Pemphigus vulgaris (PV) is a potentially fatal disorder in which autoantibodies against desmosomal cell adhesion molecules known as desmogleins cause blistering of the skin and mucous membranes. Our laboratory is interested in better understanding pathogenic mechanisms in this model organ-specific autoimmune disease, from both the immunologic and cell biologic perspectives.
A fundamental question in organ-specific autoimmune disease is why the immune system breaks tolerance against only a limited number of self-antigens. We have cloned B cell repertoires from PV patients to understand how they developed desmoglein autoreactivity. We have identified shared VH1-46 gene usage in anti-desmoglein 3 B cells from different PV patients and defined acidic amino acid residues that are necessary and sufficient to confer desmoglein 3 autoreactivity. These VH1-46 B cells are autoreactive to the disease antigen in the absence of somatic mutation or require very few mutations to develop autoreactivity, which may favor their selection early in the immune response. Common VH gene usage is significant, because it may indicate common mechanisms for developing autoimmunity in PV. Ultimately, shared structural elements of the PV B cell repertoire (e.g., VH or CH gene usage) may lead to safer targeted therapies for pemphigus. Ongoing projects aim to identify potential foreign antigenic triggers of the desmoglein autoimmune response in pemphigus, to identify the B cell subsets that produce the pathogenic autoantibodies, and to develop effective targeted therapies.
Our laboratory is also investigating the cell regulatory pathways that promote desmosomal adhesion. We have shown that the p38 MAPK/MK2 axis is a critical regulator of desmosomal adhesion in keratinocytes and that inhibition of this pathway can ameliorate pemphigus skin blistering. Ongoing projects are studying the regulation of desmosomal adhesion and desmosomal protein expression in keratinocytes to better understand how anti-desmoglein antibodies cause the loss of cell adhesion and how we might interfere with these pathways to improve disease.
This line breeds poorly. See ref: JGJ van de Winkel, Blood, 93, 1999: pp 4387-4394.
M. Gaestel, Nature Cell Biol, 1, 1999: 94-97.