Innate Immunity Flashcards
Endotoxins and Toll Like Receptors
1) Most bacteria could grow without any apparent tissue damage if toxins were not produced
2) In many cases the targets of toxins are immune cells whose death or inhibition of function would be beneficial to the microorganisms
3) Some toxins are not directly toxic to the host, but, instead induce leukocytes to produce inflammatory mediators that are toxic
Endotoxin
- membrane component of cell wall
- not directly toxic
- induces the body to produce toxic molecules
- gram negative bacteria
- the polysaccharide end is often antigenic and is the determinant of the O antigen
- the actual endotoxicity resides in the Lipid A region
Gram Negative Sepsis
- systemic bacterial infection
- or Infusion of contaminated IV solution
- hypovolemic shock with decreased blood pressure
- decreased cardiac output
- disseminated intravascular coagulation, DIC
- Acute Respiratory Distress Syndrome, ARDS
LPS is hard to get rid of
- LPS is heat stable (autoclave)
- LPS goes through many filters
- LPS can be destroyed by baking glassware at high temperature
- Measure LPS using a Limulus Amebocyte (horseshoe crab) Lystate assay- develops DIC in response to gram negative sepsis
- Negative reagents are referred to as “pyrogen free”
Mediators of the response
- most important IL-6, TNF-alpha, IL-1
- IL6: fever induces acute phase protein production by hepatocytes
- TNF-alpha: Activates vascular endothelium and increases vascular permeability, which leads to increased entry of complement and cells to tissues and increased fluid drainage to lymph nodes; fever, mobilization of metabolites, shock
- IL-1: activates vascular endothelium, activates lymphocytes, local tissue destruction increases access of effector cells; fever, production of IL-6
- CXCL8- chemotactic, recruits neutrophils and basophils to site of infection
- IL12- Activates NK cells
Functions of IL-1/IL-6/TNF-alpha mediators in the body
liver: acute phase proteins (C reactive protein, mannose-binding protein) -> activation of complement, Opsinization
bone marrow-endothelium: neutrophil mobilization -> phagocytosis
hypothalamus: increased body temperature
fat-muscle: protein energy mobilization to generate increased body temperature -> decreased viral and bacterial replication, Increased antigen processing, Facilitates adaptive immune response
Dendritic cells: TNFalpha stimulates migration to lymph nodes and maturation -> initiation of adaptive immune response
Toll-Like Receptor
- macrophage expresses several receptors for bacterial constituents
- CD14 recognize LPS and bring it to the TLR receptor
- use a lot of overlapping signal transduction pathways- explain why so many diverse molecules induce the same patterns of cytokine production
- a lot of things in bacterial and parasites stimulate TLRS
Superantigenic toxins
- staph enterotoxins A-E, TSST-1 and strep erythrogenic toxin A
- bind to MHC II and TCR unspecifically -> IL1 and TNF: symptoms like gram negative sepsis
Complement overview
- the complement system does much more than leads to cell lysis
- complement components are important (perhaps the most important) inflammatory mediators. C5a is the most important component for this
- one critical role for complement is opsinization
- the terminal complement reaction is only absolutely important in killing one type of bacteria, Neisseria
- complement is important in clearing immune complexes
Classical Pathway
- First the C1 component- there are C1q, C1r, C1s subunits
- Pentameric IgM molecule binds to antigens on bacterial surface and adopts staple form, could bind 1 IgM or multiple IgG molecules
- C1q binds and the conformation changes allowing C1r to become a protease and then activate C1s
- activated C1s cleaves C4 to C4a and C4b. C4b binds to microbial surface
- activated Cls also cleaves C2 to C2a and C2b, C2a complexes with C4b
- C4b2a binds C3 and cleaves it to C3a and C3b, C3b binds to microbial surface
- C5-9- lysis of pathogen
Alternative Pathway
- activated by things of microbial surface
- C3b is on the surface
- Factor B comes and binds and then is activated and factor D comes in and cleaves B to BB and Ba
- iC3Bb initiates the alternative pathway by being a convertase to C3 -> amplify
Two types of C3 convertase
Classical- C4b2a
Alternative- C3bBb
Ways to turn off complement
- properdin stabilizes C3 convertase C3bBb on a pathogen surface
- inactivation of C3b by factor H and factor I to give fragment iC3b- still a target for opsinization now
- DAF and MCP disrupt C3 convertase C3bBb on a human cell surface- our own cells don’t want the alternative pathway on them
Deposition of C3b leads to binding to complement receptors
-opsonization
-clearance of immune complexes
CR1- ligands are C3b, C4b- promotes C3b and C4b decay, stimulate phagocytosis, erythrocyte transport of immune complexes
CR2- ligands are C3d, C3dg, iC3b, B cell coreceptor
CR3- ligand iC3b, stimulates phagocytosis, macrophages, monocytes, PMNs, leukocytes
CR4- iC3b, stimulates phagocytosis, macrophages, monocytes, PMNs leukocytes
Complement and encapsulated bacteria
- encapsulated bacteria cannot be engulfed by neutrophils
- antibody bound to bacteria activates complement and bonding of C3b to bacteria
- engulfment of bacteria to neutrophils is mediated by Fc receptors and complement receptors
- granules fuse with phagosomes releasing toxic oxygen metabolites that kill bacteria
