Epitope Spreading: Lessons from Autoimmune Skin Diseases

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REVIEW Epitope Spreading: Lessons From Autoimmune Skin Diseases

Lawrence S. Chan,*† Carol J. Vanderlugt,‡ Takashi Hashimoto,§ Takeji Nishikawa,¶ John J. Zone,** Martin M. Black,†† Fenella Wojnarowska,‡‡ Seth R. Stevens,§§ Mei Chen,† Janet A. Fairley,¶¶ David T. Woodley,*† Stephen D. Miller,‡ and Kenneth B. Gordon†‡ *Medicine Service, Section of Dermatology, Lakeside Division, VA Chicago Health Care System, Chicago, Illinois, U.S.A.; Departments of †Dermatology and ‡Microbiology and Immunology, Northwestern University Medical School, Chicago, Illinois, U.S.A.; ¶¶Department of Dermatology, Kurume University School of Medicine, Kurume, Japan; ¶Department of Dermatology, Keio University School of Medicine, Tokyo, Japan; **Medicine Service, Section of Dermatology, Salt Lake City VA Medical Center, Salt Lake City, Utah, U.S.A.; ††Department of Dermatopathology, Guy’s and St. Thomas Medical and Dental School, London, U.K.; ‡‡Department of Dermatology, The Oxford Radcliffe Hospital, Oxford, U.K.; §§Department of Dermatology, Case Western Reserve University School of Medicine, Cleveland, Ohio, U.S.A.; ¶¶Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A.

Autoimmune diseases are initiated when patients develop In experimental autoimmune animal diseases, ‘‘epitope aberrant T and/or B cell responses against self proteins. spreading’’ seems to have significant physiologic impor- These responses presumably are directed to single tance in determining the course and duration of disease. immunogenic epitopes on these proteins. Recent data in In this paper, we review the current concepts in animal animal models of autoimmune diseases suggest that the models of autoimmune diseases in order to define the targets of immune responses in autoimmunity do not ‘‘epitope spreading’’ phenomenon, and we then propose remain fixed, but can be extended to include other how this phenomenon might play a significant role in epitopes on the same protein or other proteins in the the development and the course of autoimmune skin same tissue, a phenomenon termed ‘‘epitope spreading.’’ diseases. Hopefully, an understanding of ‘‘epitope The ‘‘epitope spreading’’ phenomenon also applies to spreading’’ will help the dermatology community to situations in which tissue damage from a primary better understand the pathogenesis of autoimmune skin inflammatory process causes the release and exposure of diseases and to rationally fashion disease-specific immune a previously ‘‘sequestered’’ antigen, leading to a secondary therapy in the future. Key words: antibody-mediated/autoim- autoimmune response against the newly released antigen. munity/cell-mediated. J Invest Dermatol 110:103–109, 1998

or many years, both clinical and investigative dermatologists episode of mucosal epithelial injuries due to Stevens–Johnson syndrome, have noted the linkage of one disease with another, developed ocular cicatricial pemphigoid (Chan et al, 1991), the particularly the clustering of autoimmune diseases. In some hypothesis that we and Stingl and Holubar put forward was that instances, an autoimmune disease occurs in association with the basement membrane zone (BMZ) injuries that occurred during a second autoimmune disease, whereas in others it occurs the inflammatory process of lichen planus or the Stevens–Johnson Fin association with another inflammatory disease. Several hypotheses syndrome may have exposed the ‘‘hidden’’ antigens to the immune have been suggested to explain such intriguing disease associations. system, and subsequently induced an autoimmune response against the Among these is the hypothesis that autoimmune diseases are genetically BMZ components. Not until the recent investigations employing determined. Therefore, the occurrence of one autoimmune disease animal models of autoimmune diseases, however, has further light been heralds a genetic predisposition and susceptibility to develop another shed on this hypothesis. These animal models have increased our autoimmune disease. While acknowledging the genetic influence on understanding of how a primary autoimmune or inflammatory process autoimmune diseases, one must also consider other factors that may can induce a secondary autoimmune response. The autoimmune animal contribute to autoimmunity because identical genetic traits linked with models allow step-by-step dissection of disease processes and have disease-affected patients may also be present in healthy individuals. successfully documented the phenomenon of autoimmune reaction to The development of cicatricial pemphigoid, a putative autoimmune previously ‘‘sequestered’’ antigens that are released from injured tissue disease, may serve as an example (Ahmed et al, 1991; Chan et al, 1997). by a primary autoimmune or inflammatory process. This phenomenon When Stingl and Holubar reported the coexistence of lichen planus has been termed ‘‘epitope spreading.’’ In this article, we define ‘‘epitope and bullous pemphigoid (BP) (Stingl and Holubar, 1975), and we spreading’’ and provide examples that occur in animal models of reported three patients who developed BP subsequent to lichen planus autoimmune diseases. Selected examples of human autoimmune skin (Davis et al, 1991), and five patients who, subsequent to an acute diseases that are possible manifestations of ‘‘epitope spreading’’ are illustrated. Because experimental autoimmune diseases cannot be induced in humans for obvious ethical reasons, the examples of ‘‘epitope spreading’’ in human skin diseases are not documented with the same Manuscript received July 28, 1997; revised September 22, 1997; accepted scientific vigor as the animal models. for publication October 14, 1997. Reprint requests to: Dr. Lawrence S. Chan, Department of Dermatology, EPITOPE SPREADING: DEFINITION Northwestern University Medical School, Tarry 4–721, Mail Code T225, 300 E. Superior Street, Chicago, IL 60611–3010. ‘‘Epitope spreading’’ can be defined as a specific autoreactive lympho- Abbreviation: NOD, nonobese diabetic. cyte (T or B cell) response to endogenous epitopes, which are distinct

of clinical relapse, these mice demonstrate proliferative and delayed type hypersensitivity responses to a secondary, ‘‘subdominant epitope’’ of 14 amino acids (amino acid 178–191) that is distinct and at a distance from the primary immunodominant epitope (McRae et al, 1995). Interestingly, the induction of tolerance to the secondary subdominant epitope prior to clinical relapse can prevent ongoing clinical disease based on autoimmunity to the primary epitope. Thus, not only is epitope spreading within proteolipid protein evident during the course of relapsing experimental autoimmune encephalomyelitis, it also seems to be responsible for the relapsing nature of the disease (Vanderlugt and Miller, 1996).

Epitope spreading in T cell mediated autoimmune responses involving different proteins within the same tissue The non- Figure 1. Model of epitope spreading in chronic cell-mediated and obese diabetic (NOD) mouse is a model of the human disease, in antibody-mediated autoimmune diseases. The presentation of the primary which diabetes mellitus occurs spontaneously in inbred NOD mice. (1°) epitope to the T helper cells (Th) leads to cell- or antibody-mediated tissue The initial pathology in the pancreas of an NOD mouse is a T cell injury and release of a secondary (2°) ‘‘new’’ antigen (Ag) or 2° epitope of the immune reaction, at µ4 wk of age, against a specific pancreatic β cell same Ag. The presentation of the 2° epitope to the naı¨ve Th subsequently leads to the development of cell- or antibody-mediated autoimmunity against protein, glutamic acid decarboxylase; however, there is no clinical the 2° Ag (or epitope). APC, antigen presenting cells (Langerhans cells, manifestations of diabetes at this time. Yet, as this reactivity against β macrophages, dendritic cells, B cells); Mac., macrophages; PC, plasma cells; cell continues, new reactions develop against other β cell proteins Com., complements; PMN, polymorphic nuclear leukocytes; Eos., eosinophils; including carboxypeptidase H, insulin, and heat shock protein 65. It Lym. Tiss., lymphoid tissues; Prolif., proliferation; Differ., differentiation; is only after the spread of immune reactivity to the proteins other than MIP1α, macrophage inflammatory protein 1α; IFNγ, interferon-γ; TNFβ, the original target (glutamic acid decarboxylase) has occurred that tumor necrosis factor-β; LT, leukotriene; (ϩ), help. (Vanderlugt and Miller, insulitis (massive cellular infiltration of the pancreatic islets) and clinical 1996.) diabetes develops (Kaufman et al, 1993; Tisch et al, 1993). Thus, as in the case of relapsing experimental autoimmune encephalomyelitis, from and non-cross-reactive with the disease-inducing epitopes, on epitope spreading may play a role in the development of spontaneous the (same or different) proteins secondary to the release of such self diabetes in the NOD mouse model. protein during a chronic autoimmune or inflammatory response Epitope