Patients with epidermolysis bullosa (EB), an inherited connective tissue disease causing blisters in the skin and mucosal membranes, experience extreme pain even with the slightest touch. Previously unknown, the causes underlying this disease have now been discovered by Dr. Li-Yang Chiang, Dr. Kate Poole and Professor Gary R. Lewin of the Max Delbrück Center for Molecular Medicine (MDC) in Berlin-Buch. The researchers believe that it is the lack of laminin-332 formation due to a genetic defect that causes the patients to experience pain, even to gentle tactile stimulus. Laminin-332 is a structural molecule of the skin that in healthy individuals inhibits the transduction of tactile stimuli and neuronal branching (Nature Neuroscience, doi: 10.1038/nn.2873).
Inflammation of skin, blisters all over the body and throbbing pain upon slightest touch are some typical features of this disease. “Butterfly Children” is a term often used to describe younger patients, because the skin is said to be as fragile as a butterfly’s wing. The severe pain hardly allows patients with EB to live a normal life. It is even difficult for the patients to walk, because the stress on the soles of the feet causes stabbing pain.
The genetic defect of the absence of laminin-332 in patients with EB causes the separation of the two layers of skin i.e. epidermis and dermis. The epidermis is the outer layer while the dermis is the underlying layer. In otherwise normal individuals both these layers are held together by this structural molecule (laminin-332) that acts as a kind of cellular ‘glue’.
Scientists from MDC have stated that laminin-332 plays other vital roles in addition to acting as cellular ‘glue’. They believe that it inhibits touch transduction and prevents the branching of the sensory neurons that are responsible for receiving the sense of touch in the skin.
Sensory neurons have ion channels sensitive to touch at their endings. These ion channels are nothing but specialized proteins within the cell membrane that allow a controlled flow of charged particles into the cell. Upon touch, pressure on the extracellular matrix opens up these channels and allows the charged particles to flow through, causing excitement of the neuron and enabling the perception of the stimulus.
The researchers, by using cell cultures, have been able to demonstrate that physical stimuli such as touch trigger ion currents (charged particle inflow) in all neurons that are not surrounded by laminin-332. In contrast, the number of responsive cells was much less in presence of laminin-332.
Professor Lewin stated:
“To a great extent, laminin-332 blocks the tether mechanism that opens the ion channels, thus impeding stimulus transduction. Because patients with epidermolysis bullosa are deficient in laminin-332, the transduction of the stimulus is unsuppressed. Their sensory neurons are excited much more strongly, and thus they react much more sensitively to mechanical stimuli.”
In addition, excessive branching of neurons was found in the skin of EB patients compared to the skin of individuals without the disease.
Professor Lewin commented:
“From cell-culture experiments we know that laminin-332 inhibits neuronal branching. Without laminin-332 this inhibition does not take place. Presumably, this effect also contributes to the increased perception of tactile stimuli.”
Although a lot has been achieved till now in treating this disease, the researchers in future studies aim to focus on identifying new drug targets for its more effective treatment.
The authors state:
“Because the causal mechanisms are now understood, we can focus on the patient’s pain situation and on administering more efficient pain therapies. We recommend that in treating the disease, neurologists should be consulted in addition to dermatologists.”
Nature Neuroscience (2011) doi:10.1038/nn.2873
Written by Barry Windsor