Cutaneous Immune System PDF

The Skin: The Cutaneous Immune System Dr. Noha M. Elemam B Pharm, Msc., Ph.D., Dr. rer. hum. biol Year 1 Week 8 Man & His Environment Unit 16th October 2023  Learning Objectives 1. Cutaneous Immune System 2. Elements of Ski...

The Skin: The Cutaneous Immune System Dr. Noha M. Elemam B Pharm, Msc., Ph.D., Dr. rer. hum. biol Year 1 Week 8 Man & His Environment Unit 16th October 2023  Learning Objectives 1. Cutaneous Immune System 2. Elements of Skin Innate Immunity 3. Review: TLRs 4. Review: Complement 5. Immune Players in the Skin: Langerhans Cells 6. Immune Players in the Skin: T Cells 7. Inflammation Process 8. Immune Reaction to Infection  Cutaneous Immune System The skin is the largest organ of the body, and in humans, there may be up to 106 immune cells/cm2. Part of innate immunity. The first line of defense is provided by epithelial barriers of the skin to block the entry of microbes. The immune system of the skin consists of most of the cells of innate and adaptive immunity. Thin outer epidermis and thick underlying dermis to impede entry and provide an effective barrier against microorganisms. Sebum, produced in sebaceous glands, is made of lactic acid and fatty acids that effectively reduce skin pH to 5.5, which inhibits organism growth. Elements of Skin Innate Immunity  Epithelial Barriers Keratin on the surface of the skin prevents most microbes from interacting with and infecting or getting through the epithelia. Epithelial cells also produce antimicrobial peptides including defensins and cathelicidins, which kill bacteria and some viruses by disrupting their outer membranes. Epithelia contain lymphocytes called intraepithelial T lymphocytes that belong to the T cell lineage. They recognize microbial lipids and react against infectious agents that attempt to breach the epithelia.  Innate Immune Components in Skin Most microbial infections are acquired through the epithelial barrier of the skin, gastrointestinal, respiratory and genitourinary systems. The earliest defense mechanisms active at these sites are epithelia, providing physical barriers and antimicrobial molecules, and lymphoid cells. Receptors of innate immunity have evolved to be specific for microbial structures. Pattern Recognition Receptors (PRRs) Toll-like Receptors (TLRs) Review: Toll Like Receptors  Review: Complement Once the complement cascade is initiated, the number of activated molecules increases, amplifying the reaction. Many complement proteins are present as inactive precursors, which are activated by either conformational changes or proteolytic cleavage by other complement proteins. Eventually, this leads to the generation of a rigid protein-lined transmembrane channel, the membrane attack complex (MAC).  Immune Players in the Skin Keratinocytes, express high levels of IL-1, which may be released when the skin is damaged, to promote inflammation and repair. Fibroblasts in the dermis respond to TNF⍺ by releasing IL- 15, which activates effector T cells.  Langerhans Cells Type of immature conventional dendritic cells that reside in the skin. Rich in MHC class II molecules and carry processed antigens. They are actively phagocytic and contain large granules known as Birbeck granules-which are an endosomal recycling compartment formed by the accumulation of langerin, a transmembrane lectin with mannose-binding specificity. Dermal DC Migration  Q. What function could the migration of Langerhans’ cells to the lymph nodes from the mucosa or skin serve? A. The migration of Langerhans’ cells provides an efficient mechanism for carrying antigens from the skin to the T helper cells in the lymph nodes. Lymph nodes provide the appropriate environment for lymphocyte proliferation.  Langerhans Cells Langerhans cells take up antigens in the skin, migrate to the peripheral lymphoid organs, and present foreign antigens to T cells.  T cells in the Skin T cells are present in normal skin and immune responses are characterized by T cell infiltration. T cells constitute the major cell type present both in normal skin and in immune reactions. They are characterized by a skin-homing marker CLA (cutaneous lymphocyte antigen) and the chemokine receptors. CLA is a sialylated molecule that binds to E-selectin/ELAM-1 (endothelial leukocyte adhesion molecule-1), a lectin-like molecule that is strongly expressed on endothelium in the skin. T cells in the Skin Types of T helper cells  Inflammation Inflammation is the response of tissue to injury, with the function of bringing serum molecules and cells of the immune system to the site of damage. Three components of the inflammatory response: 1. Increased blood supply to the region. 2. Increased capillary permeability. 3. Emigration of leukocytes from blood vessels into the tissues. Different players are involved in the inflammatory process including the complement, mediators released by mast cells, basophils, and platelets. Generally, neutrophils are the first cells to appear at acute inflammatory sites, followed by macrophages and lymphocytes. Immune Reaction to Infection  Immune Reaction to Infection Langerhans cells ingest microbes and are activated by bacterial LPS through the TLR signaling pathway. Bacterial LPS induces 2 changes in Langerhans cells, stimulating them to migrate and to initiate adaptive immunity by activating CD4 T cells. 1. Change in behavior and location. The activated Langerhans cells become migrating cells and enter the lymphatic system that drains the tissues. The migrating cells are carried to regional lymph nodes, where they become mature dendritic cells. 2. Drastic alteration in their cell-surface molecules. Resting Langerhans cells in the skin are highly phagocytic and macropinocytic but lack the ability to activate T lymphocytes. Mature dendritic cells in the lymph nodes have lost the ability to ingest antigen but have gained the ability to stimulate T cells. This is due to an increase in the number of MHC molecules on their surface and the expression of the co-stimulatory molecules such as CD86. Immune Reaction to Infection Immune-mediated Skin Diseases Hypersensitivity Atopic Dermatitis Psoriasis Pemphigus Lupus References