spreading in autoantibody-mediated autoimmune (Vanderlugt and Miller, 1996). That means, in essence, that a primary response Patients with systemic lupus erythematosus are well known autoimmune or inflammatory process may cause tissue damage in such to have autoantibodies directed against multiple epitopes of the a manner that certain protein components that are immunologically Ro/La ribonucleoprotein complex and against spliceosomes. Clinical ‘‘hidden’’ from the immune system become ‘‘revealed’’ and evoke a disease in the form of a systemic lupus erythematosus–like syndrome secondary autoimmune response. (manifested with proteinuria and cytopenia, and the presence of EPITOPE SPREADING: LESSONS FROM ANIMAL MODELS antinuclear antibodies) can be elicited in mice by immunization of a OF AUTOIMMUNE DISEASES human spliceosome peptide. In the mice immunized with spliceosome protein, or in mice immunized with the human La protein, the original Animal models of autoimmune diseases have provided much of the antibody response against either of the immunized peptides quickly information available concerning the spreading of antigenic epitopes spreads to other regions of these complexes, leading to a multi-epitope during the course of autoimmune disease. Unlike human diseases, immune response (James et al, 1995; Topfer et al, 1995). Thus, the animal models provide a system in which autoimmune responses can initial singular peptide antibody response spread to other proteins that be studied in a controlled fashion from the initiation of the response could account for the strikingly variable antibody responses against against self-antigens, even before the clinical symptoms and signs numerous proteins commonly seen in human patients with systemic become apparent, and followed at each stage of disease thereafter. In lupus erythematosus. these animal models, epitope spreading can be predominantly B cell (antibody) or T cell mediated. In either case, epitope spreading within EPITOPE SPREADING: LESSONS FROM HUMAN the same protein (intramolecular) and/or to other distinct proteins AUTOIMMUNE SKIN DISEASES (intermolecular) within the same tissue or protein complex has been observed. Importantly, the data obtained from these animal models Epitope spreading resulted from injuries in autoimmune indicate that, not only does the phenomenon of ‘‘epitope spreading’’ dermatoses exist, it is indeed very important for the clinical manifestations of autoimmune diseases. Figure 1 is a schematic diagram depicting a Intramolecular (intra-protein) epitope spreading model of epitope spreading in chronic cell-mediated and antibody- Pemphigus vulgaris Pemphigus vulgaris is a blistering disease character- mediated autoimmune diseases. ized by autoantibodies directed against desmoglein 3, an important structural component of epidermal desmosomes. Clinically, this disease Epitope spreading in T cell mediated autoimmune responses frequently begins with oral lesions and later progresses to diffuse within the same protein The most intensively studied of all animal involvement of the skin. Recently, it has been observed that patients models of autoimmunity is experimental autoimmune encephalomyel- with lesions restricted to the mucosa have antibodies that recognize itis. In one form of this disease—relapsing experimental autoimmune specific epitopes of desmoglein 3. These autoantibodies do not cross- encephalomyelitis—relapsing/remitting hind limb paralysis of the react with the pemphigus foliaceus antigen, desmoglein 1, and are animals can be elicited in SJL/J mice after immunization with proteoli- generally not able to induce blister in neonatal mice in passive pid protein in complete Fruend’s adjuvant. A disease course that is transfer experiments; however, in patients with mucocutaneous lesions identical to the disease induced by immunization with whole protein autoantibodies, which recognize a secondary and distinct epitope on can be induced by immunization with a small domain of the whole desmoglein 3 and are cross-reactive to desmoglein 1, are detected. protein. This small peptide domain, the so-called ‘‘immunodominant And these autoantibodies are able to induce blister in neonatal mice. T cell epitope peptide,’’ consists of only 13 amino acids (amino Thus, in patients whose disease has progressed from mucosal pemphigus acid 139–151). As expected, the mice immunized with this peptide to mucocutaneous pemphigus, epitope spreading has likely occurred developed a strong T cell proliferative response and delayed type which accounts