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Go Back to the Top 3 To Order, Visit the Purchasing Page for Details MEMO Clinical symptoms resulting from abnormalities of complements Various skin diseases, including those with systemic lupus erythematosus (SLE) like symptoms, Raynaud’s syndrome, angioneurotic edema and opportunistic infections, may be caused by congenital abnormalities and deficiencies of complementary proteins. B. Immunocompetent cells a. Immunocompetent cells in general 1. T cells T cells express T-cell receptors that recognize the antigen information associated with MHC molecules (Fig. 3.3). T cells are produced in the bone marrow and develop in the thymus. T cells are classified by function into CD4 positive helper T cells (helper T lymphocyte; Th) and CD8 positive cytotoxic T lymphocytes (Tc). Th contains CD4 on the cell surface, by which Th adheres to MHC class II. Therefore, Th reacts against antigen-presenting cells and B cells, which contain MHC class II. Th differentiates into subtype Th1 or Th2, depending on the surrounding cytokine environment (Fig. 3.3). Th1 secretes cytokines such as IL-2 and IFN-g , activating histiocytes (macrophages) primarily, and it induces cellular immunity by evoking various inflamatory reactions. Th2 secretes IL-4 and IL-5, activates antibody production in B cells, and inactivates foreign substances (humoral immunity). It is known that Th1 is involved mostly in type IV allergy while Th2 is involved in type I allergy (atopic diseases). Tc contains CD8, by which Tc is associated with MHC class I to initiate cytotoxic immunity (Fig. 3.3); in this way, non-self cells and virus-infected cells are destroyed. Tc is important in transplantation immunity, tumor immunity and viral infections. Recently, the presence of another subtype – regulatory T cell (Treg) – has been identified. Treg is considered to be involved in immune control, including suppression of autoimmune disease onset. It is also known that some Th and Tc circulate in the blood after an immune reaction to guard against re-infection. 2. B cells B cells derive from hematopoietic stem cells in the bone marrow, after which they differentiate. They react against foreign antigens in lymph nodes, the spleen, and peripheral tissues to differentiate into antibody-forming cells (plasma cells); B cells produce antibodies in this process. B cells contain MHC class II and B. Immunocompetent cells activate T cells as antigen-presenting cells. Immunoglobulins expressed on the surface of B cells react to the corresponding targeted antigens to convey information to T cells. When activated, most of the B cells differentiate into antibody-producing cells that provide antibodies against the antigens and die in the course of time – except for some that differentiate into memory B cells so that they are able to produce antibodies immediately upon reinfection. 3. Histiocytes (macrophages) Histiocytes (macrophages) are bone marrow-derived cells that have intense phagocytic reactivity. There are dermal-originated histiocytes and monocytes circulating in the blood. Histiocytes degrade phagocytosed antigen proteins into peptides and present the antigen information to T cells by MHC class II (Fig. 3.3). In inflammation, histiocytes proliferate, migrate to loci, leave various cytokines, and induce phagocytosis of causative factors and injure the infected cells. Histiocytes may fuse to form enlarged cells. They are the main cells to form granulomas in chronic inflammation (Chapter 2). 43 MEMO Th1 is involved in cytotoxic immunity, including apoptosis; Th2 is involved in humoral immunity, including type I allergy. Th1 and Th2 release mutually inhibitive cytokines; it is thought that this maintains a balance between the two (Th1/Th2 balance). In recent years, various allergies and malignant tumors have been explained by the concept of Th1/Th2 imbalance. For example, atopic dermatitis and type I allergy are thought to be caused by a Th2-dominated immune reaction, and organ-specific autoimmune diseases and arterial sclerosis are thought to result from a Th1-governed immune reaction. Th1/Th2 balance 4. Mast cells Mast cells play a central roll in type I allergy. They contain high-affinity IgE receptors (FceRI) and considerable amounts of histamines. When binded with IgE and further cross-linked by an antigen to react to IgE, mast cells are activated to release inflammatory cytokines that lead to dermal edema in erythema or urticaria. Mastcytosis is caused by tumorous proliferation of mast cells. 5. Eosinophils Eosinophils have phagocytic and cytotoxic functions. They are associated with atopic diseases (type I allergy), autoimmune blistering diseases, and parasitic infections. Eosinophils are activated by Th2-derived IL-5. Morphologically, they are characterized by having multiple eosinophilic granules (Fig. 3.5). They do not usually exist in normal skin. 20 m m Fig. 3.5 Eosinophil. The cytoplasm is eosinophilic (stained red in Hematoxylin-Eosin). Note the multiple nuclei. 