Immunol Res DOI 10.1007/s12026-014-8547-7

IMMUNOLOGY AT THE UNIVERSITY OF IOWA

Unraveling the significance of IgE autoantibodies in organ-specific autoimmunity: lessons learned from bullous pemphigoid K. A. N. Messingham • H. M. Holahan • J. A. Fairley

Ó Springer Science+Business Media New York 2014 J. A. Fairley

Abstract Bullous pemphigoid (BP), a cutaneous autoimmune blistering disease, has provided a useful model to elucidate a role for IgE in autoimmunity. IgE antibodies specific for the BP180 autoantigen are detected in sera and biopsy samples from the majority of BP patients. In BP biopsies, both IgE and BP180 antigen localize to the surface of mast cells, and incubation of circulating basophils from these patients with BP180 protein triggered degranulation. The in vivo pathogenicity of BP180-specific IgE was confirmed in mouse models, where injection of purified BP IgE into human skin grafted onto nu/nu mice replicated the early phase of lesion development, including mast cell degranulation, eosinophil infiltration and development of urticarial plaques. In addition, IgE antibodies from patient sera bind to BP180 on basal keratinocytes, resulting in internalization of BP180, production of inflammatory cytokines, IL-6 and IL-8, and a decrease in the number of hemidesmosomes at the basement membrane zone. These findings have led to therapeutic trials of the anti-IgE monoclonal antibody omalizumab in BP, resulting in substantial improvement in the patients’ disease. Overall, the work in BP provides the first evidence for a pathogenic role for IgE in autoimmunity. Keywords

IgE  Autoantibody  Bullous  Pemphigoid  BP180  Type XVII collagen

Introduction IgE is best known for its role in parasitic immunity and type I hypersensitivity responses, including asthma, allergy, some types of chronic urticaria and atopic dermatitis [1, 2]. Recently, a role for IgE in the regulation of immunity and development of autoimmune disease has been proposed [3]. IgE autoantibodies were reported several decades ago [4, 5] and, since then, have been documented in an ever-increasing number of autoimmune diseases. IgE autoantibodies are present in anti-SSA-positive women who experience fetal loss, in patients with K. A. N. Messingham  H. M. Holahan  J. A. Fairley (&) Department of Dermatology, University of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA e-mail: [email protected] J. A. Fairley Department of Dermatology, VA Medical Center, Iowa City, IA, USA

Graves’ disease, targeting thyroid peroxidase in Hashimoto’s thyroiditis, and targeting myelin peptides in patients with multiple sclerosis [6–9]. Furthermore, IgE-targeting dsDNA has been linked with disease activity and the presence of nephritis in lupus patients [10]. Despite these observations, relatively little is known about the pathogenicity of IgE in these diseases. In contrast, we and others have established a critical role for IgE autoantibodies in the pathogenesis of bullous pemphigoid (BP), an autoimmune blistering disease affecting the skin. BP predominantly affects patients over the age of 65 and has no bias in relation to gender, ethnicity or race. An immunologic origin of the disease was first suggested by Beutner and Jordan [11], who demonstrated IgG and complement (C3) bound to the basement membrane zone (BMZ) of skin biopsies, and anti-BMZ autoantibodies in the serum of patients with active disease. The target of BP autoantibodies was identified as the hemidesmosomal cellsubstrate adhesion molecule, BP180 (type XVII collagen) [12]. Autoantibody binding to BP180 expressed by basal

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keratinocytes leads to activation of complement, recruitment of inflammatory cells and release of proteases. Mast cell degranulation is the earliest identifiable event in lesion formation, followed by lymphocytic infiltration and then eosinophil and neutrophil influx [13, 14]. This autoimmune and inflammatory cascade results in weakening of the epidermal–dermal junction and formation of tense, fluid-filled blisters. If left untreated, the clinical signs and symptoms of BP can last for months or years and lead to significant morbidity or death. In the absence of more targeted therapies, systemic immune suppression remains the treatment of choice. Most of the investigations into the mechanisms of BP pathogenesis are focused on IgG autoantibodies. However, we hypothesized that IgE could play a role in lesion progression based on reports describing elevated levels of circulating IgE [15–18], deposition of IgE at the BMZ of affected skin [5, 15] and IgE’s accepted role as a mediator of allergic mast cell degranulation [19, 20]. Over the last few years, both clinical and experimental studies have underscored IgE’s role as a critical component of autoimmunity in BP. In this report, we will discuss these findings as a conceptual framework for our current model of BP pathogenesis.

