Innate Immunity Flashcards
Innate vs. Acquired Immunity
Innate immunity (nonspecific) Inflammation: phagocytes, pro-inflammatory cytokines, complement Anti-viral defense: NK cells, interferon
Acquired Immunity (antigen specific and lymphocyte-mediated) Humoral immunity (secreted antibody) Cell-Mediated immunity (cytotoxic T cells and Th-dependent macrophage activation)
Innate Immunity
Present at birth
Nonspecific: response does not target one specific immunogen
Limited diversity: fixed, repeating, broad responses to a limited number of foreign substances
No memory: primary and secondary responses are identical
Innate Immunity Components
Physical/mechanical barriers: intact skin, epithelial layers, cough, fever
Nonspecific chemical factors: antimicrobial peptides (defensins, cathelicidins) in epithelial layers, fatty acids, gastric pH, lysozyme
Inflammation: phagocytes (engulf and digest microbes), cytokines (proinflammatory factors), complement proteins (inflammatory and membranolytic)
Natural killer cells (nonspecific cytotoxic cells), anti-viral
Interferons (a & b) (anti-viral cytokines)
Phagocyte Functions
Chemotaxis = directed migration toward chemoattractive compounds released during infection or tissue injury
Microbe recognition via “pattern recognition receptors” that detection conserved molecular patterns on microbes
Phagocytosis & killing of ingested microbes
Cytokine secretion (pro-inflammatory proteins)
enzyme secretion (lysozyme, proteases)
Antigen presentation to lymphocytes
Migration of Leukocytes
Adhesion molecules - P-selectins and integrins and PMN have ligands for attachment on endothelial surface and roll then eventually go through vessel into tissues
Expression of these molecules and increased vessel permeability allow neutrophils to go through and act on infection/injury
IL-1 and TNF affect permeability and upregulate the expression of adhesion molecules and the WBC ligands where cytokines are being released
Integrins are low affinity state normally, but in response to chemokines there is a high affinity to WBCs and can fight the shear force of the blood flow
Cytokines: encompasses all soluble proteins, but chemokines are a subset of cytokines
PAMPs, DAMPs, PRRs, and TLRs
Phagocytes recognize pathogen-associated molecular patterns (PAMPs) and danger- associated molecular patterns (DAMPs) via “pattern recognition receptors” such as Toll-like receptors (TLR)
TLR ligation stimulates phagocytosis and production of proinflammatory cytokines and chemokines
Cytokines and Chemokines
Cytokines (lymphokines, interleukins) are proteins made by cells that affect the behavior of other cells
Cellular sources: macrophages, dendritic cells, infected cells, injured cells
Examples: IL-1, TNF-α, IL-6
Chemokines are small chemoattractant proteins that stimulate the migration and activation of cells, especially phagocytic cells and lymphocytes
Example: IL-8 attracts and recruits neutrophils
>50 human chemokines exist
Local Inflammation and Cytokine Signaling
Local Inflammation: endothelial cells release IL-1 and chemokines which increase permeability of endothelial cells; leukocytes are activated by TNF and IL-1 to secrete IL-1, IL-6, and chemokines
Systemic Protective Effects and Cytokine Signaling
Systemic Protective Effects: brain, liver, and bone marrow are signaled by IL-1 and 6 to induce fever, release acute phase proteins, and leukocyte production, respectively
Systemic Pathological Effects and Cytokine Signaling
Systemic Pathologic Effects: TNF induces the heart, endothelial/vascular cells, and other tissues to have low output, increased permeability/thrombus formation, and resist insulin, respectively
IL-1, IL-6, CSF, and TNF alpha with Symptoms
Fever (via IL-1)
Elevated acute phase proteins (via IL-6) = elevated ESR, CRP, MBL
Leukocytosis (via CSF, colony stimulating factors)
Sickness behavior (via IL-1 and TNF-a) such as malaise, headache, anorexia, sleepiness
Opsonic and Non-Opsonic Phagocytosis
Non-opsonic
Direct engulfment via innate pattern recognition receptors. Slow, limited, inefficient
Opsonic
Engulfment of complement-coated or antibody-coated microbes via complement receptors (CR) or antibody receptors (FcR). Rapid, very efficient
Ab Mediated Opsonization
Opsonization of microbe by IgG causes binding of opsonized microbes to phagocyte Fc receptors, which signals from the Fc receptor activate the phagocyte in order to ingest and kill the microbe
Oxygen Dependent Mechanisms of Phagocytes
Oxygen-dependent (ROI & RNI): Hydrogen peroxide, H2O2 Superoxide anion, O2- Hypochlorite, OCl- Nitric oxide, NO Peroxynitrite, ONOO-
Oxygen Independent Mechanisms of Phagocytes
Oxygen independent
Hydrolases (lysozyme, glycosidases, proteases)
Acid pH
Antimicrobial proteins (Lactoferrin, defensins)
Neutrophil extracellular nets (released granule proteins and chromatin that form extracellular fibers that bind and kill pathogens)
NK Cell Function and Macrophages
