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Anaya JM, Shoenfeld Y, Rojas-Villarraga A, et al., editors. Autoimmunity: From Bench to Bedside [Internet]. Bogota (Colombia): El Rosario University Press; 2013 Jul 18.

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Autoimmunity: From Bench to Bedside [Internet].

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Chapter 34Dermatological autoimmune diseases

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Introduction

The skin is the largest organ in the human body, representing 16% of the total body weight. The skin is also one of the largest organs in humans and is formed by a layer (termed the epidermis) that enables the body to interact with the environment through physico-chemical mechanisms and sophisticated sensorial stimuli. Moreover, the epidermis provides protection for the human body through specialized cells involved in immunity, which are distributed throughout the organ. The epidermis is comprised of the following five layers (listed in order from the innermost layer to the outermost layer): the basal or germinate layer that consists essentially of keratinocytes that are attached to the basement membrane by a structures called the hemidesmosome and the focal contact. The hemidesmosome plays an important role in autoimmune bullous skin. Next to the basal layer are the basal cells, which are cuboidal and migrate to the surface in a process termed cell differentiation. These cells allow the expression of certain types of keratins in the keratinocytes. The next layer is the stratum spinosum, which consists of five rows of polygonal flattened cells. The cytoplasm of these cells exhibit discrete basophilic staining, and in this stratum, the presence of tonofibrils is evident, and the cells are joined by structures called desmosomes. The desmosome is a molecular complex formed by desmogleins proteins (Dsg) that are involved in triggering a pathogenic immune response in blistering autoimmune diseases, such as pemphigus. The next layer is the granular stratum, the surface of which is formed by three rows of cells containing round nuclei. The keratinocyte layer is characterized by the presence of electron-dense granules composed of sulfur-rich amino acids present in the precursor molecule of filaggrin. The next layer is the stratum lucidum, which is comprised of two rows of flattened cells that do not contain nuclei and have poorly defined shapes. The cells produce a thin eosinophilic zone containing large amounts of keratins and are found mainly in the palms and soles, which is of clinical relevance in autoinflammatory diseases, such as keratoderma palmoplantar. Finally, the stratum corneum corresponds to the outermost layer of the epidermis, which consists of between 15 and 20 layers of flattened cells with a dense keratin content, termed corneocytes. Corneocytes are insoluble, and the process of the cornified cell envelopes is determined by the molecule involucrin. In the cornification process, the multiple bridges that crosslink the structure are induced by epidermal transglutaminase. The corneocytes are replaced by cells from the basal layer, and the epidermic renewal process takes approximately 21 to 28 days. The last step in this process is termed desquamation, which involves the degradation of lamellar lipids in the intercellular spaces, and this process is accelerated in autoinflammatory diseases, such as psoriasis.

The dermis is another component of skin tissue and is located below the epidermis. The dermal tissue is distributed in two regions; the innermost region is termed the reticular area, which is extensively vascularized and hosts appendices, such as the hair follicles and the sweat and sebaceous glands. The reticular zone has clinical significance in a number of autoimmune diseases of the skin that affect the ability to sweat, such as scleroderma. The upper area of the dermis is termed the papillary dermis, and in this area, the blood vessels are involved in superficial vasculitis processes in diseases such as lupus.

The origin of the skin

Skin emerges during the very early stages of embryonic development. In the early gastrula, the mesoderm migrates and generates the dermis. The mesoderm is also essential for the differentiation of epidermal structures including the hair follicle, and in turn, the dermis is essential for maintaining the adult epidermis. The development of the epidermis involves a fine balance, which plays a key role, between the opposing signals of Notch and Wnt (wingless related) and involves beta-catenin, Lef1, and the Notch peptide. The sonic hedgehog pathway signaling promotes neural tube development, and morphogenic proteins (BMPs) that promote signaling during the development of the ectoderm are also involved; therefore, these elements establish complex interactions and justify the presence of nerve terminals and Merkel cells in the skin. The fibroblast growth factor (FGF) induces an additional control on the Wnt pathway that influences the epidermal development. Hemidesmosomes and desmosomes appear at approximately the 10th week of development and are followed by the emergence of keratins after 14 weeks, and the filaggrin protein is present in the granular layer at 15 weeks (1). The rudiments of hair follicles emerge at approximately 9 weeks, and after the apocrine glands appear between the 13th and 15th week of development. Eccrine or sweat glands develop from the germinate layer at 14–15 weeks, after which they penetrate deep into the dermis, and the intra-epidermal duct is formed by the coalescence of intra-cytoplasmic cavity groups formed by two adjacent layers of cells. Nail development begins between 16 and 18 weeks, after which the keratinized cells of the dorsal and ventral matrix are differentiated (1).

Approximately 90% of the cellular components of the epidermis correspond to squamous epithelium cells; keratinocyte growth in culture depends initially on fibroblast support; however, epidermal growth factor (EGF) delays senescence in epidermal cells (2,3). Another component of development is the melanocyte cell lines that are generated in the neural crest; these cells appear transiently and re-emerge after 4–6 months of gestation. Melanocytes are responsible for the production of melanin, which produces skin color and are attacked in vitiligo disease (4). Langerhans cells belong to the histiocytic lineage and are antigen-presenting cells derived from the monocyte-macrophage line that migrate from the blood to the skin after the 12th week of gestation (5). Finally, Merkel cells are sensory cells that appear in the nails, fingertips, lips, and other parts of the skin at 16 weeks of intrauterine life (6). The cells of the dermis, such as the mesenchymal stem cells, are widely expressed in a variety of cells, including blood-derived cells, cells that form the connective tissue including fibroblasts, mast cells, and skin-derived precursor cells (SKF). Other skin cells include adipocytes, smooth muscle cells, neurons, etc (1).

