Abstract
Bullous pemphigoid (BP) is the most common autoimmune blistering disease caused by autoantibodies to hemidesmosomal proteins; type XVII collagen (COL17 or BP180) and BP230. Regulatory T cells (Tregs) are crucial for peripheral immune tolerance and maintaining cutaneous immune homeostasis. However, it remains largely unknown whether failure of peripheral immune tolerance has an influence on the production of autoantibodies to the epidermal components. To address this, we investigated scurfy mice, which lack functional Tregs due to the mutation in Foxp3, a master transcriptional factor of Tregs. Utilizing direct and indirect immunofluorescence (IF) studies, we found that scurfy mice developed autoantibodies to the dermal-epidermal junction of the skin. The production of IgG autoantibodies, which had been class-switched from IgM, started within 12 days after birth. The autoantibodies reacted to the epidermal side of artificial blisters induced by 1M NaCl by indirect IF. From these findings, we focused on BP antigens. Immunoblotting using recombinant proteins of murine BP230 and COL17 demonstrated the presence of autoantibodies to those proteins in most scurfy sera. However, autoantibodies in scurfy sera have no reactivity to NC14A domain of murine COL17, corresponding to NC16A domain of human COL17, a domain responsible for subepidermal blister formation. This result may explain the fact that blister formation is not observed in scurfy mice. Furthermore, by using a CD4+ T cell-transferred model we revealed that CD4+ T cells mediate the production of those autoantibodies in scurfy mice. These results suggested that Tregs contribute to maintain immune tolerance to COL17 and BP230 at a steady state in mice.
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