6. Neutrophils Neutrophils are phagocytic and play a large role in fighting bacterial infections (Fig. 3.6). They are hardly ever found in normal skin. They are also activated in inflammatory diseases. Neutrophilic infiltration (pustule) is observed in psoriasis vulgaris and Sweet’s disease. 20 m m Fig. 3.6 Neutrophil. In skin, cytoplasm of neutrophils is less eosinophilic than that of eosinophils. A neutrophil has a multiple segmented nuclei. 3 44 3 Immunology of the Skin 7. Basophils 3 Like eosinophils and neutrophils, basophils are also granular leukocytes, and they contain multiple basophilic granules. They contain histamines in the granules and have FceRI on the surface. They are involved in type I allergy. The functions of basophils are similar to those of mast cells. b. Immunocompetent cells specific to skin 1. Langerhans cells Fig. 3.7 Langerhans cell electron micrograph. Langerhans cells are bone marrow-derived cells and appear as dendritic cells. They contain the characteristic racquet-shaped Birbeck granules in the cellular cytoplasm (Figs. 3.7 and 3.8). Langerhans cells are antigen-presenting cells that are specific to the skin. Langerhans cells adhere to the epidermal keratinocytes by E-cadherins, functioning as sentinels against foreign antigens. When presenting an antigen to T cells, Langerhans cells are known to detach from the epidermis to reach the regional lymph nodes through the lymphatic vessels (Fig. 3.9). On the surface of the human Langerhans cells are MHC class II, CD1a, and S-100 proteins; this is useful for identifying them. With stimulation by antigens, they express CD80 and CD86 by the functions of GMCSF and TNF-a secreted from keratinocytes to strongly activated T cells. Langerhans cells disappear in lesions in graft-versus-host disease (GVHD). 2. Keratinocytes Fig. 3.8 Birbeck granules (arrows). High-power magnification of Fig.3.7. Birbeck granules look like tennis racquets in sectional image. Keratinocytes are involved not only in cornification but also in skin immunity. They produce and secrete various cytokines to stimulate immuno-incompetent cell activation (Table 3.3). IL-1 a is particularly abundant in keratinocytes. When keratinocytes are destroyed by inflammation or injury, IL-1a is released to evoke activation of lymphocytes, histiocytes (macrophages), and vascular endothelial cells, which induces an inflammatory reaction. 3. Dermal dendrocytes Dermal dendrocytes are bone marrow-derived cells found in the upper dermal layers. Since dermal dendrocytes are characterized by expressing the factor XIIIa on their surface and have antigen-presenting ability, dermal dendrocytes are considered to be Langerhans-related cells in the dermis. They increase in number in inflammatory diseases and Kaposi sarcoma. C. Immunity, Allergic reactions 45 Table 3.3 Main cytokines secreted by keratinocytes. Classification, cytokines Main functions Multifunctional cytokines IL-1a IL-6 IL-7 IL-12 IL-15 IL-18 TNF-a MIF Induction of secondary cytokines 6444447444448 Interleukin (IL) Modulation of adhesion molecules Modulation of activation and migration of T cells, B cells and macrophages Activation of endothelial cells and fibroblasts Modulation of activation and migration of Langerhans cells (IL-1a, TNF-a) Induction of fever and acute inflammatory proteins Chemotactic factor: associated with leukocyte migration IL-8 Activation and migration of T cells and neutrophils Colony stimulating factor: associated with leukocyte proliferation GM-CSF Activation of granulocytes, macrophages, T cells and Langerhans cells G-CSF Proliferation of granulocytes M-CSF Proliferation of macrophages Growth factor: associated with local cutaneous reactions TGF-a Proliferation of keratinocytes b-FGF, PDGF Proliferation of fibroblasts and endothelial cells Suppression factor: modulates immunity TGF-b Suppression of keratinocytes and endothelial cells IL-10 Suppression of immunity through Th1 cells IL: interleukin, TNF: tumor necrosis factor, MIF: macrophage migration inhibitory factor, GM-CSF: granulocyte macrophage colony-stimulating factor, G-CSF: granulocyte colony-stimulating factor, M-CSF: macrophage colony-stimulating factor, TGF: tumor growth factor, b-FGF: basic fibroblast growth factor, PDGF: platelet derived growth factor C. Immunity, Allergic reactions Skin is a major organ where immune/allergic reactions occur. Various skin diseases have been increasingly understood by the concept of immunity and allergic reactions, which are generally classified into the four categories established by Coombs & Gell (Table 3.4). 1. Type I allergy Type I allergy is caused mainly by mast cells. Since a reaction occurs 5 to 15 minutes after an antigen (allergen) is administered, it is also called an immediate hypersensitivity. Mast cells with IgE on the surface react to antigens, and chemical mediators such as histamines and leukotrienes are then secreted by the mast cells (Chapter 8). These chemical mediators enhance vascular permeability, to produce edema; in addition, they induce migration of Go Back to the Top To Order, Visit the Purchasing Page for Details 3