What's new in the pathogeneses and triggering factors of bullous pemphigoid

Abstract

Bullous pemphigoid (BP) is a subepidermal blistering disease induced by autoantibodies to type XVII collagen (COL17, also called BP180) and BP230. Previous studies using patients' samples and animal disease models elucidated the complement-dependent and complement-independent pathways of blister formation, the pathogenic roles of immune cells (T and B cells, macrophages, mast cells, neutrophils, eosinophils), and the pathogenicity of IgE autoantibodies in BP. This review introduces the recent progress on the mechanism behind the epitope-spreading phenomenon in BP, which is considered to be important to understand the chronic and intractable disease course of BP, and the pathogenicity of anti-BP230 autoantibodies, mainly focusing on studies that used active disease models. To clarify the pathogenesis of BP, the mechanism behind the breakdown of immune tolerance to BP antigens should be investigated. Recent studies using various experimental models have revealed important roles for regulatory T cells in the maintenance of self-tolerance to COL17 and BP230 as well as in the suppression of inflammation triggered by the binding of antibodies to COL17. Notably, physical stresses such as trauma, thermal burns, bone fractures, irradiation and ultraviolet exposure, some pathologic conditions such as neurological diseases and hematological malignancies, and the use of dipeptidyl peptidase-IV inhibitors and immune checkpoint inhibitors have been reported as triggering factors for BP. These factors and certain underlying conditions such as genetic background, regulatory T-cell dysfunction or aging might synergistically affect some individuals and eventually induce BP. Further studies on the breakdown of self-tolerance and on the identification of key molecules that are relevant to blister formation and inflammation may expand our understanding of BP's etiology and may lead to the development of novel therapeutic approaches.

Keywords: BP180; BP230; epitope spreading; immune checkpoint inhibitor; regulatory T cell.

FIGURE 1

Epitope‐spreading in the skin‐grafted mouse model and in the active bullous pemphigoid (BP) mouse model. A schematic of COL17, BP230, and antibodies. In the skin‐grafted mouse model at day 35, the antibodies mainly react to the NC16A domain and weakly react to the extracellular domain epitopes of COL17. After the adoptive transfer of immunized spleen cells, there is intramolecular epitope‐spreading to extracellular domain epitopes and to the outer portion of the intracellular domain of COL17, and there is intermolecular epitope‐spreading to BP230. This is followed by intramolecular epitope‐spreading to the inner portion of the intracellular domain of COL17.

FIGURE 2

Characteristics of the anti‐BP230 antibody. A schematic of COL17, BP230, and the anti‐BP230 antibody. BP, bullous pemphigoid.

FIGURE 3

Treg cell dysfunction (Foxp3 mutation) induces autoantibodies to COL17 and BP230. This dysfunction triggers the activation of autoreactive CD4⁺ Th2 and follicular helper T (Tfh) cells mediated by STAT6, which helps B cells to differentiate into autoantibody‐secreting plasma cells. Some of these plasma cells can produce IgM and IgG autoantibodies to COL17 and BP230.

FIGURE 4

Our hypothesis on the pathogenesis of bullous pemphigoid (BP). We hypothesize that the patient's background, such as genetic background, Treg cell dysfunction and aging, as well as triggers such as trauma, irradiation, infection, neurological diseases, hematological malignancies, DPP‐4 inhibitors, immune checkpoint inhibitors, and the like, cooperatively or synergistically induce the breakdown of immune tolerance to COL17, resulting in the production of autoantibodies and the development of BP.