Characterization of IgE autoantibodies For many decades, studies examining the pathogenic mechanisms of BP autoantibodies focused solely on IgG, despite the fact that IgE was also observed at the BMZ of lesional skin [5]. This approach was likely based on the overwhelming presence of IgG (mg/ml), compared to IgE (ng/ml), in the circulation and the readily accepted role of IgG-class autoantibodies in other autoimmune diseases. Indeed, the level of IgG autoantibody reactivity to BP180 has been correlated with disease activity in several reports [21–24]. As studies progressed, several laboratories also noted elevated levels of circulating IgE in C70 % of untreated BP patients [15, 25]. Through epitope mapping studies utilizing immunoblot against recombinant fragments of BP180, our laboratory demonstrated that these IgE autoantibodies predominantly target the same extracellular non-collagenous 16A domain (NC16A) of the BP180 protein recognized by the IgG autoantibodies [26– 28]. Based on these findings, we developed an ELISA to detect NC16A-specific IgE, similar to the commercially available IgG ELISA that is used clinically. Using this ELISA to screen a large number (n = 43) of samples, IgE antibodies to NC16A were detected in most (77 %) BP sera [17]. These findings were in contrast to previous reports estimating a much lower (25–55 %) prevalence of BP180specific IgE using a variety of methods that were not optimized for the detection of IgE [28–30]. Furthermore, it

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was demonstrated that BP180-specific IgE and IgG are often present in BP sera simultaneously, and in agreement with others, levels of both autoantibody isotypes parallel disease activity [17, 28, 29]. It is our opinion that clinical BP results from the combined effects of both autoantibody isotypes and their ability to differentially regulate inflammation and activation of immune cells. Additionally, we propose that evaluation of both BP180-specific IgG and IgE may provide a better indicator of disease severity and predictor of treatment efficacy than evaluation of either autoantibody isotype alone.

Demonstration of IgE pathogenicity Application of mouse models to human BP is complicated by the fact that the pathogenic domain of the BP180 protein is not highly conserved and the low levels of IgE (ng/ml) in human sera. Because of this, two approaches were used to demonstrate pathogenicity of IgE antibodies in vivo. In the first, Zone et al. [31] developed a model utilizing an IgE monoclonal antibody directed against the shed ectodomain of the BP180 protein. Injection of the hybridoma cells, subcutaneously into the backs of SCID mice engrafted with human skin, led to the development of an autoantibodyproducing tumor. The mice developed high titers of BP180-specific IgE and developed pruritus, erythema and histologic blisters in the grafted skin [31]. In the second model, IgE was purified from the serum of BP patients and injected into human skin engrafted onto nu/nu mice (6 ng/graft) [25]. At this low dose, a visible wheal was present in the graft within 15 min of injection, and human IgE antibodies were detected at the BMZ. By 24 h, an erythematous, urticarial plaque developed that mimicked the early, urticarial phase of the disease. Biopsies of the skin grafts revealed mast cell degranulation, and influx of eosinophils, lymphocytes and neutrophils. At higher doses (47 ng/graft), separation at the dermal–epidermal junction was confirmed histologically; however, no gross blistering was observed. These studies were unique in that, unlike the IgG-based experiments [32–34], they were the first passive transfer experiments to fully replicate the early phase of lesion development in BP. Furthermore, these were the first studies to demonstrate the pathogenicity of IgE autoantibodies in a human disease model.

