Immunoglobulins consist of two antigen-binding F(ab’)2 variable regions and one constant (Fc) region. Several proteins have the ability to bind to the Fc region, e.g. Fc-receptors, complement C1q, protein A and rheumatoid factor (RF). It is well known that some Fc-binding proteins, including complement C1q and rheumatoid factor, are physiologically present in the body. Regarding blistering mechanisms in pemphigoid diseases, autoantibodies play a critical role in the activation of inflammatory cells via Fc-receptors. However, little is known about the impact of Fc-binding proteins, other than Fc-receptors, on the pathogenicity of antibody-induced autoimmune diseases. BP180 is a hemidesmosomal component and is targeted by autoantibodies in pemphigoid diseases, including bullous pemphigoid (BP) and mucous membrane pemphigoid (MMP). BP-IgG targeting the non-collagenous NC16A (NC16A) domain of BP180 is thought to be a pathogenic antibody that induces skin fragility in mice and the depletion of BP180 in keratinocytes. In this study, stimulation with mAbs against NC16A in combination with Fc-binding proteins, such as protein G and the anti-IgG Fc antibody, was found to enhance BP180 depletion. Although mAbs against the C-terminus of BP180 show pathogenicity neither in vivo nor in vitro, the treatment of mAbs targeting the C-terminus with Fc-binding proteins, such as protein G and the anti-IgG Fc antibody, was found to clearly induce skin fragility in mice and BP180 depletion in keratinocytes. The BP180 depletion was observed under stimulation with mAbs against BP180 and sera containing rheumatoid factor. Our results suggest that Fc-binding proteins may enhance the pathogenicity of autoantibodies in pemphigoid diseases.

The impact of Fc-binding proteins on IgG targeting BP180