Mechanism of Action of Atopic Dermatitis

Author: Sanofi

Editorial Team

Atopic Dermatitis Mechanism of Disease Webpage

Atopic Dermatitis Pathophysiology^1,2:

Figure 1: Life Cycle of Atopic Dermatitis^1,2

Epidermal Barrier dysfunction^1-3:

Figure 2: Pathophysiology- Epidermal barrier dysfunction,^1-3

Mechanism² •

Primary: FLG mutations; secondary: Itch-scratch cycle

• Reduced expression of epidermal structural proteins or lipids in response to T2 and T22 cytokines^1,2

Epidermal changes^1-3

• Increased pH

• Trans epidermal water loss

• Easy irritability • Increased permeability

• Increased susceptibility to infection

• Altered lipid composition

EBD promotes inflammation²

• Dysregulation of immunomodulatory proteins

• Release of DAMPs

• Release of alarmins and cytokines -IL-1β, IL-4, IL-13, IL-25, IL-17A, IL-33 and TSLP

Molecular changes^1-3

• Abundance of Staphylococcus aureas and Malassezia yeasts

• T2 mediated downregulation of skin barrier genes and stratum corneum lipids

• Keratinocytes send pro-inflammatory and pruritogenic signals

• Reduced expression of tight junction proteins

Itch-scratch Cycle^1,2,4:

Figure 3: Pathophysiology- Itch-scratch cycle^1,2,4

• Induced by pruritogens - antigens, histamines, endothelin 1, T2 cytokines^1,2,4

• Sensory nerves transmit signals to spinal cord^1,2,4

• Pathways: Histamine-dependent or independent and T2 signaling^1,2,4

• T2 cytokines (IL-4, IL-13, TSLP and IL-31) contribute to itch¹

• TSLP released by keratinocytes activate TRPA1 and T2 cytokines stimulate afferent neurons through IL-4 alpha and JAK1 ²

Microbiome^1,2

Figure 4: Microbiome^1,2

• One of the functions of the normal skin microbiota is suppression of Staphylococcus aureus growth^1.2

• Decreased microbiota favor Staphylococcus and S. aureus in particular²

• Staphylococcus aureus commonly found on skin of patients with AD; 30-100% depending on age and disease severity^1,2

• Staphylococcus aureus expresses numerous virulence factors through keratinocytes and immune cells^1,2,5

• In addition, yeasts, Malassezia can directly stimulate skin inflammation²

Figure 5: Mechanisms facilitating adhesion, epidermal dysfunction, and proinflammatory mechanisms by S. aureus⁵

References:

MAT-BH-2600009