Dr. Katz

Buenos Aires, Argentina — Recent advances in the understanding of the skin immune system are represented in four major areas of research: Langerhans cell trafficking, innate immunity, complex genetic diseases with an immunologic basis and psoriasis, according to Stephen I. Katz, M.D., Ph.D., director, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Md. Dr. Katz says, in each of these areas, there are potential therapeutic interventions.

Dr. Katz presented an overview of recent advances in the skin immune system at the XXIV ReuniAnual dos Dermatologistas Latino-Americanos Conference here.

The burden of AD

Langerhans cell trafficking Langerhans cells play a critical role in a number of disease conditions, including allergic contact dermatitis, atopic dermatitis, histiocytosis X, graft versus host disease, HIV disease and psoriasis.

"Langerhans cells act as the sentinel cell to sense adversity," Dr. Katz says. Langerhans cells are derived from bone marrow cells and serve as antigen-presenting cells in the dermis. Langerhans cells are being used in targeted gene therapy for tumor immunity, autoimmunity and infectious disease.

An example of the role that Langerhans cells play in the disease process is seen in the early events in the induction of contact sensitivity.

"There are many areas of the sequence where therapeutic intervention could occur," Dr. Katz says.

Epidermal Langerhans cells are activated by contact with the antigen. One of the first steps in the events leading to contact sensitivity is the upregulation of pro-inflammatory cytokine gene expression. Keratinocytes upregulate IL-1, TNF-α, GM-CSF, MIP-2 and IP-10. Langerhans cells upregulate IL-1, IL-6, and IL-12. As Langerhans cells mature, their immunostimulatory function increases and MHC expression is increased. Finally, activated Langerhans cells enlarge, detach from the surrounding keratinocytes and migrate towards regional lymph nodes. Activated Langerhans cells produce metalloproteinases to break barriers of the basal membrane zone.

Opportunities for therapeutic interventions occur at many steps in this sequence. For example, it might be possible to block one of the steps involved in the maturation of Langerhans cells or their migration into the lymphatics. Alternatively, one of the cytokines upregulated by activated Langerhans cells could be targeted.

Innate immunity A promising area of current research focuses on the role of antimicrobial peptides, particularly cathelicidins and beta-defensins, in normal and diseased skin. Comparison of the expression patterns of these peptides in different inflammatory skin diseases provides insight into the underlying disease mechanisms.

Differential expression of antimicrobial peptides appears to be an important component in the susceptibility to infection seen in many chronic inflammatory skin diseases. For example, expression of human cathelicidins and beta-defensins is upregulated in keratinocytes in psoriasis, but downregulated in atopic dermatitis. Secondary infection is rare in psoriasis but very common in atopic dermatitis. If the increased susceptibility to infection in atopic dermatitis arises from insufficient expression of antimicrobial peptides, then therapeutic intervention with exogenous antimicrobial peptides might be appropriate.

Another promising area of research in innate immunity is the role that toll-like receptors (TLR) in keratinocytes and Langerhans cells play in antimicrobial defense in skin. Stimulation of these receptors by TLR ligands can initiate a signal transduction pathway that leads to expression of the chemokine IL-8. Keratinocytes express TLR1, TLR2, TLR3, TLR5, TLR6 and TLR10, and Langerhans cells express TLR2, TLR4 and TLR9.

Genetic diseases Complex, immune-related genetic diseases that affect the skin include disorders such as psoriasis, atopic dermatitis, alopecia areata and lupus. One of the most significant scientific breakthroughs in this area of research has come with the identification of important "autoimmunity" genes.