1. Psoriasis
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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

2. CD8+ cytotoxic (‘killer’) T cell
T cells
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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

3. Activation of cytotoxic T cells
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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-

4. Common cytokines Main function Cytokine TNF (alpha and beta) IL-6 IL-8
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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

5. Immunological cascade in psoriasis
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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