Mechanisms of Immunity BSC 9/12 Flashcards
1
Q
Patterns of Pathology: Extracellular Bacteria
A
- Local Toxicity: bacteria cause diseases due to the release of a single toxin or because of their ability to attach to epithelial surfaces (immunity may require humoral Ab production to neutralize the function of endo and exo-toxins)
- Local Invasiveness: Bactera that are not toxic can cause disease by invasion of tissues and cells- damage results from the bulk or organisms (immunity may require cell-mediated immunity to resolve)
- Most organisms however fall between the two extremes, with some local invasiveness assisted by local toxicity and enzymes that degrade the ECM (humoral and cell-mediated responses are both involved in resistance)
2
Q
Neisseria Gonorrhoeae
A
* the perfect Extracellular pathogen
N. gonorrhoeae is an example of a bacterium that uses several strategies to avoid the damaging effects of antibody.
- First, it fails to evoke a large antibody response, and the antibody that does form tends to block the function of damaging antibodies.
- Second, the organism secretes an IgA protease to destroy antibody. (it is found on the mucosal surfaces, thus IgA is the main Ab targetting it)
- Third, blebs of membrane are released, and these appear to adsorb and so deplete local antibody levels.
- Finally, the organism uses three strategies to alter its antigenic composition:
- the LPS may be sialylated, so that it more closely resembles mammalian oligosaccharides and promotes rapid removal of complement;
- the organism can undergo phase variation, so that it expresses an alternative set of surface molecules;
- the gene encoding pilin, the subunits of the pilus, undergoes homologous recombination to generate variants.
3
Q
Extracellular Bacteria: Innate Immunity mechanisms
A
- First challenge: Epithelia barrier, normal flora
- Second part: Alternative C’ cascade
- Phagocytic Cells: Mf, Neutrophils are first on site to Extracellular bacteria
- Pro-inflammatory cytokines/chemokines (principle mechanisms against extracellular bacteria)
Mechanisms:
- Bacterial PAMPs are recognized by molecules present in serum and by receptors on cells. (resident macrophages)
- Activation of the alternative complement pathway (factors C3, B, D, P), with consequent release of C3a and C5a
- Activation & migration of neutrophils, macrophages, and NK cells
- Triggers of cytokine/chemokine release; mast cell degranulation
- Increased blood flow in the local capillary network; increased adhesion of cells and fibrin to endothelial cells.
- These mechanisms, plus tissue injury caused by the bacteria, may activate the clotting system and fibrin formation, which limit bacterial spread.
4
Q
Extracellular Bacteria: Adaptive Immunity Mechanism
A
Humoral: major effector branch!!!
- antibody production and activation of CD4+ helper T cells.
Antibodies:
- Antibodies neutralize and eliminate microbes and toxins by several mechanisms. (neutralization by binding, handed off to erythrocytes and cleared by kupfier cells in spleen, have opsonization and phagocytosis, and Ab dependent cellular cytoxocity, complement actiation and bacterial lysis)
- Helper T cells produce cytokines that stimulate B cell responses (IFNgamma, IL4/5/13), macrophage activation, and inflammation.
5
Q
Opsonization: Extracellular Bacteria
A
- Bacteria that are coated with an Ab and C’ (C3b) increases adherence to phagocytes and results in more rapid opsonization. This allows for greater bacterial clearance
6
Q
Role of Abs in Extracellular Bacterial Elimination
A
- Humoral (antibody mediated system) response is the major effector branch!
- Ags are soluble and the 3-D conformation is recognized by Abs
- Ab block attachment of the bacterium to the host cell membrane.
- Ab triggers complement-mediated damage to some bacteria.
- Ab directly blocks bacterial surface transport proteins.
- Ab opsonizes the bacteria via Fc and C3 receptors for phagocytosis.
- Abs block bacterial factors that interfere with normal chemotaxis or phagocytosis.
- Ab neutralize bacterial toxins, as well as bacterial spreading factors that facilitate invasion (e.g. by the destruction of connective tissue or fibrin).
7
Q
Consequences of Host Responses: Extracellular Bacteria
A
- Excessive release of cytokines can lead to diffuse intravascular coagulation with consequent defective clotting, changes in vascular permeability, loss of fluid into the tissues, a fall in blood pressure, circulatory collapse, and hemorrhagic necrosis, particularly in the gut.
- LPS= Endotoxic shock
- TNF (secreted first) and IL-1 cause endothelial cells to express cell adhesion molecules and tissue thromboplastin.
