Diagnostics and Therapy in Veterinary Dermatology. Группа авторов

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.

Subcutis

The subcutaneous tissue is mainly composed of fat and the primary cell type is the adipocyte. This tissue is highly innervated and vascularized. Historically, adipocytes’ only functions were thought to be energy storage, protection, and thermogenesis; however, new evidence suggests that adipocytes can play an important role in local and systemic immunity. Adipocytes express various innate immune receptors such as Toll‐like receptors and Nod‐like receptors. They can secrete inflammatory cytokines and can serve as antigen‐presenting cells for lymphocytes.

Defense from Harmful Substances

      Acids, bases, free radicals, UVR, and natural or synthetic poisons are not always avoidable, thus the immune system is essential for protecting the host from these harmful substances. While it is intuitive that the innate immune system would protect against toxins and chemicals, both adaptive and immune responses are involved. Solar UVR causes formation of damaging free radicals. Natural moisturizing factors in the stratum corneum (specifically urocanic acid), keratinocyte DNA, and Langerhans cells all function as chromophores that absorb the UVR. When the UVR is absorbed, these cells produce TNF‐ α, IL‐10, and IL‐4 that encourage an adaptive immune response. TNF‐α and IL‐10 limit the recruitment of inflammatory cells to ensure an environment with just enough neutrophils and NK cells to eliminate any pathogens breaking through the temporarily damaged skin barrier.

Dysfunction of the Immune System

      The immune system is a marvelous and extremely complex machine able to recognize and respond to an innumerable number of stimuli. Occasionally the system produces an excessive or inappropriate response to a stimulus, and this is the basis of hypersensitivity reactions.

      Type I (Immediate) Hypersensitivity Reaction

      Type I hypersensitivity is an acute inflammatory response to antigens (allergens) recognized by IgE receptors on tissue mast cells. Once the allergen cross‐links several IgE molecules, the mast cell degranulates, releasing inflammatory mediators into the surrounding tissue and causing acute inflammation. This type of hypersensitivity is typical of allergic reactions such as anaphylaxis.

      Type II (Cytotoxic) Hypersensitivity Reaction

      Type II hypersensitivity reactions are characterized by the presence of antibodies (mainly IgG) and complement proteins attached to host cells, which leads to the destruction of these cells. This type of hypersensitivity reaction is characteristic of autoimmune diseases. Medications, vaccinations, pathogens, toxins, and neoplasia can alter host cell morphology, thereby signaling that the cell is foreign rather than self; however, many autoimmune diseases occur without any known trigger. Pemphigus foliaceus is a common cutaneous autoimmune disease in which IgG antibodies are formed against desmosomal proteins, the attachment structures of keratinocytes.

      Type III (Antigen–Antibody Complex) Hypersensitivity Reaction

      Immune complexes are antigens bound to their antibodies. When excessive amounts of antigen are present in the body, more complexes than can be cleared efficiently by the body are formed. These complexes precipitate in tissue in large amounts and cause severe inflammation. The antigen–antibody complexes may remain at the initial site of attack or move through the bloodstream and lodge in distant locations such as capillaries or renal glomeruli. Once in the tissue, they trigger the accumulation of neutrophils, which release oxidants, inflammatory mediators, and enzymes that trigger additional inflammation and tissue damage. This type of hypersensitivity reaction is seen in many tick‐borne diseases and leishmaniasis, as well as autoimmune diseases such as systemic lupus erythematosus and vasculitis.

      Type IV (Delayed or Cell‐Mediated) Hypersensitivity Reaction

      Delayed hypersensitivity reactions involve Th lymphocytes, macrophages, and cytotoxic T lymphocytes. Delayed‐type hypersensitivities are induced by chronic intracellular infectious disease agents such as Mycobacteria spp. or Leishmania spp., as well as contact