Cell junctions relevant for autoimmunity

Different cell junctions bind keratinocytes to maintain the mechanical integrity of the skin and are responsible for biochemical and mechanical interactions and cellular communication; these junctions include hemidesmosomes, desmosomes, adherent junctions (AJ), gap junctions, and tight junctions. The basement membrane zone (BMZ) is an ultra-structurally adhesive zone located between the internal part of the epidermis and the external part of the dermis. The BMZ is subdivided into four distinct ultrastructural areas: 1) the hemidesmosome and top of the lucid membrane, 2) the lower lucid lamina, 3) the lamina densa, and 4) the sub-lamina densa. The components of the BMZ that are best characterized are the hemidesmosome and the upper lucid lamina. The hemidesmosomes are composed of the pemphigoid antigens BP230 and BP180, integrins 6β4 and 7, and plectin. The lower part of the lucid lamina includes the laminins 1, 5, and 6, p105, and enactin/nidogen. The lamina dense is formed by IV collagen and perlecan. Finally, the sub-lamina densa is formed by collagen VII (COL7), which is the antigen of the epidermolysis bullosa acquisita (7). In 1956, Keith Porter defined the ultrastructure of the desmosome as an adherent complex that anchors the intermediate keratin filaments and the cell membrane of two adjacent cells, which interact to form symmetrical joints with spaces of 30 nm. Electron microscopy can distinguish the plaque formed by electro-dense material near the BMZ, a less dense band, a fibrillar area, and the intermediate filament that crosses the plaque. Desmosomal molecules are products of the cadherin gene superfamily and include desmosome cadherins, armadillo family proteins, and plakins (desmoplakin and plakofilin stabilize keratinocyte adhesion). Transmembrane cadherins are involved in the heterophilic associations between desmogleins (Dsg) and desmocollins (Dsc). There are four types of Dsg (Dsg 1–4): Dsg1 is expressed primarily in the surface layers of the epidermis, whereas Dsg3 is expressed mainly in the basal layer, and this difference is important for the classification of the disease pemphigus (1,8,9). Dsg4 is expressed in the hair, and Dsg2 is expressed at low levels in the stratified epithelia, such as the human epidermis, and is restricted to the proliferative basal cell layer. AJ correspond to electrolucid transmembrane structures related to cellular shape. These structures participate in cellular interactions, and the major component of AJ is E-cadherin, which links the cytoskeleton via α-catenin and other components (p120ctn, β-catenin, plakoglobin, α-actinin, and vinculin). The AJ joints are important for actin polymerization. Gap junctions are groups of intracellular channels (connexons) formed by six connexin subunits that connect the cytoplasm of two adjacent keratinocytes. Tight junctions regulate the epithelial permeability via proteins called claudins, and occludin, a member of this family of proteins, is altered in autoinflammatory diseases such as psoriasis (1).

Autoimmunity

Over a hundred years ago, Paul Ehrlich wrote, “We pointed out that the organism possesses certain contrivances by means of which the immunity reaction, so easily produced by all kinds of cells, is prevented from acting against the organism’s own elements and so giving rise to autotoxins … so that one might be justified in speaking of a ‘horror autotoxicus”’ (10). His proposal was mistakenly interpreted as “autoimmunity cannot occur,” which remained a dogma for 50 years until Noel Rose described his model of experimental thyroiditis in 1956 (11). In reality, Ehrlich was proposing the existence of “mechanisms to prevent the immune reaction against their own elements,” which is nothing less than what we now know as immune tolerance. Clearly, these mechanisms prevent or stop the production of autotoxins (autoantibodies) to avoid autointoxication (self-damage). This seminal but imperfect concept of horror autotoxicus by Ehrlich was indeed very wise because he realized the need for some type of immunological control to avoid autoimmunity, and at the time when his hypothesis was proposed, there were no experimental data at the cellular and/or molecular levels to begin to understand tolerance and autoimmunity (12,13).

Historically, Donath and Landsteiner described paroxysmal cold hemoglobinuria as the first autoimmune disease in 1904 (14). It is a rare form of hemolytic anemia caused by complement-dependent cold-acting autoantibodies that produce hemolysis in vivo in a temperature-dependent reaction that occurs between 18 and 20°C. Another advance in the understanding of the spectrum of autoimmune disease was made in 1962, when Milgrom and Witebsky proposed a number of postulates for the classification of autoimmune diseases (15) as follows: 1) direct evidence of the transfer of pathogenic antibody, 2) indirect evidence based on the reproduction of autoimmune diseases in experimental animals, and 3) circumstantial evidence from clinical clues. Later, Rose and Bona revised the criteria, assembling the original postulates with autoantibody markers of certain autoimmune diseases (16). Next, autoimmune diseases were classified as localized or organ-specific autoimmune diseases in which pathogenic autoantibodies were directly related with the affected tissue, as in the case of pemphigus. The other category was systemic autoimmune diseases; however, their pathophysiology was complex, and organ non-specific autoantibodies were considered markers rather than pathogenic autoantibodies because in most cases, they were not directly involved in tissue damage; the best example in this category is likely systemic lupus.

Nevertheless, the classification of autoimmunity has become more complex since the rapid evolution of the understanding of genetics and the molecular mechanisms involved in the pathophysiology, which has challenged the old autoimmunity paradigm of classification. In addition, recent efforts to reappraise autoimmunity takes into account the genes and cells involved in certain types of autoimmunity and other diseases that are not strictly autoimmune but are autoinflammatory. These efforts have fostered the development of a classification system that provides for five types of diseases as follows: 1) monogenic autoimmune diseases, 2) polygenic diseases exhibiting a prominent autoimmune component, 3) monogenic autoinflammatory diseases, 4) polygenic disease exhibiting a prominent autoinflammatory component, and 5) mixed pattern diseases (17). Most autoimmune skin diseases belong to the second category, as is the case for autoimmune bullous disease (pemphigus and pemphigoid), and one example of autoinflammatory skin disease is psoriasis. Differences between autoimmunity and autoinflammation are as follows: autoimmunity is a self-directed inflammation caused by aberrant dendritic cells and T and B cell behaviors that disrupt tolerance, resulting in an adaptive immune response that plays a central role in the phenotypical clinical expression of autoimmune diseases. In sharp contrast, autoinflammation leads to the activation of the innate immunity and may result in tissue damage through the alteration of cytokine cascades, which induce site-specific inflammation and is independent of the adaptive immune response (17).