Mechanisms of IgE pathogenesis The earliest stage of BP is characterized clinically by urticarial lesions consisting of edema and eosinophilic infiltration into the upper dermis, termed eosinophilic spongiosis. Elegant studies examining sequential biopsies

University of Iowa Immunology 2014 Fig. 1 The proposed mechanism of action of IgE in BP. IgE autoantibodies bind to the surface of cutaneous mast cells via the IgE receptor, FceRI. Binding of the antigenic NC16A domain of BP180 to IgE causes receptor crosslinking with subsequent release of mediators including cytokines and proteases. An immune cascade is triggered, recruiting additional effector cells such as eosinophils and neutrophils, resulting in further destruction of the basement membrane zone. Alternatively, the IgE autoantibodies can bind via their variable region directly to the target antigen, NC16A, on the basal keratinocyte cell membrane. Binding to the keratinocyte BP180 results in internalization of the antibody and a decrease in hemidesmosomes that mediate cell-substrate attachment. Together, these events contribute to the inflammation and degradation of the basement membrane zone in BP

taken during the development of individual lesions revealed that early mast cell degranulation is closely followed by eosinophil migration into the lesion [13, 14]. Additionally, the presence of mast cell granule proteins in blister fluid confirms activation of these cells in the affected skin [13, 35]. Within the skin, mast cells are poised for immediate action via the production of inflammatory mediators and/or degranulation. Using a mouse model of BP, Chen [36] demonstrated that mast cells play a crucial role in neutrophil recruitment in experimental BP through release of IL8. Clinically, many of the manifestations of allergies and other inflammatory reactions can be attributed to mast cell degranulation triggered by IgE [37, 38]. Therefore, we hypothesized IgE autoantibodies might play a role in mast cell activation in BP skin. When autoantibody and mast cell distribution were evaluated in lesions of untreated BP patients with immunofluorescent microscopy, IgE was observed at the BMZ and co-localized with the detection of mast cell tryptase, a specific granule protein [15]. Detection of IgG did not coincide with dermal mast cells. Furthermore, many of these mast cells also labeled with a monoclonal antibody against BP180, indicating that BP180 is bound to their surface in lesional skin. This observation can be attributed to the constitutive shedding of BP180 ectodomain from the keratinocyte membrane, which

provides a source of free antigen capable of interacting with cell-surface bound autoantibodies [39, 40]. To examine the potential relevance of BP180-specific IgE-coated mast cells in BP skin, we examined whether circulating basophils released histamine when exposed to the NC16A domain of BP180 [15]. Peripheral basophils were used because of the difficulty in extracting mast cells from skin, and lack of shed BP180 in the circulation. BP180-specific degranulation was observed by basophils from untreated BP patients, but not healthy controls or treated BP patients. These studies were the first to provide a potential pathogenic mechanism for the contribution of IgE autoantibodies to lesion development. Our working model of BP is dependent on IgE-mediated activation of dermal mast cells via the high affinity IgE receptor, FceRI (Fig. 1). Because of its extremely high affinity (Ka * 1010\M) for IgE, surface FceRI is always bound with antibody [41]. In this scenario, lesional mast cells coated with IgE specific for the NC16A domain of BP180 would release cytokines and proteases upon receptor crosslinking by BP180 protein in the skin. This event initiates a cascade of events including influx of additional effector cells, such as eosinophils and neutrophils, resulting in additional mediator release and weakening of the BMZ. In addition to the effects of IgE mediated through autoantibody interaction with immune cells via FceRI

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binding, receptor independent functions of IgE have also been identified in BP [42]. Since BP antibodies target an antigen within the skin and can bind to the antigen directly through their variable region, the effects of IgE treatment of keratinocytes were examined in a series of in vitro experiments. In these studies, IgE purified from BP sera (BP IgE) bound directly to human keratinocytes, was internalized, and stimulated the release of the pro-inflammatory cytokines IL-6 and IL-8. Treatment of human skin organ cultures with BP IgE resulted in similar cytokine release, and a dramatic decrease in the number of hemidesmosomes localized at the cutaneous BMZ. These findings are similar to studies examining the effects of BP IgG on keratinocytes in vitro [43–46] and suggest that the direct effects of these autoantibodies contribute to inflammation and fragility of the BMZ in BP.

