Mechanisms of Disease, Lecture 2
January 12th, 2006
- Innate and Adaptive Immunity
- Two Arms of the Human Immune System
- Response to Infection
- Innate immunity:
- Immunity present from birth
- Adaptive immunity:
- Specific to known pathogens and antigens: immune "memory".
- Acquired by exposure to pathogens and antigens
- Development of adaptive immunity is dependent on RAG-modulated recombination in B and T cells.
- One source of adaptation is modification of antibodies by somatic mutation.
- Adaptation is a source of memory, since cells which have been upregulated by a specific immune insult maintain their specificity.
- Antigen-specific T cell-B cell interaction generates long-lived antigen-specific plasma cells, memory B cells, and memory T cells.
- Many barriers prevent pathogens from crossing epithelia and colonizing tissues.
- Mechanical barriers include the tight junctions between epithelial cells, the mucociliary elevator of the respiratory system, and longitudinal flow of air and fluids which sweep away potential pathogens.
- Chemical barriers include acidity (low pH), salivary, lacrymal, and digestive enzymes, antibacterial peptides, and fatty acids.
- Normal microbiota assist in preventing infection by competing with possible pathogens.
- The skin is home to a large number of benign and beneficent bacteria. If these bacteria are removed (say, by antibacterial soaps), possibility of pathogenic recolonization increases.
- As well, epidermal bacteria are important to the production of some chemical barriers.
- Initial response to an infection occurs in three phases:
- Innate immunity (first four hours), in which infectious agents are recognized and removed by preformed, nonspecific effectors.
- Early induced response (first four to ninety-six hours), which involves recognition of microbial molecular patterns, inflammation, recruitment and activation of effector cells, and subsequent removal of the infectious insult.
- Adaptive immunity (beyond ninety-six hours), which involves transportation of the antign to lymphoid organs, its recognition by naive B and T cells, clonal expansion and differentiation of matching cells, and the agent's subsequent removal.
- Macrophages are activated by pathogens and both engulf them and initiate inflammatory responses.
- They recognize bacteria generically through "pattern recognition receptors," such as CD14 (LPS receptor), mannose receptor, and glucan receptor.
- Mannose-binding lectin recognizes bacterial surfaces by their particular spacing of carbohydrate residues.
- Natural antibodies secreted by B-1 B cells bind carbohydrate antigens such as bacterial polysaccharides.
- The complement pathway can be activated by antigen-antibody complexes, mannose-binding lectin binding of bacteria, and simply pathogen surfaces.
- Assembly of the membrane-attack complex generates a pore in the lipid bilayer membrane of the bacteria.
- Toll-like receptors expressed by antigen-presenting cells sense and transduce danger signals, eliciting an adaptive immune response.
- Infection stimulates macrophages to release cytokines and chemokines, which in turn elicit an inflammatory response.
- Cytokines are small protens released by various cells in response to an activating stimulus.
- They induce a response by binding to specific receptors on responder cells.
- Activated macrophages release a range of cytokines with various local and long-distance effects:
- Release of TNF-α (alpha) by macrophages induces local protective effects, but it can have damaging effects when released systemically.
- Endothelial cells express adhesion molecules upon exposure to inflammatory cytokines, assisting extravasation of white blood cells through endothelia.
- Chemokines are a family of proteins that bind chemokine receptors, a large family of G-protein coupled receptors.
- Chemokines are released by phagocytes and dendritic cells to recruit other cells to an infection site.
- Chemokines are chemotactic agents which attract T cells.
- T-cell activation requires both antigen and co-stimulatory signals.
- In absence of co-stimulation (probably by Toll-like receptors), a naive T-cell recognizes its antigen but becomes unresponsive.
- Such a design helps preclude autoimmunity, since even those self antigens which are recognized by mature naive T cells are unlikely to stimulate Toll-like receptors.
- Dendritic cells are directly activated by pathogens, and can them prime antigen-specific T cells.
- Activated antigen-specific T cells induce proliferation and differentiation of like-specificity B cells.
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