Читать книгу Diagnostics and Therapy in Veterinary Dermatology - Группа авторов - Страница 16

The major physical defense of the skin is the stratum corneum. This outermost layer continuously sheds into the environment, taking pathogens along with it. In addition to keratinocyte exfoliation, compounds present in the intercellular lipid cement create an environment unfavorable to pathogen invasion. These compounds include sodium chloride, albumin, complement components, transferrin, interferons, lipids, and antibodies donated by the adaptive immune system.

Below the stratum corneum the living epidermis is composed mainly of keratinocytes that are bound together by various junctional structures, including desmosomes, hemidesmosomes, and tight junctions. In addition to forming the major structural component of the epidermis, keratinocytes are many times the first to detect pathogens. By initiating the immune response, they act as sentinel cells for both the innate and adaptive immune systems. Keratinocytes produce small quantities of AMPs on a regular basis. AMPs are small cationic molecules that are a first line of defense against pathogens. They block lipopolysaccharides (a major negatively charged component of the outer membrane of gram‐negative bacteria), directly kill microbes, and induce histamine release from mast cells. Keratinocytes also detect highly conserved microbial surface structures (e.g. lipopolysaccharides, flagellins, teichoic acids) called pathogen‐associated molecular pattern (PAMP) molecules via pattern‐recognition receptors such as Toll‐like receptors. Other pattern‐recognition receptors on the keratinocyte surface detect damage‐associated molecular pattern molecules (DAMP) that are endogenous ligands/markers produced by injured or dying host tissue. These are important in the detection of irritants and toxins. Once pattern‐recognition receptors are triggered, the keratinocyte is activated. Depending on the type of assault and which pattern‐recognition receptors are triggered, the activated keratinocyte then produces more AMPs, and various pro‐inflammatory cytokines (a large group of small molecules important in cell signaling). Some of these cytokines have immediate effects on the invaders (innate response) that directly neutralize the pathogen, while others are important in recruiting and activating B and T lymphocytes (adaptive response). Once activated, keratinocytes express a wider variety of pattern‐recognition receptors. Keratinocytes can also act as antigen‐presenting cells for the adaptive immune response. They can express both major histocompatibility complex molecules (MHC) I and II on their surface. They are not able to prime naïve T cells, but can present antigen to both T‐helper (CD4+) and cytotoxic (CD8+) T lymphocytes.

Figure 1.2 Adaptive skin immune system. 1. Langerhans cells (LCs) are activated once they uptake and process the antigen. 2. Some will mature and migrate along with some activated dermal dendritic (DD) cells to the local lymph node. 3. The antigen in association with major histocompatibility complex (MHC) I or II will prime naïve T and B cells. 4. The primed T‐helper (CD4+) and cytotoxic cells (CD8+) enter the blood system and return to the area of inflammation along with other inflammatory cells via adhesion molecules like intercellular adhesion molecule (ICAM)‐1 and vascular cell adhesion molecule (VCAM)‐1. 5. The primed T lymphocytes mature into various types of T‐helper (Th) cells, depending on which cytokines are produced by keratinocytes and dendritic cells. These mature T‐helper cells are responsible for amplifying the inflammatory response. 6. Primed T‐helper cells are also able to prime B cells in the skin that are displaying the same antigen in association with MHC on the B cell’s surface. The B cell will then mature into plasma cell and produce immunoglobulins against that antigen. CF, chorion factor; IFN, interferon; IL, interleukin; M, macrophage; NK, natural killer cell; NO, nitric oxide; TGF, transforming growth factor; TNF, tumor necrosis factor.

Melanocytes and Langerhans cells are the other major immunologically active cell types in the epidermis. Melanocytes’ major function is the production of melanin to protect keratinocytes from the harmful effects of ultraviolet radiation (UVR). However, they also play an important regulatory role in both the innate and adaptive immune systems by promoting phagocytosis and producing a series of pro‐inflammatory cytokines. Like keratinocytes, they can also express various pattern‐recognition receptors such as Toll‐like receptors.

Langerhans cells and dermal dendritic cells are the most important antigen‐presenting cells in the skin, as they are the only cells able to activate naïve T lymphocytes. Depending on the microenvironment and the immunologic triggers present, Langerhans cells can mediate a tolerogenic response through the production of interleukin 10 (IL‐10), or they can promote an inflammatory response. Once in contact with an invader, Langerhans cells phagocytose the antigen, process it, and represent it on their surface in association with MHC‐II. This causes the maturation of the Langerhans cells, which then migrate to the regional lymph node to prime naïve T lymphocytes.

The epidermis also hosts resident memory T lymphocytes, part of the adaptive immune system. These cutaneous memory T lymphocytes may possess either α/β or γ/δ T‐cell receptors. Those with γ/δ receptors are considered a hybrid between an innate and an adaptive immune cell. They bind to common PAMP molecules or respond to the class Ib MHC molecules produced by stressed, cancer‐, or virus‐infected cells.