Epidermolysis Bullosa: Pathophysiology

00:01 Welcome. In this talk, we're going to continue with our series of blistering lesions. This one is epidermolysis bullosa.

00:10 It sounds like a single entity.

00:12 In fact it's many different ones with very similar manifestations.

00:17 So epidermolysis bullosa is a collection of relatively rare genetic blistering disorders.

00:25 And when I say collection, it has to do with where the genetic mutation is in all the connective tissue proteins or the proteins that link the connective tissue to the epithelium, and where those which ones are affected will give us a slightly different disease. So the epidemiology not a public health menace.

00:49 It's relatively rare. The incidence is 20 per million live births in the US.

00:54 It's about the same worldwide.

00:56 The prevalence how much is in the population is actually about half of that.

01:00 That's because these diseases can be fairly lethal.

01:04 So a number of people, a number of individuals with disorders will die. Pathophysiology. So the pathophysiology, as I've already intimated, depends on where the mutations in the various structural proteins involved in cell- cell or cell-basement membrane adhesion occur. And there is some genetic heterogeneity too because of variable gene expression copy number and things like that.

01:33 And environmental environmental factors that can influence either the synthesis of proteins or their stability.

01:41 And certainly, inflammatory diseases by causing local protease activation can exacerbate the disease.

01:49 So to get into the pathophysiology, we have to go back to histology and understand how the cell biology of the skin works.

01:57 The box here is really important because that's the interface between the epidermis and the dermis. And there's a lot going on there.

02:05 There are a variety of proteins in the dermis that interact with the basement membrane that can also cross the basement membrane.

02:12 Those proteins interact with basement membrane proteins, which in turn interact with epithelial proteins to create one integrated structure.

02:24 So if we now look at kind of a higher molecular level within the epithelial cells themselves. So these are the basal epithelial cells.

02:34 They're going to be sitting on a basement membrane. What are the proteins that are important there? Well we've talked about in other blistering lesion talks about the importance of the integrity of the Desmosome that connects epithelial cell to epithelial cell and certain of the proteins.

02:49 There can rarely be a cause of blistering, mutation or blistering diseases.

02:55 In the Hemidesmosome, that is to say, the connection between the epithelial cell and the underlying basement membrane.

03:01 There are a number of proteins, but those proteins also interact with intracellular intermediate filaments, in particular keratin 5 and 14 and mutations in keratins or the proteins that form the hemidesmosome, can also cause blistering mutations.

03:21 There are additional focal adhesion complexes that involve another set of proteins that cross the plasma membrane of the basal epithelial cell and interact with the basement membrane, and Kindlin is going to be an important protein in the focal adhesion complexes that gets mutated in certain blistering diseases.

03:43 I know it makes your head spin.

03:45 Don't worry, you probably don't need to memorize all of these, but just be kind of aware of the conceptual basis by which blistering can occur.

03:53 Okay. And now we're going into the basement membrane proper.

03:57 There are a number of proteins that kind of cross that zone, including the laminins very importantly, but also collagen 17.

04:06 And then finally into the underlying dermis.

04:11 And there are a variety of anchoring proteins there as well.

04:15 And collagen seven turns out to be very important, but there are a whole bunch of proteins in there. In this very narrow zone, there are probably in excess of 100 proteins that are involved in stably, stably anchoring epithelial cells to the basement membrane into the underlying dermis.

04:35 Mutations in any of those can lead to a loss of function that will lead to blistering.

04:41 Okay, so there are four major subtypes of epidermolysis bullosa.

04:49 And we're not going to get into all of the gory details.

04:52 And so you're going to be thankful for that.

04:54 But do just keep in mind that the proteins that are there and that there are different subtypes of epidermolysis bullosa.

05:04 So there's simplex. This is mutations in the keratins the intracellular keratins that interact with the hemidesmosomes.

05:13 So keratin 5. Keratin 14.

05:15 There's junctional epidermolysis bullosa, these are mutations in the Laminins.

05:21 Okay. Remember, the laminins are important part of the of the basement membrane complex.

05:26 There's dystrophic epidermolysis bullosa where there are mutations in collagen seven.

05:32 And then finally kindler mutations that are part of the junctional adhesion complexes.

05:39 There are mutations in that particular gene that can lead to another form of epidermolysis bullosa.

05:47 I doubt that the national boards would make you memorize these, but as a concept you can kind of understand why lesions or mutations, loss of function mutations in each of these areas might lead to blisters.

06:02 Okay. So each area, whether it's in the actual epithelial cell, the basal epithelial cell or it's in the basement membrane or it's below the basement membrane will determine where the blisters occur.

06:18 So all epidermolysis bullosa is not created equal.

06:22 There were simplex lesions.

06:23 Et cetera. Et cetera. So if there is, if there is a defect in, say, those keratins, we're going to have an intraepithelial blister.

06:35 If we have junctional epidermolysis bullosa that is mutations say in laminin it's going to be a subepithelial blister.

06:45 And if we have mutations in the collagen molecules that are deeper within the dermis it's going to be a subbasal membrane blister.