The clinical and immunopathological manifestations of anti-epiligrin cicatricial pemphigoid, a recently defined subepithelial autoimmune blistering disease

ARTICLE

Cicatricial pemphigoid (CP) is a subepithelial blistering disease that primarily involves mucosal surfaces but may also involve the skin. On mucosal surfaces, it is characterized by blisters that rapidly evolve into erosive lesions which usually heal with scarring. CP is typically a chronic and locally progressive disease. It often compromises function of involved mucosae because of its propensity for scar formation.

Patients with CP were initially thought to have a benign scarring form of pemphigus vulgaris. Lever separated this disorder from pemphigus and called it benign mucosal pemphigoid [1]. Because its course is often not benign, most groups now refer to this disorder as CP or mucous membrane pemphigoid. CP is typically a disease of the elderly with a mean age of onset in the mid 60's [2]. CP is not a common disease; its reported annual incidence is 1.16 and 0.87 per million of the population in France and Germany, respectively [3, 4].

In situ deposits of immunoreactants consisting of IgG (and/or IgA) and complement are found in perilesional epithelial basement membranes in all cases. Circulating autoantibodies of low to moderate titer are found in many patients' sera. These autoantibodies have been shown to be directed against a variety of different autoantigens within epidermal basement membrane. Therefore, CP is a disease phenotype thought to result from autoantibody mediated injury to epithelial basement membranes. The antigen most commonly targeted by these patients' circulating autoantibodies is a basement membrane protein known as bullous pemphigoid antigen 2 (BPAG2) or BP180. Over the last 10 years it has become apparent that a subset of CP patients have circulating autoantibodies directed against another basement membrane protein, laminin 5 (alpha3beta3gamma2). This autoantigen was originally shown to be identical to a keratinocyte-derived protein known as epiligrin, giving rise to the name of anti-epiligrin cicatricial pemphigoid or AECP. This review will provide an overview of recent advances in the understanding of CP with special emphasis on describing the salient features of AECP.

Clinical features of cicatricial pemphigoid

The mucosal sites most commonly affected by CP include the mouth and conjunctiva. These sites are also usually the first to become involved. The skin, nasopharynx and genitalia are each involved in about one third of patients; the esophagus, larynx, and genital mucosa are less commonly involved [5]. Oral lesions most commonly occur on the gingivae, buccal mucosa, and palate; they may also occur on the alveolar ridge, tongue, and lips [2-6]. A common presentation of the disorder in the mouth is as a desquamative gingivitis; the latter often leads to periodontal disease and loss of teeth. Elsewhere in the mouth, lesions may present as tense vesicles that quickly progress to erosions which characteristically heal with scar formation. When lesions involve the frenulum, ankyloglossia or limited mobility of the tongue may result.

Ocular involvement is a threatening aspect of CP due to its potential to result in blindness. Patients with ocular involvement typically present with a mild conjunctivitis and complaints of eye dryness, burning, or foreign body sensation. Erosions subsequently develop leading to scarring and symblepharon formation; the latter may result in ankyloblepharon or a frozen ocular globe. Scarring may also result in malalignment of the eyelashes leading to entropion with trichiasis (i.e., in-turning of the eyelashes) resulting in corneal abrasions and irreversible scarring. Scarring may also interfere with the normal tearing process, disrupting the tear film by destroying mucosal goblet cells and obliterating lachrymal ducts. Nasopharyngeal lesions may present with discharge, epistaxis, or crusting secondary to erosions of the nasopharyngeal epithelium. This may result in scarring with a reduction in air flow and a predisposition for chronic sinusitis [6]. Nasal involvement is typically chronic, and patients generally require long term intervention and treatment (see below).

Laryngeal involvement is also a potentially serious complication of CP. Initial lesions on the vocal cords or in the supraglottic area may lead to hoarseness or dysphonia; severe involvement may lead to airway stenosis or frank compromise requiring a tracheostomy [7]. Hypopharyngeal and proximal esophageal lesions may impair swallowing and contribute to vocal compromise as well as chronic aspiration. Lower esophageal involvement in CP is often asymptomatic or overlooked until late in the disease course when serious irreversible stenosis may have occurred [8]. This can result in dysphagia, gastroesophageal reflux disease, and/or weight loss in affected patients. Involvement of the genitourinary tracts and rectum is uncommon in CP, but when present may result in significant morbidity (e.g. pain and/or difficulty urinating and defecating). Advanced disease may result in urethral, vaginal, or rectal stenosis.

Skin involvement occurs in about one-third of patients with CP [5, 9]. When it occurs, two patterns of involvement may be seen: 1) widespread blistering similar to that seen in BP [10]; or 2) recurrent vesicles most commonly affecting the scalp, head, neck and upper trunk. However, unlike BP, skin involvement is not a dominant feature of CP. Instead mucous membrane involvement with progression to scarring of involved sites is usually its presenting and most prominent feature.

