Atopic Dermatitis (Eczema): An Inflammatory Skin Disease from University of Portsmouth

UNIVERSITYOF PORTSMOUTH

METTE

Atopic dermatitis (Eczema)- An inflammatory disease of skin

UNIVERSITYOF PORTSMOUTH Learning Objectives

On completion of this session you should be able to

1. Provide an overview of the skin and the structure of the epidermis
2. Understand the pathophysiology of atopic dermatitis
3. Outline and explain the current treatments

UNIVERSITYOF PORTSMOUTH Sectional View of Skin and Subcutaneous Layer

Hair shaft Papillary plexus Epidermal ridges Free nerve ending Dermal papillae Capillary loop EPIDERMIS Sweat pore Sebaceous (oil) gland Papillary region Corpuscle of touch (Meissner corpuscle) Arrector pili muscle Hair follicle Reticular region - DERMIS Hair root Eccrine sweat gland Apocrine sweat gland Lamellated (pacinian) corpuscle Subcutaneous layer Sensory nerve Adipose tissue Cutaneous plexus Blood vessels: Vein Artery

The skin, also known as the cutaneous membrane or integument covers the external surface of the body and is the largest organ of the body in terms of surface area and weight. In adults the skin covers about 2 square meters and weighs 4.5-5 kg, about 16% of body weight. It is thinnest on the eyelids (0.5 mm) and thickest on the heel (4 mm) but on average it is 1-2 mm thick. It is composed of two main parts; the outer epithelial tissue called the EPIDERMIS and the thicker connective tissue part called the DERMIS. Under the dermis is the subcutaneous layer of fatty adipose tissue. The epidermis contains no blood vessels and relies on diffusion of oxygen and nutrients from the blood vessels in the dermis. The dermis is composed of strong connective tissue made up of collagen and elastin, which gives skin its elasticity. Blood vessels, nerves, glands and hair follicles are embedded in the dermis. Sweat glands produce watery sweat for thermoregulation (eccrine glands) and a protein rich secretion during emotional sweating (apocrine glands). Apocrine sweat glands are responsible for body odour when the components of the sweat, lipids and proteins, are metabolised by bacteria on the surface of the skin. Sebaceous glands produce an oil to prevent dehydration of skin and hair. Phagocytic macrophages are found in the dermis to protect this layer from microbes.

(a) Sectional view of skin and subcutaneous layer

UNIVERSITYOF The Cells of the Epidermis

The epidermis contains four major types of cells: 1.Keratinocytes (90%) Keratin & lamellar granules containing ceramide 2.Melanocytes (8%) Produce melanin keratinocytes 3.Langerhans cells Antigen presenting cells of skin 4.Merkel cells Contact sensory neurones and detect touch

Keratin Melanin granule

(a) Keratinocyte

(b) Melanocyte

Tactile (Merkel) disc Sensory neuron

(c) Langerhans cell

(d) Merkel cell

The EPIDERMIS contains four main types of cells, keratinocytes, melanocytes, Langerhans cells and Merkel cells. 90% of the cells are keratinocytes arranged in layers (stratified), that produce the protein keratin, a tough horn-like fibrous protein that helps to protect the skin and underlying tissue against heat, microbes and chemicals. Keratinocytes also produce lamellar granules that release water-repellant lipids, such as ceramide, to decrease water loss and entry and to inhibit the entry of foreign material. About 8% of epidermal cells are melanocytes. These cells transfer melanin containing granules to the keratinocytes. Melanin is a brown-black or yellow-red pigment that contributes to the skin colour and absorbs damaging UV radiaition. Langerhans cells are the antigen presenting cells of the skin and are important in recognition of an invading microbe and stimulating the immune response to destroy it. Merkel cells are present in the smallest numbers and contact sensory neurones to detect touch.

UNIVERSITYOF PORTSMOUTH Structure of the Epidermis

Several distinct layers of keratinocytes can be distinguished in various stages of development from deep to superficial layers. Most regions of the body have thin skin and four layers , but in the regions of the body with thick skin ((fingertips, palms, soles) there are 5 layers, with the additional stratum lucidum. The stratum basale; the deepest layer is a single layer of cuboidal or columnar keratinocytes. These cells contain intermediate filaments that are the precursor of keratin which is formed in the cells of the stratum granulosum. Melanocytes and Merkel cells are found in this layer. The cells of the stratum spinosum have spiny projections of filaments that tightly join the cells together, to give strength and flexibility. Langerhans cells and projections from melanocytes are found in this layer. The stratum granulosum consists of keratinocytes that are undergoing apoptosis and produce keratin. Lamellar granules release lipids to fill the spaces between the cells in the epidermis. As these cells die they become the dead cells of the stratum lucidum and the stratum corneum. The stratum corneum consists of 25-30 layers of flattened dead cells called corneocytes. Within these cells formation of the cornified cell envelope involves a protein called filaggrin, which aggregates the keratin cytoskeleton, causing the cell to collapse and flatten in the outermost cell layer. Filaggrin is important for normal hydration of the epidermal layer Anti-bacterial lipids such as ceramide and sphingosine, in the extracellular matrix between the cells protects the underlying layers from bacteria. Cells move from the metabolically active stratum basale to the dead layers of the stratum corneum of a period of 4 weeks.