In addition to understanding autoimmunity classification, it is important to understand tolerance mechanisms and the reasons why physiological control is disrupted. In this chapter, we will discuss a number of autoimmune diseases that affect mainly the skin and mucous membranes (pemphigus, pemphigoid, dermatitis hepetiformis, and vitiligo), and we will discuss one common autoinflammatory disease (psoriasis).

Pemphigus

Pemphigus (in Greek, pemphix means blister) is a group of blistering diseases with an organ-specific autoimmune pathogenesis that affects the skin and mucous membranes. The disease is characterized by blisters and erosions caused by intraepidermal cell detachment in a process termed acantholysis. The lesions are induced by the presence of autoantibodies against proteins in the desmosomes, which are the attachment structures of keratinocytes (18). The clinical hallmark of this group of diseases is the presence of intraepidermal bullae; the lesion can be produced artificially by pressing the skin between two fingers and the positive Nikolsky sign consisting of the detachment of the surface layers of the skin (19). Another simple assay for this disease is the Tzanck test in which the microscopic analysis of a sample of cells from the blister basement demonstrates the presence of acantholytic cells (20). Pemphigus has a worldwide distribution, with an incidence of 0.1 to 0.5/100,000 and occurs more often in women (1.5:1) between the fourth and fifth decade of life (21). In addition to the disease in humans, this disease is also observed in horses, dogs, and cats. The histopathology findings reported by Civatte in 1943 described the loss of cell-cell adhesion, and the process was designated “acantholysis.” This term is important because it reflects its mechanism, which is the disease hallmark (22). After keratinocyte detachment, the cells become deformed and acquire a spherical shape because of the loosening of the intercellular connections; therefore, the keratinocytes are isolated within the blisters as acantholytic cells (23). The epidermal location of the blisters allows the histological classification as suprabasal pemphigus, sub corneal, or intragranular pemphigus.

A milestone in the study of pemphigus was made in 1964 when Beutner and Jordon (24) first described the pemphigus antibodies that reacted to the keratinocyte surface. This description allowed the recognition of the autoimmune nature of the disease. Beutner and Jordon used an immunofluorescence technique, describing the “honeycomb” pattern of the pemphigus antibodies induced by the antibody recognition of the structures attached to the epidermal cell surface. They also proposed the quantification of circulating antibodies in the serum of patients by reciprocal dilution of the patients’ serum, and the titers correlated with the extent of the blistering. This anti-epithelial antibody determination has been used as a predictor for disease activity and therapy response (25). Pemphigus autoantibodies are IgGs (IgG1 and IgG4 isotype) and target different proteins in the desmosome complex. The pathogenic properties of these antibodies were demonstrated elegantly by Anhalt and Diaz (26) in 1982 when they reproduced the disease in Balb/c newborn mice by the passive transfer of human pemphigus IgG. This experimental model has been established as the principal tool for studying the effect of pemphigus autoantibodies in vivo by inducing acantholysis. Additionally, the pathogenesis of pemphigus autoantibodies has been demonstrated during pregnancy in pemphigus patients as a “phenomenon of nature.” Pemphigus depends on the maternal autoantibody titer and has been found in newborns as neonatal pemphigus. Therefore, the transfer of the pemphigus IgG4 isotype maternal autoantibodies via the trans-placental pathway induces blisters in newborns; however, this transient disease disappears after weeks or months when the maternal pemphigus autoantibodies become degraded (27,28) Pemphigus antibodies recognize Dsg1 and Dsg3; however, according to the type of pemphigus, the antibodies may recognize other desmosome proteins, such as Dsc, envoplakin, periplakin, etc. (20,25).

Keratinocytes are firmly bound together by desmosomes, which consist of two types of proteins: a) the transmembrane glycoproteins, Dsg, and Dsc and b) the cytoplasmic plate proteins desmoplakins and plakoglobin. Dsg are transmembrane glycoproteins that require Ca+2 for their adhesive function. Dsg and Dsc belong to the type 1 desmosomal cadherin family. Both Dsg and Dsc contain an extracellular domain with four cadherin repeats and an intracytoplasmic domain at the carboxyl terminal (23). The expression of these proteins in the epithelia varies; Dsg1 is expressed in the stratum granulosum of the epidermis, and Dsg3 is restricted to the lower layers of the epidermis, practically distributed above the basal layer. Based on this finding, John Stanley (29) explained the involvement of these cells in the pemphigus disease subsets; those affecting the skin exhibit anti-Dsg1 activity, and pemphigus in the mucosa exhibits anti-Dsg3 activity, while patients with anti-Dsg1 and anti-Dsg3 specificities exhibit skin and mucous membrane involvement (Figure 1). In addition to Dsg, other autoantibodies have been described in pemphigus, including autoantibodies against adhesion molecules, cell membrane receptors, anti-muscarinic receptors, annexins, hematological antigens, carcinoembryonic cells and microsomal antigens, the clinical and pathogenic significance of which is unknown (30). The pathophysiological mechanism that induces acantholysis affects the amino terminus of the extracellular domain 1 of Dsg; therefore, the interaction between anti-Dsg antibodies and epitopes of this immunodominant region triggers a cascade of events including the following: 1) steric hindrance that affects desmosome adhesion directly; 2) induction of a downstream signaling transduction cascade mediated by protein kinases and calcium that induces Dsg phosphorylation and is followed by plakoglobin dissociation and desmosome break–down; 3) plasminogen activation (urokinase) with the conversion of plasminogen in plasmin, followed by the digestion of the extracellular domains of the desmosome resulting in acantholysis; 4) clustering of Dsg3 induced by pemphigus IgG binding, with the clustering followed by endocytosis and desmosome degradation in a p38MAPK-dependent manner; 5) digestion with metalloproteinases; and 6) apoptosis resulting in cell detachment, which creates or feeds a pathogenic cycle through the Fas pathway; this mechanism involves other mediators of inflammation including TNF (18,19,25,31-33). The genetic factors associated with pemphigus susceptibility are the HLA class II genes. Population studies have shown an association between certain class II alleles and pemphigus in different ethnic groups; for example, HLA-DRB1*0402 is associated with over 90% of Ashkenazi Jews with pemphigus vulgaris (PV), and HLA-DQB1*0503 is associated with non-Jewish populations. Likewise, DRB1*1404 is the most important risk factor in an Indo-Asian population, and in Brazilian pemphigus, HLA-DRB1*0102 is a risk factor (34). In the year 2000, studies of SNPs (single nucleotide polymorphisms) corresponding to a variation in DNA sequences by a single nucleotide change demonstrated that the genome consists of physically linked SNP variants. The DSG3 gene contains 46 coding SNPs, and one study demonstrated an association between 2 SNPs and PV; notably, these 2 SNPs were in the context of the PV alleles. Below, we describe the main pemphigus subsets (31,34).