for the heterogenous antibody response seen in these hypersensitivity response to the inciting peptide; however, at the time patients. One could envision that the autoimmune reaction against VOL. 110, NO. 2 FEBRUARY 1998 EPITOPE SPREADING IN CUTANEOUS AUTOIMMUNITY 105 specific desmoglein 3 epitope on mucosae may have induced injuries kDa BP antigen 2 (Pas et al, 1997).1,2 It has also been demonstrated and exposed a secondary ‘‘new’’ desmoglein 3 epitope to the autoreac- that IgG class autoantibodies may be involved (Zone et al, 1994; Chan tive lymphocytes, leading to autoimmune reaction against the secondary et al, 1995; Darling et al, 1995). Moreover, it has been shown that IgG epitope, which is apparently present in the skin and shares significant or IgA circulating autoantibodies from these patients also recognized homology with desmoglein 1. Thus, these data suggest that the the 230 kDa BP antigen 1, in addition to the 180 kDa BP antigen 2 evolution of the heterogenous antibody response to desmoglein 3 may (Collier et al, 1994; Chan et al, 1995; Darling et al, 1995). This initial account for the progression of disease seen in patients with pemphigus autoimmunity to the BP antigen 2 that then expands to involve BP vulgaris (Ding et al, 1997). antigen 1 is consistent with the concept of ‘‘epitope spreading.’’ Epidermolysis bullosa acquisita Patients with epidermolysis bullosa acqui- BP with autoantibodies to another basement membrane antigen p105 BP sita have IgG autoantibodies against epidermolysis bullosa acquisita is characterized histopathologically by subepidermal blister and an antigen (type VII collagen). These autoantibodies target the noncolla- inflammtory cell infiltrate along the skin BMZ that is rich in eosinophils genous globular amino terminal domain termed NC1 and do not (Cohen et al, 1997). The initial injury caused by the subepidermal recognize the collagenous helical portion of the molecule, nor the blistering process may expose other skin BMZ components to auto- noncollagenous globular domain (NC2) at the carboxyl terminus reactive lymphocytes, and subsequently lead to autoimmune response (Gammon et al, 1993; Lapiere et al, 1993). As suggested by many against another BMZ protein termed p105, located in the lower lamina examples of autoimmune disease models in animals (Lehmann et al, lucida (Chan et al, 1993; Cotell et al, 1994). 1992; McRae et al, 1995), the original development of autoimmunity Systemic lupus erythematosus associated with epidermolysis bullosa to type VII collagen in epidermolysis bullosa acquisita patients likely acquisita Systemic lupus erythematosus is a systemic autoimmune involved primarily or exclusively a single antigenic epitope within the disease characterized by the development of autoantibodies against NC1 domain. Nevertheless, Gammon et al (1993), Lapiere et al (1993), multiple self proteins in various tissues. Some patients with systemic and Tanaka et al (1994) have documented that ‘‘epitope spreading’’ lupus erythematosus have immunoglobulins deposited at the skin BMZ occurs in cases of epidermolysis bullosa acquisita. All three laboratories despite the absence of overt skin lesions, i.e., a positive lupus band. have reported that the serum from a single epidermolysis bullosa Presumably, the immune deposits at the skin BMZ could result in acquisita patient contained IgG autoantibodies that recognized multiple subclinical injury, and expose the anchoring fibril (type VII collagen) regions of the NC1 domain (Gammon et al, 1993; Lapiere et al, 1993; to the autoreactive lymphocytes, which ultimately sensitized and Tanaka et al, 1994). The mechanism of ‘‘epitope spreading’’ in this invoked autoimmunity to type VII collagen and produced a disease situation may be very similar to that envisioned in animal models. phenotype similar to epidermolysis bullosa acquisita (Gammon et al, Bullous pemphigoid Assuming that autoimmunity against the BP anti- 1985; Barton et al, 1986; Yell et al, 1995). gens located in the upper lamina lucida/hemidesmosome also initially Epitope spreading resulted from injuries in inflammatory involved predominantly or exclusively a single antigenic epitope, dermatoses and other inflammatory diseases studies have suggested that epitope spreading occurs in BP. Using recombinant proteins, synthetic peptides, or blocking methods, Rico Lichen planus associated with BP Lichen planus is an idiopathic chronic et al, Tanaka et al, and Sugi et al have demonstrated that a single BP inflammatory skin disease characterized histopathologically