- Promote adhesion of circulating cells and deposition of fibrin, respectively. Platelet activating factor (PAF) enhances these effects.
“Cytokine Storm”: Gram+ bacteria can induce shock by massive release of cytokines mediated by superantigens.
SIRS = Systemic Inflammatory Response Syndrome: local inflammatory response starts to have a systemic effect
8
Q
Extracellular Bacterial Evasion of C’
A
- An outer capsule or coat prevents complement activation.
- An outer surface can be configured so that complement receptors on phagocytes cannot obtain access to fixed C3b.
- Surface structures can be expressed that divert attachment of the lytic complex (MAC) from the cell membrane.
- Membrane-bound enzyme can degrade fixed complement or cause it to be shed.
- The outer membrane can resist the insertion of the lytic complex.
- Secrete decoy proteins that cause complement to be deposited on them and not on the bacterium itself.
9
Q
Evasion of Phagocyte Killing: Intracellular Bacteria and Fungi
A
- Secrete repellents or toxins that inhibit chemotaxis
- Others have capsules or outer coats that inhibit attachment by the phagocyte (S. pneumoniae or C. neoformans)
- Phagocytosed, but release factors that block subsequent killing mechanisms. Once ingested, inhibit lysosome fusion with the phagosome. May also inhibit the proton pump that acidifies the phagosome, so the pH does not fall.
- Some secrete catalase (staphylococci), which breaks down hydrogen peroxide.
- Organisms such as M. leprae have highly resistant outer coats. M. leprae surrounds itself with a phenolic glycolipid, which scavenges free radicals.
- Mycobacteria also release a lipoarabinomannan, which blocks the ability of macrophages to respond to the activating effects of IFNγ.
- Cells infected with Salmonella enterica, M. tuberculosis, or Chlamydia trachomatis have impaired antigen-presenting function.
- Several organisms (Listeria and Shigella spp.) can escape from the phagosome to multiply in the cytoplasm.
- Finally, the organism may kill the phagocyte via either necrosis (staphylococci) or induction of apoptosis (Yersinia spp.)
10
Q
Types of Intracellular Bacteria:
A
- Rickettsia
- Mycobacterium
11
Q
Immune Response to Intracellular Bacteria:
A
- Innate immune response to intracellular bacteria: phagocytes, NK cells, IL-12 and IFN-γ
- Limits growth, spread
- IFNgamma is most important to inhibit bacterial growth, followed by IL-12
- Adaptive immune response is cell-mediated immunity
- T cells activate phagocytes to eliminate the microbes.
- T-cell dependent Ags
- Linear protein peptides
- HLA recognition
12
Q
Cell- Mediated Immunity: Intracellular Bacteria
A
*** This is the major effector branch
- Intracellular bacteria are phagocytosed by macrophages and may survive in phagosomes and escape into the cytoplasm.
- CD4+ T cells respond to class II MHC-associated peptide antigens derived from the intravesicular bacteria.
- Produce IFN-γ activating Mfs to destroy the microbes in phagosomes.
- CD8+ T cells respond to class I–associated peptides derived from cytosolic antigens and kill the infected cells.
Innate immunity may control bacterial growth, spread. But elimination of the bacteria requires adaptive immunity: CD4+ & CD8+ T cells
13
Q
Cross-presentation
A
- important for intracellular bacterial infection control
- DC’s ingest virall infected cells and can display Ag to CTL’s using both CLass I and Class II HLA at the same time to simultaneously stimulate CD4+ and CD8+ cells
14
Q
Consequences of Host Responses: Intracellular Bacteria
A
Granuloma formation: collection of Mfs: trying to wall off the spreading in the area
- Activated Mfs fuse to form multinucleated giant cells
- May or may not contain necrotic center
Individual genetics influence outcomes: this is influenced through production of Th1/Th2- Th1 would be the most protective cell type
15
Q
Mechanisms of Immune Evasion by Bacteria
A
Extracellular Bacteria:
- Antigenic Variation: N. gonnorrhoeae, E. Coli, Salmonella Typhimurium
- Inhibition of C’ Activation: many bacteria
- Resistance to phagocytosis: Pneumococcus
- Scavenging of reactive oxygen intermediates: Staph
Intracellular Bacteria:
- Inhibition of phagolysosome formation: M. tuberculosis, L. pneumophilia
- Inactivation of ROS/NOS: M. leprae
- Disruption of phagosome membrane, escape into cytoplasm: L. Monocytogenes
