To begin to develop new treatment strategies for any disease, it is important to better understand the underlying biology that causes the disease and that is associated with disease physiology. Targeting pathways with drugs is the ultimate goal and it is all the better if the drugs used are specific to these pathways as this will limit potential side-effects associated with their use. This would seem to exclude the use of steroids such as those that are a standard of treatment currently. In their current work, the groups of Dr. Grando and Dr. Ping Wang (Journal of Biological Chemistry, http://www.jbc.org/cgi/doi/10.1074/jbc.M113.472100) examine the effects of antibodies (IgGs) known to be present in PV patients and find that they deleteriously affect specific functions of the mitochondria of skin cells (keratinocytes). The mitochondria are the compartments within cells where all of the energy, in the form of ATP, is generated.
Protecting mitochondria, the authors believe, should help to alleviate the cell death that is associated with PV.
IgGs produced in PV cause keratinocytes to die due to their being “split” apart or detached from each other within the epithelial layers of the skin (fact check). However, the mechanisms by which IgGs cause this splitting and in fact, whether there are more than one type of IgG generated in PV has not been determined. Previous work from Dr. Grando’s group has contributed to a theory where various antibodies that bind to keratinocytes, including the well-described anti-desmoglein antibodies, work together to cause the cellular effects that lead to PV.
As well, previous work has implicated the mitochondria in PV. Indeed, the mitochondria that have been tested from lesions of PV patients are defective in many of their key functions. These include maintaining a balance of antioxidants and limiting the production of reactive oxygen species (ROS) that lead to untold cellular damage.
The current paper solidifies the model that multiple targets of keratinocytes (both on the surface – the desmogleins, and inside – the mitochondria) are at play in PV. As well, it suggests that multiple antibody types are involved in the end result – cell death. The antibodies that the authors focused on are called mitochondrial antibodies (MtAbs) because of their ability to enter keratinocytes and bind to mitochondrial proteins. MtAbs make up what may be the most important class of IgGs in PV patients. Removing MtAbs from the serum of PV patients makes the serum incapable of causing keratinocyte detachment. Serum is what remains of the blood after you remove all of the cells – including proteins, antibodies and small molecules from metabolism. The authors have now found that the IgGs from the serum of PV patients can cause the mitochondrial dysfunction seen in previous work.
These IgG mixtures, which contain the MtAbs, cause numerous changes in the vital functions of mitochondria. For instance, they saw an increase in the production of ROS from keratinocytes, a decline in ATP production, and changes in the mitochondrial membrane potential, a hallmark of the tidy cell death pathway called apoptosis. This is the first time scientists have shown such dramatic changes in mitochondrial functions with patient IgGs. Even more striking is that compounds that protect mitochondria could help the keratinocytes resist the adverse effects of the IgGs. These compounds, minocycline, nicotinamide (a well-known over-the-counter antioxidant supplement), and cyclosporine A have previously been used, often in combination, with beneficial effects on PV patients, but an understanding of why they are effective hasn’t been clear until now.
Since these three mitochondria-protecting drugs are already in use in some PV patients, the authors argue that optimizing their use, by determining at what levels they need to be dosed in individual patients, for starters, should make them an ideal non-steroid treatment for PV.