Translational applications While our understanding of the pathogenesis of autoimmune blistering diseases has increased significantly over the past 20 years, progress in the therapy of these disorders has been much more limited. Broad-based immunosuppression with steroids remains the mainstay of treatment and is associated with significant morbidity in the elderly. A better understanding of the pathologic components of the disease will provide new avenues of therapeutic intervention. Based on the early urticarial stage of BP and our work demonstrating a critical role for IgE in experimental BP, we and others explored the effect of inhibition of IgE/IgE receptor interaction in clinical BP [47, 48]. Omalizumab (OMZ) is a recombinant humanized IgG1j monoclonal antibody specific that specifically binds free IgE, thus preventing interaction with FceRI on target cells. Developed clinically for use in asthma [49, 50], OMZ’s mechanism of action is via decreased IgE-mediated activation and degranulation of primarily basophils and mast cells [51]. As free IgE is depleted by OMZ, the FceRI receptors are downregulated on basophils, mast cells and dendritic cells [52–54]. Interestingly, OMZ treatment also results in a decline in peripheral eosinophil numbers [55, 56]. Recent pilot studies have investigated whether OMZ, administered based on weight and total IgE levels as in asthma, might be of therapeutic benefit in BP [47, 48, 57]. In our initially reported case, dramatic clinical improvement was observed within 16 weeks of initiating OMZ monotherapy in a BP patient who had failed traditional therapies [57]. At the time of enrollment, the patient had elevated circulating levels of BP180-specific IgG (129 U; normal \ 9), BP180-specific IgE (44 U; normal \ 19), total IgE (222 IU; normal \ 100 IU) and peripheral

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eosinophilia. One week after the first dose, the patient reported a decrease in itching, and the intact blister count was decreased by 44 % (89–50). By week 16, the body surface area affected with urticarial plaques had declined from 50 to 5 %, the tense blisters characteristic of BP were resolved and eosinophils had declined from 3,427 to 460/ mm3 (normal \ 400). Interestingly, her anti-BP180 IgG remained above 100 IU throughout the treatment course, suggesting that IgE is a critical component of the disease. Two other groups reported similar results utilizing OMZ as a steroid-sparing agent in recalcitrant patients [47, 48]. These cases are the first to confirm the pathogenicity of IgE in human autoimmunity and providing proof of concept for the use of anti-IgE in the therapy of BP. In addition, agents with higher affinity for IgE are currently under development and may lead to additional advances in the treatment of IgE-mediated immune disorders. Furthermore, therapies targeting other parts of the IgE–mast cell–eosinophil interaction may also be promising areas to explore. Our current studies are focused on understanding the role of IgE in eosinophil activation in BP.

Conclusions Autoimmune diseases remain a significant source of morbidity and mortality in developing nations, accounting for tens of billions of dollars in healthcare spending every year [58]. Understanding the fundamental causes of these diseases will allow for more effective therapies with fewer complications. Organ-specific autoimmune diseases of the skin provide unique models to study human autoimmunity in vivo. Overall, these studies demonstrate that IgE autoantibodies are relevant to human autoimmunity [4, 6–9] and contribute directly to disease pathogenesis in BP [15, 17, 25, 31, 47, 48, 57, 59]. Unraveling the events leading to IgE autoantibody production and the events downstream of autoantibody binding will expand the field of potential therapeutic targets for the treatment of a variety of IgEmediated diseases.

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Unraveling the significance of IgE autoantibodies in organ-specific autoimmunity: lessons learned from bullous pemphigoid.

Bullous pemphigoid (BP), a cutaneous autoimmune blistering disease, has provided a useful model to elucidate a role for IgE in autoimmunity. IgE antib...
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