Figure 1. Skin biopsies of Pemphigus.

Figure 1

Skin biopsies of Pemphigus. A. Pemphigus vulgaris (H&E) showing a suprabasal blister. B. Indirect immunofluorescence showing IgG deposition on intercellular spaces at basal keratinocytes (Dsg3). C. Pemphigus foliaceous (H&E) showing blister (more...)

Pemphigus Vulgaris (PV), the most common form of pemphigus, affects men and women equally. The disease is chronic and progressive and is characterized by flabby blisters and erosions on the skin and/or mucous membranes. The oral mucosa is affected primarily in approximately 70% of cases, causing dysphagia for months after the blisters appear on the skin surface (trunk, buttocks, and feet). The genitourinary tract may be particularly affected in women. Blisters can erupt and leave erosions and crusts, and if the lesions are extensive, then electrolyte abnormalities, fluid loss, and hypoproteinemia may be observed. The most common complication of this disease is secondary infection. Histopathology demonstrates blisters above the basal cells, which form a layer resembling headstones. Eosinophilic infiltration can be detected. The antibodies are directed against Dsg3 in the mucosa involved, against Dsg1 in the skin involved, or against both proteins in the mucocutaneous features (18,20,21). Figure 2.

Figure 2. Pemphigus vulgaris show blisters, erosions and crusts (A, B, C), positive anti-epithelial antibodies detected in cow nose (D), and direct immunofluorescence that show intraepidermal blister with acantholytic cells (E).

Figure 2

Pemphigus vulgaris show blisters, erosions and crusts (A, B, C), positive anti-epithelial antibodies detected in cow nose (D), and direct immunofluorescence that show intraepidermal blister with acantholytic cells (E).

Pemphigus Foliaceous. In 1844, Cazenave described the pemphigus foliaceus, then two clinical features are recognized: the non-endemic pemphigus foliaceus and the endemic or fogo selvagem. The first occurs in middle age or late adulthood and affects the face, scalp, trunk, and back. The blisters are superficial, fragile, and easily broken, with the erosion of the erythema and crusting being the common lesions; the mucous membranes are not affected, and the patients test positive for the Nikolsky sign (18,20). Endemic pemphigus foliaceus occurs in children, young adults, and genetically related family members in Brazil, Colombia, and Tunisia (35). The lesions do not differ from non-endemic pemphigus. Diaz et al. (36) studied this type of pemphigus at the molecular, cellular and epidemiological levels and reported the presence of endemic foci, suggesting that a vector triggers the disease (37). Skin biopsies revealed superficial intraepidermal blisters and antibodies directed against Dsg1 (38,39).

Pemphigus erythematosus (PE) is also known as Senear-Usher syndrome. In PE, the blistering coincides with a seborrheic erythematous rash resembling the rash associated with lupus. Serologically, PE patients have autoantibodies similar to individuals with pemphigus foliaceus and cutaneous lupus erythematosus (18-20). Likewise, the skin immunopathology of PE is characterized by acantholysis with immunoglobulin deposition in desmosomes and at the dermal-epidermal junction (lupus band test). The histology and anti-Dsg1 serological marker of pemphigus foliaceus and PE are the same. The clinical hallmarks of PE are seborrheic lesions in the nose, nasolabial folds, and malar areas that resemble the “butterfly” distribution of lupus. Lesions may also affect the preauricular region. Hyperkeratotic scars with erythema and superficial blisters can be present on the chest. The immunopathology of PE was described by Chorzelski et al. (40), demonstrating the presence of immunoglobulin and complement at the dermo-epidermal junction (DEJ) resembling the lupus band test. PE patients also exhibited antinuclear antibodies, and the report proposed the coexistence of pemphigus and lupus erythematosus. We recently described Dsg1 and Dsg3 and antinuclear antibodies specific for Ro, La, Sm, and double-stranded DNA antigens in patients with this form of the disease. After eluting specific anti-epithelial or anti-nuclear antibodies, a lack of cross-reactivity was demonstrated between desmosomes and nuclear and cytoplasmic lupus antigens (41). This result suggests that the autoantibodies in PE are directed against different antigens and that independent clones produce these autoantibodies. The DQB1*0301 allele may handle desmosomal and/or hemidesmosomal epitopes, and under different stereochemical conditions, the same allele interacts with ribonucleoproteins, raising two independent clones that produce different and unrelated autoantibodies. Taking into account these clinical and serological data, we suggest that PE behaves like a multiple autoimmune disease (18,19,23,34,42).

