Immuno Test 2 (Part 2) Flashcards
(171 cards)
The Infectious- Nonself Model
- APCs recognize EVOLUTIONARY DISTANT PATHOGENS
- APCs activated via PRR
- PRR recognize PAMP on bacteris
- Upon activation, APC up-regulate COSTIMULATORY SIGNALS, process the bacterial ANTIGENS, and PRESENT them to passing T CELLS
***The PRR allow APC to DISCRIMINATE between “INFECTIOUS-NONSELF” and “NONINFECTIOUS-SELF”
Danger Theory Model
- APCs are ACTIVATED by DANGER/ DAMAGE Signals
- Danger Signals are generated by:
1) Injured Cells
2) Pathogens
3) Toxins
4) Mechanical Damage
What is the Danger Signal?
Potential Danger Signals:
1) Infection by Microbial Pathogens
2) Products of Injured (Necrosis) or Stressed Cells
3) Immunostimulatory Compounds (HEPARAN SULFATE)
4) Inflammatory Cytokines (IFN-alpha/ beta or TNF-alpha)
5) Rupture of vessels or chemotaxis of Blood-Borne Cells
- ***For POTENT ACTIVATION:
1) MHC Signal
2) CD28 to B7
Humoral Response to Danger Signals
- Activation of Complement
- Activated Immune Cells Release:
1) Chemokines
2) Leucotrienes and Prostaglandins
3) Reactive Oxygen Intermediates (ROI)
4) Nitric Oxide (NO)
Necrosis Generates Danger Signals and Inflammation
***NECROSIS: a Passice, Catabolic cell DEATH in response to EXTERNAL TOXIC FACTORS
- Necrosis is a dirty FORM of cell death characterized by SWELLING and RUPTURE of cell membrane (cell lyse) which may cause INFLAMMATION or harm other neighboring cells
**INFLAMMATION: a response to the INNATE IMMUNITY that involves activation of leukocytes and release of inflammatory mediators
- Immune cells are activated by the DANGER SIGNALS
Necrosis and Danger/ Damage Signals
1) HMGB1: High Mobility Group Box 1, is a protein passively released during Necrosis:
- Activates NF-kB pathway
- RAGE is a receptor for HMGB1
* * HMGB1 is an ENDOGENOUS DANGER SIGNAL*
2) URIC ACID is another diffusible danger signal:
- Activated NF-kB
3) HSPs are another danger signal:
- HSPs induce NF-kB pathway and release Inflammatory cytokines (TNF-alpha and IL-1beta)
HSP: Heat Shock Proteins
RAGE: Receptor of Advanced Glycation End Products
Acute Inflammatory Response
1) Increased BLOOD SUPPLY to the affected areas —> REDNESS and HEAT
2) Increased in CAPILLARY PERMEABILITY —> Leak from the BLOOD VESSELS —> SWELLING AND PAIN
3) Massive INFLUX of NEUTROPHILS
4) Arrival of MACROPHAGES (16-48hrs)
5) Macrophage mediated PHAGOCYTOSIS of debris, restoring the HOMEOSTASIS
Stages of Acute Inflammatory Response
1) DETECTION of Danger/ Damage Signal:
- VERY EARLY
- The inflammatory process begins with VASCULAR COAGULATION (clotting) and the DETECTION of pathogens or cellular injury by PATTERN RECOGNITION RECEPTORS (PRR)
- MAST CELLS release HISTAMINE
2) LEUKOCYTE RECRUITMENT and ELIMINATION Stimuli
- Signaling through PRR induces RELEASE of Inflammatory mediators which ACT ON BLOOD VESSELS (Endothelial cells) to PROMOTE recruitment of Leukocytes and EXUDATION of plasma into the DAMAGED TISSUE
- PHAGOCYTOSIS of OPSONIZED pathogens and cellular debris!!!!!
3) RESOLUTION:
- After ELIMINATION OF MICROORGANISMS and necrotic tissue, Leukocyte Recruitment ceases and apoptotic neutrophils are phagocytized by Macrophages
* *** MACROPHAGES clean cell debris using SCAVENGER RECEPTORS (another type of PRR)!!!!!!!!
4) WOUND HEALING:
- Tissue repair and remodeling involves the development of NEW BLOOD VESSELS (Angiogenesis), RESURFACING of the WOUND (Re-epithelization) and COLLAGEN DEPOSITION
* *** MACROPHAGES stimulate Fibroblasts by releasing TGF-beta!!!!!!1
Inflammation in Atherosclerosis
1) Monocytes recruites though the activated endothelium differentiate into MACROPHAGES
2) Several endogenous and microbial molecules are recognized by TLRs and ACTIVATE THE CELLS
3) Inflammatory CYTOKINES, CHEMOKINES, ROI, NO, and other inflammatory molecules are released
4) Inflammation and tissue DAMAGE OCCURS
5) MACROPHAGE accumulate LIPIDS and become FOAM CELLS
Apoptosis vs Necrosis
- Cell Death may occur by Necrosis or Apoptosis:
1) NECROSIS: is a DIRTY form of cell death characterized by SWELLING and RUPTURE of cell membrane (cell lyse) which may cause INFLAMMATION or harm other neighboring cells
2) APOPTOSIS: is a CLEAN form of cell death in which any harm done to the organism by this process is MINIMIZED!!!
