Beruflich Dokumente
Kultur Dokumente
Reviews Of Interest: Basic Background: NEJM 2000 343 (1) pp 37-49; & pp 108-117 NEJM 2001 344 (9) pp 655-664 Psoriasis: Nature 2007 455 pp 866-873 Autoimmunity: Nature 2005 435 pp 583-627
Learning Objectives
Knowledge of innate (passive) and adaptive (active) immunity, barrier properties of the skin, key cell types involved, how different pathogens trigger immune responses. How skin structure, immunosuppression, ageing and sunlight affect the immune response. Understand the pathophysiology of the skin immune system in relation to barrier function and inappropriate immune response such as hypersensitivity and autoimmunity.
Immune System
Defence
Non-specific (innate) immunity Specific (adaptive) immunity
Antigen (Ag) = Usually a protein/peptide or polysaccharide that elicits an immune response (antibody generator)
Stratum Corneum/Keratinocytes
Outer layer of the skin. Formed by terminal differentiation of keratinocytes (KC) to corneocytes. Filaggrin/Involucrin/keratin Antimicrobial peptides
Eg. defensins
Lipid-rich barrier
T Cells (Lymphocytes)
Produced in bone marrow Sensitised in thymus Basis of cell-mediated immunity
Many subgroups exist , including: Helper T Cells: CD4+ Th1: Activate macrophages to destroy microorganisms IL2, IFN Th2: Help B cells to make Ab IL4, IL5, IL6
Mast Cells
Location : Dermis especially
Activated by: IgE-Ag binding (allergy) Physical trauma, drugs Microbes, fungi & parasites
Granules: Preformed mediators include: Tryptase, chymase, TNF, histamine Newly synthesised mediators include: IL (3,5,6,8,13,16,18), TNF, TGF , IFN , PGD2, PGE2, LTB4, LTC4, VEGF, bFGF, IP-10, MIP-1 , MIP-1 .
Neutrophils
Recruited to the sites of injury/bacterial infection and some cancers by chemotactic mediators released by other cell types (IL-8, IFN- ).
Cytokines Phagocytes Reactive intermediates
B Cells (Lymphocytes)
Produced in bone marrow (act. Bursa of fabricus) Produce antibodies (Ab or Ig =immunoglobulin) Basis of humoral immunity
B cells make Ab molecules with a unique Ag binding site Abs are initially inserted into the B cell plasma membrane, where they act as Ag receptors.
Ag binding to the receptors activate the B cell, usually with the help of a TH cell, to proliferate and mature into memory cells and Ab-secreting plasma cells.
Psoriasis
Common & complex (2-3% globally). Genetic & environmental factors involved
(Twin studies; Koebner phenomenon; infection; interferon therapy; drugs).
T-cell dependent disease. Hallmark of skin lesions is inflammation. Plaques are reversible. Adaptive and innate immune system cells involved in pathogenesis.
Psoriasis
CD4+ Th1 cells (INF ) CD4+ Th17 (IL-17) Keratinocytes DC MC Neutrophils Macrophages
Activation of T cells and their secreted products. Aberrant KC terminal differentiation: failure of corneocytes to stack. Neutrophils & inflammatory cells infiltrate the SC, epidermis & dermis. Dilated blood vessels: erythema. Factors produced by KC directly affect Tcells & DC...and vice versa.
Atopic Eczema
Commonest in children. Genetic & environmental factors involved
(Twin studies; Koebner phenomenon; infection; drugs).
No cure.
Antibody mediated: IgE. Early exposure to allergen causes the production of IgE, which binds to Fc R1 receptor on the MC. Later exposure causes rapid crosslinking of the receptors, signal transduction and degranulation of the MC. Ag binding causes degranulation of mast cells and basophils Very rapid early response: minutes (wheal & flare) Late response: hours (cellular infiltration, nodule) Pollen (birch, oilseed rape) Drugs (penicillin) Food (nuts, eggs, seafood) Insects & animals (bee sting, cat hair)
Skin testing in type III hypersensitivity leads to an Arthus reaction, which is slower than a type I skin response, but faster than a type IV skin response
Type IV hypersensitivity
Cell mediated: TH1 cells Delayed type hypersensitivity is based on a Tcell/Ag interaction, which then recruits other cells to the site
Tuberculin reaction Contact allergy
Immunosuppression
Ageing
Changes in skin structure (access) Decreased ability to detect malignant cells- Cancer Decreased ability to detect Ag- Infection risk - - Autoimmunity Vaccinations (eg. flu) less effective and not as long lasting
Immune Response
Immune response elicited depends on how the immune This impacts on the chemical mediators (cytokines, chemokines, leukotrienes etc) which are released by the cell. These mediators influence the behaviour of the neighbouring cells and other immune cell types (eg. attracting neutrophils to site of infection), and thus the type of immune response which is launched. Inappropriate activation of the immune system can result in chronic inflammation seen in some skin conditions including psoriasis, atopic eczema and some skin cancers.