Diagnostics and Therapy in Veterinary Dermatology. Группа авторов

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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.

Schematic illustration of adaptive skin immune system.

      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.

      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.

      The dermis is mainly composed of extracellular matrix proteins that provide structure and elasticity to the skin. It is separated from the epidermis by the basal membrane, a thin layer of extracellular matrix proteins. This membrane regulates the movement of cells and substances from the dermis to the epidermis and anchors the basal epidermal keratinocytes to the dermis via hemidesmosomes. The dermis contains hair follicles, glandular structures, specialized neural receptors, as well as blood and lymphatic vessels essential for the support and maintenance of dermal and epidermal cells.

      Fibroblasts are the most abundant immunologically active cells in the dermis. Their primary function is production of the extracellular matrix that provides structural support for the dermis and a scaffolding that allows cells of the immune system to move easily through the dermis. Fibroblasts secrete a variety of cytokines, including chemoattractants for T lymphocytes, and direct the inflammatory response that is part of wound healing. Fibroblasts produce matrix metalloproteinases, a group of enzymes responsible for the degradation of the extracellular matrix, but they also produce tissue inhibitors of matrix metalloproteinases. Therefore, fibroblasts facilitate both activation and termination of inflammation.

      Endothelial cells and neurons are also essential for the dermal immune response. Endothelial cells regulate the influx of inflammatory cells from the blood into the dermis through the activation of adhesion molecules and cytokines. During the initial phase of inflammation, endothelial cells activate multiple Toll‐like receptors and various adhesion molecules, including intercellular adhesion molecule‐1 (ICAM‐1), vascular cell adhesion molecule‐1 (VCAM‐1), and selectins E and P. As the inflammatory response progresses, endothelial cells secrete more pro‐inflammatory cytokines such as IL‐1, tumor necrosis factor alpha (TNF‐α), and interferon gamma (IFN‐γ), which in turn increase the expression of adhesion molecules to further facilitate leukocyte migration and extravasation.

      Nerves are important for sensation and they also have an intimate connection with memory T cells. Neurons modulate signals between the innate and adaptive branches of the immune system by producing substance‐P, calcitonin gene‐related peptide, and alpha melanocyte‐stimulating hormone. These substances support a healthy level of inflammation and help to resolve the inflammatory response when needed.

      The dermis is home to other cells of the innate immune system (granulocytes, NK cells, dendritic cells, macrophages) and lymphocytes (adaptive immune system cells). Neutrophils and macrophages are part of the first line of defense against microorganisms. As soon as an invader is detected, these cells are called to the site of infection by potent chemoattractants. Once there, they express receptors that recognize, bind, capture, and phagocytose microorganisms. Neutrophils are also able to externally project their DNA and DNA‐associated proteins to form “sticky” neutrophil extracellular traps (NETs) that trap pathogens like flies on a spider’s web.

      Macrophages are a bridge between the innate and adaptive arms of the immune system. In addition to phagocytosing microorganisms, macrophages remove debris, dead cells, and exogenous or endogenous inflammatory stimuli (e.g. free melanin or keratin). They also act as antigen‐presenting cells. Macrophages can recognize, bind, capture, and destroy microorganisms directly or via their recognition of antibody molecules, complement proteins, or lectins. Macrophages secrete various cytokines that direct the immune response. Different types of macrophages have recently been identified: M0, M1, M2, M4, M17, and Mreg. M1 macrophages secrete TNF‐α, IL‐6, and IL‐12, cytokines that promote a T‐helper type 1 pro‐inflammatory immune response. M2 macrophages promote an anti‐inflammatory immune response through the secretion of IL‐10 and IL‐4. M4 macrophages secrete TNF‐α, IL‐6, matrix metalloproteinases 7 and 12, and macrosialin, all of which reduce phagocytosis and induce a pro‐inflammatory immune response. Finally, M17 and Mreg cells have been proposed, but their characterization and involvement in the inflammatory process need further clarification.

      Mast cells in the skin are highly associated with blood vessels and have both immunoglobulin (Ig) E and complement receptors on their surface. Upon activation, mast cells release a variety of vasoactive and pro‐inflammatory substances, including histamine, serotonin, proteases, leukotrienes, prostaglandins,


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