Interaction and feedback between macrophages and NK cells to get macrophages to be activated and enhance activity
One of the early cytokines is IL-12 that macrophages release and causes NK cells to proliferate and release INF gamma and feedback and activates functions of macrophages
INF: induce enzyme nitric oxide synthase leading to NO production and enhanced killing
Resting macrophage will not release NO unless induced via INF gamma coming from T helper cells or NK cells
Different types of INF gamma, but this type is the inducible type
Complement Cascade System
Composition: proenzyme→ enzyme plasma protein cascade system with >25 proteins (enzymes, receptors, and complement inhibitors)
Synthetic source: liver, macrophages
Function: mediates inflammation by increasing vascular permeability attracting phagocytes enhancing phagocytosis causing microbial lysis
Alternative, Lectin, and Classical Pathway Induction
Alternative pathway: microbe itself can interact with complement proteins
Lectin pathway: mannose binding lectin (acute phase proteins) and microbes have repeating mannose and lectin bind
Classical: involved Ab and only active with Ab response (secondary); Ab binding to microbe surface and interact with complement proteins to initiate cascade
C3 and C5 Convertase
C3 convertase: in plasma and in highest concentration; generates enzyme and converts from C3 to C3a and C3b
C3a induces inflammation, and C3b causes opsonization and phagocytosis
C3a diffuses away, and C3b is highly made and covalently links to anything next to it (microbe surface) and coats it and also serves as a base for the next enzyme
C5 convertase and high rate of production and C5b has reactive groups and assembly point for topical components
Initial Steps of Alternative, Lectin, and Classical Pathways
C3b binds to microbe surface
Membranes in our cells have complement regulatory proteins that dissociate the proteins when they bind, but microbes do not have that to stabilize the C3b component and then subsequent factors associate with C3b
Factor B is cleaved into Bb and Ba fragments and create C3 convertase
When you get multiple C3b, you get C5
Some microbes can resist this, and this is what makes them virulent and cause clinical illness
Mannose binding lectin serine protease that cleaves C4 and C2 into two fragments and C4b and C2a will bind on microbe surface and that forms lectin pathway C3 convertase and opsonization occurs
Once you make specific Ab (IgG or IgM) and binds the Ig clustering on surface of microbe C1 is cross linked and conformational change with enzymatic activity and generate molecules for the classical pathway C5 convertase (C3 and C5 convertase are essentially the same but elicit different pathways)
Details of Alternative, Classical, and Lectin Pathways to MAC
Alternative Pathway: spontaneous generation of C3 + factor B = C3Bb (C3 convertase) then + properdin = C3Bb3b (C5 convertase) = initiates terminal sequence (C5-9 to MAC)
Classical Pathway: start with C1q and eventually make C4b2a (C3 convertase) + C3 = C4b2a3b (C5 convertase) = initiates terminal sequence
Lectin Pathway: MBL + serine proteases = C4b2a (C3 convertase) + C3 = C4b2a3b (C5 convertase) = initiates terminal sequence
Terminal Complement Cascade
Plasma membrane of activating microbial surface
C5 is cleaved and get C5b and assembles with complement proteins 6-9 (C5a diffuses away) and get polymerization and lysis of membrane
Generally gram negative bacteria have outer lipid membrane that is exposed and are subject to this process, but gram positive bacteria have this hidden and not susceptible to complement lysis
Certain viruses will acquire lipid envelop sometimes and the complement proteins are able to destroy this
C3 convertase in the alternative pathway is SPONTANEOUSLY cleaved
Complement Inhibitors
Self Membrane-associated (not present on microbes), (DAF, MCP, etc.)
Soluble inhibitors (C1inh, Factor H, etc.)
Self membrane associated sialic acid (also on virulent microbes): promotes plasma Factor H and Factor I inhibition of C3 convertase and promote properdin to stabilize C3 convertase on microbial surface
A lot of our cell membranes have sialic acid on the membranes that promotes H and I to degrade C3, and therefore inhibit the pathway. Some microbes also have this, and this makes them virulent since they inhibit the process
Bioactive Complement Peptides
C3a & C5a anaphylatoxins release histamine from mast cells to increase vascular permeability
C5a chemotaxin, recruits phagocytes
C3b & C3bi opsonins (coat microbes to enhance recognition & uptake by phagocytes)
C5b6789n membrane attack complex (lyses membranes on gram-negative bacteria and enveloped virus particles)
Lab indicators of complement activation during recurrent infection, angioedema, immune-complex diseases, or transplanted tissue rejection
Decreased complement protein levels in plasma (C3, C4),
Decreased complement lytic activity (CH50)
Increased peptide levels (Ba, C3a, C4a, C5a, C3dg, C4d)