Drug-induced pemphigus is induced by thiol or sulfide groups such as penicillamine, penicillin, captopril and propranolol, indomethacin, beta-blockers phenylbutazone, piroxicam, and tuberculostatic agents. The clinical picture of drug-induced pemphigus resembles pemphigus foliaceous but can be similar to that of PV or PE; the autoantibodies recognize Dsg3 and Dsg1. Interestingly, this syndrome may also occur after treatment with interferon-γ and interleukin 2 or may precede a lymphoma or lung cancer (18,42).

IgA pemphigus is characterized by the presence of confluent pustules prone to forming circinated blister patterns. The condition is rare, and immune deposits of IgA antibodies that recognize the epidermis and the Dsc I and II can be found in the skin lesions (42).

Pemphigus vegetans was described by Neumann in 1886 and is considered a subtype of PV. The lesions present as vesicles and erosions in the intertriginous areas, such as the axillae and groin. In addition to blisters and pustules, vegetations or papillomatous verruciform may be found and oral lesions may occur. Pemphigus vegetans of the Neumann type can resemble PV, and the Hallopeau type presents with pustules and has a more benign prognosis (18,42).

Paraneoplastic pemphigus. This rare subset was described in 1990 by Anhalt (43) and usually accompanies a lymphoproliferative or hematologic malignancy or is associated with benign tumors, such as thymoma and Castleman’s tumor. The lesions are distributed in the oral mucosa, lips, and pharynx. Erosions, ulcerations, and crusting blood can be found, which can leave synechiae pseudomembranous conjunctivitis, and erythema multiform-like lesions on the palms and soles can be observed. This pemphigus subset may involve the lung epithelium, causing respiratory failure, which is a terminal complication in 30% of patients. Biopsies reveal antibodies against the epithelial intercellular space; however, immune deposits in the dermal-epidermal BMZ are found in virtually all cases. The autoantibodies are directed against Dsg1, Dsg3, and other desmosome proteins, such as desmoplakins I and II, bullous pemphigoid (BP) antigen 1 (BP230), envoplakin, and periplakin, among others. It is also important to identify the anti-epithelial antibodies attached to the skin overlying the tumor (18,42).

The diagnosis of autoimmune blistering diseases is based on the evaluation of clinical outcomes, histopathology, direct immunofluorescence (DIF), and indirect immunofluorescence (IIF). Histological examination should be performed in a recent intact blister, including adjacent skin. The biopsy for DIF should be performed on perilesional normal-appearing skin. The determination of antibodies by IIF for anti-epithelial antibodies remains the gold standard for diagnosis. However, anti-Dsg1 and anti-Dsg3 antibody determination using ELISA is important because antibody follow-up allows the assessment of the treatment response or the prediction of a relapse. Accurate diagnosis is a prerequisite for accurate forecasting and effective treatment (25,39,42).

Treatment. Conventional treatment involves the administration of corticosteroids and immunosuppressive agents. In the case of resistant pemphigus, using IVIG and Rituximab is effective (44,47). Other experimental therapies have been proposed to neutralize the pemphigus IgG by means of anti-idiotype antibodies or apoptosis inhibitors, and these have demonstrated experimental success in controlling blistering (45,46). Additionally, support therapy including the treatment of infections and fluid control is important for a positive outcome (47).

Bullous penphigoid (bp) diseases

BP is a blistering autoimmune disease described in 1953 by Walter Lever (48). BP is characterized by the separation of the dermal-epidermal junction (DEJ) accompanied by inflammatory cell infiltration in the upper dermis. Another important contribution was made by Jordon et al (1967), who demonstrated that the BP autoantibodies were reactive to the basal membrane, which is the hallmark of the disease (49). The autoantibodies recognize the BP180 antigen (BPAg2), a type of XVII collagen and the BP230 antigen (BPAg1), a cytoplasmic plakin protein family member that links the hemidesmosome to the keratin of intermediate filaments; both antigens are components of the hemidesmosome. The disease affects mainly the elderly; however, a small number of cases have been reported in children (50,51). The incidence of BP is 1.2 to 2.1 cases per 100,000 people (52,53). The disease is clinically characterized by subepidermal blisters that form tense bullae, which do not disrupt easily. Other characteristic lesions include erythematous urticarial plaques that cause pruritus and blistering that appears along flexural areas and that is distributed on the chest and abdomen (over time, these lesions often become excoriated). Oral involvement is rare even though a special pemphigoid subset affects the mucosa.

In antigenic triggering, two major antigens have been described: the BP180 antigen described by Luis Diaz group (54-56), and the BP230 antigen described by John Stanley et al. (57). BP180 is a transmembrane glycoprotein that extends from the lamina lucida to the lamina densa in a stick-like form that contains an extracellular collagen domain. The immunodominant region of the molecule is a non-extracellular collagen domain (NC16A), and most patients generate pemphigoid IgG class antibodies (58). Likewise, reactivity with epitopes in the C-terminal region appears to be associated with the participation of the mucosa and a more severe disease of the skin. The pathogenicity of the BP180 antibodies is well established in animal models. BP230 is a 230-kDa protein with an intracellular component associated with the hemidesmosome plate belonging to the family of plakin proteins. The immunodominant epitopes are located in the C-terminal globular region. The mechanism of tissue damage begins with the antibody binding to the BP180 and/or BP230 antigens, which induces complement activation leading to the accumulation of the eosinophils and neutrophils that release proteolytic enzymes. Additionally, the autoantibodies interfere directly with the function of BP180 and BP230 and induce pro-inflammatory cytokine release. Furthermore, there is evidence of clinical association with disease activity from the high concentrations of IgG autoantibodies reactive to the NC16A ectodomain epitope from BP180 (59). Anti-BP180 antibodies of the IgE class might contribute to tissue damage by stimulating basophil and mast cell degranulation. The BP230 antigen is a disease marker, and 60% of patients develop antibodies against the BP230 epitopes. Autoantibodies of the IgG class recognize the COOH-terminal domain of BP230; however, the pathogenic role of these autoantibodies remains to be defined. The understanding of the pathophysiology of BP has been advanced in animal models. Liu et al. (60) raised antibodies in rabbits directed against the murine NC16A region of BP180, and the antibodies induced a disease similar to BP in neonatal mice. In contrast, other animal models for assessing the role of BP230 in blister induction were inconclusive and will require further investigation. Additionally, numerous non-immune factors have been implicated as BP triggers, such as trauma, burns, radiation, ultraviolet radiation (UV), and a variety of drugs (aldosterone antagonists and phenothiazines) (58).

