Collagen XVII Processing and Blistering Skin Diseases

Abstract

SIGNIFICANCECollagen XVII (COL17, also known as BP180) is an im portant molecule, which maintains stable adhesion between the dermis and epidermis. Genetic and acquired dysfunc tions of COL17 lead to blistering skin diseases. However, the expression of COL17 is tightly regulated, depending on various settings, including woundhealing, proliferation and differentiation. Dysregulation of COL17 processing may be associated with the development of blistering skin di seases; thus, it is important to understand the mechanism by which COL17 is processed and the diseases associated with such processing.Collagen XVII (COL17) is a hemidesmosomal trans membrane protein in the skin, which, in several auto immune blistering skin diseases, may be targeted by autoantibodies. In addition, lossoffunction muta tions in the COL17A1 gene induce a subtype of junctio nal epidermolysis bullosa. The extracellular domain of COL17 can be physiologically cleaved from the cell surface by ADAM family proteins in a process known as ectodomain shedding. COL17 ectodomain shedding is thought to be associated with the migration and proli feration of keratinocytes. Furthermore, the Cterminal cleavage of COL17 may be associated with basement membrane formation. COL17 can be targeted by va rious proteases, including MMP9, neutrophil elastase, plasmin and granzyme B, which may be associated with blister formation in pemphigoid diseases. Inte restingly, cleavage of COL17 may induce neoepitopes on the proteolysed fragments, and such induction is associated with dynamic structural changes. This re view summarizes the current understanding of clea vage of COL17, and how such cleavage relates to blis tering skin diseases.

Autoantibodies Against the Immunodominant Bullous Pemphigoid Epitopes Are Rare in Patients With Dermatitis Herpetiformis and Coeliac Disease

“…It is not fully understood why in LABD the 120 and 97 kDa fragments of BP180 are targeted by IgA rather than IgG autoantibodies (11,12). Also, BP patients have IgA autoantibodies that recognize the aminoterminal epitopes of the BP180 ectodomain particularly strongly (39).…”

“…Previous reports that LABD IgA autoantibodies target the shed ectodomain and 97 kDa fragment of BP180 particularly strongly (11,19,20) prompted us to investigate whether plasmin digestion of BP180 would produce neoepitopes that would be recognized by IgA autoantibodies in samples from DH (n = 20), CD (n = 20), and BP (n = 20) patients and healthy controls (n = 22). After partial plasmin digestion, the remaining undigested full-length BP180 was recognized by 5% of DH samples, 10% of both CD and BP samples and 13.6% of control samples ( Figure 2B, Table 1).…”

“…The major autoantigen in BP is BP180, which is one of the structural proteins required to adhere basal keratinocytes to the cutaneous basement membrane (11). The subepidermal blistering characteristic of BP is caused by IgG class autoantibodies binding to BP180, thereby interfering with hemidesmosome function.…”

“…The immunodominant epitope of BP180 is the NC16A domain and BP180-NC16A IgG autoantibodies are commonly measured using ELISA tests. IgA autoantibodies against 120 and 97 kDa ectodomain fragments of BP180 cause linear IgA bullous dermatosis (LABD), another disease of the pemphigoid group (11,12).…”

Dual roles of granzyme B

“…Cleavage of basement membrane components can directly damage the integrity and function of the dermal-epidermal junction, promoting epidermal shedding and blistering, thus causing the development of autoimmune blistering diseases. 92,93 Furthermore, Matsubara et al have revealed that exogenous GZMB induces the cleavage of retinal pigment epithelial-derived tight junctional and ECM proteins, and exacerbates ECM remodelling in Bruch's membrane and degradation of the blood-retina barrier, which is considered an early signal event for the development of age-related macular degeneration (a multifactorial, chronic inflammatory eye disease). 16 Turner et al have confirmed that GZMB contributes to barrier dysfunction in oxazoloneinduced skin inflammation through E-cadherin and filaggrin cleavage.…”