Autoimmunity and immunological tolerance in autoimmune bullous diseases

Abstract

Autoimmune diseases are devastating conditions in which the immune system is directed against the host, leading to life-threatening destruction of organs. Although autoantigens are ill-defined in most autoimmune diseases, this is not the case in the skin. Autoimmune bullous diseases have been extensively studied with detailed characterization of autoantigens, the epitopes that are targeted, and the mechanisms of action that mediate autoimmune tissue destruction. Pemphigus is an autoimmune bullous disease caused by circulating IgG that targets two desmosomal proteins, desmoglein 1 and 3, which are crucial for cell–cell adhesion of keratinocytes. Binding of auto-antibodies to desmogleins impairs keratinocyte adhesion, leading to severe blistering disease. Mouse models that recapitulate the human disease have been instrumental in elucidating the detailed pathophysiology. Taking advantage of the fact that desmogleins are specifically targeted in pemphigus, studying humoral and cellular autoimmunity against these autoantigens provides us with an opportunity to understand not only the effector mechanisms of B and T cells in mediating pathology but also how autoreactive lymphocytes are regulated during development in the thymus and post-development in the periphery. This review introduces pemphigus and its subtypes as prototypic autoimmune diseases from which recent basic and translational developments should provide insight into how autoimmunity develops.

Mechanisms of skin autoimmunity: Cellular and soluble immune components of the skin

“…Here, celiac disease caused by immune reactivity against tissue transglutaminase 2 induces cross-reactive autoantibody formation against epidermal transglutaminase 3. 36 In pemphigus, Dsg-specific autoantibodies have been shown to cross-react with pathogen-directed antibodies 13,110,111 or in a recent report with walnut antigens. 112 Also, T-cell-driven ncISDs have been associated with molecular mimicry.…”

“…In contrast to most T-cell autoantigens, a disease-causative role is clearly proven for some antibodies, in particular in blistering autoimmune diseases such as pemphigus. 13 Here, autoreactive T cells, predominantly T H 2 cells, form IgG 1 and IgG 4 autoantibodies against Dsgs. 14,15 Dsg antibody levels correlate with disease activity and directly lead to loss of keratinocyte cohesion.…”

Pemphigus Vulgaris and Bullous Pemphigoid: Update on Diagnosis and Treatment

“…Dsg3-specific autoreactive T cells are deleted in periphery, and regulatory T cells (Tregs) play an important role in such peripheral tolerance [17]. Environmental factors, in particular pathogens, have been hypothesized as causes of reverting immunological tolerance with resulting autoantibody production [18]. A possible link with rotavirus infection has been suggested because of cross-reactive VH1-46 antibodies, which are able both to disrupt keratinocyte adhesion and inhibit rotavirus replication [19].…”

“…Autoreactive CD4+ T lymphocytes have been implicated in the regulation of the production of pathogenic anti-Dsg3 autoantibodies by B cells [21]. There is a strong association between PV and distinct major histocompatibility complex class II haplotypes, which are considered essential for the presentation of specific Dsg3 peptides to autoreactive CD4+ helper T cells [18,22].…”

A Novel Regulatory Pathway of Desmoglein-3 in Keratinocyte Stress Response

“…Desmosomes occur in abundance in tissues, such as the skin and mucous membrane that are subjected to extensive mechanical stress. In addition to its role in cell-cell adhesion, Dsg3 also functions as a surface regulator for various intracellular signaling pathways in epithelial cells [1][2][3][4][5][6][7]. Many of these findings are achieved from the studies of the pathogenesis of Pemphigus Vulgaris (PV), an autoimmune bullous disease in which Dsg3 serves as a major autoantigen and is targeted by circulating autoantibodies that cause disruption of desmosomes, resulting in blistering affecting both the skin and mucous membrane [2, 3,6].…”