Clinically, BP blisters are large and tight and are surrounded by erythema and urticarial plates. After several days, the blisters can erupt and cause erosion and scabs in flexural areas of the abdomen; most patients have accompanying itching that is severe. Diagnosis is based on clinical criteria, with DIF data from a perilesional biopsy, demonstrating linear immune deposits of the IgG class at the dermal-epidermal junction, although deposits of IgA and IgE can also be observed (Figure 3). The source of the antigen for the IIF is the splitting of the normal skin using 1 mol NaCl; the separation allows the differentiation of the antibody (BP180/BP230) binding to the roof blister (61). Likewise ELISA tests are useful for the detection and quantitation of both antibodies. BP can also occur in dogs, small pigs, horses, and cats, exhibiting the same clinical and immunopathological features as in humans. Immunogenic studies have demonstrated that HLA-DQB1*0301 is a susceptibility gene involved in BP development.

Figure 3. A. BP blisters are large and tight and are surrounded by erythema and urticarial plates. B. IgG deposits along BMZ by direct immunofluorescence. C. Mucous membrane pemphigoid. D. BP IgG autoantibodies detected by indirect immunofluorescence.

Figure 3

A. BP blisters are large and tight and are surrounded by erythema and urticarial plates. B. IgG deposits along BMZ by direct immunofluorescence. C. Mucous membrane pemphigoid. D. BP IgG autoantibodies detected by indirect immunofluorescence.

The BP subsets that have been described are as follows: Mucous membrane pemphigoid is a BP subset that chronically affects the DEJ, predominantly at the mucosal level. This subset of BP is also known as cicatricial pemphigoid; however, this term is now used to define a clinically severe form of the disease affecting the skin that leaves scars and involves the mucosa. The incidence of this BP subset is 1.3 - 2 per 1 million/year, the disease onset occurs after 60 years of age, and the susceptibility gene is HLA-DQB1*0301, similar to BP. Clinically, this disease affects the mucous membranes, with a predilection for the oral and conjunctivae mucosas, which causes a foreign body sensation in the dry mucous membranes, and conjunctive synechiae can progress to blindness. The diagnosis is similar to BP, and the antibody profile recognizes several of the hemidesmosome proteins, such as BP180, BP230, laminin 332, α6β4 integrin, and collagen VII (58,59). Treatment is difficult because it is a progressive condition, and therapy includes systemic steroids, dapsone, immunosuppressants such as cyclophosphamide (daily or bolus), intravenous immunoglobulin, and Rituximab. The treatment should be multidisciplinary, with an emphasis on ophthalmology (62). Pemphigoid gestationis disease was previously known as herpes gestationis and is a bullous autoimmune condition associated with pregnancy that is mediated by autoantibodies against BP180 NC16A. The frequency is 1 case per 10,000 to 40,000 pregnancies, and the disease is expressed in the 2nd or 3rd trimester of pregnancy and in 10% of patients, within 4 weeks after delivery. Clinically, the disease onset exhibits pruritic papules and urticaria in the periumbilical area that can later become generalized blisters. The risk of preterm delivery occurs in 20% of the cases. Relapses are frequently observed in subsequent pregnancies, during menstruation, or during contraceptive oral therapy. Few cases (5%) evolve to BP. Childhood BP is a rare pathological condition, similar to the adult disease, which occurs most frequently before 8 years of age, and 60% of patients exhibit generalized blistering. Criteria have been proposed for the early diagnosis of the disease, which include the following: 1) patients under 18 years with tense bullae on erythematous or normal skin, with or without the involvement of mucosal epithelia, and histological subepidermal blister with eosinophils, and 2) perilesional skin biopsy exhibiting linear deposits of IgG and C3 on the BMZ or circulating IgG antibodies against the BMZ, observed using IIF. Lichen planus pemphigoid is an infrequent variant that combines two entities: pemphigoid and lichen planus. The disease is characterized by the development of blisters in patients with active lichen planus, antibodies against BP180 and BP230 and anti-p200/anti-laminin-γ1. Lichen planus pemphigoid occurs in the fifth decade of life, and the course of the disease is relatively benign.

Dermatitis herpetiformis (DH)