Histopathology

The characteristic histological finding in CP is that of a subepithelial blister. There is usually a dermal leukocytic infiltrate of variable intensity. Lymphocytes tend to be the predominant cell type seen in established lesions. Neutrophils and eosinophils are often present in early lesions. In older lesions, a characteristic finding is lamellar fibrosis (i.e., fibrosis characterized by collagen bundles ordered parallel to the surface epithelium) in the upper dermis [11]. Mucosal lesions may have a lichenoid infiltrate in the upper submucosa.

Immunopathology

Immunoreactants are found in a continuous pattern along epithelial basement membranes of the skin or mucosae from patients with CP using the technique of direct immunofluorescence microscopy [12]. The most commonly detected immunoreactants are IgG and C3, with the predominant IgG subclass being IgG4 [13-15]. IgA autoantibodies may be found in a linear pattern along the basement membrane in addition to (or in place of) IgG [16, 17]. In indirect immunofluorescence microscopy, 1M NaCl split skin is the preferred test substrate for detection of these patients' anti-basement membrane autoantibodies [18, 19]. In the majority of patients, circulating autoantibodies react with the epidermal side of this substrate; a minority of sera react with both sides or only the dermal side of 1M NaCl spilt skin. While one study suggested that mucosal test substrates improved the sensitivity of indirect immunofluorescence microscopy for detection of anti-basement membrane autoantibodies in CP patients' sera [18], other studies have refuted this notion [20, 21].

A recent large prospective study of CP patients found that the circulating antibody response has prognostic significance in that individuals with a dual circulating antibody response (i.e., those with both IgG and IgA anti-basement membrane autoantibodies), have a worse prognosis as defined by the need for medication to control active disease and clinical severity score [5]. Further study of these patients demonstrated that higher titers of circulating autoantibodies correlated with more severe disease activity [22].

Reflecting the heterogeneous nature of the immunofluorescence findings, the basement membrane antigens targeted by these patients' circulating autoantibodies are varied. In the majority of patients with circulating autoantibodies against the epidermal side of 1M NaCl split skin, the target antigen is BPAG2 [23, 24]. In contrast to BP where circulating IgG autoantibodies bind epitopes of BPAG2 just outside the plasma membrane of basal keratinocytes (i.e., the so called NC16A domain) [25], IgG autoantibodies in CP patients' sera bind to BPAG2 near its carboxyl terminus (alone or in addition to the NC16A domain) [26]. This region of BPAG2 is located at the lamina lucida-lamina densa interface, giving a clue as to why lesions in CP may scar [26, 27]. Interestingly, another well characterized CP autoantigen is laminin 5 (alpha3beta3gamma2) - a heterotrimeric adhesion protein positioned within epidermal membrane in close proximity to the carboxyl terminus of BPAG2. Other less well characterized CP autoantigens include, a 45 kD keratin targeted by circulating IgA autoantibodies in some patients with ocular CP [28, 29], a 168 kD mucosal epithelial antigen [30], and a 205 kD antigen that has partial sequence homology with the beta4 integrin subunit [31].

Anti-epiligrin cicatricial pemphigoid

In 1992, a subgroup of CP patients were defined based on the following characteristics of their IgG anti-basement membrane autoantibodies: 1) low to moderate titer; 2) exclusive reactivity with the dermal side of 1M NaCl split skin (Fig. 1F); 3) specific targeting of the interface between the lamina lucida and lamina densa of epidermal basement membrane; and 4) ability to immunoprecipitate a distinct protein synthesized and secreted by human keratinocytes [32]. Because this autoantigen was present in human keratinocyte extracellular matrix and specifically reactive with anti-epiligrin monoclonal antibodies, this disease was termed anti-epiligrin cicatricial pemphigoid [33]. Subsequent studies demonstrated that epiligrin is identical to laminin 5. The clinical features of AECP do not significantly differ from that of other types of CP. All patients identified to date have had oral mucosal involvement; other mucosal surfaces have been involved less frequently (Fig. 1A, 1B). In distinction to classical CP, the majority of AECP patients also have some degree of skin involvement (Fig. 1C, 1D). A number of case reports have suggested that AECP may be associated with underlying cancer, malignancies identified in such patients include cancers of the lung [34-36] uterus [37] and gastrointestinal tract [38-40]. All of these malignancies were solid cancers. This issue requires further study before a definite association is established.

Laminin 5

Laminin 5 is a heterotrimeric adhesion protein that has also been called kalinin, epiligrin, or nicein. Laminins are formed by the assembly of three different polypeptides, namely alpha, beta, and gamma subunits that are disulfide bonded to yield cross-like molecules [41]. Laminin 5 consists of alpha3, beta3, and gamma2 subunits. Laminin subunit alpha3 exists as a cell associated precursor of 200 kDa that is rapidly processed following secretion to a 165 kDa polypeptide. Laminin subunit gamma2, like alpha3, exists in two forms, a 155 kDa cell associated form and a 105 kDa processed polypeptide. Laminin subunit beta3 exists solely as a 140 kDa polypeptide that does not undergo processing following secretion [42].

