SKINIPEDIA - Skin Encyclopedia Studies: Bullous Pemphigoid

Bullous Pemphigoid Skin Disease Study by Lawrence S Chan, MD, Dr Orville J Stone Professor of Dermatology, Head, Department of Dermatology, University of Illinois College of Medicine

Bullous pemphigoid is a chronic, autoimmune, subepidermal, blistering skin disease that rarely involves mucous membranes. Bullous pemphigoid is characterized by the presence of immunoglobulin G (IgG) autoantibodies specific for the hemidesmosomal bullous pemphigoid antigens BP230 (BPAg1) and BP180 (BPAg2).

In spontaneous animal models, bullous pemphigoid has been reported to occur in dogs (canine) and horses (equine). Bullous pemphigoid has been found to occur in domestic cats (feline) and Yucatan minipigs (porcine). In experimental animal models, passive transfer of antibodies to mouse BPAg2 causes blistering in newborn mice similar to that seen in humans. Active induction of anti-BPAg1 antibodies in rabbits enhances inflammation and deposition of immunoreactants at the basement membrane but does not result in spontaneous blistering.

In canine bullous pemphigoid, histologic analysis reveals a subepidermal blistering process with prominent eosinophil infiltration identical to the classic pathology of humans. Similar findings have been observed in feline, porcine, and equine bullous pemphigoid. As in humans with bullous pemphigoid, the sera from dogs with bullous pemphigoid bind to the epidermal roof of salt-split skin and BP180. The antigenic epitopes of BP180 identified by the canine bullous pemphigoid IgG map to the same epitopes as human bullous pemphigoid autoantibodies. Similar findings were observed in cats, pigs, and horses with bullous pemphigoid.

 

Pathophysiology

IgG autoantibodies bind to the skin basement membrane in patients with bullous pemphigoid. The binding of antibodies at the basement membrane activates complement and inflammatory mediators. Activation of the complement system is thought to play a critical role in attracting inflammatory cells to the basement membrane. These inflammatory cells are postulated to release proteases, which degrade hemidesmosomal proteins and lead to blister formation. Eosinophils are characteristically present in human patients' blisters as demonstrated by histopathologic analysis, although their presence is not an absolute diagnostic criterion.

The precise role of bullous pemphigoid antigens in the pathogenesis of bullous pemphigoid is not completely clear. BPAg1 (BP230) is an intracellular component of the hemidesmosome; BPAg2 (BP180, type XVII collagen) is a transmembranous protein with a collagenous extracellular domain. Passive transfer experiments in newborn mice have demonstrated that rabbit antibodies against mouse BPAg2 can induce subepidermal blisters similar to those observed in patients with bullous pemphigoid. However, the eosinophil infiltration that is frequently observed in human bullous pemphigoid lesional skin was not detected in the passive transfer experimental model. Furthermore, anti-BP180 NC16A domain autoantibodies purified from patients with bullous pemphigoid are capable of inducing dermal-epidermal separation in cryosections of normal human skin.

Studies from 2006 on autoreactive T and B cells from 35 patients with acute-onset bullous pemphigoid revealed that the percentage of T- cell and B-cell reactivity from these bullous pemphigoid patients against the BPAg2 is much higher than that against BPAg1, further suggesting a more prominent role of BPAg2 in disease development. Serum levels of autoantibodies against BPAg2 are reportedly correlated with disease activity in some studies. Induction of antibodies against BPAg1 in rabbits does not induce primary blistering, but it can enhance the inflammatory response at the basement membrane. The role of autoantibodies specific for bullous pemphigoid antigens in the initiation and the perpetuation of disease is unknown.

Although BPAg2 has been identified as the major antigen involved with bullous pemphigoid disease development, in 2005, autoantibodies against alpha 6 integrin and laminin-5, 2 other skin basement membrane components, were identified in human patients affected by bullous pemphigoid. Although no perfect active experimental model is available currently, an active animal model was generated by transferring splenocytes from wide-type mice that had been immunized by grafting human BP180-transgenic mouse skin into Rag-2(-/-)/BP180-humanized mice. The recipient immunodeficient mice developed antihuman BP180 antibodies, manifested with blisters that are consistent with the clinical, histological, and immunopathological features of human bullous pemphigoid, except eosinophil infiltration. In addition, the autoantibody response can be induced in healthy BALB/c mice by immunizing the mice with synthetic peptides of the mouse type XVII collagen NC16A domain, the target region of autoantibodies in human patients affected with bullous pemphigoid.

Eotaxin, an eosinophil-selective chemokine, is strongly expressed in the basal layer of the epidermis of lesional bullous pemphigoid skin and parallels the accumulation of eosinophils in the skin basement membrane zone area. It may play a role in the recruitment of eosinophils to the skin basement membrane area. Other cytokines and chemokines have also been studied in bullous pemphigoid. Interleukin 16, a major chemotactic factor responsible for recruiting CD4 + helper T cells to the skin and for inducing functional interleukin 2 receptors for cellular activation and proliferation, was found to be expressed strongly by epidermal cells and infiltrating CD4 + T cells in lesional bullous pemphigoid skin. Significantly higher levels of interleukin 16 were detected in sera and blisters of bullous pemphigoid patients compared with healthy subjects. These data (reported in 2004 and involved 39 bullous pemphigoid patients with active disease) suggest a role of interleukin 16 in bullous pemphigoid development.

In other study of 27 bullous pemphigoid patients (reported in 2006), serum levels of monokine induced by interferon gamma (MIG, a Th1-type chemokine) and serum levels of CCL17 and CCL22 (Th2-type chemokines) were significantly increased in bullous pemphigoid patients compared with healthy subjects.

Matrix metalloproteinase (MMP)–2, MMP-9, and MMP-13 were significantly increased in lesional bullous pemphigoid skin compared with that of healthy skin, with T cells comprising the majority of MMP cellular sources. These data (reported in 2006) suggest a role of MMP in the blistering of bullous pemphigoid.

In another study of 39 bullous pemphigoid patients (reported in 2006), a cytokine named BAFF (B-cell activating factor belonging to the tumor necrosis factor family) that functions to regulate B-cell proliferation and survival was found to be significantly increased in sera of bullous pemphigoid patients compared with healthy subjects, although no significant association was noted between serum BAFF levels and titers of anti-BPAg2 antibodies. In 2008, a role for IgE class of autoantibodies, particularly those that target BP180, has been established. The higher level of IgE anti-BP180 was correlated with a more severe clinical phenotype.

In an animal model in which C57BL/6 type of mice engrafted with syngeneic mouse skin transgenically expressed human BPAg2 in the epidermal basement membrane zone, antibodies against the human BPAg2 extracellular domain developed first, followed by the occurrence of antibodies to the intracellular domain of the same human BPAg2. Interestingly, the development of later antibodies was associated with the loss of the graft. IgG autoantibodies from bullous pemphigoid patients are found to deplete cultured keratinocytes of the BPAg2 and weaken cell attachment in vitro, which further supports the pathogenic role of these autoantibodies.

The coagulation cascade is found to be activated in bullous pemphigoid patients, and such activation is found to be correlated with the disease severity and with eosinophilia, suggesting a role of eosinophils in this activation of coagulation, which may contribute to the potential thrombotic risk, as well as inflammation, tissue damage, and blister formation.

A 2009 report of bullous pemphigoid developed after adalimumab treatment for psoriasis raises some question about whether biologics can play a role in inducing the disease or it may just suggest the association of bullous pemphigoid with psoriasis.