- Apoptotic cells are removed WITHOUT TISSUE INFLAMMATION
- Apoptosis is NORMAL PHYSIOLOGICAL PROCESS occurring in embryonic development and immune response
- DANGER SIGNALS are NOT RELEASED
- When Ag is ELIMINATED, then only MEMORY CELLS left
Apoptosis and Anti-Inflamamtory Response
Immunological Tolerance is the process by which the Immune System does not respond to Ag*
- Apoptosis provide NO DNAGER SIGNALS —> NO Immune Response
- HMGB1 is NOT RELEASED during Apoptosis
- APOPTOSIS can render APCs into a Tolerant State
- Anti-inflammatory IL-10, TGF-beta, and Regulatory T cells may contribute to the process
Molecular Mechanisms of Apoptosis
1) Triggers:
- DNA Damage
- Cytokine Starvation
- Hypoxia
- Temperature
- Death Receptor
2) Regulators: PRO-APOPTOTIC: - Death Domain Factors - Cytochrome C - p53 ANTI-APOPTOTIC: - BCL-2 Family - Myc/ Oncogenes
3) Executioners
- Capsase 9 (Intrinsic) and Capsase 8 (Extrinsic) activate CASPASE 3 for cell death!!!!!
- Each cell express Fas, but only ACTIVATED LYMPHOCYTES express Fas LIGAND (FasL)
Caspases in Apoptosis
- Caspases are the Major Executioners
- Caspases are CYSTEINE PROTEASES
- Caspases directly and indirectly ORCHESTRATE the MORPHOLOGIC CAHNGES of the cell during APOPTOSIS
- Capsases exist as LATENT PRECURSORS
- When activated, Caspases initiate apoptosis by DESTROYING KEY COMPONENTS of the Cellular Infrastructure
Intrinsic Mitochondrial Pathway
3 Main Triggers:
1) Bcl-2 Family proteins
2) CALCIUM!!!!!!!!
3) FREE RADICALS!!!!!!!
4 Downstream Regulators:
1) CYTOCHROME C!!!!!!!!!
2) Protein Smac/Diablo
3) Apoptosis-inducing factor
4) Endonuclease G
EXECUTIONERS:
- Caspase 9
- CASPASE 3!!!!!!!
- Apaf-1
Extrinsic Apoptotic Pathway
1) Fas Ligand binds to Fas!!!!
2) FADD recruits to the intracellular portion of the Fas receptor (Death Domain)
3) Caspase 8 is ACTIVATED and activates CASPASE 3 (Caspase Cascade)!!!!!!
- Once Caspase 3 is made there is no turning back
4) APOPTOSIS
- Mitochondrial damage
- Membrane Changes
- Proteolysis
- Nuclear Condensation and DNA fragmentation
Apoptosis In Action
-
Once Viral CLEARANCE happens then the CTL Response will also decrease**
- CTL will go through APOPTOSIS when there is no more Viral Antigens
Autoimmune Lymphoproliferative Syndrome (ALPS)
*** The Majority of ALPS patients have HETEROZYGOUS MUTATIONS in the gene encoding fas
Patients have:
1) CHRONIC ADENOPATHY and/or SPLENOMEGALY in the early years of life
2) CHRONIC PERSISTENCE and ACTIVATION of BOTH T CELLS that stimulate B-CELL maturation (Abs in BLOOD)
3) The EXTENDED SURVIVAL of LYMPHOCYTES due to the DEFECTIVE Fas-mediated APOPTOSIS may allow MALIGNANT TRANSFORMATION to occur!!!!!
Overview of Immune Responses to Microbes
- Survival and Pathogenicity of microbes is influenced by the ability of microbes to EVADE or RESIST the effector mechanism of immunity
- Many microbes establish LATENT, or PERSISTENT, INFECTIONS in which the immune response controls but DOES NOT ELIMINATE the microbe and the microbe survives WITHOUT PROPAGATING the INFECTION
- Tissue INJURY and disease may be caused by the host response to the MICROBE (COLLATERAL DAMAGE) RATHER THAN by the microbe itself
- Inherited and acquired DEFECTS in innate and adaptive IMMUNITY are important causes of SUSCEPTIBILITY to INFECTIONS
What happens without Immunity?
- Lack of INNATE IMMUNE MECHANISMS leads to very quick expansion of the pathogen
- Without ADAPTIVE IMMUNITY the infection is initially controlled by Innate Immunity, however, the PATHOGEN can NOT be ELIMINATED completely
Immune protest against Extracellular Microbes
1) Antibodies are PRESENT
2) Complement is PRESENT
3) Neutrophils are PRESENT
4) Th2 are PRESENT and ACTIVE (DOMINATES!!!!!!!)
