Autoimmune bullous diseases: pathogenesis and clinical management

Abstract

Autoimmune bullous diseases (AIBDs) represent a heterogeneous group of immune-mediated disorders characterized by life-threatening blistering of the skin and mucous membranes. This Review synthesizes current understanding of AIBD pathogenesis, clinical phenotypes, diagnostic approaches, and therapeutic strategies, emphasizing recent advancements and translational opportunities. At the core of AIBDs is autoantibody-mediated disruption of structural proteins in the epidermis or basement membrane zone, particularly at desmosomal and hemidesmosomal junctions. Key subtypes, including pemphigus, paraneoplastic pemphigus, pemphigoid, and IgA-related diseases, are distinguished by their target antigens, clinical manifestations, and immunopathological profiles. Diagnostic workflows rely on direct immunofluorescence, and serological assays, yet subtype differentiation remains challenging due to overlapping features. Traditional therapies, such as systemic corticosteroids and immunosuppressants, have improved outcomes but are limited by toxicity. Recent breakthroughs highlight targeted interventions, including B-cell depletion with rituximab, cytokine modulation via dupilumab, and JAK inhibitors for inflammatory pathways. Innovative strategies like chimeric autoantibody receptor T-cell (CAART) therapy further address refractory cases by eliminating autoreactive B cells. Additionally, the Review underscores the emerging role of inflammation-driven mechanisms and the necessity of multidisciplinary care, given AIBDs' associations with malignancies, autoimmune comorbidities. Despite progress, challenges persist in early diagnosis, personalized therapy optimization, and understanding antigen-specific immune responses. Future directions include refining diagnostic biomarkers, exploring novel targets, and developing precision medicine approaches.

Keywords: Autoantibody; Autoimmune bullous diseases; Immunogenic domain; Inflammation; Pathogenesis; Targeted therapy.

Fig. 1

Diagnostic flow chart for autoimmune bullous diseases. Diagnosing autoimmune bullous diseases requires a combination of clinical manifestations, histopathology, immunofluorescence, and detection of circulating antibodies. Abbreviations: DIF direct immunofluorescence, BMZ basement membrane zone, IIF indirect immunofluorescence, COL 7 Type VII collagen, Dsg1 Desmoglein1, Dsg3 Desmoglein3, Dsc desmocollin, PF pemphigus foliaceous, PV pemphigus vulgaris, PNP paraneoplastic pemphigus, BP bullous pemphigoid, LAD linear IgA bullous dermatosis, MMP mucous membrane pemphigoid, EBA epidermolysis bullosa acquisita, DH dermatitis herpetiformis

Fig. 2

Pathogenesis of pemphigus vulgaris. This figure shows the pathogenesis of pemphigus vulgaris (PV). Autoantibodies binding to autoantigens can directly impair desmosomal function, leading to acantholysis. In the skin, antigen-presenting cells such as Langerhans cells initiate their activation by capturing Dsg peptides and presenting them to CD4 + T cells. Th1 cells enhance the immune response, while Th2 cells regulate the production of pathogenic Dsg-specific IgG antibodies. Th17 cells release IL-17, which drives an inflammatory response, whereas Treg cells inhibit the proliferation of Dsg3-autoreactive T cells and antibody production. Additionally, Tfh cells interact with B cells to facilitate autoantibody production. Some patients develop tertiary lymphoid structures at lesion sites, which may contribute to disease recurrence. Created in https://BioRender.com

Fig. 3

Major clinical and laboratory findings in pemphigus and pemphigoid. Major clinical and laboratory findings in pemphigus and pemphigoid. a Extensive erosions with crusts and hyperpigmentation on the back of a female patient with pemphigus vulgaris. b Histopathological examination reveals sub-corneal acantholysis and an inflammatory infiltrate. c Direct immunofluorescence microscopy analysis of a perilesional skin biopsy shows deposits of IgG with an intercellular pattern in the epidermis. d Blisters, and erosions with crusts on an erythematous background in a male patient with bullous pemphigoid. e Histopathological examination reveals subepidermal cleavage with an inflammatory infiltrate consisting predominantly of eosinophils and neutrophils. f DIF shows IgG with a linear deposition pattern in the basement membrane zone

Fig. 4

Pathogenesis of bullous pemphigoid. This picture shows the pathogenesis of bullous pemphigoid (BP). BP is characterized by the presence of IgG autoantibodies and complement component C3, which target the dermoepidermal basement membrane—the adhesion structure of the epidermis. Immune complex formation initiates complement activation, recruiting mast cells, neutrophils, and eosinophils, and triggering the release of proteases and inflammatory mediators, leading to dermal–epidermal separation. Th17 cells infiltrate skin tissues, where their production of IL-17 activates neutrophils, amplifies the inflammatory response, and causes tissue damage. Th2 cells and IL-4 promote B cell proliferation, antibody production, and immunoglobulin class switching. Pathogenic Th17 cells exacerbate the inflammatory immune response, while dysregulated Treg cells lead to spontaneous activation of autoreactive CD4 + T cells and promote autoantibody production. Increased Tfh cell activation aids B cells in producing autoantibodies in BP. Created in https://BioRender.com