-considered rapid and first line response of innate immune system to microbial pathogens

-Together with their antimicrobial effects, AMPs exert immunomodulatory effects by inducing cell migration, proliferation, diferentiation, regulating cytokine/chemokine production, improving angiogenesis and wound healing and sustaining the barrier function of the skin

-Claudin-1 is an essential Tight Junction protein in the epidermal barrier

-It has been observed in the lesional skin of AD

-Deficiency of skin barrier generally plays a crucial role in AD via epidermal gene mutations, deficiency of AMPs, TJ dysregulation and immune abnormalities

-Cathelicidins are produced by skin and production of AMPs can be altered by allergic response

-Cathelicidins are host defense peptides with antimicrobial and immunomodulatory functions

-They are produced by cells that are in contact with the environment (mucosal epithelium, keratinocytes) and cells of the innate immune system.

-VDR activation is important for cathelicidin production as a Vit D response element sequence is present in the promoter region of the Cathelicidin gene

-Vit D supplementation increases cathelicidin expression in lesions of AD patients and increases activated macrophage production of cathelicidin

-Cathelicidins serve a critical role in mammalian innate immune defense against invasive bacterial infection

-Cathelicidin family of peptides are classified as AMPs

-Defensins are members of a large family of cationic antimicrobial peptides that form an essential element of innate immunity.

-They are small, cationic peptides that contribute to antimicrobial activity of phagocytes, the skin and mucosa (including that of the lung)

-Defensins are capable of killing bacteria or inhibiting bacterial growth through a multiplicity of antimicrobial mechanisms such as direct membrane disruption and inhibition of bacterial cell wall synthesis

-Defensins can also reduce bacterial infection by neutralizing secreted toxins

-The FLG gene provides instructions for making a large protein called profilaggrin which is found in cells that make up the outermost layer of the skin (the epidermis)

-Profilaggrin is cut (cleaved) to produce multiple copies of the filaggrin protein, which is important for the structure of the epidermis

-leads to a poorly formed SC (ichthyosis)

-this promotes water loss (xerosis)

perturbation of skin barrier function is the result or reduction of complete loss of filaggrin expression which leads to enhanced percutaneous transfer of allergens

-Filaggrin is a frontline defense that protects the body from the entry of foreign environmental substances and can trigger aberrant immune responses

-Reduced expression of structural proteins

-Imbalances in protease/protease inhibitors

-Altered composition and organization of lamellar layers

-Altered lipid metabolism

-Reduced expression of tight junction proteins

-Dysbiosis with increased pathogenic staphylococci

-Loss of filaggrin is sufficient to induce inflammatory and immune changes similar to atopic dermatitis

-disconnect occurs between the epidermal proteome and transcriptome

-Unbound ceramides at the extracellular domain consist of ceramides, cholesterol, and very-long-chain FFA

-Covalently bound ceramides (CLE) consist of glycine residues in involucrin. Require oxidized linoleic acid to act on AcylGlcCer to result in Omega-GlycCer and build a stable CLE

1) Specialized control of apoptosis

2) Bundling of keratin filaments to contract and flatten cells (filaggrin)

3) Replacement of the cell membrane with cornified envelope (TG1)

4) Formation of lipid bilayers and CLE

5) Desquamation (pH dependent)

1) Profilaggrin becomes filaggrin (in the keratohyalin granule)

2) Keratin fibrils are packaged into keratin macrofibers by Filaggrin

3) Caspase 14 acts in a process called deamination to degrade filaggrin into Urocanic acid, Pyrrolidone carboxylic acid and lactic acid ("Natural Moisturizing Factors" that provide UV protection and pH)

• Neutral lipids and spingolipids increase as phospholipids decrease