5) Th1 small number present so NOT MUCH ACTIVITY
6) Macrophages are present in a low number
7) Cytotoxic T cells are NOT PRESENT
8) NK Cells are PRESENT along with CYTOKINES
Defenses Against Extracellular Bacteria
- Complement
- Phagocytes
- Antibodies
Steps of Immune Response Gains Infections with Extracellular Bacteria (Steps 1 -6)
1) Break in epithelial surface allows BACTERIA ENTRY and PROLIFERATION
2) Surface LIPOPOLYSACCHARIDES may activate the ALTERNATIVE COMPLEMENT pathway or MANNAN-BINDING LECTIN pathway leading to BACTERIAL LYSIS
- Other complement activators operating at this stage include C-REACTIVE PROTEIN, which binds Bacterial COAT POLYSACCHARIDES
3) MAST CELL DEGRANULATION enhance BLOOD Flow!!! The increased blood flow and LOCAL EDEMA are perceived as ITCHINESS and IRRITATION in the inflamed areas
4) ROLLING, MARGINATING Neutrophils adhere to the vein wall as locally released cheekiness and bacterial derived molecules (ENDOTOXINS) ACTIVATE both the ENDOTHELIUM and the NEUTROPHILS, resulting in ADHESION BETWEEN THE TWO
5) BACTERIAL PRODUCTS (Formyl-Methionyl-Leucyl-Phenylalanine tripeptide), COMPLEMENT FRAGMENTS (C5a) and CHEMOKINES (IL-8/CXCL8) ATTRACT Neutrophils to the site (CHEMOTAXIS)!!!!!!!!
6) Opsonized Bacteria are RAPIDLY ENGULFED and KILLED by Neutrophils. DENDRITIC CELLS Engulf and Internalize Bacteria, are ACTIVATED via PATTERN RECOGNITION RECEPTORS (Toll-Like Receptors) and MIGRATE via the LYMPHATICS
Steps of Immune Response Gains Infections with Extracellular Bacteria (Steps 7-11)
7) Dendritic Cells enter the Local LYMPH NODES and moves to GERMINAL CENTER.
- Local Inflammation leads to UPREGULATION of ADHESION MOLECULES on high Endothelial VENULES of Lymph Node, and Lymphocytes enter directly from the blood
- Many lymphocytes become TRAPPED in the LOCAL INFLAMED NODE, and the consequent SWELLING, along with local HYPEREMIA, leads to the symptom of SWOLLEN PAINFUL/TENDER LYMPH NODES!!!!!
8) Th cells are RECRUITED and ACTIVATED by PROFESSIONAL APCs in the Lymph Node, and by B CELLS, promoting the production of BACTERIA-SPECIFIC ANTIBODIES
- Naive T Cells become differentiated towards Th1 and Th2, according to the DENDRITIC CELL SIGNALS
- Initially IgM CLASS AB is PRODUCED, followed by CLONAL EXPANSION and SWITCHING to other classes (IgG or IgA) for MUCOSAL PATHOGENS
9) Early ANTIBACTERIAL AB production is of the IgM CLASS.
- This relatively LOW AFFINITY interaction is enhanced by the FIVE ADHESION sites on IgM, leading to HIGH EFFICIENCY of BINDING
- IgM is a VERY POTENT Complement ACTIVATOR and OPSONIN
- Opsonized bacteria are LYSED by Complement
10) Following the resolution of the BACTERIAL INFECTION, protective mechanisms for future encounters are put in place by laying down of MEMORY CELLS and PRODUCTION OF ABs
11) In the Resolution of an infection, bacterial debris is removed by LOCAL MACROPHAGES and NEUTROPHILS, or by ANTIBODY as SOLUBLE immune complexes!!!
- IgM is not a good SOLUBLE Ab because it is a pentamer and does not go into tissue easily
- IgG is more likely to go into the tissue because of its Monomer Configuration
Immunity to Extracellular Bacteria
- EXTRACELLULAR bacteria are capable of REPLICATING OUTSIDE host cells in the blood, Conn Tissue, Epithelial surfaces, the GI Tract etc
PATHOGENIC Extracellular Bacteria have 2 MECHANISMS:
1) INFLAMMATION causes tissue DESTRUCTION at side of infection
2) Bacteria produce TOXINS which ahem diverse Pathological effects
Bacterial Toxins have 2 Categories:
1) Endotoxins:COMPONENTS OF BACTERIA CELL WALLS
2) Exotoxins: SECRETED BY THE BACTERIA
- ENDOTOXIN (LPS) of Gran Neg bacteria is a POTENT ACTIVATOR of Macrophages, Dendritic Cells, and Endothelial cells
- Many EXOTOXINS are CYTOTOXIC including:
1) DIPHTHERIA TOXIN: Shuts down protein synthesis in infected cells
2) CHOLERA TOXIN: Interferes with ion/ water transport
3) TETANUS TOXIN: Inhibits Neuromuscular transmission - Other Exotoxins interfere with Normal Cellular functions without killing cells, and yet other EXOTOXINS STIMULATE THE PRODUCTION OF CYTOKINES THAT CAUSE DISEASE