Читать книгу Diagnostics and Therapy in Veterinary Dermatology - Группа авторов - Страница 17

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.

Eosinophils are more abundant in the later stages of inflammation. They are important in the pathogenesis of allergic and parasitic diseases, both driven by T‐helper type 2 cytokines. Once eosinophils reach the site of inflammation, they release granular proteins highly toxic to parasites. Eosinophils are also essential in secreting cytokines characteristic of an allergic response. Finally, eosinophils release prostaglandins and leukotrienes that cause vasodilation and chemotaxis of neutrophils and prolong an allergic response. Eosinophils have a very strong connection with mast cells, mononuclear granulocytes essential for the allergic response and wound healing.

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, and cytokines. Along with pro‐inflammatory mediators, mast cells also secrete large quantities of transforming growth factor beta (TGF‐β), platelet‐derived growth factor (PDGF), and fibroblast growth factors (FGFs), all of which are essential mediators of tissue repair.

NK cells and dendritic cells represent the other innate immune cells present in the dermis. NK cells are lymphocytes that express neither T‐ nor B‐cell receptors. Until recently, they were thought to belong exclusively to the innate immune system because of their ability to recognize patterns more than specific antigens. However, more recent studies have shown that NK cells have memory, making them part of the adaptive immune system. Another peculiarity of NK cells is their ability to recognize MHC‐I on cell surfaces. This ability makes NK cells the major sentinel cells in the recognition of virally infected or cancerous cells. Finally, NK cells can bind IgG‐coated pathogens and cells (antibody‐dependent cellular cytotoxicity), leading to the release of cytotoxins (granzyme, granulysin, and perforin), which kill the infected cell. Another cell that has characteristics of both innate and adaptive immunity is the NK T cell, which is a hybrid between T cells and NK cells.

Dendritic cells are found in the dermis as well as the epidermis. They reside in the upper dermis just below the basal membrane. Dermal dendritic cells along with Langerhans cells in the epidermis are the major antigen‐presenting cells of the skin. They deliver processed antigen to lymph nodes to prime naïve T lymphocytes of the adaptive immune system. Once dermal dendritic cells are stimulated by antigen, they begin the maturation process, which involves a decrease in their phagocytic ability and an increase in expression of MHC‐II glycoproteins, increasing their antigen‐presenting function. Mature dermal dendritic cells are also able to redirect the local immune response through the secretion of inflammatory cytokines. In addition, they can express epithelial cell adhesion molecules and stimulate the transformation of B lymphocytes into plasma cells.

The dermis is also home to B and T lymphocytes, the major cells of the adaptive immune system. It has been estimated that the healthy dermis contains twice as many lymphocytes (~20 billion T cells) as there are in the blood. Most of these dermal lymphocytes are a heterogeneous population of T memory lymphocytes, including T‐helper (Th) type 1, 2, and 17, and T‐regulatory cells (Treg). More recently, Th3, 9, 22, and 25 lymphocytes have also been identified. These cells form an intricate network of resident adaptive immune cells ready to act in case of exposure to previously encountered antigens. They are mainly localized around capillaries, the dermoepidermal junction, and hair follicles and glands. Each one of these T‐cell subsets produces a specific pattern of cytokines. Th1 cells are mainly involved in fighting infection with intracellular microorganisms and secrete IFN‐γ, which activates macrophages. Th2 cells are mainly involved in fighting infections with extracellular microorganisms and allergies and secrete IL‐4 and IL‐13. Th17 cells are mainly involved in the inflammatory response against bacteria and fungi, and their role in atopic dermatitis and other cutaneous inflammatory diseases is being investigated. Th17 cells secrete IL‐17 and IL‐22. Th22 cells secrete only IL‐22, so are considered by some to be a subset of Th17 cells. Th22 cells are essential for keratinocyte proliferation and, like Th17 cells, are involved in atopic dermatitis and other inflammatory skin diseases. Treg cells secrete IL‐10 and TGF‐β. This subset of T lymphocytes is mainly involved in the suppression of the inflammatory response and plays a fundamental role in decreasing the immune response once the trigger has been eliminated. Alterations in the number of Treg cells and their characteristics have been associated with allergic and inflammatory skin diseases.

B lymphocytes are also found in the dermis, but in much lower numbers than T cells. B lymphocytes have multiple roles in the immune response besides producing antibodies once they have transformed into plasma cells. They express MHC‐II glycoproteins so they can present antigens, and they produce a variety of cytokines affecting both local and systemic immune responses. Recent evidence suggests that skin‐associated B cells may play a significant role in host defenses, regulation of microbes, and wound healing.