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BIOL 444
Christine Dupont

BIOL444 – Microorganisms & Diseases Fall 2012 Set 02 – Overview of the Immune System Innate vs. Adaptive Immune Responses (Adaptive is unique to Jawed vertebrates) st - Inflammation (1 line of defense): A sequence of innate physiological events that is triggered by invading microbes or tissue damages, it initiates immune defenses (active recruitment of WBC). o General: RBC (Capillary) & WBC (Lymphatic or in or out of tissues & capillaries)  WBC (Leukocytes, e.g. neutrophils or macrophages) patrols for foreign substances @ all time o Inflammation initiates innate immune response to limit damage  Bacteria enters the damaged tissue  Mast cells that circulates in the blood releases vasodilator molecules (e.g. Prostaglanding, Histamine, and Serotonin)  Vasodilation of blood vessels (↑ diameter)  ↑ Blood flow to damaged site o Redness & ↑ in local temperature (37⁰C)  ↑ Capillary permeability  ↑ movement of immune cells, antibodies, clotting factors, complement factors & fluids to damaged tissue (Passive Extravasation) o Local swelling, painful edema (bradykinin produced & binds pain receptors)  Antibody & complement factors binds bacteria  Phagocytes engulfs bacteria  Cell signalling, inflammatory molecule, cytokines ↑ in *], creates a chemical gradient  Actively recruits Leukocytes – Phagocytes from the circulatory system  Epithelial cells of blood vessel (Endothelium) expresses adherence receptors (ICAMs) that specifically grabs passing immune cells out of the vessel into the tissue  Facilitate extravasation & clotting - Systematic Inflammation: System wide, out of control, very rapid inflammatory response o Occurs when the infecting microbe or its bacterial components (e.g. LPS of Gram – bacteria) escapes the initial site of infection & distributes to other sites or the blood stream  Results of Inflammation: Fluid leakage/loss & vasodilation  “Septic shock” drastic ↓ in BP  Results in organ shut-down, difficult to reverse, 30-50% fatality rate  E.g. Meningitis: Brain/CNS (Closed System)  Long term damage - Local Inflammation: Locally, site specific o Vasodilation  Extravasation  Adhesion Molecules (ICAMs)  Aid Extravasation (grab phagocytes)  Phagocytes release Cytokines through Phagocytosis  Active attracts Leukocytes Innate Immunity st - 1 Defense System that recognizes Self vs. Non-self substances, produced by everyone at all times - Cells & Molecules are produced to combat infection o Cells (Microbe specific): Neutrophils (PMNs), Macrophages, & Natural Killer (NK) cells o Molecules: Pattern Recognition Receptors (PRR), Antimicrobial Peptides (Defensins  Pore formation @ microbe membrane) & Complement Factors Molecules of the Innate Immune System Pattern Recognition Receptors (PRR) – Innate Opsonins How the body 1 “senses” the presence of non-self molecules/microbes - Produced by host cell as Secreted or Membrane bound molecules - Recognizes & binds Pathogen-Associated Molecular Patterns (PAMPs) o PAMPs: Molecular motifs that are not found in host (unusual = non-self origin)  E.g. Chains of mannose, LPS, Peptidoglycan, & Lipoteichoic acid (LTA) - E.g. PRR (Mannose-binding lectin) binds PAMPs (mannose of bacterial & fungal cell walls) o PRR: Mannose-binding Lectin, LPS-binding Protein, Complement factor C3b - Opsonins: Molecules secreted by the host that binds foreign substances - Small varieties of PRR can recognize huge diversities of microbes (bacteria, fungi, viruses, protozoa) BIOL444 – Microorganisms & Diseases Fall 2012 o Identification of the microbe is non-specific, recognizes bunch of microorganisms with similar PAMPs, but can’t distinguish b/w them (Adaptive system can tell the difference b/w microorganisms) o Serves as the broad spectrum surveillance for foreign substances - Membrane Bound PRRs “Toll-like Receptors” (TLR) o 10 identified in human but not all are characterized, occurs singly or paired up, can be expressed in the plasma membrane or the endosome membrane  For engulfed microbes or virus residues  Sentinels for invaders or Spies for central intelligence o TLR-4: Recognizes LPS of Gram-negative bacteria o TLR-9: Recognizes unmethylated CpG DNA & DNA viruses (Eukaryotes has methylated CpG)  TLRs + PAMPs  Transcription factors (e.g. NF-κB) are recruited  TFs enters nucleus  Initiate transcription of 2xCytokine genes  Proinflammation Cytokine Genes (e.g. IL-1, IL-12 & TNF-α)  Type I Interferon Genes (Evokes Anti-Viral State in cells) o H. Pylori gets around the system by producing modified lipid A (functional part of LPS) that has biological functions of LPS but cannot be detected by TLR-4, and modified flagellin protein that can drill across mucus layer into epithelial cells but cannot be detected by TLR-5 - Secreted PRRs “Complement Factors” (C#) o 30 serum proteins involved in the binding, lysis of microbial cells & inflammatory/immune responses o Inactive precursors are produced @ all times  Activation  Sequential cleavage  Cascade-like action o Result: Formation of Membrane