by a band- patient’s serum containing IgG autoantibodies that are able to recognize like dermal infiltrate of predominantly lymphocytes along the skin multiple epitopes within the 230 kDa glycoprotein designated as BP BMZ and liquefaction degeneration of basal keratinocytes (Toussaint antigen 1 (Sugi et al, 1989; Rico et al, 1990; Tanaka et al, 1991). and Kamino, 1997). These pathologic injuries in lichen planus perturb Similarly, intraprotein epitope spreading may occur in some cases of the skin BMZ (Smoller and Glusac, 1994; Marren et al, 1994). Thus, autoimmunity against the BP antigen 2, a 180 kDa protein with an this inflammatory process may expose skin BMZ components to extracellular collagenous domain (Balding et al, 1996). If the same autoreactive lymphocytes that then induce autoimmunity against skin assumption holds, interprotein epitope spreading also occurred in BP, BMZ components, such as the BP antigens (Stingl and Holubar, 1975; because many BP patients have IgG autoantibodies against both BP230 Sobel et al, 1976; Hintner et al, 1979). Clinical BP with autoantibodies and BP180 (Labib et al, 1986) that are products of two completely against the BP antigens have been documented in such patients (Davis different genes located on two separated chromosomes. The mechanism et al, 1991; Tamada et al, 1995). Figure 2 illustrates another example: of this type of ‘‘epitope spreading’’ is probably identical or very similar a patient who had a long history of lichen planus with characteristic to that described in animal models (Lehmann et al, 1992; McRae nonbullous poligonal papules and plaques and then developed a new et al, 1995). blistering disease. The new blistering disease had features identical to those of BP as documented by histopathology, linear IgG deposits at Intermolecular (inter-protein) epitope spreading the patient’s perilesional skin BMZ, and circulating IgG autoantibodies Pemphigus vulgaris conversion to pemphigus foliaceus One very illustrative that bound to the epidermal side of salt-split skin and labeled the example of epitope spreading was reported in patients who initially 180 kDa BP antigen 2 (Fig 2). developed pemphigus vulgaris with typical clinical manifestations, histopathology, immunopathology, and autoantibodies to desmoglein Psoriasis associated with BP and pemphigoid-like blistering disease Psoriasis 3; and who later converted to pemphigus foliaceus. This conversion is a chronic inflammatory and hyperproliferative skin disease character- to pemphigus foliaceus was associated with an alteration of the ized histopathologically by dermal and epidermal inflammatory infiltra- pemphigus vulgaris clinical phenotype towards the phenotype of tion (Toussaint and Kamino, 1997). These inflammatory cells include pemphigus foliaceus with typical clinical manifestations, histopathology, neutrophils, activated T cells and macrophages (a professional antigen immunopathology, and autoantibodies to desmoglein 1 (Kawana et al, presenting cell), and perivascular dendritic cells (Stingl et al, 1977; 1994). The interesting and puzzling aspect of these cases is why the Baadsgaard et al, 1989, 1990; Morganroth et al, 1991). In addition to disease phenotype was changed from a severer form of disease to a the inflammatory and hyperproliferative characteristics, psoriasis skin is milder form, as a result of ‘‘epitope spreading.’’ easily injured with even gentle removal of scale over a psoriasis lesion Linear IgA bullous dermatosis with autoantibodies to BP antigen 1 Linear

IgA bullous dermatosis is an IgA-mediated blistering skin disease 1 characterized by subepidermal blisters and a neutrophilic inﬁltration Zone JJ, Taylor TB, Meyer LJ, Petersen MJ: The 97-kDa linear IgA bullous disease antigen is a portion of the extracellular domain of the 180-kDa bullous along the skin BMZ (Wojnarowska et al, 1988; Cohen et al, 1997). pemphigoid antigen. J Invest Dermatol 108:563, 1997 (abstr.) Although the target antigen in linear IgA bullous dermatosis was 2Tran HH, Schumann H, Balding S, Giudice GJ, Bruckner-Tuderman L, initially thought to be a distinct BMZ component (Zone et al, 1990), Marinkovich MP: LAD-1 is a collagenous component of keratinocyte adhesion more recent evidence suggests that the target antigen for these IgA complexes which assembles into a high molecular weight complex and which autoantibodies is an epitope within the extracellular portion of the 180 has homology to BP180. J Invest Dermatol 108:586, 1997 (abstr.) 106 CHAN ET AL. THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

