Innate Immune System PDF

 INNATE IMMUNE SYSTEM Inflammation concentrates defensive cells and antimicrobial molecules at sites of microbial invasion and tissue damage  Inflammation triggers the migration of leukocytes, from the bloodstream to sites of invasion where they attack and des...

 INNATE IMMUNE SYSTEM Inflammation concentrates defensive cells and antimicrobial molecules at sites of microbial invasion and tissue damage  Inflammation triggers the migration of leukocytes, from the bloodstream to sites of invasion where they attack and destroy invaders.  Likewise, many protective proteins, such as antibodies and complement components, are normally found only in blood and can only enter tissues during inflammation  Inflammation is therefore a mechanism by which defensive cells and proteins are focused on sites of microbial invasion. Together, they destroy the invaders and then repair any subsequent tissue damage  EXOGENOUS SIGNALS (invading organisms) ENDOGENOUS SIGNALS (dead and dying cells)  EXOGENOUS SIGNALS (invading organisms) pathogen-associated molecular patterns (PAMPs)  damage-associated molecular patterns (DAMPs) ENDOGENOUS SIGNALS (dead and dying cells)  Together, the DAMPs and PAMPs are recognized by PATTERN RECOGNITION RECEPTORS (PRRs) on sentinel cells located throughout the body. Once recognized, they activate the innate immune system.  Microbes not only grow very fast but also are highly diverse and can mutate and change many of their surface molecules very rapidly For this reason, the innate immune system does not attempt to recognize all possible microbial molecules.  walls of Gram-positive bacteria are largely composed of peptidoglycans (chains of alternating N-acetylglucosamine and N- acetylmuramic acid cross-linked by short peptide side chains) Gram-positive bacterial cell walls also contain lipoteichoic acids  The cell walls of Gram-negative bacteria consist of peptidoglycans covered by a layer of lipopolysaccharide (LPS). Acid-fast bacteria are covered in glycolipids.  Yeasts have a mannan- or β-glucan–rich cell wall Viruses, in contrast, grow within infected host cells, so the main targets of antiviral PRRs are unique viral nucleic acids. Cell Surface TLRs SENTINEL CELLS  Myeloid differentiation response 88 Mitogen-activated protein kinase kinase Interleukin receptor associated kinase Mitogen activated TIR-domain-containing protein kinase adapter-inducing interferon-β (TRIF) Nuclear factor – kappa B Interferon regulatory factor 3 TLRs are also expressed on the bone marrow stem cells that are the source of leukocytes. An increase in leukocyte numbers in the blood (the white cell count) is a consistent feature of infectious diseases. Retinoic acid inducible gene (RIG)-like receptors (RLRs) Nucleotide-binding oligomerization domain (NOD)-like receptors Nucleotide-binding oligomerization domain (NOD)-like receptors  MICROBIAL ATHOGEN-ASSOCIATED MOLECULAR PATTERNS Lipopolysaccharides Peptidoglycans Nucleic Acids LPS MD-2 (myeloid differentiation factor-2) LPS-binding protein (LBP) CD14 Cytokines  MICROBIAL ATHOGEN-ASSOCIATED MOLECULAR PATTERNS Peptidoglycans PEPTIDOGLYCAN RECOGNITION PROTEINS (PGRPs)  MICROBIAL ATHOGEN-ASSOCIATED MOLECULAR PATTERNS Nucleic Acids  unmethylated Bacterial deoxyguanosine cytosineguanosine (CpG) dna (dG)  Viral Nucleic Acids damage -ASSOCIATED MOLECULAR PATTERNS DAMPs or Alarmins  Soluble Pattern-recognition receptors P-type lectins - Pentraxins S-type lectin - Galectins C-type lectin - Collectins HERE ARE THE THINGS I HOPED YOU LEARNED Two types of signal trigger the body’s innate defenses.  One signal generated by the presence of invading microorganisms is detected by sensing their characteristic surface molecules, or nucleic acids. These are called pathogen-associated molecular patterns (PAMPs). Cells also detect molecules released from damaged tissues and broken cells. These are called damage-associated molecular patterns (DAMPs) or alarmins.  Both PAMPs and DAMPs bind to pattern-recognition receptors (PRRs) on cell surfaces or located within cells. PRRs are found on many different cell types. The most important of these “sentinel” cells are macrophages, dendritic cells, and mast cells. A major group of PRRs are called toll-like receptors (TLRs).  Signals generated when PAMPs bind TLRs activate sentinel cells and stimulate them to secrete many different molecules. Some of these molecules are proteins called cytokines that “turn on” the inflammatory process. These molecules trigger local increases in blood flow, attract defensive cells such as neutrophils, and increase blood vessel permeability, allowing antimicrobial molecules and cells to flood affected tissues.