Oral mucosal manifestations of autoimmune skin diseases

Abstract

A group of autoimmune diseases is characterised by autoantibodies against epithelial adhesion structures and/or tissue-tropic lymphocytes driving inflammatory processes resulting in specific pathology at the mucosal surfaces and the skin. The most frequent site of mucosal involvement in autoimmune diseases is the oral cavity. Broadly, these diseases include conditions affecting the cell-cell adhesion causing intra-epithelial blistering and those where autoantibodies or infiltration lymphocytes cause a loss of cell-matrix adhesion or interface inflammation. Clinically, patients present with blistering, erosions and ulcers that may affect the skin as well as further mucosal surfaces of the eyes, nose and genitalia. While the autoimmune disease may be suspected based on clinical manifestations, demonstration of tissue-bound and circulating autoantibodies, or lymphocytic infiltrates, by various methods including histological examination, direct and indirect immunofluorescence microscopy, immunoblotting and quantitative immunoassay is a prerequisite for definitive diagnosis. Given the frequency of oral involvement and the fact that oral mucosa is the initially affected site in many cases, the informed practitioner should be well acquainted with diagnostic and therapeutic aspects of autoimmune dermatosis with oral involvement. This paper reviews the pathogenesis and clinical presentation of these conditions in the oral cavity with a specific emphasis on their differential diagnosis and current management approaches.

Introduction

Oral mucosa and skin are composed of highly specialized stratified epithelium that functions as a first-line barrier against physical and chemical damage. The integrity of this epithelial barrier is essentially dependent on structures maintaining cell-cell and cell-matrix adhesion [1]. Autoimmune bullous diseases are associated with autoantibodies directed against structures that mediate cell-cell and cell-matrix adhesion in skin and mucous membranes [2]. In pemphigus diseases tissue injury is mediated by autoantibodies against the cell-cell junction causing intra-epithelial blistering, whereas in subepidermal autoimmune diseases autoantibodies are directed against the epithelial – connective tissue junction at the basement membrane zone (BMZ) [3]. Primary or extensive oral involvement is the hallmark of further inflammatory autoimmune conditions, including lichen planus (LP), erythema multiforme (EM), lupus erythematosus (LE) and chronic ulcerative stomatitis (CUS).

Skin and oral mucosa are stratified epithelia, in which the cell-cell adhesion is mainly mediated by desmosomes and adherens junctions, whereas the adhesion of basal epithelial cells on the underlying basement membrane essentially depends on hemidesmosomes and focal contacts (Fig. 1) [4]. Desmosomes are anchoring complexes that link epithelial cells to each other and attach the keratin filaments to the cell surface. Desmosomes consist of calcium-dependent adhesion molecules called cadherins, including desmogleins and desmocollins, which are transmembrane proteins that extend across the plasma membrane and mediate cell-cell adhesion by homo- or heterophilic interactions between their extracellular protein domains. An additional group of intracellular proteins resides on the cytoplasmic face of desmosomes and constitutes the desmosomal plaque. Desmosomal plaque is associated with different types of proteins including plakoglobin, the desmoplakins, the plakophilins, envoplakin, and periplakin. It provides adhesion by linking the desmosomal transmembrane cadherin proteins to the cytoplasmic keratin filaments [1], [5].

Hemidesmosomes are specialized junctional complexes on the ventral surface of the basal keratinocytes that maintain the epithelial cell attachment to the underlying basement membrane. In the oral cavity they can also be found in the junctional epithelium in contact to the tooth surface [6]. The basement membrane zone comprises the basal cell plasma membrane, the lamina lucida, the lamina densa and the sublamina densa. Anchoring filaments traverse the lamina lucida perpendicularly from the basal cell membrane to the underlying lamina densa [3]. At molecular levels, the basement membrane zone contains a mixture of structural components and antigens including collagen VII, which is the major structural component of anchoring fibrils, and collagen IV, which is a major ubiquitous component of vertebrate basement membranes. Laminins, which exist in various molecular forms as abundant non-collagenous glycoproteins of basement membranes, are heterotrimers consisting of alpha, beta and gamma chains [3], [6].

Hemidesmosomes, together with the anchoring filaments, form the hemidesmosomes anchoring filament complex, which plays an important role in cell-basement membrane adhesion. The molecular organization of hemidesmosomes is based on three classes of proteins. The first class is the cytoplasmic plaque proteins, which connect the intermediate keratin filament cytoskeleton to the plasma membrane. These include bullous pemphigoid antigens BP230 (BPAG 1) and plectin. BP230 was the first recognized targeted antigen in patients with bullous pemphigoid. The second class consists of transmembranous proteins, including α6β4 integrin and collagen XVII/BP180 (also termed BPAG2), which connect the hemidesmosomal plaque to the extracellular matrix and may serve as cell receptors [7]. The extracellular domain of α6β4 integrin is crucial for cell adhesion and acts as a receptor for various laminin types with particular high affinity to laminin 332. BP180 is a collagenous molecule that can interact with α6β4 integrin. A further main class of proteins of the epidermal basement membrane are components of the extracellular matrix and include different laminin isoforms and collagen IV. Laminins are large family of glycoproteins serving as major cell adhesion substrates at the basement membranes. They interact with different subsets of integrins such as α6β1, α3β1 or α6β4. Such an interaction at the cell surface regulates not only epithelial cell adhesion to the basement membrane zone but also further physiological cellular functions such as proliferation, migration polarity and differentiation [6], [7].

Various autoimmune diseases may involve oral epithelium, including pemphigus vulgaris, mucous membrane pemphigoid, epidermolysis bullosa acquisita, lichen planus, erythema multiforme, lupus erythematosus and chronic ulcerative stomatitis. Affected individuals present with variable degrees of oral mucosal lesions associated with extraoral manifestations due to involvement of the skin and/or further mucosal surfaces, including nasal mucosa, pharyngeal mucosa or the conjunctiva [8], [9]. The clinico-epidemiological features of autoimmune diseases have been studied in different populations worldwide. However, the majority of existing reports focus on the epidemiology of a single disease or a group of diseases and only a few describe the epidemiological features of the whole spectrum of autoimmune diseases in particular population. Studies from Eastern Europe show that pemphigus is the most common autoimmune blistering disease with an estimated incidence and prevalence of 4 and 24.8 per 100 000 inhabitants, respectively [10]. Similar results also emerged in studies conducted in Western Asia, East Asia and Africa, where pemphigus was also found to be the most prevalent autoimmune bullous dermatoses [11], [12], [13]. In contrast, in Western Europe and North America, bullous pemphigoid was found to be the most common autoimmune blistering disease with an incidence ranging from 0.6 to 4.3 cases per 100 000 inhabitants [14], [15], [16]. Several descriptive epidemiological studies on lupus erythematosus have been also conducted worldwide. The most extensive available data come from the European Union and the United States of America. The incidence rate of SLE in Europe is 3.3–4.8 cases per 100,000 population and year and in the USA 2.2–7.6 [17], [18].

The prevalence of oral mucosal involvement in immune-mediated disorders varies according to the type of disease. Studies show that oral lichen planus is the most common immune-mediated disorder affecting the oral cavity, followed by pemphigus vulgaris and mucous membrane pemphigoid [19], [20], [21], [22], [23] (Table 1). Moreover, oral mucosa can be the first affected mucosal surface in many of these conditions, a fact that emphasizes the need for better understanding of clinical features and diagnostic tools for autoimmune diseases among practitioners. Precise and early diagnosis greatly facilitates timely, effective and specific treatment [19].