T lymphocytes expressing the CLA antigen constitute a subset of effector memory lymphocytes that are functionally involved in T-cell-mediated cutaneous diseases. Skin-seeking lymphocytes recirculate between inflamed skin and blood during cutaneous inflammation. Many studies in different T-cellmediated inflammatory cutaneous diseases have clearly related their pathologic mechanisms to CLA+ T cells. Based on common features of these cells in different cutaneous disorders mediated by T cells, we propose that circulating CLA+T cells could constitute very useful peripheral cellular biomarkers for T-cell-mediated skin diseases.

Streptococcal throat infection is associated with a specific variant of psoriasis and with HLA-Cw6 expression. In this study, activation of circulating psoriatic cutaneous lymphocyte-associated antigen (CLA)(+) memory T cells cultured together with epidermal cells occurred only when streptococcal throat extracts were added. This triggered the production of Th1, Th17, and Th22 cytokines, as well as epidermal cell mediators (CXCL8, CXCL9, CXCL10, and CXCL11). Streptococcal extracts (SEs) did not induce any activation with either CLA(-) cells or memory T cells cultured together with epidermal cells from healthy subjects. Intradermal injection of activated culture supernatants into mouse skin induced epidermal hyperplasia. SEs also induced activation when we used epidermal cells from nonlesional skin of psoriatic patients with CLA(+) memory T cells. Significant correlations were found between SE induced upregulation of mRNA expression for ifn-γ, il-17, il-22, ip-10, and serum level of antistreptolysin O in psoriatic patients. This study demonstrates the direct involvement of streptococcal infection in pathological mechanisms of psoriasis, such as IL-17 production and epidermal cell activation.

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 celltransferred 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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