Th1, Th2 and Th3 cytokines in the pathogenesis of bullous pemphigoid

Bullous pemphigoid (BP) is an autoimmune bullous skin disease mediated by autoantibodies against hemidesmosomal proteins. In addition to humoral immunity, the contribute of infiltrating T-helper (Th) autoreactive lymphocytes and their related cytokines to the pathomechanism of blistering is now growing in interest. To investigate T-cell activation markers and the presence of inflammatory and fibrogenic cytokines (i.e. IL2, IL-4, IL-5, IFN-gamma, TGF-beta) in BP lesional skin, we performed an immunohistochemical study and an in situ hybridization procedure on five BP patients, comparing them with two psoriatic patients and four healthy subjects. Our aim was to expand suitable information about tissutal expression of cytokines, secondly to further investigate the role of TGF-beta (a Th3-like or T-regulatory (T-reg) cytokine) in a non-scarring disorder like BP, in order to highlight its pleiotropic activity. The immunohistochemical analysis revealed a moderate to strong staining for IL-4 and IL-5 with a prevalent perivascular localization in the upper dermis. The staining for IFN-gamma showed a moderate/focal expression on the dermal perivascular infiltrate. IL-2 protein was observed in four cases. While no positive staining for IL-4 mRNA was detected in all BP subjects with in situ hybridization, IL-5 mRNA was documented in four BP specimens. A focal nuclear staining for IFN-gamma was observed in the epidermal layers and on the cellular infiltrate of lesional skin. In all BP cases, a moderate/diffuse positivity for TGF-beta(1) mRNA was documented in both cytoplasm and nucleus of the infiltrating perivascular cells of lesional and perilesional skin. Our results suggest a balance between Th1, Th2 and Th3 activity, with quantitatively different impact of the various cytokines on the pathomechanism of blistering, depending on the reciprocal network. The supposed participation of each cytokine analyzed in the pathogenesis of BP is discussed. The newest data obtained consist of TGF-beta detection in a non-scarring disease like PB, that had never been documented before, and in the confirmation of a mixed cytokine pattern in the fully developed phase of the disease.