The innate immune system

• 4 components

  1. physical barriers = epithelial surfaces

  2. cellular components = phagocytes and NK cells

  3. complement system and inflammation mediators

  4. cytokines
• epithelial surfaces


  - line skin, GI, respiratory and urinary tracts

  - secrete anti-microbial substances: defensins and mucus

  - secretion increased by cytokines (IL-1 and TNFa)

  - epithelia contain lymphocytes, mast cells and cilia
• phagocytes and NK cells

  1. neutrophils = multi-lobed nucleus, many organelles, phagocytosis

  2. macrophages = large cell + rounded nucleus, many organelles, phagocytosis

  3. dendritic cells = large cell + smaller nucleus:cytoplasm ratio, membrane protrusions, antigen presentation

  4. NK cells = smaller than macrophage, similar morphology, lysis of virally infected cells

  
• pattern recognition receptors


  proteins on or in cells that recognize specific compounds unique to microbes or tissue damage, allowing the cells to sense the presence of invading microbes or damage
• PRR examples


  1. mannose = carbohydrate not on human cells but in bacterial cell walls

  2. opsonins = coats bacteria/virus that enhances binding to receptors and increases phagocytosis

  3. toll-like = recognise epitopes on pathogen surfaces

  4. 7TMa helical = recognise peptide sequences on surfaces
• what does pathogen binding to receptors on innate cells result in?

  1. phagocytosis of pathogen by macrophages/neutrophils

  2. killing of infected cell by NK cells

  3. presentation to T cells by APCs (dendritic cells)
• toll-like receptors (TLR)


  - found on most cells of innate system

  - respond to microbial markers (e.g. LPS, dsRNA, PGs)

  - result in upregulation of inflammatory gene expression (TNFa, IL-1, IL-6)

  - TLR agonists could stimulate immune system to fight infection/cancer

  - TLR antagonists could dampen immune system for treatment of chronic inflammation
• LPS/endotoxin


  - released from bacterial cell walls following cell lysis

  - stimulates the innate system (TLR4)

  - induces local and systemic inflammation

  - potent activator of macrophages inducing cytokine release and reactive O2 bursts (good as increases immunity but bad if overstimulated)

  - could cause systemic inflammation response syndrome (SIRS) = fever, sepsis
• NK cells


  - appearance of large lymphocytes w/o TCR or membrane-bound Ig

  - recognise markers on surface of infected cells

  - perforins make holes in membrane allowing entry of granzyme

  - cell dies of apoptosis

  - NK cells activated by IL-12 from macrophages, IFNy activates macrophages

  - action inhibited by MHC class 1 binding inhibitory receptor on NK cell

  
• complement system


  - cascade of plasma proteins activated by microbes resulting in their destruction

  - zymogens = gain enzymatic activity by cleavage

  - 3 pathways = classical, alternative and lectin

  - all result in cleavage of C3-C3a and b leading to opsonisation and phagocytosis - C5a chemotactic for neutrophils

  - excessive activation causes high levels of inflammation and more severe prognosis
• cytokines


  - mediate many effector functions of innate system

  - small peptides released from immune cells to act in autocrine/paracrine manner

  - TNF/IL-1 = mainly produced by LPS challenged macrophages, pro inflammation cytokines and stimulate neutrophil migration to infection site

  - IL-12 = produced by macrophages and dendritic cells - promotes NK cytolysis and stimulates IFNy production in T + NK cells which stimulates macrophages to kill microbe