T cell control in autoimmune bullous skin disorders
Michael Hertl, … , Rüdiger Eming, Christian Veldman
Michael Hertl, … , Rüdiger Eming, Christian Veldman
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1159-1166. https://doi.org/10.1172/JCI28547.
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Review Series

T cell control in autoimmune bullous skin disorders

Abstract

Autoimmune bullous disorders are a group of severe skin diseases characterized clinically by blisters and erosions of skin and/or mucous membranes. A hallmark of these disorders is the presence of IgG and occasionally IgA autoantibodies that target distinct adhesion structures of the epidermis, dermoepidermal basement membrane, and anchoring fibrils of the dermis. This Review focuses on the potential role of autoreactive T cells in the pathogenesis of these disorders. Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are the best-characterized bullous disorders with regard to pathogenesis and T cell involvement. Activation of autoreactive T cells in PV and BP is restricted by distinct HLA class II alleles that are prevalent in individuals with these disorders. Autoreactive T cells are not only present in patients but can also be detected in healthy individuals. Recently, a subset of autoreactive T cells with remarkable regulatory function was identified in healthy individuals and to a much lesser extent in patients with PV, suggesting that the occurrence of autoimmune bullous disorders may be linked to a dysfunction of Tregs.

Authors

Michael Hertl, Rüdiger Eming, Christian Veldman

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Figure 5

Putative T cell network in PV and health.

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Putative T cell network in PV and health. Dsg3- and Dsg1-reactive Th1 an...
Dsg3- and Dsg1-reactive Th1 and Th2 cells are present in patients with PV and healthy carriers of PV-associated HLA class II alleles, which recognize identical epitopes of the Dsg3 ectodomain presented by APCs such as dendritic cells and B cells. There is a predominance of Dsg3-reactive Th2 cells in PV and of autoreactive Th1 cells in healthy individuals. In addition, Tr1s specific for Dsg3 are present at higher frequencies in healthy individuals than in PV patients. These Tr1s express the phenotypic markers glucocorticoid-induced TNF receptor (GITR), membrane-bound TGF-β (mTGF-β), and cytotoxic T cell antigen–4 (CTLA-4) and inhibit the activation of Dsg3-specific autoreactive Th1 and Th2 cells via the secretion of IL-10 and TGF-β and the uptake of exogenous IL-2 produced by the Th cells. Inactivation of the regulatory transcription factor Foxp3 by antisense deoxynucleotides converts Tr1s into a Th2-like population with regard to cytokine profile, loss of inhibitory function on Th cells, and the ability to develop a proliferative response to Dsg3. Thus an imbalance of the putative relationship between autoreactive Th and Tr1 cells may be critical in the pathogenesis of PV. Hence Dsg-specific Tr1s may be critical for the maintenance of tolerance against Dsg3 and Dsg1 in health and the restoration of tolerance against these autoantigens in remittent PV.