Laminin 5 was initially thought to be localized to anchoring filaments [43]. However, when affinity-purified rabbit polyclonal antibodies specific for the alpha3 or gamma2 chains of laminin 5 were studied in post-embedding immunoelectron microscopy studies of normal human skin, the reactivity of these antibodies was localized to the upper lamina densa. Moreover their reactivity was localized directly under the hemidesmosomes [27]. This was in keeping with the finding that circulating autoantibodies in patients with AECP deposit in a linear fashion on the dermal side of 1M NaCl split human skin [32] and bind the lamina lucida-lamina densa interface in patient skin [33].

Laminin 5 is a major laminin isoform in epidermal basement membrane. It plays an important role in epidermal adhesion. In skin, laminin 5 binds to integrin alpha6beta4 in hemidesmosomes of basal keratinocytes [44]. Preliminary evidence suggests that laminin 5 may also interact with BPAG2 [45]. Moreover, in human skin lacking laminin 5, the extracellular domain of BPAG2 is abnormally localized, suggesting that laminin 5 helps to position the carboxyl terminus of BPAG2 in the lamina lucida [46]. The large, non-collagenous (i.e., NC1) domain of collagen VII can also bind laminin 5 [47, 48]. The importance of laminin 5 in epidermal adhesion is demonstrated by the inherited blistering disorder, Herlitz' junctional epidermolysis bullosa (H-JEB). H-JEB is the most severe form of junctional epidermolysis bullosa. Patients with this disease have widespread erosions of their skin and mucous membranes often leading to death early in life. In H-JEB, mutations may occur in any of the 3 genes encoding subunits of laminin 5 (i.e., LAMA3, LAMB3, LAMC2). Interestingly, the majority (~ 80%) of such mutations reside in the gene encoding the beta3 subunit.

Initial investigations showed that IgG from patients with AECP immunoprecipitated intact laminin 5 from extracts or media of biosynthetically radiolabeled human keratinocytes. Subsequent immunoblot studies showed that autoantibodies from most patients with AECP bind the alpha subunit of this laminin isoform [49]. AECP sera containing autoantibodies against the alpha subunit are also able to immunoprecipitate polypeptides of 190 and 200 kD from biosynthetically radiolabeled human keratinocyte media. This is because laminin 6 (alpha3beta1gamma1), another laminin isoform produced and secreted by human keratinocytes, contains an alpha subunit that is immunologically crossreactive with (or identical to) that in laminin 5 [50, 51].

The pathogenesis of AECP

The importance of autoantibodies to laminin 5 in disease pathogenesis has been demonstrated in passive transfer animal models [52, 53]. In these studies, rabbit anti-laminin 5 IgG was shown to be capable of inducing noninflammatory subepidermal blisters of skin and mucous membranes following injection into neonatal mice. The induced blisters had clinical, histological, and immunopathological features like those seen in patients with AECP. These blisters developed in a dose-dependent fashion in normal (i.e. BALB/c) as well as complement-, mast cell deficient-, and T cell-deficient mice. Fab fragments of this experimental antibody also produced lesions in vivo, thus verifying the complement-independent basis of anti-laminin 5 IgG-mediated blister formation [54]. In addition, recent studies showed that rabbit anti-laminin 5 IgG was also capable of inducing blisters in human skin grafted onto immunodeficient mice as was AECP patient IgG [53]. Studies in this passive transfer model demonstrated that anti-laminin 5 IgG is pathogenic in vivo; this model depicts the acute (i.e., blister induction), but not the chronic (i.e., scarring) phase of AECP.

Management of CP

CP is usually a chronic and locally progressive disorder that rarely goes into spontaneous remission. Treatment of all subsets of CP, including AECP, is usually dictated by site and severity of involvement [55]. It is important to treat patients aggressively if important structures (e.g., the eyes, larynx) are involved to prevent irreversible scarring. For oral lesions, initial therapy with topical glucocorticoids may be helpful [56]. However, for progressive disease, initial therapy with prednisone or other systemic agents is warranted. Dapsone has been reported to be effective by some groups but not by others. However, dapsone may be especially appropriate for patients in whom an IgA antibody response is prominent. For ocular disease, systemic corticosteroids alone or in addition to immunosuppressive agents such as azathioprine or cyclophosphamide are indicated [9, 57, 58]. In patients with nasal disease, regular irrigation with isotonic sodium chloride solution and an intranasal lubricant (e.g., Ponaris) are important. Despite aggressive medical treatment, CP may be insidiously progressive. Such patients often require the care of multiple physicians (e.g., dermatologists, ophthalmologists, otolaryngologists, general surgeons, gynecologists, or urologists).

CONCLUSION

Cicatricial pemphigoid is a relatively rare subepithelial blistering disease of mucous membranes and skin that may be associated with significant morbidity. It is usually insidiously progressive and resistant to therapy. AECP is a newly recognized form of CP whose clinical and histological features are indistinguishable from those of classical CP. AECP is suggested by the finding of circulating IgG autoantibodies exclusively reactive with the dermal side of 1M NaCl split skin and defined by the specificity of such autoantibodies for laminin 5.

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