Psoriasis slide A common scaly and inflammatory skin disorder that is both painful and disabling Thought to be an autoimmune disease with a possible genetic link The activation of T cells is the key trigger Psoriasis Psoriasis is a common, chronic remitting and relapsing scaly and inflammatory skin disorder that is both painful and disabling Skin cells multiply and accumulate faster than they can be sloughed off Thought to be an autoimmune disease with a possible genetic link Autoimmunity is a misdirected immunologic response against a person’s own tissues The key trigger is the activation of T cells (see next slide), which: stimulates keratinocytes to hyperproliferate and differentiate abnormally causes inflammatory infiltration in the dermis and epidermis

CD8+ cytotoxic (‘killer’) T cell T cells slide CD4+ T helper cell CD8+ cytotoxic (‘killer’) T cell Thymus CD8+ T cell Pre T cells T suppressor cell T cells T cells are lymphocytes involved in the cell mediated immune response Unlike B cells, which react to extracellular antigens (substances that trigger the immune system), T cells respond only to a specific antigen that has already been processed by a phagocytic cell T cells develop from pre-T cells that originate in red bone marrow and migrate into the thymus While in the thymus, the pre-T cells mature and acquire several distinctive surface proteins; they then exit as either CD4+ or CD8+ T cells (i.e. display either a protein called CD4 or one called CD8 on their membrane) These two types of T cells (called T4 and T8 cells) have very different functions Helper T cells are mainly derived from T4 cells They amplify the immune response by secreting chemicals such as cytokines (discussed in slides 5–6) and helper factor These chemicals increase the proliferation of B cells, enhance phagocytosis, stimulate other helper T cells, cytotoxic and memory T cells and activate natural killer (NK) cells Cytotoxic (or ‘killer’) T cells that display the CD8 protein destroy infected or foreign cells by breaking down the cell membrane However, in order to be able to destroy cells, cytotoxic T cells require the presence of co-stimulatory molecules produced by the helper T cells Suppressor T cells secrete chemicals that suppress the production of antibodies from B cells and so play an important role in controlling and ‘switching off’ the immune response Memory T cells ‘remember’ the original invading antigen and mount a swift reaction if this antigen reappears Memory T cell

Activation of cytotoxic T cells slide Antigen presenting cell Cytotoxic T cell Activated T cell IL-6, IL-8 Activation TNF- Activation of cytotoxic T cells Cytotoxic T cells are activated by the interaction with an antigen that is displayed on the surface of the phagocytic cell (called the antigen presenting cell, APC) APCs include macrophages, B cells and dendritic cells (e.g. Langerhans cells), present in the skin and in mucous membranes Activation of T cells also requires the presence of co-stimulatory molecules such as intracellular adhesion molecule (ICAM)-1 Once activated, T cells release several types of cytokines, including tumour necrosis factor (TNF), interleukin (IL)-6, IL-8, interferon gamma (IFN-) and granulocyte macrophage colony stimulating factor (GM-CSF) T cell receptor Antigen GM-CSF Interferon-

Common cytokines Main function Cytokine TNF (alpha and beta) IL-6 IL-8 slide Main function Cytokine TNF (alpha and beta) IL-6 IL-8 GM-CSF IFN- Stimulates accumulation of neutrophils and macrophages at sites of inflammation Stimulates cells to produce proinflammatory cytokines Induces synthesis of CSF by endothelial cells and fibroblasts Affects B-lymphocytes, T-lymphocytes and hybridoma cells Affects cytotoxic T-cells in combination with other factors such as IL-2 and gamma interferon Promotes neutrophil chemotaxis and degranulation Potent species-specific stimulator of bone marrow cells Stimulates precursor cells of granulocytes, macrophages and eosinophils Possesses potent anti-viral activity Has also been shown to stimulate macrophages and natural killer (NK) cells Common cytokines and main functions Tumour necrosis factor (TNF): Produced mainly by activated macrophages, but also by monocytes, lymphocytes (i.e. T cells) and injured keratinocytes Stimulates accumulation of neutrophils and macrophages at sites of inflammation and stimulates their killing of microbes Stimulates the production of proinflammatory cytokines Induces the synthesis of colony-stimulating factors (CSF, which stimulate the development of white blood cells) by endothelial cells and fibroblasts Interleukin (IL)-6: A potent lymphoid cell growth factor Affects B-lymphocytes, T-lymphocytes and hybridoma cells (cells formed by fusion of normal lymphocytes and tumour cells) Affects cytotoxic T-cells in combination with other factors such as IL-2 and interferon gamma IL-8: Mainly secreted by monocytes and lymphocytes Promotes neutrophil chemotaxis (attraction of phagocytes to microbes by a chemical stimulus) and degranulation Granulocyte macrophage colony stimulating factor (GM-CSF): A potent species-specific stimulator of bone marrow cells Stimulates precursor cells of granulocytes, macrophages and eosinophils Interferon gamma (IFN-): A lymphoid factor that possesses potent anti-viral activity Has also been shown to stimulate macrophages and natural killer (NK) cells

Immunological cascade in psoriasis slide Proinflammatory cytokines magnify effects TNF- GM-CSF IL-1 IL-8 Epidermis Dermis TNF- activated endothelium Blood vessel Cytokines increase keratinocyte proliferation, decrease their maturation and trigger inflammation Immunological cascade As already mentioned, the two major pathological lesions seen in psoriasis are: Thickening of the epidermal layer, with abnormal distribution of the proliferating and differentiating cells In addition, the terminal differentiation of keratinocytes in psoriasis leads to excessive cornification, resulting in the hardened lesions Inflammatory infiltration in the dermis and epidermis These processes are mainly driven by activated T cells or antigen-presenting cells (APCs) such as macrophages or Langerhan’s cells When T cells recognise an unidentified antigen in the skin, they attack the areas where the antigen is found When in the blood, the T cells ‘roll’ along the endothelium until they encounter the APC The interaction between the cells activates the T cells, which then release various cytokines These cytokines signal the keratinocytes to hyperproliferate, ultimately leading to abnormal proliferation The cytokines are also involved in the inflammatory response The cytokines include TNF-α, IL-6, IL-8, GM-CSF and interferon gamma TNF-α is also released by injured keratinocytes The activated T cells then ‘spread’ along the endothelium via interaction with intracellular adhesion molecules (ICAM)-1 on the endothelial cells Finally, the activated T cells migrate through the endothelium into the skin and activate epidermal keratinocytes 3. Arrest/ spreading 4. Migration into skin 1. Rolling 2. Activation