Eczema: Pathophysiology

00:01 Welcome. The topic for today is eczema, which is literally an atopic dermatitis, meaning that it has an allergic component. It is a combination of a disordered skin barrier and immune dysregulation, and it presents as a chronic relapsing inflammatory disease, a rash.

00:24 The epidemiology is that it's incredibly common.

00:27 The prevalence is upwards of 20% among school-aged children, and it's still fairly significant in the adult population.

00:35 It presents typically as a triad.

00:38 So it's not just a skin rash, but because of the allergic basis for this, in 30 to 50% of patients, not only will they have eczema, the atopic dermatitis, but also allergic rhinitis.

00:50 Their nose is going to be running, they're going to be having typical seasonal allergies and they may or may not have asthma.

00:57 So again, kind of that triad occurs quite frequently in the setting of eczema. With regard to the pathophysiology, we need to understand again the barrier function of the skin that occurs as a result of the maturation of the epithelial cells and also the interaction of that barrier function with the immune system.

01:19 So in a previous talk we discussed how epithelium undergoes gradual maturation differentiation from the basal layer up through the stratum spinosum into the stratum granulosum and into the stratum corneum.

01:33 I'm just going to briefly review that again now because it's germane to this discussion of eczema. Within the stratum spinosum we have epithelial cells that are becoming flatter and more filled up with intermediate filaments. The intracellular keratin, when they reach the granular layer cells in that region are now going to produce a protein called filaggrin.

01:56 And the filaggrin is going to be very, very important for lubricating the skin and also for driving the subsequent maturation of the keratinocytes into the stratum corneum into the layer that's going to be just all intermediate filaments and dead keratinocytes. That process needs to involve normal filaggrin production and filaggrin metabolism. That filaggrin is going to be really important because what it does is a number of things in the stratum corneum the proteolysis, the breakdown of the filaggrin releases histidine and other amino acids that can be quite hydroscopic.

02:40 So they pick up water, and the subsequent metabolism of things like histidine to urocanic acid leads to something that makes a very potent emollient over the surface of the skin.

02:52 It lubricates it. It also provides kind of a barrier function to the loss of water, and it also provides a barrier to external antigens or allergens and bacteria coming in.

03:05 In addition, glutamic acid that is released from the filaggrin metabolism is also converted to other metabolites, and that's forming natural moisturizing.

03:14 Glutamic acid is also released by the metabolism of the filaggrin, and metabolites of the glutamic acid also function as natural moisturizing substances.

03:26 The filaggrin aggregates are also going to be important for cross-linking the keratin filaments and finally altering the shape of the dead keratinocytes so that we have that barrier.

03:39 So you can see the filaggrin is a really important component of the entire maturation process at the very superficial portion of the epidermis.

03:49 If that is aberrant, if there is insufficient filaggrin, if there is mutated filaggrin, if there is insufficient metabolism of filaggrin. All those things will alter the barrier function.

04:01 And now evil forces from the outside world, antigens, allergens, microbes can potentially get across the barrier and now can access the Langerhans cells.

04:14 Ooh, now we have intersected the outside world with the immune surveillance function of the skin.

04:21 And that will lead to a profound immune response.

04:25 So the overall etiology is multifactorial.

04:29 A lot of different things contribute to it.

04:31 And it's not completely understood.

04:35 Not everyone gets atopic dermatitis or eczema through the same final pathway. There are many ways to get there.

04:43 Genetics plays a very important role.

04:45 Remember that there's a significant family history of atopy.

04:48 So allergies in a significant number of the patients who will have eczema. And remember there is that triad associated with 30 to 50% of patients with atopic dermatitis.

04:59 That also includes allergic rhinitis and asthma.

05:03 Clearly, filaggrin gene mutations, typically loss of function or insufficient copy number, will be related to loss of the important barrier function, allowing antigens, allergens to get in and access the Langerhans cells within the epidermis.

05:21 Immune activation tends to have a predominance of Th2-like cells, so it's going to be more allergy oriented.

05:27 Again, this is probably genetically driven by the individual that these the people with eczema tend to be more allergic type.

05:36 They tend to have more of the other components we associate with allergies like asthma or allergic rhinitis.

05:43 Clearly. Also it depends on what is getting access.

05:46 So the microbiome plays a role in the driving of the etiology of this as well. And we find that patients who have certain species or certain bacteria or certain viruses on their surface at a higher prevalence will tend to have a greater incidence of eczema.

06:04 So staph aureus and herpes simplex virus colonization of the skin seems to be more commonly associated with eczema development. So histologically, what we're going to be looking at is the changes related to loss of the barrier function.

06:23 That's going to be histologically characterized by spongiosis.

06:27 What is spongiosis. It's just the dermatopathology way of saying that there is edema or water and electrolyte within the epidermis, that edema leads to breaking of the intercellular attachments.

06:40 And we get vesicle formation.

06:41 So we often will see histologically something called spongiotic dermatitis.

06:47 And then part and parcel of all this is that we are recruiting in inflammatory cells.

06:51 And there will typically be a relatively denser lymphocytic infiltrate present within the dermis.

06:59 So what we're seeing here is water loss.

07:01 That's because of breaking of the barrier function.

07:04 And we are also seeing the recruitment of mononuclear inflammatory cells, lymphocytes.