Immunological Aspects of Skin Diseases
The skin is the largest human organ, and its surface (measuring about 2 square meters) protects the body from invading organisms, toxins, and viruses. Loss of the protective epidermal barrier (secondary to burns or disease states) results in an increased risk of infection from a variety of organisms.
Normal skin may be divided into three major parts: epidermis, dermis, and hypodermis. The epidermis is a stratified, squamous epithelia composed mainly of keratinocytes that differentiate to a physi-cal barrier (the stratum corneum). The dermis is composed largely of collagen and elastin fibers synthesized by dermal fibroblasts. The dermis also contains a rich vascular supply, nerves, and various appendages such as hair follicles, eccrine glands, and apocrine glands. The hypodermis contains subcutaneous adipose tissue with associated vascular and neural ele-ments and contributes the largest bulk of the cutaneous organ.
The skin is also an important immuno-logical organ and is capable of mediating or initiating both innate and acquired immune responses. Keratinocytes synthesize a range of proteins such as defensins that directly kill bacteria. Activated keratinocytes can also rapidly recruit neutrophils and other innate immune cells through release of a large number of mediators such as S100 proteins, chemokines, cytokines, and lipid-derived molecules. Keratinocytes can also activate acquired immunity through syn-thesis of heat shock proteins that activate dendritic cells (DCs) in the skin.
Normal skin contains at least two resi-dent populations of antigen-presenting DCs Langerhans cells and dermal DCs Langerhans cells are randomly distrib-uted throughout the living cell layers of the epidermis and constitute about 1 per-cent of all epidermal cells. Although this cell type originates from precursors in the bone marrow, continued proliferation of Langerhans cells in the epidermis appears to sustain steady state levels. However, if large numbers of Langerhans cells are lost from the epidermis (e.g., induced migra-tion after antigen exposure or epidermal damage), bone marrow precursors can replete epidermal stores. Langerhans cells may be identified visually by their char-acteristic tennis racket–shaped organelles known as Birbeck granules that are a sub-domain of the endosomal recycling com-partment. CD1a and langerin (CD207) are antigens used to identify Langerhans cells on a molecular level. CD1a is an MHC-like protein that mediates the presentation of nonpeptide antigens to T cells, and lan-gerin (CD207) is an endocytic receptor that recognizes bacterial mannose residues and transports them to the Birbeck granules. Langerhans cells are “immature” DCs that survey the epidermal environment for foreign antigens.
If these cells capture an antigen, or are triggered by cytokines or other danger signals, maturation ensues such that the cells up-regulate MHC and co-stimulatory molecules and migrate through dermal lymphatics to skin-drain-ing lymph nodes. Activated, or “mature,” Langerhans cells, in turn, activate naïve T cells, inducing T-cell proliferation and differentiation into effector T cells. These Langerhans cell-induced effector T cells home specifically to the skin because they express cutaneous lymphocyte-associated antigen (CLA) that binds to E-selectin on endothelial cells.
Presumably, dermal DCs (HLA-DR+ cells that possess co-stimulatory markers and the integrin CD11c, but lack Birbeck granules, CD1a, and CD207) have a similar potential to activate, mature, and migrate to lymph nodes; however, there is less experimental evidence for this outcome. Potentially, activation of CLA+ T cells is not limited to lymph nodes via Langerhans cell migration but may also occur directly in the skin with activated dermal DCs.