DH is a pruritic papulo-vesicular skin disease that affects extensor surfaces and is considered a cutaneous component among the celiac disease spectrum. DH is characterized by rash and blisters associated with cutaneous IgA deposition. Duhring identified DH disease in 1884, and this pathology affects middle-aged patients, causing intense itching and erythema or urticarial-like wheals. In some cases, the lesions disseminate, particularly to the elbows, buttocks, and knees. Usually, mucous membranes are unaffected. The skin histopathology demonstrates a neutrophilic infiltration and micro abscesses, and the immunofluorescence studies detect granular deposition of IgA in the dermic papillae. Because DH belongs to the celiac disease spectrum and this pathology is caused by a wheat allergy, wheat proteins could trigger the skin inflammation in some DH patients. The disease is more prevalent in Caucasians (1 case per 10,000 individuals), affecting them at any age but is observed more frequently in the fourth decade of life and is more frequent in men than in women. These patients exhibit a high prevalence of the HLA-DQ2 haplotype in approximately 90% of cases, and the HLA-DQ8 allele is associated with a low prevalence (approximately 5%) (63). The pathogenesis is not fully understood because the factors that determine the clinical expression in the bowel or the skin are unknown. The immunopathology is characterized by the granular deposition of IgA in the dermic papillae of the skin (64), which is the hallmark of DH. The IgA autoantibody deposition induces clusters of neutrophil infiltration, and these cells infiltrate the vesicles in the lamina lucid. Experimental data have shown that transglutaminase-3 (TG3) triggers the IgA deposition and induces the in situ immune complex formation, which subsequently triggers the neutrophil infiltration and vesicle formation (65,66). In 1996, Dietrich demonstrated the importance of tissue transglutaminase (tTG), and this enzyme was defined as the autoantigen of celiac disease (67). The enzyme belongs to a protein family containing nine Ca2+ isoform members that catalyze the cross-linking reaction that results in the N-isopeptide bond formation between the substrates (68). TG3 is involved in epidermal differentiation, and Sárdy demonstrated that TG3 was the major antigen in DH (65). Interestingly, there are two TG3 isoforms produced by alternate splicing, which is not regulated during differentiation, and whether the isoforms are involved in pathogenesis is not known (69). Another interesting observation is that in celiac disease, the antigenic peptide presentation by antigen-presenting cells to CD4+ T cells is restricted to DQ2 or DQ8 alleles, and the pockets of these class II molecules better accommodate glutamic acid residues of epitopes, which are deaminated by the tTG enzyme (70,71). Therefore, it would be reasonable to assume that the initial antigen of DH is the gluten-derived epitope, which after deamination becomes a posttranslationally modified epitope that in complex with the TG3 enzyme might induce epitope spreading and ultimately become the major target of DH CD4+ T cells. The therapy is integrative, based on the new pathophysiology notions, and includes a gluten-free diet combined with dapsone or steroids at low doses. Alternatively, sulphasalazin is used, and other therapies are directed to immunomodulatory targets, such as IL-10, to promote tolerance. Additionally, promising biologics, such as anti-IL-15, are under evaluation (72).

Epidermolysis bullosa acquisita (EBA)

EBA is a rare acquired sub-epidermal bullous disease that exhibits certain clinical similarities to the genetic forms of dystrophic epidermolysis bullosa. Autoimmune EBA affects the structures that anchor the BMZ to the dermis. These structures are the anchoring fibrils (AF), and the principal component of these fibrils is collagen VII (COL7). In this disease, patients develop anti-COL7 autoantibodies, causing skin fragility, erosions, and blisters (73,74). EBA prevalence is as low as 0.2 per million but is variable according to race and has been reported at a higher prevalence in Koreans. This pathology can present in a wide range of ages from childhood to middle age; however, most cases begin at 40 and 50 years of age. The genetic factor is HLA-related, and the DR2 phenotype is associated with EBA. Evidence that EBA is an autoimmune disease includes the deposition of class IgG autoantibodies reactive to COL7; these autoantibodies deposited along the DEJ can be detected by immunofluorescence studies (75). Different clinical subsets have been described and include the following: 1) classical feature, consisting of skin fragility and mechano-bullous disease with acral involvement. The healing process produces scarring and milia (cysts), the oral mucosa is frequently implicated, and the pathology demonstrates dermal-epidermic splitting at the BMZ with discrete inflammation. 2) BP-like feature, which is a form of EBA in which vesicles and bullous pruritic lesions are disseminated along the trunk, abdomen, and extremities, and inflammatory infiltrates are prominent and are composed of neutrophils, mononuclear cells, and a small number of eosinophils. 3) cicatricial pemphigoid-like feature involves different mucous epithelia including the mouth, esophagus, conjunctiva, anus, and vagina, with a histopathology demonstrating the splitting of the DEJ with little infiltrates. 4) Brunsting-Perry pemphigoid-like feature is located in the neck, the bullous lesions are recurrent, and the immunopathology demonstrates IgG deposition along the DEJ. 5) linear IgA bullous dermatosis-like disease is accompanied with linear IgA deposition along the BMZ. Clinically, the disease is characterized by the presence of tense vesicles arranged in an annular pattern, and the autoantibodies against COL7 are of the IgA and IgG classes (75). Therefore, anti-COL7 autoantibodies target different epitopes. This differentiated molecular reactivity to epitopes is associated with the different clinical features (76,77). EBA is linked to other systemic diseases including inflammatory bowel disease (78). The diagnosis can be made using the following guide: A) a bullous disorder within the defined clinical spectrum, B) absence of a family history of a bullous disorder; C) skin biopsy with subepidermal blistering, D) DIF of perilesional skin showing IgG deposition within the DEJ, E) immunoelectron microscopy of perilesional skin showing IgG deposition within the lower lamina densa; and F) alternative laboratory tests to demonstrate autoantibodies, including immunofluorescence, ELISA, western blot, and other tests (79,80). The treatment depends on the clinical features of the EBA and includes general measures to avoid skin trauma. The classical therapy includes colchicine, dapsone, steroids, and immunosuppressive therapy, and recently, the use of anti-CD20 that targets mature and immature B cells has been used with success (78,81).

