Resolution in bullous pemphigoid

Abstract

Pemphigoid diseases are a group of autoimmune blistering skin diseases defined by an immune response against certain components of the dermal-epidermal adhesion complex. They are prototypical, autoantibody-driven, organ-specific diseases with the emergence of inflammatory skin lesions dependent on the recruitment of immune cells, particularly granulocytes, into the skin. During an acute flare of disease, inflammatory skin lesions typically progressing from erythema through urticarial plaques to subepidermal blisters erosions erupt and, finally, completely resolve, thus illustrating that resolution of inflammation is continuously executed in pemphigoid disease patients and can be directly monitored on the skin. Despite these superb conditions for examining resolution in pemphigoid diseases as paradigm diseases for antibody-induced tissue inflammation, the mechanisms of resolution in pemphigoid are underinvestigated and still largely elusive. In the last decade, mouse models for pemphigoid diseases were developed, which have been instrumental to identify several key pathways for the initiation of inflammation in these diseases. More recently, also protective pathways, specifically IL-10 and C5aR2 signalling on the molecular level and T_regs on the cellular level, counteracting skin inflammation have been highlighted and may contribute to the continuous execution of resolution in pemphigoid diseases. The upstream orchestrators of this process are currently under investigation. Pemphigoid disease patients, particularly bullous pemphigoid patients, who are predominantly above 75 years of age, often succumb to the side effects of the immunosuppressive therapeutics nowadays still required to suppress the disease. Pemphigoid disease patients may therefore represent a group of patients benefiting most substantially from the introduction of non-immunosuppressive, proresolving therapeutics into the treatment regimens for their disease.

Keywords: Autoimmunity; Blistering; Bullous pemphigoid; Complement; IL-17; Pathophysiology; Resolution.

Fig. 1

Typical co-existence of inflammatory skin lesions in different stages of development, including an emerging skin lesions in the shape of an urticarial plaque (blue arrow), a skin blister (red arrow), an erosion (yellow arrow), a resolving/healing erosion (grey arrow), and a resolved/healed skin lesions (black arrow) on the medial aspect of the upper arm of a BP patient during an acute flare

Fig. 2

Sequence of events leading to dermal-epidermal separation and potentially proresolving pathways in bullous pemphigoid (BP). Binding of autoantibodies (red) against type XVII collagen (Col17, yellow) initiates Fc-independent events, e.g. the release of IL-8 from basal keratinocytes (1). Complement is activated at the dermal-epidermal junction (DEJ) and C5a released (2). Mast cells degranulate after binding of C5A or anti-Col17 IgE (3) and inflammatory cells attracted by C5a appear in the upper dermis (4, 5). Their secretion of additional inflammatory mediators such as IL-17A, LTB4, and to a lesser extent, of IL-1β further increases and maintains the inflammatory reaction. Subsequently, neutrophils and eosinophils line along the DEJ (6) and release reactive oxygen species and specific proteases that ultimately induce dermal-epidermal separation (7). In animal models of BP and BP-like epidermolysis bullosa acquisita, the anti-inflammatory effect of regulatory T cells (T_reg), C5aR2, and IL-6 (via IL-1 receptor antagonist, IL-1RA, and tissue inhibitor of metalloproteinase-1, Timp-1) was shown and point to potentially proresolving mechanisms in BP. Modified from [4] and [3]