are still unknown. EBA shows autoimmunity to type VII collagen, the major component of anchoring fibrils, and EBA pathogenesis has been studied in various disease models. Previous studies suggested that, following binding of autoantibodies to type VII collagen, activation of complement, cytokine release, neutrophil migration, Fcγ receptors (FcgRs) and metalloproteinases play important roles in induction of subepidermal blisters. In this issue of the Journal of Pathology, Kasperkiewicz and colleagues reveal important roles of activating FcgRIV and inhibitory FcgRIIB in EBA pathogenesis that were recognized by conducting elegant studies using both genetic analysis and functional animal model methods. The expression equilibrium of the activating and inhibitory FcgRs can be modulated towards the inhibitory FcgRIIB by IVIG therapy, resulting in beneficial clinical effects of IVIG in EBA and other autoimmune skin-blistering diseases.

Hashimoto T ，Ishii N ，Ohata C ，Furumura M ... -  《-》

Bullous autoimmune dermatoses.

Pathophysiologically, bullous autoimmune dermatoses are caused by autoantibodies directed against adhesion molecules or structural proteins of the skin and mucous membranes, clinically resulting in blister formation. Depending on the respective target proteins of the autoimmune response and their location in the skin, a distinction is made between intraepidermal (pemphigus disorders), junctional (pemphigoid disorders), and subepidermal (epidermolysis bullosa acquisita, dermatitis herpetiformis) autoimmune blistering diseases. The most common bullous autoimmune dermatosis, bullous pemphigoid is characterized by marked clinical variability and intense pruritus. Predominantly affecting elderly individuals, there has been a significant increase in its incidence in recent years. While mucosal lesions occur in less than 30 % of bullous pemphigoid patients, the second most common bullous autoimmune dermatosis, pemphigus vulgaris, typically presents with oral erosions as the predominant and - frequently - initial symptom. Its onset is usually in the 4th to 6th decade of life. Scarring is typically found in subepidermal blistering disorders such as epidermolysis bullosa acquisita or mucous membrane pemphigoid. Diagnosis is based on clinical and histological findings as well as direct and indirect immunofluorescence and detection of circulating autoantibodies. Although a number of controlled clinical trials have been conducted in recent years, treatment of bullous autoimmune disorders is still primarily based on clinical experience. Therapeutic options include topical and systemic corticosteroids as well as adjuvant immunosuppressants. Recalcitrant cases may require treatment with immunoadsorption, intravenous immunoglobulins, or the monoclonal anti-CD20 antibody rituximab.

Hofmann SC ，Juratli HA ，Eming R 《-》