Figure 2. Lichen planus associated with BP. Western blot analyses detected a 180 kDa BP antigen recognized by the IgG autoantibodies from a patient affected with lichen planus (lane 2) who subsequently developed a new blistering disease with IgG autoantibodies that label the epidermal side of salt-split skin substrate. Controls include sera from two BP patients (lanes 1 and 3) and serum from a normal volunteer (lane 4). resulting in dermal bleeding, so-called Auspitz sign (Toussaint and Kamino, 1997). Furthermore, neutrophil elastase, identified along the BMZ of psoriatic lesional skin, could play a role in the destruction of the epidermal–dermal junction (Glinski et al, 1990). One could envision that the combination of psoriatic injuries caused by chronic inflammation, the trafficking of activated lymphocytes, and the abund- ance of antigen presenting cells could expose BMZ components to autoreactive lymphocytes and induce autoimmunity against these BMZ components, such as the BP antigens. Such autoimmune reaction may then subsequently lead to autoimmune disease BP. As reported by Grattan, seven patients developed BP after the onset of psoriasis from 1 to 30 y (Grattan, 1985). Kirtschig et al also reported four patients who, after a long history of psoriasis, developed BP with circulating autoantibodies against the BP antigens (Kirtschig et al, 1996). Figure 3 illustrates another clinical example, in which the patient had a long history of psoriasis with characteristic nonbullous sharply demarcated scaly plaques predmoninantly on her extensor surfaces, and then developed a new blistering disease after receiving a course of Psoralen- UVA treatment. The new blistering disease had features identical to those of BP as documented by histopathology, in situ and circulating IgG autoantibodies that bound to the skin BMZ, and circulating IgG autoantibodies that recognized the 230 kDa BP antigen 1 (Fig 3). BMZ injuries induced by ultraviolet light in psoriasis patients receiving Psoralen-UVA treatments may promote the exposure of BMZ components to autoreactive lymphocytes (Thomsen and Schmidt, 1976; Abel and Bennett, 1979; Kirtschig et al, 1996). In addition, primary psoriasis has also been linked to the development of a secondary BP-like blistering disease 20 y after the onset of psoriasis. This blistering disease is characterized by IgG autoantibodies targeting a undefined 200 kDa lower lamina lucida component (Chen et al, 1996). Stevens–Johnson syndrome associated with secondary onset of cicatricial pemphigoid Stevens–Johnson syndrome is an acute inflammatory disease involving mucous membranes and skin. Histopathologically, the acute lesion has a mononuclear cell infiltration along the skin BMZ, hydropic degeneration of basal keratinocytes, and subepidermal blisters (Cohen et al, 1997). Chan et al have reported five patients who, after an acute episode of Stevens–Johnson syndrome, developed chronic ocular scarring inflammation confirmed to be cicatricial pemphigoid Figure 3. Psoriasis associated with BP. Clinical observation of new onset of BP in a patient with long history of psoriasis (a). Histopathology confirmed (Chan et al, 1991). In this scenario, one could envision that the initial the diagnosis of BP in the blister (curved →) in association with psoriasis plaques pathologic injuries associated with florid Stevens–Johnson syndrome (straight →). The diagnosis of BP was further documented by linear IgG released skin BMZ components and exposed them to autoreactive deposition in the patient’s peri-blister skin BMZ and by patient’s circulating lymphocytes and induced autoimmunity against these structural self IgG autoantibodies that bound to skin BMZ (b) and recognized a 230 kDa BP proteins. Figure 4 illustrates one of these cicatricial pemphigoid patients antigen by western blot [c, lane 2 was reacted with this patient’s serum, lanes 1 (Chan et al, 1991). A patient was also reported to develop cicatricial and 3 were reacted with sera from two BP patient controls, normal human pemphigoid 5 y after the onset of a primary chronic inflammtory skin serum showed negative reaction (not shown)]. VOL. 110, NO. 2 FEBRUARY 1998 EPITOPE SPREADING IN CUTANEOUS AUTOIMMUNITY 107