Vitiligo

Vitiligo is a chronic depigmentation disease that affects the melanocytes, and the destruction of the melanocytes is the central pathological event that causes the depigmentation. This pathology can be presented clinically as a primary disease or can be a component of multiple autoimmune processes such as thyroid disease, pernicious anemia, rheumatoid arthritis, lupus, adult onset autoimmune diabetes, and Addison’s disease (Figure 4). Vitiligo is present in 0.5% of the population (82), is distributed equally in males and females, and the disease starts during the second decade of life. Autoimmune depigmentation is expressed clinically as generalized vitiligo (GV), which is a result of diverse mechanisms involving multiple genes and environmental factors that are not well determined. However, clinical and experimental data have demonstrated enough evidence to support that GV is an autoimmune disease (83,34). Several chromosomal loci have been implicated in autoimmunity or in autoinflammatory disease. In vitiligo, one locus of particular interest is on chromosome 17p13 and is linked in lupus patients who simultaneously develop vitiligo (85). This locus is located in the NALP1 gene, which encodes NACHT leucine-rich-repeat protein 1, a regulator of the innate immune response, and contributes to the risk of GV susceptibility (86,87). Another gene involved in vitiligo is TYR (encodes tyrosinase), which is involved in melanin biosynthesis and is the major GV autoantigen (88). The major histocompatibility complex (MHC) demonstrates the association of HLA-A02 with GV (89). The pathophysiology of GV is the result of infiltrating CD8+ T cells, which are activated by melanocyte-specific peptides (tyrosinase), melanoma antigen recognized by T-cells-1 (MART1), melanin-concentrating hormone receptor-1 (MCHR1), gp100, and tyrosine hydroxylase (TH). In response, the CD8+ T cells express IL-17, TNF-α, and IFN-γ and cytotoxic molecules, e.g., as granzyme B, that induce melanocyte apoptosis. The expression and extension of the disease depends strongly on IFN-γ and CXCR3; therefore, antagonists of these molecules have been proposed as possible therapies to preserve skin pigmentation (90). The humoral immune response is frequently found in GV, and autoantibodies against tyrosinase, MART1, MCHR1, gp100, TH, and PMEL17 can be detected in approximately 42% of the patients. However, the autoantibodies do not correlate with disease activity (89). Different therapeutic approaches have been used with variable results, including the traditional therapy using corticosteroids, calcineurin inhibitors, and narrow-band UVB or UBA radiation combined with the administration of oral photosensitizing molecules such as psoralen. More recently, immunomodulatory therapies have been studied using an engineered mouse model of this condition (91,92).

Figure 4. Vitiligo.

Figure 4

Vitiligo. A. Depigmentation as component of multiple autoimmune processes such as thyroid disease, note the thyroid enlargement. B and C. Lesions clinically presented as a primary disease.

Psoriasis

Psoriasis is a papulo-squamous and desquamative disorder characterized by sharply demarcated erythematous plaques covered with silvery whitish scales. Psoriatic lesions are distributed mainly on the scalp, elbows, knees, trunk, and gluteus creases. The fingernails are involved in 50–80% of patients, displaying pitting, leukonychia, nail plate crumbling, red spots in the lunula, and nail-bed psoriasis (onycholysis, oil-spots, hyperkeratosis, erythronychia, and/or splinter hemorrhage). The clinical subsets of psoriasis are guttate, plaque, pustular, erythrodermic, and inverse (Figure 5). Psoriatic arthritis is an extra-cutaneous manifestation observed in 5–20% of patients. The clinical evolution of psoriasis exhibits a cyclical pattern, improving during the summer and worsening in the winter (93-95). Psoriasis is associated with a group of susceptibility genes: PSOR 1–7, the LCE3B/3C gene (related to epidermal differentiation), the IL-23 gene, and the gene encoding transcription factor NF-kB (96). The HLA-Cw6 allele constitutes a risk factor for the development of psoriasis (96,97). In summary, psoriasis is associated with a genetic background accompanied by autoinflammation. The inflammasome plays a role in the pathogenesis of psoriasis, and for this reason, it is considered an inflammasome-mediated pathology (98,99). There are biochemical differences according to the clinical subsets; for example, chronic plaque and guttate psoriasis differentially express the skin proteins SCCA2, cytokeratin 14, cytokeratin 17, enolase, superoxide dismutase, and galectin (100-103). The psoriatic abnormality is related to epidermal proliferation, hyperkeratosis, skin regeneration, skin metabolism, and inflammation. The transcription of genes involved in the disease induces pathologic changes in the skin and other tissues such as entheses and joints. The pathophysiology depends on a complex network of cellular interactions between T cells, monocytes, and activated macrophages, which results in the over-regulation of cytokines, e.g., TNF, IL-6, IL-12, IL-2, and IFN-γ and produces psoriatic inflammation of the skin and joints (104,105). An initial trigger, such as an infection (Streptococcus, Klebsiella, or a virus), trauma (Koebner phenomenon), stress, or drugs could set off the disease; next, a number of different transcription factors, receptors, and cytokines may induce and support keratinocyte hyperproliferation and inflammatory infiltrates along with plaques. These infiltrates become recurrent through IL-8 participation, which enhances neutrophil accumulation in psoriatic plaques. Because psoriasis is an autoinflammatory disease, beyond the traditional treatments, current therapeutic approaches focus on biological agents to ameliorate inflammation, including the use of chimeric or human anti-TNF monoclonal antibodies and recombinant anti-cytokine receptors. Lately, IL-12 and IL-23 blockage has been suggested as a new strategy to prevent the production of TNF, IFN-γ, and IL-2 cytokines and may represent an effective way to arrest the differentiation of the Th17 phenotype via IL-1 signaling, which drives the inflammation pathway in psoriasis (106,107).

Figure 5. Clinical subsets of psoriasis are: A. guttate, B. plaque, C. Generalized, D. erythrodermic, E. Histology.

Figure 5

Clinical subsets of psoriasis are: A. guttate, B. plaque, C. Generalized, D. erythrodermic, E. Histology.

Concluding remarks

The various autoimmune blistering diseases reviewed in this chapter have in common the blistering triggered by autoimmune reactions that lead to the loss of cell adhesion in skin components at different levels, depending on the disease. Early diagnosis and rational therapies are required to terminate the fatal or disabling course of skin autoimmune diseases. New therapeutic approaches based on a pathogenic approach are the current challenges. However, future therapeutics point toward restorative tolerance approaches that are not yet available for clinical use. Therefore, these diseases should be taken as research challenges with the long-term task of eradicating autoimmunity issues.

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