Genetics and Omics Analysis of Autoimmune Skin Blistering Diseases

Abstract

Autoimmune blistering diseases (AIBDs) of the skin are characterized by autoantibodies against different intra-/extracellular structures within the epidermis and at the basement membrane zone (BMZ). Binding of the antibodies to their target antigen leads to inflammation at the respective binding site and degradation of these structures, resulting in the separation of the affected skin layers. Clinically, blistering, erythema and lesions of the skin and/or mucous membranes can be observed. Based on the localization of the autoantigen, AIBDs can be divided into pemphigus (intra-epidermal blistering diseases) and pemphigoid diseases (sub-epidermal blistering diseases), respectively. Although autoantigens have been extensively characterized, the underlying causes that trigger the diseases are still poorly understood. Besides the environment, genetic factors seem to play an important role in a predisposition to AIBDs. Here, we review currently known genetic and immunological mechanisms that contribute to the pathogenesis of AIBDs. Among the most commonly encountered genetic predispositions for AIBDs are the HLA gene region, and deleterious mutations of key genes for the immune system. Particularly, HLA class II genes such as the HLA-DR and HLA-DQ alleles have been shown to be prevalent in patients. This has prompted further epidemiological studies as well as unbiased Omics approaches on the transcriptome, microbiome, and proteome level to elucidate common and individual genetic risk factors as well as the molecular pathways that lead to the pathogenesis of AIBDs.

Keywords: HLA class II genes; autoantigens; autoimmune bullous diseases; genetics; systems medicine; transcriptomics.

Figure 1

Structural composition of human epidermis and basement membrane zone (BMZ). (A) Shows the composition of the human skin, including melanocytes [1] (3) and immunocompetent Langerhans cells [2] (4). The approximate distribution of pemphigus antigens within the layers of the epidermis is depicted on the right-hand side. While desmogleins 1 and 4 and desmocollin 1 are expressed in the upper layers of the epidermis; desmogleins 2 and 3 as well as desmocollin 2 and 3 are expressed in the lower layers of the epidermis. (B) Depicts the BMZ with its cellular adhesion proteins, connecting epidermis and dermis, which are the main autoantigens in pemphigoid diseases.