disease, lichen sclerosis et atrophica, a condition characterized by inflammatory cell infiltration and skin BMZ disruption (Marren et al, 1996, 1997). Dermatitis herpetiformis associated with autoantibodies against BP antigens Dermatitis herpetiformis is a pruritic inflammatory blistering skin disease characterized histopathologically by subepidermal separation and a prominent neutrophilic infiltration along the papillary dermis of the skin BMZ (Cohen et al, 1997). Although IgA is deposited high within the papillary dermis juxtaposed to the skin BMZ, circulating autoantibodies to skin BMZ components are not detected. Therefore, it does not fulfill the complete criteria for an autoimmune disease (Rose and Bona, 1993), and, for the purpose of this paper, will be classified as an inflammatory disease. Within the setting of primary and chronic dermatitis herpetiformis, there have been several documented cases of BP autoantibodies developing from 4 mo to 5 y after the onset of dermatitis herpetiformis (Sander et al, 1989; Setterfield et al, 1997). One plausible explanation for these occurrences would be that the neutrophilic inflammation inherent in dermatitis herpetiformis per- turbed the BMZ and lead to exposure of BMZ components to autoreactive lymphocytes and autoimmunity against the BP antigens. Discoid lupus erythematosus associated with autoantibodies against BP antigens Discoid lupus erythematosus is a cutaneous form of lupus characterized histopathologically by liquefaction degeneration of basal keratinocytes and a patchy lymphocytic infiltration around the BMZ of adnexal structures (Jaworsky, 1997). Ishikawa et al have documented the occurrence of autoantibodies to BP antigens developing after the onset of discoid lupus erythematosus (Ishikawa et al, 1997). Presumably, the chronic BMZ injury from the initial discoid lupus erythematosus releases and exposes BMZ components to autoreactive lymphocytes and induces autoimmunity against the BP antigens (Marren et al, 1994; Ishikawa et al, 1997). Crohn’s disease associated with autoantibodies against type VII collagen Inflammatory bowel disease, especially Crohn’s disease, is frequently associated with epidermolysis bullosa acquisita, an autoimmune disease characterized by autoantibodies against the noncollagenous (NC1) domain of type VII collagen (Lapiere et al, 1996). We recently identified the presence of type VII collagen in the intestinal epithelial BMZ. Interestingly, a significant number of patients affected by Crohn’s disease had circulating IgG autoantibodies against the NC1 domain of type VII collagen.3 Moreover, a dog with inflammatory bowel disease also had a high titer of circulating IgG autoantibody against the NC1 domain of type VII collagen.3 One could envision that the inflammation originally invoked by Crohn’s disease could perturb the intestinal epithelial BMZ in such a way that BMZ components are exposed and perhaps altered while in close juxtaposition with antigen presenting cells, and T and B lymphocytes, and this process results in on-going autoimmunity to type VII collagen. Ulcerative colitis associated with linear IgA bullous dermatosis and BP Another inflammatory bowel disease, ulcerative colitis, is known to be associated with linear IgA bullous dermatosis (Smith and Zone, 1996). A recent study of 70 adult patients with linear IgA bullous dermatosis in the U.K. revealed a 7.1% prevalence of ulcerative colitis in the patients affected by linear IgA bullous dermatosis, much higher than the 0.05% prevalance of ulcerative colitis in the general U.K. population (Paige et al, 1997). Paige et al documented eight cases of linear IgA bullous dermatosis preceded by ulcerative colitis by a median of 6.5 y (Paige et al, 1997). Although there is no literature on the Figure 4. Stevens–Johnson syndrome associated with cicatricial presence of BP antigens in human colonic epithelial BMZ, Dr. Giudice pemphigoid. Histopathology documented the occurence of primary Stevens– had documented the presence of BP antigen 2 in mouse colorectal Johnson syndrome (a) that affected a patient who 6 mo later developed a epithelial BMZ (Dr. George Giudice, Medical College of Wisconsin, secondary chronic inflammatory scarring ocular disease (b). At the time of acute personal communication). As in the case of autoantibodies against episode of Stevens–Johnson syndrome, extensive eosinophilic necrosis of keratinocytes, prominent mononuclear cell infiltration, and hydropic degeneration of the basal keratinocytes were observed (a). At the time of chronic ocular disease, biopsy showed linear IgG (c) deposition at the basement 3Chen M, O’Toole EA, Sanghavi J, Mahmud N, Kelleher D, Woodley DT: membrane. The patient had a high titer (1:2560) of circulating anti-basement Type VII (anchoring fibril) collagen exists in human intestine and serves as an membrane IgG autoantibodies that recognized a 120 kDa epidermal antigen antigenic target in patients with inflammatory bowel disease. J Invest Dermatol (Chan et al, 1991). 