Innate immunity

• Innate Immunity


  Immediate response to the pathogen represent the first line of defense, which is not directed against any particular pathogen but is a general defense mechanism
• Adaptive Immunity


  Takes time but has memory
• Innate Immunity can be found in all multicellular plants and animals
• Adaptive Immunity evolved in jawed vertebrates
• Innate Immunity components


  • Anatomical barriers
  • Mechanical, chemical, biological barriers
  • Humoral components (Complement, coagulation system, cytokines)
  • Cellular components (Neutrophils, monocytes & macrophages, NK cells, eosinophils)

  
• Mechanical/physical barriers

  • Skin
  • Mucous membranes
• Skin

  Few microorganisms are capable of penetrating intact skin, but many can enter sweat or sebaceous glands and hair follicles and establish themselves there
• Sweat and sebaceous secretions


  Have antimicrobial properties (acid pH and certain chemical substances like fatty acid)
• Lysozyme


  A hydrolytic enzyme present in all mucous secretions including tears, saliva, skin, in respiratory and cervical secretions that can lyse gram positive by cleaving peptidoglycan layer found in bacterial cell wall
• Psoriasin


  Protein with antibacterial prosperities produced by skin. Antibacterial activity to E. coli: Help when skin is scratched or cut to prevent infection since we are exposed to E.coli in fecal material
• Mucous Membrane


  • In the respiratory tract: Bacteria tend to stick to a film of mucous covers the surface and is constantly being driven upward by ciliated cells toward the natural orifices. Lysozymes, IgA, Phagocytes, Hair at the nares and cough reflex
  • In the gastrointestinal tract: Saliva contains numerous hydrolytic enzymes, Acidity of the stomach, Proteolytic enzymes in small intestine
• Innate cellular components


  • Neutrophils (Phagocytosis and intracellular killing, Inflammation and tissue damage)
  • Macrophages (Phagocytosis and intracellular killing, Extracellular killing of infected or altered self targets, Tissue repair, Antigen presentation for specific immune response)
  • NK and LAK cells (Killing of virus-infected and altered self targets)
  • Eosinophils (Killing of certain parasites)
• Innate humoral components


  • Complement (Lysis of bacteria and some viruses, Opsonin, Increase in vascular permeability, Recruitment and activation of phagocytic cells)
  • Coagulation system (Increase vascular permeability, Recruitment of phagocytic cells, B-lysin from platelets (A cationic detergent)
  • Lactoferrin and transferrin (Compete with bacteria for iron)
  • Lysozyme (Breaks down bacterial cell walls)
  • Cytokines (Various effects)
• Microbial Sensors

  When a pathogen enters the skin, it is confronted with macrophages and other phagocytic cells possessing "Microbial sensors"
• Major groups of microbial sensors

  • Tool like receptors (TLRs)
  • NOD-like receptors (NLRs)
  • RIG-1 like helicases and MDA-5
• Pathogen associated molecular patterns (PAMPs)


  The microbial molecules that stimulate innate immunity and present in infectious agents
• Pattern recognition receptors (PRR)


  The receptors of innate immunity that recognize the structures shared by microbes; Can recognize PAMPs
• Damage-associated molecular patterns (DAMPs)


  The innate immune system recognizes molecules that are released from damaged or necrotic host cells. Example: high mobility group box protein 1 (HMGB1)
• Toll-like Receptors (TLRs)


  • A family of evolutionary conserved pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs). They constitute a first line of defense against a variety of pathogens and play a critical role in initiating the innate immune response

  
• To date, 13 human TLRs have been identified, and each receptor appears to be involved in the recognition of a unique set of microbial patterns


  TLR2 recognizes several glycolipids and peptidoglycan that are made by

  Gram- positive bacteria.

  ✓TLR3 engages dsRNA in viral replication.

  ✓TLR1 and TLR6 recognize multiple diacyl peptides (e.g. Mycoplasma) .

  ✓TLR4 is specific for Gram-negative lipopolysaccharide (LPS).

  ✓TLR5 recognizes bacterial protein called flagellin.

  ✓TLR7 and TLR8 interact with ssRNA in viral replication.

  ✓TLR9 binds bacterial DNA.

  ✓TLR10 remains an orphan receptor.
• NOD-like receptors


  A large family of innate receptors sense DAMPs and PAMPs that are located in the cytosol of cells. Serve as intracellular sensors for microbial products. They activate the nuclear factor kappa-light chain-enhancer of activated B cells (NF-ҡB) pathway and drive inflammatory responses similar to the TLRs
• RIG-1-like helicases


  Cytoplasmic sensors of viral ssRNA. The engagement of ssRNA with these sensors triggers type 1 IFN production. These IFNs are highly effective inhibitors of viral replication
• Process of Phagocytosis

  1. Extension of pseudopodia to engulf attach material

  2. Fusion of the pseudopodia to trap the material in a phagosome

  3. Fusion of the phagosome with a lysosome to create a phagolysosome

  4. Digestion

  5. Exocytosis of digested contents
• Antimicrobial mechanisms used by phagocytes

  • Acidification occurs within the phagosome. The phagosome pH is 3.5-4, and this level of acidity is bacteriostatic or bactericidal
  • Toxic oxygen-derived products are generated and include superoxide Oˉ2, hydrogen peroxide H2O2, and singlet oxygen Oˉ2
  • Toxic nitrogen oxides
  • Antimicrobial peptides participate in killing
• Inflammation


  Injured or infected tissues become inflamed as a result of phagocytic cell activation. The initial inflammatory response becomes amplified through the recruitment to the affected area of fresh phagocytic (inflammatory) cells from the circulation. The classical description of the inflammatory response: pain, redness, swelling and heat. The migration of inflammatory cells is associated with increase in capillary permeability and accumulation of fluid (edema) to the affected area
• Diapedesis


  1. Rolling

  2. Activation by chemoattractants

  3. Arrest and adhesion

  4. Transendothelial migration
• Complement


  A group of naturally-occurring plasma proteins produced mainly – but not exclusively- by the liver that play a major role in the killing and removal of pathogens. One part is a collection of proteins that form aggregates that punch holes in pathogen's cell membrane causing lysis. Include serum glycoproteins that promote uptake of pathogens by phagocytes (opsonization). Complement system ties innate and adaptive immunity

  
• Complement Activation


  1. Immune complex

  2. C3 convertase

  3. C5 convertase

  4. Membrane attack complex

  
• Signal Transduction Pathways


  1. Signal

  2. Receptor

  3. Signal Transduction

  4. Effector Mechanism
• Microbial product


  Extracellular portion of TLR
• Signal Transduction


  Interactions of intracellular molecules – phosphorylation; signal transduction pathway – promotes phosphorylation of transcription factors in nucleus
• Effector Mechanism


  Production of proteins, Cell differentiation, inflammation, antigen-presentation, etc
• Innate immunity in non vertebrates and plants:

  Sea squirt (chordate) – complement, TLRs;

  Fruit Fly – TLRs, antimicrobial proteins;

  Tomato – oxidative bursts, enzymes that digest fungi, plant can isolate infection by strengthening cell walls
• Process whereby inflammatory cells cross the vascular endothelium

  diapedesis