Pemphigus studies teach laboratory, life lessons

Key Points

Philadelphia - Dermatologists dedicated to research require thick skin, humility, patience, creativity and effective mentors, an expert says.

Before starting in research, says John R. Stanley, M.D., "Get good armor, because there are many things that will happen to you that may hurt a little - like getting papers and grants rejected." He also emphasizes that "It is critical for your career to have a good mentor - probably many mentors" to help navigate difficulties and disappointments. Dr. Stanley is Milton B. Hartzell Professor and chairman, department of dermatology, University of Pennsylvania School of Medicine, Philadelphia.

Additionally, Dr. Stanley says researchers must recognize that "we all stand on the shoulders of others." For instance, the first clinical description of pemphigus appeared before 1800, Dr. Stanley notes, but it took more than a century for the next major advance - establishing a histologic definition.

More specifically, Dr. Stanley says that in PV, lesions occur where keratinocytes come apart, just above the basal layer.

"In PF, cells come apart in the granular layer. So these are similar diseases in that they include acantholysis, but they're different in the localization and histology," he says. "If we could understand why cells come apart in those areas, we could understand the disease. This is a very simple concept."

Patients with pemphigus have autoantibodies against the cell surface of keratinocytes (Beutner EH, Jordon RE. Proc Soc Exp Biol Med. 1964;117:505-510). "Because of that discovery, we can ask, 'What do the autoantibodies bind to cause the cells to come apart?'"

The first experiments to address this question utilized immunoprecipitation. However, he says, "You should see something first with your eyes before you spend a lot of time doing biochemical and chemical experiments."

PV antigen

With regard to pemphigus, Dr. Stanley says he and his colleagues first analyzed whether it was possible to see PV antigen in cell culture.

"We could. Therefore, we said that if we can see it, it's being synthesized, and we should be able to immunoprecipitate it with the patient's serum." This proved true as well, yielding a 130 kilodalton molecule (Stanley JR, Koulu L, Thivolet C. J Clin Invest. 1984;74(2):313-320).

"We were very proud of this," Dr. Stanley says, until during a talk on the topic, an audience member asked what this molecule's discovery meant. Having no answer, Dr. Stanley says, "I was deflated. I was too young to realize that science occurs in small steps and that you must make those steps to get to the next step."

Dr. Stanley and his colleagues then began looking for the antibody responsible for PF.

"At about that time, desmoglein was discovered and described as a transmembrane glycoprotein of the desmosome (Koulu L, Kusumi A, Steinberg MS, et al. J Exp Med. 1984;160(5):1509-1518)." Immunoprecipitation ultimately showed that the PF antigen was desmoglein 1, bringing the researchers closer to the answer they sought, he says. "In this case, we identified an antigen in the desmosome. The desmosome holds cells together, and PF antibodies cause cells to fall apart."