108:542, 1997 (abstr.) 108 CHAN ET AL. THE JOURNAL OF INVESTIGATIVE DERMATOLOGY type VII collagen in Crohn’s disease, one could envision that the Barth JH, Kelly SE, Wojnarowska F, Savin JA, Whittaker S, Cream JJ, White JE: inflammation originally invoked by ulcerative colitis could perturb the Pemphigoid and ulcerative colitis. J Am Acad Dermatol 19:303–308, 1988 Barton DD, Fine J-D, Gammon WR, Sams WM: Bullous systemic lupus erythematosus: an intestinal epithelial BMZ in such a manner that BMZ components are unusual clinical course and detectable circulating autoantibodies to the epidermolysis exposed while in close juxtaposition with antigen presenting cells, and bullosa acquisita antigen. J Am Acad Dermatol 15:369–373, 1986 T and B lymphocytes, and this process thus results in on-going Chan LS, Soong HK, Foster CS, Hammerberg C, Cooper KD: Ocular cicatricial autoimmunity to linear IgA bullous dermatosis antigen (now part of pemphigoid occurring as a sequela of Stevens–Johnson syndrome. JAMA 266:1543– 1546, 1991 BP antigen 2). In addition, BP has been reported to develop in patients Chan LS, Fine J-D, Briggaman RA, Woodley DT, Hammerberg C, Drugge RJ, Cooper who suffered from ulcerative colitis for a period ranging from 3 to 20 KD: Identification and partial characterization of a novel 105-kDalton lower lamina y before the onset of BP (Barth et al, 1988; Harrison et al, 1996). lucida autoantigen associated with a novel immune-mediated subepidermal blistering disease. J Invest Dermatol 101:262–267, 1993 Chan LS, Traczyk T, Taylor TB, Eramo LR, Woodley DT, Zone JJ: Linear IgA bullous CONCLUSION dermatosis: characterization of a subset of patients with concurrent IgA and IgG In this paper, we define the autoimmune phenomenon termed ‘‘epitope anti-basement membrane autoantibodies. Arch Dermatol 131:1432–1437, 1995 Chan LS, Hammerberg C, Cooper KD: Significantly increased of HLA-DQB1*0301 allele spreading’’ and provide examples of this phenomenon in animal models in patients with ocular cicatricial pemphigoid. J Invest Dermatol 108:129–132, 1997 of autoimmune diseases and selected examples of human autoimmune Chen KR, Shimizu S, Miyakawa S, Ishiko A, Shimizu H, Hashimoto T: Coexistence of skin diseases. Whereas the molecular events in which ‘‘epitope psoriasis and an unusual IgG-mediated subepidermal bullous dermatosis: identification spreading’’ occurs in human autoimmune skin diseases remain to be of a novel 200-kDa lower lamina lucida target antigen. Br J Dermatol 134:340– 346, 1996 elucidated, we hypothesize that skin injuries from autoimmune or Cohen LM, Skopicki DK, Harrist TJ, Clark WH: Non-infectious vesiculobullous and inflammatory processes could induce autoimmunity to a normally vesiculopustular diseases. In: Elder D, Elenitsas R, Jaworsky C, Johnson B (eds). ‘‘sequestered’’ antigen (or epitope). This hypothesis is consistent with Lever’s Histopathology of the Skin, 8th edn. Lippincott-Raven, Philadelphia, 1997, pp at least two general principles regarding the development of auto- 209–252 immunity. First, an autoimmune or inflammatory event is capable of Collier P, Wojnarowska F, Allen J, Kirtschig G: Molecular overlap of the IgA target antigens in the subepidermal blistering diseases. Dermatol 189 (Suppl. 1):105–107, 1994 bringing all the neccessary components together at a localized tissue Cotell SL, Lapiere JC, Chen JD, Iwasaki T, Krusinski PA, Chan LS, Woodley DT: A site for autoimmunity to be promoted and expanded. These components novel 105-kDa lamina lucida autoantigen: association with bullous pemphigoid. J include: the autoantigen (the skin components: desmosomal or BMZ Invest Dermatol 103:78–83, 1994 components), antigen presenting cells (Langerhans cells, macrophages, Darling TN, Cardenas AA, Beard JS, Sau P, Yee CL, Zone JJ, Yancey KB: A child with antibodies targeting both linear IgA bullous dermatosis and bullous pemphigoid B cells, and other dendritic cells), and possibly autoreactive lymphocytes, antigens. Arch Dermatol 131:1438–1442, 1995 an environment for optimal antigen presentation. Second, the distressed Davis AL, Bhogal BS, Whitehead P, Frith P, Murdoch ME, Leigh IM, Wojnarowska F: skin cells involved in the primary autoimmune or inflammatory process Lichen planus pemphigoides: its relationship to bullous pemphigoid. Br J Dermatol may have triggered a ‘‘danger’’ signal. 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