Background

(1)

Misdiagnosis Association & Society, Seattle, WA, USA

Keywords

EpidermalBasement membraneAnatomyBasal keratinocyte layerLamina lucidaLamina densaSublamina densaEpidermal pemphigusSubepidermal pemphigoidPemphigus vulgarisPemphigus foliaceusParaneoplastic pemphigus

Basement membranes are thin layers of extracellular connective tissue that divide epithelial cells from the underlying connective tissue or from different types of cells [1]. Basement membranes are very complex structures that play different roles and have different compositions and structures, depending on the type of tissue they are found in. Functionally, basement membranes play many different roles. For instance, they are the site of attachment for many cells; can influence the behavior of cells such as their growth, apoptosis, development, and differentiation; and can also be the backbone structure for cell and tissue repair. The basement membrane can also regulate the extracellular environment of cells by acting as a selectively permeable structure. In this book, we will specifically be discussing the structure of the epidermal basement membrane, because many of the diseases that we will discuss will require a basic understanding of this important type of basement membrane.

The epidermal basement membrane consists of four major layers [2]. The first layer is called the basal keratinocyte layer , and it consists of the plasma membrane of the basal layer of keratinocytes, the hemidesmosomes, and cytoskeletal keratin intermediate filaments inside the keratinocyte, which connect to the hemidesmosomes. The second layer is called the lamina lucida , and it contains the extracellular connections, also known as anchoring filaments, that run between the hemidesmosomes and the lamina densa [3]. The lamina densa , also known as the basement membrane proper, is the next layer of the basement membrane found beneath the lamina lucida. The fourth layer of the basement membrane is the sublamina densa region , which consists of anchoring fibrils, microfibrils, interstitial collagens, micro-thread-like fibers, and anchoring plaques, which are components of the papillary dermis that connect it to the lamina densa above (Fig. 1.1).

Fig. 1.1

Anatomy of the basement membrane . (a) The five layers of epidermis, which include the superficial layer of stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and the innermost layer of stratum basale. Stratum corneum is made up of dead keratinocytes that are linked together with proteins. Stratum lucidum contains dead keratinocytes that have not completely finished the keratinization process. Stratum granulosum is the layer containing keratinocytes that contain keratohyalin granules. Stratum spinosum is characterized by the presence of desmosomes that results in an impermeable junction between keratinocytes as seen in section B of this image. Stratum basale is the deepest layer of epidermis, which contains a single layered column of epidermal stem cells. Moreover, the epidermis also contains specialized cells that are most prominent in stratum spinosum. For example, Langerhans are present in all stratums except stratum corneum, and their primary function is to fight skin infections by becoming antigen-presenting cells. Melanocytes are melanin-producing cells responsible for skin color. Merkel cells contain mechanoreceptors responsible for the detection of light touches. (b) The desmosome junction between keratinocytes that is created by the binding of desmoglein 1 (dsg1) and desmoglein 3 (dsg3) antibodies that attach to cell surface (Source: Pooya Khan Mohammad Beigi)

Acquired immune vesiculobullous diseases are diseases in which the body starts to produce autoantibodies against protein antigens in the epidermis or in the basement membrane associated with the epidermal cells [4]. Acquired immunobullous diseases can be divided into epidermal pemphigus or subepidermal pemphigoid diseases. Pemphigus diseases involve autoantibodies against proteins in the epidermis, whereas the pemphigoid group of diseases involves subepidermal autoantibodies against proteins in the basement membrane associated with the epidermis.

Pemphigus

The pemphigus group of diseases are immune diseases involving immunoglobulin G (IgG) autoantibodies against various proteins found on the surface of epidermal cells [1]. This group of diseases is divided into three main disease groups: pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus. Pemphigus foliaceus involves autoantibodies against desmoglein 1 proteins, and paraneoplastic pemphigus involves autoantibodies against both desmoglein and plakin. There are two different variants of pemphigus vulgaris : one is the mucocutaneous variant and the other is the mucosal dominant variant [1]. The mucosal dominant variant of pemphigus vulgaris involves autoantibodies against only desmoglein 3, whereas the mucocutaneous variant involves autoantibodies against both desmoglein 1 and 3 (Fig. 1.2).

Fig. 1.2

The junction between keratinocytes that is characterized by desmosomes , which create an impermeable junction between the cells. The desmosome junction is created by the binding of desmoglein 1 (dsg1) and desmoglein 3 (dsg3) antibodies that attach to cell surface. As seen in the image, the junction is created with the help of additional proteins. For example, envoplakins interact with periplakins in order to serve as an intermediate filament in the desmosome junction. The plakoglobin serves as the cytoplasmic component. Lastly, plakophilins are proteins that link cadherins to intermediate filaments in the junction (Source: Pooya Khan Mohammad Beigi MD)

Desmoglein Compensation Hypothesis of Pemphigus Disease Presentation

On mucosal surfaces, both desmoglein 1 and 3 are expressed; however, desmoglein 3 dominates in terms of its expression in the mucosa compared to desmoglein 1 [5]. In the skin epidermis, desmoglein 1 is expressed everywhere, but is mainly expressed in the superficial upper layers of the skin epidermis, whereas desmoglein 3 is expressed in the basal lower layers of the epidermis. These differences have been hypothesized to explain the clinical features of various presentations of pemphigus based on the autoantibodies involved [6]. For instance, pemphigus vulgaris involves autoantibodies primarily directed against desmoglein 3 proteins, and since these proteins are rendered dysfunctional by the antibodies, the keratinocytes in the lower basal layers of the epidermis become detached from one another, resulting in the blisters in the basal layers of the epidermis [5]. In pemphigus foliaceus , the skin blisters are more superficial, and this can be explained by the fact that this disease involves autoantibodies to desmoglein 1, which is mainly expressed in the superficial layers of the epidermis. Pemphigus foliaceus has no mucosal erosions simply because desmoglein 3 dominates in terms of its expression in the mucous membranes [5].

Pemphigus vulgaris has two primary clinical variants, and the clinical features of these two variants can also be explained based on desmoglein expression. The mucocutaneous variant that involves autoantibodies against desmoglein 1 and 3 causes mucosal erosions and deep skin blisters [5]. The mucosal dominant variant that involves antibodies against desmoglein 3 only causes mucosal erosions and no skin lesions, because the desmoglein 1 in the lower epidermal layers makes up for the lack of desmoglein 3; however, in the mucous membranes, there is not enough desmoglein 1 to make up for the lack of desmoglein 3, since desmoglein 3 is expressed in greater quantity than desmoglein 1 in the mucous membranes [5]. There is a minority of patients that have cutaneous-only disease expression (i.e., no current or history of mucosal lesions) that cannot be fully explained by the desmoglein 3/1 compensation hypothesis. Recent literature indicates that pemphigus vulgaris patients harbor antibodies to other, nondesmoglein, targets [7–9].

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