The Role of Keratinocytes in Atopic Dermatitis Aczema – Part 2 By Gay Wardle

In the first part of this article, we covered Roles in epidermal structure, Roles in barrier proteins, Epidermal-dermal Junction & Immune regulation

Summary of part one: The keratinocyte is the principle cell in the epidermis and is responsible for generating and maintaining the integrity of the epidermis. Besides being the structural foundation of the epidermis, keratinocytes also possess functions capable of interacting with their environment immunologically.

In part two we will cover the role of the adaptive immune response and barrier proteins.

Dermatitis is a highly pruritic, chronic, multifactorial skin disease that is predisposed to bacterial and viral infections that are based on abnormalities of the innate and adaptive immune system. The innate system is quick to mobilize a first-line response against different pathogens.

The keratinocyte cell will initiate a response with T-cells with both the innate and the adaptive immunity of the skin. Dermatitis/aczema lesions have many inflammatory CD4-T-cells which accumulate in both the upper dermis and epidermis. There have been studies showing these T-cells are mostly activated memory T-cells that express cutaneous lymphocyte antigens. Antigens are presented to the T-cells by the keratinocyte cells when there is inflammation which in some cases can increase an autoimmune disease.

Epidermal barrier dysfunction results in increased protein allergen penetration through the epidermis and predisposes to secondary skin infections. Where there is a combination of a genetic predisposition for skin barrier dysfunction and dysfunctional innate and adaptive immune responses leads to a higher frequency of bacterial and viral skin infections. The innate immune system quickly mobilizes an unspecific, standardized first-line defense against different pathogens. Defects in this system lead to barrier dysfunction which results in increased protein allergen penetration through the epidermis and predisposes to secondary skin infections. The innate and adaptive immunity do not simply coexist but are linked to one another in a complex network of skin immunobiology.

Keratinocyte`s barrier proteins:

The most important cytokine in the helper T-cell subset 2 family is IL4 and has a significant involvement in the development of dermatitis/ aczema. There is a substantial reduction in serum levels of immunoglobulin E, which is essential for allergic skin reactions. Further studies have clearly demonstrated that IL4 negatively impacts keratinocyte`s abilities to produce the essential epidermal barrier protein production. There is a protein called Involucrin which is one of the skin`s barrier proteins that is produced by keratinocyte cells. This protein is either very low or not there at all in a skin that has dermatitis/aczema. There was a study that determined if IL4 could have an impact on involucrin and it was completed over a 24 hour period where different levels of IL4 were administered to skin cells. It was found that immune dysregulation with IL4 leads to a reduction of the skin barrier protein involucrin which caused an impairment to the skin barrier.

Another kin barrier protein produced by the keratinocyte is loricrin, and this protein has been also found to be either absent or very low in dermatitis skins. Like involucrin, loricrin was also downregulated by IL4.

Combinations of IL4 and IL13 were found to reduce filaggrin which is another very important barrier protein. Add to this Th2 cytokine in combination with IL4 and IL13 filaggrin was further reduced which increases the dermatitis lesions. The combination of IL4, IL13 and Th2 cytokine reduced the mRNA of the protein filaggrin. The reduction of filaggrin seems to be immunemediated rather than gene-based. Corneo-desmosomes are the proteins that hold and connect the corneocytes together, IL4, IL13 and Th2 cytokine decrease these desmosomes which increases the desquamation process. This in turn disrupts the barrier function.

Interestingly, dermatitis that is related to IL13 and Th2 cytokine, will have an impact on type IV collagen which is the collagen that connects the epidermal junction.

The three cytokines IL4, IL13 and IL31 which are commonly found in dermatitis will reduce claudin-1 with is a tight junction protein. This seems to be a result caused by the inflammatory process.

Th12 cytokines and keratinocyte`s immune barrier proteins.

It is well known the people who suffer from dermatitis/eczema will have frequent, recurrent, and at times severe infection that are caused by the impairment of the barrier where bacteria and viruses have a portal of entry.

Besides impact of the physical skin barrier proteins where the skin is broken, itchy and painful, IL4 and other Th2 cytokines will have a negative impact on antimicrobial proteins that are produced by keratinocyte cells.

Eventually the skin is scarred and discoloured from the continued assault and infection.

Keratinocytes are the major cell in the epidermis, they have a very important function for the production of many proteins that are essential for formation of the barrier function of the skin. They also play an integral role in the immune function of the skin`s barrier and its function in protecting the lower layers of the skin. When the structures of keratinocytes and their products are weakened internally, the physical skin barrier and its integrity will be under threat. Their protective and cohesive functions will be reduced, which will allow pathogens and allergens to enter the skin.

From an immunologic perspective, keratinocytes possess the machinery to synthesize various immunologic components that can affect the immune milieu of the skin. When the immune milieu is altered internally, keratinocytes can be affected in two ways. The immune milieu that has been altered can trigger proinflammatory responses from keratinocytes, which leads to vicious cycle of inflammation. Secondly, the altered immune components could have significant impact on the keratinocytes, including the effectiveness of the keratinocytes to provide immune skin barrier and healthy immune functions. The keratinocytes play such important roles for the epidermis and the skin in general.