Professor, Department of Dermatology, Graduate School of Medicine, Keio University
Masayuki Amagai, MD, PhD
Clarification of the molecular and cellular mechanisms of central and peripheral tolerance to pemphigus antigens
Pemphigus is a severe autoimmune bullous dermatosis caused by IgG autoantibodies against desmogleins. In a murine pemphigus model established by us, we were able to clarify the B and T cell aspects of the disease subsequent to the loss of immunological tolerance. In this project, we attempt to clarify how immunological tolerance to desmogleins is established under normal conditions, and also the processes leading to its disruption. Special focus will be placed on events in the thymus as well as on the dendritic cells in the skin.
Development of treatment for scarring alopecia using bioengineered human hair follicles
The goal of the present project is to bioengineer human hair follicles with maintenance of their full function and structure, for potential use in the treatment of permanent hair loss. We shall attempt to regenerate human hair follicles using a cell mixture of hair follicle bulge stem cells and dermal papilla cells with optimized hair-inductive capacity. The hair reorganization potency of the cell mixture will be assessed by hair reconstitution assays in vivo or using a 3-D culture system.
Clarification of the pathophysiological mechanisms underlying pemphigus
We have contributed to a better understanding of pemphigus by cDNA isolation of pemphigus antigens, production of recombinant desmolgeins, development of ELISA as a diagnostic tool for pemphigus, and development of an active disease mouse model. We have established that skin DCs consist of at least three identifiable subsets. In particular, Langerhans cells and langerin+ dermal DCs were shown to be unrelated and displayed differential regulation of humoral immune responses against a genetically immunized antigen (Nagao et al, PNAS, 2009)
Characterization of human hair follicles
We identified the cell surface marker of stem cell-enriched human bulge cells and, using this marker, successfully isolated and cultured living human bulge cells (Ohyama et al., J Clin Invest, 2006). We also established the culture conditions for sustained expression of genes related to trichogenic activity in human dermal papilla cells (patent filed). In-vivo assays and 3D cultures for hair follicle reconstitution have been developed. These cultivated cell components and assays will facilitate experiments for the regeneration of hair follicles.
Fig.1 Generation of the pemphigusphenotype from a single anti-desmoglein 3-specific T-cell clone
Fig.2 Regeneration of human hair follicle with cultured human dermal papilla cells inmice
- Takahashi H, Kuwana M and Amagai M: A single helper T-cell clone is sufficient to commit polyclonal naive B-cells to produce pathogenic IgG in experimental pemphigus vulgaris. J Immunol 182: 1740 1745, 2009.
- Stanley JR, Amagai M: Pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome. N Engl J Med 355, 1800-1810, 2006.
- Nagasaka T, Nishifuji K, Ota T, Whittock NV, and Amagai M. Defining the pathogenic involvement of desmoglein 4 in pemphigus and staphylococcal scalded skin syndrome. J Clin Invest 114:1484-1492, 2004.
- Amagai M, Tsunoda K, Suzuki H, Nishifuji K, Koyasu S, and Nishikawa T. Use of autoantigen knockout mice in developing an active autoimmune disease model for pemphigus. J Clin Invest 105:625-631, 2000.
- Amagai M, Matsuyoshi N, Wang ZH, Andl C, and Stanley JR. Toxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1. Nature Medicine 6:1275-1277, 2000.
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