Pemphigus vulgaris 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, and using our knowledge to develop better targeted therapies for pemphigus and other autoimmune diseases.
Mechanisms of autoimmunity in pemphigus
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 pemphigus vulgaris patients to understand how they developed desmoglein autoreactivity. We identified shared VH1-46 gene usage in anti-desmoglein 3 B cells from different pemphigus patients and defined acidic amino acid residues that are necessary and sufficient to confer desmoglein 3 autoreactivity. We also identified common as well as divergent features of the B cell response to the self-antigen desmoglein 3 and the rotavirus VP6 antigen, which suggests shared VH gene usage in the immune response to foreign and self antigens as a potential basis for triggering pathologic autoimmune reactions, but that divergent evolution limits the onset of autoimmunity after infection. Further studies have uncovered the developmental pathways and lineage relationships of IgG and IgA B cells in pemphigus, indicating that the IgG4 B cells that are predominant in active disease are clonally distinct from the shared lineages found within the IgG1-IgA1-IgA2 axis. Ongoing projects aim to better understand the features of the autoimmune response in pemphigus, including characterization of the B cell subsets that contribute to autoimmunity in pemphigus.
Regulation of desmosomal cell adhesion in primary human keratinocytes
Using the pathologic anti-desmoglein monoclonal antibodies we have isolated from pemphigus patients, our laboratory has also elucidated the cell regulatory pathways in primary human keratinocytes that promote desmosome adhesion. We have shown that the p38 MAPK/MK2 axis governs keratinocyte desmosomal adhesion and that inhibition of this pathway can ameliorate pemphigus skin blistering. We identified STAT3 as a key regulator of desmoglein 3 transcription in keratinocytes, which contributes to the rapid therapeutic effect of corticosteroids in pemphigus and may explain the loss of desmoglein 3 expression in advanced head and neck squamous cell cancers. In addition to providing insight into desmosome biology, these studies have identified adjunctive treatment strategies to block end-organ damage caused by pemphigus autoantibodies.
Antigen-specific autoimmune disease therapies
Ultimately, a better understanding of the shared structural elements of pemphigus B cell repertoires can lead to better targeted therapies for disease. Current methods for treating autoimmunity require general immune suppression to reduce antibody production, but this approach impairs protective immune responses, which can lead to potentially fatal infections and secondary cancers. We described a novel method for re-engineering chimeric antigen receptor T cells, which have led to lasting remissions of B cell-mediated cancers, for targeted immunotherapy of B cell-mediated autoimmune diseases such as pemphigus vulgaris. By using the pemphigus autoantigen desmoglein 3 as the extracellular domain of a chimeric autoantibody receptor (CAAR), we can direct a patient’s T cells to specifically seek out and kill the pemphigus-specific B cells, while sparing the good immune cells that protect from infection. We published initial proof-of-concept for the CAAR approach as well as the definitive preclinical studies that enabled an Investigational New Drug application for DSG3-CAART. We are now progressing CAAR technology to first-in-human and canine clinical trials and extending the CAAR concept to other B cell-mediated diseases.