Layers of the Epidermis

4. Stratum corneum Dead keratinocytes Superficial (corneocytes-filaggrin) 5. Stratum lucidum 3. Stratum granulosum (keratin& lipids in apoptotic cells) Lamellar granules (ceramide) Keratinocyte (4-5 layers) 2. Stratum spinosum - Langerhans cell Merkel cell Tactile disc Sensory neuron Melanocyte Dermis 1. Stratum basale (pre-keratin intermediate filaments ) Deep 4 V E E K S

UNIVERSITYOF PORTSMOUTH Normal Innate Skin Defences Against Infection

• Cornified outer layer of skin (keratin + filaggrin), an impermeable barrier
• Physical barrier-interlocking keratinocytes
• Extracellular anti-microbial lipids, eg ceramide and sphingosine
• Anti-microbial peptide defensins eg LL-37 , HBD2
• Acid pH of sweat retards growth of some microbes
• Defensins in sweat e.g. dermicidin
• Anti-bacterial effect of oil from sebaceous glands

1) Skin serves as the first line of defense against infection, utilizing multiple innate immune mechanisms to protect the body from microbial invasion. Let's go through the key components of these defenses:

1. The outermost layer of the skin is cornified, consisting of keratin and filaggrin, forming an impermeable barrier that prevents pathogens from penetrating.
2. The physical barrier is further reinforced by interlocking keratinocytes, ensuring structural integrity and resistance to microbial entry.
3. Extracellular antimicrobial lipids, such as ceramide and sphingosine, play an essential role in inhibiting bacterial growth and maintaining skin homeostasis.
4. The skin also produces antimicrobial peptides, including defensins like LL-37 and human beta-defensin 2 (HBD2), which help neutralize harmful microbes.
5. Sweat has an acidic pH, which creates an unfavorable environment for many bacteria and fungi, thereby reducing their growth.
6. Additionally, sweat contains defensins such as dermicidin, which exhibit broad-spectrum antimicrobial activity.
7. Sebaceous glands produce oil with antibacterial properties, contributing to the overall antimicrobial defense of the skin.

1) Together, these innate defense mechanisms work in synergy to maintain skin integrity and prevent infections.

Atopic Dermatitis (Eczema)

• Atopic dermatitis (AD) is a common chronic inflammatory skin disease that becomes apparent in young children. Atopy is an inherited condition that makes individuals more likely to have a group of diseases including rhinitis, asthma and AD, associated with high levels of IgE. Atopic individuals make IgE antibody in response to common environmental or food antigens. More than 80% of patients with AD make high levels of IgE. 50% of children with AD will go on to develop asthma and/or allergies by their third birthday.
• The symptoms are itch (pruritis), and dry, red skin. Typical affected skin areas include the folds of the arms, the back of the knees, wrists, face, and hands. Scratching and rubbing in response to itching worsen the skin inflammation that is characteristic of this disease. People with atopic dermatitis seem to be more sensitive to itching and feel the need to scratch longer in response. They develop what is referred to as the "itch- scratch" cycle. The extreme itchiness of the skin causes the person to scratch, which in turn worsens the epidermal damage, increases the itch, and so on.

" How atopic dermatitis affects the skin can be changed by patterns of scratching and resulting skin infections. Some people with the disease develop red, scaling skin where the immune system in the skin becomes very activated. Others develop thick and leathery skin as a result of constant scratching and rubbing. This condition is called lichenification. Still others develop papules, or small raised bumps, on their skin. When the papules are scratched, they may open (excoriations) and become crusty and infected. These conditions can also be found in people without atopic dermatitis or with other types of skin disorders.

Atopic dermatitis is a common chronic inflammatory disease apparent in young children. 80% of patients have high levels of IgE to common environmental or food allergens. 50% of patients will develop asthma/allergies by their third birthday. The symptoms are itch (pruritis), dry, red, flaky skin.

ERSITYOF TSMOUTH Epidermal Barrier Dysfunction

• Filaggrin gene impairment
• 1 Skin pH
• Į S. aureus resistance
• 1 Allergen susceptibility
• Į Ceramides
• Į Hydration

AD Pathogenesis

Immunologic Abnormalities

• Calcineurin-mediated Th2 cell activation
• 1 TEWL
• 1 IL-4, IL-13 production
• ¡ Serum IgE
• 1 PDE-4 activation

Aggravating Factors

• Dry skin
• Harsh soaps, detergents, wool
• Seasonal changes
• Heat
• Sweating
• Infections
• Stress
• Food allergies