The Skin Immune System
Pathogens will usually first be encountered at body surfaces, either the skin or the mucosae and these are therefore endowed with a variety of barriers against infection (see Figure 1.6). The outer surface of the skin is composed of keratinocytes which constitute a strong physical barrier against microorganisms.
In addition, keratinocytes express many types of pattern recognition receptors, including TLRs, NOD‐like receptors, RIG‐1‐like receptors, and C‐type lectins. Upon detectionof pathogens, these receptors trigger the keratinocytes to produce microbicidal compounds such as β‐defensins as well as a variety of cytokines (including chemokines, a family of molecules with chemotactic and other functions). In a normal, non‐inflamed state the epidermis contains resident Langerhans cells and both αβ and γδ T‐cells (Figure 6.2). The Langerhans cells can promote Th17 responses against extracellular pathogens and may also regulate the development of tolerance against nonpathogenic antigens.
The underlying dermis contains dendritic cells, macrophages, T‐cells (again both αβ and γδ), NK cells, and mast cells. About 10% of human CD4+ T‐cells in the skin express Foxp3, indicating that these cells may function as regulatory T‐cells. There is a continuous migration of leukocytes into the dermis from the blood vessels. T‐cells that are directed to migrate to the skin upregulate a number of adhesion molecules, including cutaneous leukocyte antigen (CLA), CD43, and CD44, all three of which bind to E‐selectin on the blood vessel endothelium in the skin. LFA‐1 and Mac‐1 bindingto ICAM‐1, and VLA‐4 binding to VCAM‐1, as well as CCR4 on the T‐cell binding to CCL17 on the blood vessel endothelium, are also involved in this process (Figure 6.3). The T‐cells can subsequently return to the circulation via the draining lymphatics and the lymph nodes. Should a pathogen provoke an inflammatory reaction in the skin, then other cells of the immune system will fairly rapidly appear on the scene, including neutrophils, monocytes, and eosinophils. In diseases such as atopic eczema the number of leukocytes in the skin increases substantially.