Presentation on theme: "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."— Presentation transcript:
1 PsoriasisslideA common scaly and inflammatory skin disorder that is both painful and disablingThought to be an autoimmune disease with a possible genetic linkThe activation of T cells is the key triggerPsoriasisPsoriasis is a common, chronic remitting and relapsing scaly and inflammatory skin disorder that is both painful and disablingSkin cells multiply and accumulate faster than they can be sloughed offThought to be an autoimmune disease with a possible genetic linkAutoimmunity is a misdirected immunologic response against a person’s own tissuesThe key trigger is the activation of T cells (see next slide), which:stimulates keratinocytes to hyperproliferate and differentiate abnormallycauses inflammatory infiltration in the dermis and epidermis
2 CD8+ cytotoxic (‘killer’) T cell T cellsslideCD4+ T helper cellCD8+ cytotoxic (‘killer’) T cellThymusCD8+ T cellPre T cellsT suppressor cellT cellsT cells are lymphocytes involved in the cell mediated immune responseUnlike 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 cellT cells develop from pre-T cells that originate in red bone marrow and migrate into the thymusWhile 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 functionsHelper T cells are mainly derived from T4 cellsThey amplify the immune response by secreting chemicals such as cytokines (discussed in slides 5–6) and helper factorThese chemicals increase the proliferation of B cells, enhance phagocytosis, stimulate other helper T cells, cytotoxic and memory T cells and activate natural killer (NK) cellsCytotoxic (or ‘killer’) T cells that display the CD8 protein destroy infected or foreign cells by breaking down the cell membraneHowever, in order to be able to destroy cells, cytotoxic T cells require the presence of co-stimulatory molecules produced by the helper T cellsSuppressor 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 responseMemory T cells ‘remember’ the original invading antigen and mount a swift reaction if this antigen reappearsMemory T cell
3 Activation of cytotoxic T cells slideAntigen presenting cellCytotoxic T cellActivated T cellIL-6, IL-8ActivationTNF-Activation of cytotoxic T cellsCytotoxic 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 membranesActivation of T cells also requires the presence of co-stimulatory molecules such as intracellular adhesion molecule (ICAM)-1Once 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 receptorAntigenGM-CSFInterferon-
4 Common cytokines Main function Cytokine TNF (alpha and beta) IL-6 IL-8 slideMain functionCytokineTNF (alpha and beta)IL-6IL-8GM-CSFIFN-Stimulates accumulation of neutrophils and macrophages at sites of inflammationStimulates cells to produce proinflammatory cytokinesInduces synthesis of CSF by endothelial cells and fibroblastsAffects B-lymphocytes, T-lymphocytes and hybridoma cellsAffects cytotoxic T-cells in combination with other factors such as IL-2 and gamma interferonPromotes neutrophil chemotaxis and degranulationPotent species-specific stimulator of bone marrow cellsStimulates precursor cells of granulocytes, macrophages and eosinophilsPossesses potent anti-viral activityHas also been shown to stimulate macrophages and natural killer (NK) cellsCommon cytokines and main functionsTumour necrosis factor (TNF):Produced mainly by activated macrophages, but also by monocytes, lymphocytes (i.e. T cells) and injured keratinocytesStimulates accumulation of neutrophils and macrophages at sites of inflammation and stimulates their killing of microbesStimulates the production of proinflammatory cytokinesInduces the synthesis of colony-stimulating factors (CSF, which stimulate the development of white blood cells) by endothelial cells and fibroblastsInterleukin (IL)-6:A potent lymphoid cell growth factorAffects 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 gammaIL-8:Mainly secreted by monocytes and lymphocytesPromotes neutrophil chemotaxis (attraction of phagocytes to microbes by a chemical stimulus) and degranulationGranulocyte macrophage colony stimulating factor (GM-CSF):A potent species-specific stimulator of bone marrow cellsStimulates precursor cells of granulocytes, macrophages and eosinophilsInterferon gamma (IFN-):A lymphoid factor that possesses potent anti-viral activityHas also been shown to stimulate macrophages and natural killer (NK) cells
5 Immunological cascade in psoriasis slideProinflammatory cytokines magnify effectsTNF-GM-CSFIL-1IL-8EpidermisDermisTNF- activated endotheliumBlood vesselCytokines increase keratinocyte proliferation, decrease their maturation and trigger inflammationImmunological cascadeAs already mentioned, the two major pathological lesions seen in psoriasis are:Thickening of the epidermal layer, with abnormal distribution of the proliferating and differentiating cellsIn addition, the terminal differentiation of keratinocytes in psoriasis leads to excessive cornification, resulting in the hardened lesionsInflammatory infiltration in the dermis and epidermisThese processes are mainly driven by activated T cells or antigen-presenting cells (APCs) such as macrophages or Langerhan’s cellsWhen T cells recognise an unidentified antigen in the skin, they attack the areas where the antigen is foundWhen in the blood, the T cells ‘roll’ along the endothelium until they encounter the APCThe interaction between the cells activates the T cells, which then release various cytokinesThese cytokines signal the keratinocytes to hyperproliferate, ultimately leading to abnormal proliferationThe cytokines are also involved in the inflammatory responseThe cytokines include TNF-α, IL-6, IL-8, GM-CSF and interferon gammaTNF-α is also released by injured keratinocytesThe activated T cells then ‘spread’ along the endothelium via interaction with intracellular adhesion molecules (ICAM)-1 on the endothelial cellsFinally, the activated T cells migrate through the endothelium into the skin and activate epidermal keratinocytes3. Arrest/ spreading4. Migration into skin1. Rolling2. Activation
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