Attack Complex (MAC/MAC Attack)  Pore formation @ Microbial membrane  Fluids rushes in  Lysis of microbial cell  Amplification: Many holes are added during a very short period of time o Activation of Complement Factors can be done through 3 Different Pathways  Classical Pathway “Antibody-dependent”  Threshold: Many antibodies binds antigens @ close proximity is required for activation o Antibodies & Antigens are part of the adaptive system  C1 can bind to the Fc portion “stalks” of the antigens once threshold is exceeded  C1 undergoes conformational change (activation) & cleaves C4 into 2 components  1 of the C4 components binds C1 complex, and cleaves C2 into 2 components  1 of the C2 components binds C1+C4 complex, forming C3 convertase that cleaves C3  C3b component binds the original complex, forming C5 convertase to cleave C5 o C3a component is a chemoattractant for leukocytes (Inflammation) o C3b component is also an opsonin (PRR that binds LPS  Phagocytosis)  Phagocytes have CR3 receptors that binds C3b of microbial membrane  C5 cleaved into 2 components, C5b is inserted into microbial membrane (Initiation of MAC Attack, required for the rest pore formation) o C5a component is a chemoattractant for leukocytes (e.g. neutrophils) & also causes the mast cells to release vasoactive components (e.g. histamine) (Inflammation)  C6, C7, C8 & C9 then binds C5 sequentially, forming MAC  Lectin Binding Pathway “Antibody-Independent” “Back-up system”  Mannose Binding Leptin (MBL) binds foreign mannose  C1-like complex (C1+C4) o Innate system, functions in the absence of the adaptive classical pathway  Alternative Pathway “Antibody-Independent” “Back-up system”  C3 is not a stable protein, spontaneous hydrolysis occurs @ all times in serum o Always low amount of C3b are present  C3b binds Serum Factor B to form C3 convertase-like complex, that cleaves C3 into C3a & C3b, C3b binds C3 convertase-like complex to form C5 convertase-like complex BIOL444 – Microorganisms & Diseases Fall 2012 o Bypass the need for C5 convertase formation to indirectly activate G5 cleavage Inflammation Opsonization MAC formation C4a, C3a, C5a, C5b C3b C5b, C6, C7, C8, 19 Requires cleavage of C3 & C5 Cells of the Innate Immune System Neutrophils (PMNs) - Multinucleated, predominant professional phagocytes, 1 to arrive en masse @ infected site - Indiscriminately phagocytose extracellular microbes through opsonization o Doesn’t recognize the specific pathogen, only job is to kill all - Phagolysosome formation: o Phagocytes (Neutrophil or Macrophages) have receptors that binds opsonized microbes  Phagocytes contain lysosomes with digestive enzymes (e.g. proteases & lysosomes) o Phagocytes engulfs the bound microbe through membrane fusion  Phagosome inside Phagocyte o Phagosome fuses with lysosomes  Phagolysosome “The Killing Chamber”  End of Infection  Oxidative burst: Production of toxic 2 species (e.g.2H2O , ROS) within phagolysosome o Cellular debris are expelled through membrane fusion – Exocytosis Macrophages (Precursors: Monocytes) - Has long extending pseudopodia, circulates or resides within tissues, called to infected site by cytokines released by activated neutrophils, acts as supports - “Links Innate to Adaptive”: Different from neutrophil in which macrophages phagocytose extracellular microbes & presents degraded microbe particulates as antigens to T-cells of the adaptive response through MHC II or MHC I receptors Natural Killer (NK) Cell - Always circulating in the blood, kills all host cells that are infected with intracellular microbes (e.g. mycobacteria, Salmonella, chlamydia, viruses) o Intracellular microbes cannot be phagocytised directly, the host cell must be killed instead o Apoptosis “Programmed cell death”: Method to kill host cells by the immune system  Surrounding cells give the infected host cell signal to undergo apoptosis  Infected cell packages & shrinks into apoptotic bodies with intact membrane  Phagocytes digests/engulfs the apoptotic bodies  No Inflammation o Necrosis “Uncontrolled death”: Cell death due to significant physical or chemical damage via infection  Damage to cell membrane results in leakage of intracellular enzymes (e.g. endosomes & lysosomes), which impacts surrounding cell & creates more damage  Inflammation - NK cells detects abnormal host cell by their ↓ in cell surface MHC I (Major Histocompatibility Complex I) o MHC I are present on all host cells except RBC o NK cells has intracellular granules containing perforin & granzymes  Inhibitory Signal: NK receptor binds MHC I of host cell  No killing  Activation Signal: Absence of MHC I of infected host cell results in no binding to NK receptor  Kill  NK releases perforin & granzymes onto the infected host cell to initiate apoptosis  Resulting apoptotic bodies are engulfed by macrophages or neutrophils. - NK cells also detects & triggers Antibody-dependent cell-mediated cytotoxicity (ADCC) o Viral genome are actively transcribed & translated and are expressed on th
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