The Diagnosis and Blistering Mechanisms of Mucous Membrane Pemphigoid

Abstract

Mucous membrane pemphigoid (MMP) is a mucous membrane-dominated autoimmune subepithelial blistering disease that is caused by autoantibodies against various autoantigens in basement membrane zone (BMZ) proteins, including collagen XVII (COL17). Clinicians face diagnostic problems in detecting circulating antibodies and targeted antigens in MMP. The diagnostic difficulties are mainly attributed to the low titers of MMP autoantibodies in sera and to heterogeneous autoantigens. Additionally, no unanimous diagnostic criteria have been drawn for MMP, which can result in delayed diagnoses or misdiagnoses. This review aims to integrate and present currently available data to clarify diagnostic strategies and to present diagnostic criteria for MMP. The ultimate blistering mechanism in MMP has not been elucidated, and such mechanism is especially obscure in COL17-type MMP. In bullous pemphigoid (BP), which is the most common autoimmune subepidermal blistering disease, some patients show oral lesion as well as predominant skin lesions. However, there is no fundamental explanation for the onset of oral lesions in BP. This article summarizes innovative research perspectives on the pathogenesis of oral lesions in pemphigoid. Finally, we propose a potential pathogenesis for COL17-type MMP.

Keywords: C-terminas; collagen IV; direct immunofluorescence; mucous membrane pemphigoid; steric hindrance; type XVII collagen.

Figure 1

Diagnostic strategy for MMP. The diagnosis of MMP is confirmed by clinical features and positive DIF results. In DIF-negative or DIF-unavailable cases, at least one serological or histological finding is needed. DIF, direct immunofluorescence; IIF, indirect immunofluorescence; ELISA, enzyme-linked immunosorbent assay; H&E, hematoxylin and eosin staining.

Figure 2

Potential blistering mechanisms in oral mucosa. (A) The oral mucosal blistering in BP. COL17 molecules are located in both the hemidesmosomal and the non-hemidesmosomal plasma membranes. In the skin, autoantibodies targeting COL17-NC16A lead to the internalization of non-hemidesmosomal COL17 and result in COL17 depletion. The internalization and depletion of COL17 disturb the supply of hemidesmosomal COL17 and impair hemidesmosome formation. Eventually, intra-lamina lucida separation is caused by mechanical stress, complement activation, and/or inflammatory cell infiltration. This is mainly observed in the skin; therefore, the blisters predominantly occur in the skin (left panel). In the oral mucosa, autoantibodies targeting the C-terminus of COL17 enhance COL17 depletion induced by autoantibodies targeting COL17-NC16A. The blister formation in oral mucosa may be a result of the enhancement of COL17 depletion induced by autoantibodies targeting the C-terminus of COL17 in BP patients (right panel). (B) The predominant oral mucosal blistering in MMP. The direct binding of COL17 to COL4 is disrupted by IgG against the C-terminus in the oral mucosa. Autoantibodies in MMP targeting the C-terminus of COL17 inhibit the protein–protein interaction in the oral mucosa and reduce hemidesmosomal adhesion without the internalization of COL17.