Innate Immunity Flashcards
What are the four major roles of the innate immune response?
- Control colonization of non-sterile niches
- Prevent spread into sterile niches
- Detect infection of sterile tissue and mount an immediate, non-specific response to eliminate the infection or prevent spread
- transport antigens to lymph organs to stimulate pathogen-specific response (adaptive immune system)
What are normal mechanical barriers in the skin, gut, repiratory, and urogenital tracts?
- epithelium joined by tight junction
- longitudinal air/fluid flow (skin/gut)
- Cilia movement of mucus (lungs)
What are the chemical barriers enlisted by the skin?
- Fatty acids
2. Antibacterial peptides (defensins)
What are the microbiological barriers of the skin?
Normal, commensal flora
What are the major chemical barriers of the gut?
What are the major microbiological barriers?
- low pH, enzymes (pepsin), antibacterial peptides (defensins)
- normal commensal flora
What are the chemical barriers employed by the lungs?
Defensins (antibacterial peptides)
What are three ways simple mechanical barriers can be breached?
- Microscopic trauma
- Major trauma
- Vector induced
What does microscopic trauma usually lead to?
the breach of a mechanical barrier by bacteria like staph aureus to infect skin or blood
What is an example of a major trauma introduced pathogen?
Clostridium perfringens is the cause of gangrene and is introduced with implantation of soil or bacteria
Bites can also introduce “major trauma”
What are two major examples of vector breach of mechanical barriers?
- mosquitos- malaria or west nile
2. ticks- lymes disease
What does mechanical obstruction to urine flow or bowel peristalsis lead to?
increased frequency of UTI
How does the cough/gag reflex help protect normal mechanical barriers?
In what people is this reflex reduced?
Prevents contents of mouth from getting into the lungs to prevent pneumonia.
Reduced in people who abuse narcotics, alcohol or have severe brain injury
Smoking and the influenza virus both largely reduce ____________________ leading to an increase of ______________________.
mucocilliary removal; bacterial pneumonia
What is the bodies first response to a breach in the barrier between non-sterile and sterile?
Phagocytosis by macrophages
Where do tissue macrophages reside?
What cell do they differentiate from?
They underlie the epithelial surfaces to engulf pathogens that break the tight junction mechanical barrier
The differentiate from blood monocytes
What are the steps of phagocytosis?
- bacteria attaches to cell surface and are engulfed into endosomic vesicles called phagosomes.
- Phagosomes are acidified which kill many bacteria
- the phagosome fuses with a lysosome that contains degradative enzymes, proteins and peptides
What are the three major forms of phagocytosis?
- phagocytosis of large molecules
- Receptor-mediated endocytosis
- Pinocytosis (engulf everything in the area, no receptors necessary)
What are the receptors on the macrophages specific for?
Carbohydrates (polysaccharide bacterial and fungal cell walls)
- mannose (fungi)
- LPS (gram -)
- glucan
What three roles does the inflammatory response play in combating infection?
- deliver extra effector molecules to the site of infection
- induce local blood clotting to make a physical barrier to prevent sepsis
- promote damage repair of tissue
What initiates inflammation at the site of the infection?
the release of cytokines and chemokines by macrophages
What are the five major cytokines released by macrophages?
IL-1B TNF-alpha IL-6 CXCL8 IL-12
What are the local effects of the IL-1B cytokine?
What are the systemic effects?
Local: 1.Activates vascular endothelium 2. Activates lymphocytes 3. Local tissue destruction 4. Increased access of effector cells Systemic: 1. Fever 2. Produces IL-6
What are the local and systemic effects of TNF-alpha?
Local: 1. Increase vascular permeability to allow increased entrance of IgG, complement and cells to tissue 2. Increase flow to lymph nodes Systemic: 1. Fever 2. Mobilize metabolites 3. Shock
What are the local and systemic effects of IL-6?
Local: 1. Lymphocyte activation 2. Increased antibody production Systemic: 1. Fever 2. Induces acute-phase protein production by hepatocytes
What are the local and systemic effects of CXCL8?
Local:
1. Recruits neutrophils, basophils and T cells
Systemic:
none
What are the local and systemic effects of IL-12?
Local:
- activates NK cells
- Induces differentiation of CD4 T cells into Th1 cells
What cytokines are majorly responsible for increasing vascular permeability and activating the vascular endothelium to localize immune cells to the site of infection?
IL-1B and TNF-alpha
What cytokines activate lymphocytes and immune cells at the site of infection?
IL-6, IL-12
What cytokines recruit neutrophils, basophils, and T cells to the site of infection via chemotaxis?
CXCL8
What five areas of the body to systemic cytokines affect?
- Liver
- Bone marrow endothelium
- hypothalamus
- Fat, muscle
- Dendritic cells
What systemic effects take place in the liver upon induction by cytokines?
Acute-phase proteins (C-reactive, mannose-binding lectin) lead to activation of complement opsonization
What three cytokines have systemic effects?
IL-1B, TNF-alpha and IL-6
What do systemic cytokines induce in the bone marrow endothelium?
neutrophil mobilization and phagocytosis
What do systemic cytokines induce in the hypothalamus?
Increased body temperature to decrease viral and bacteria replication and to increase antigen processing
What do systemic cytokines induce in fat and muscle?
Protein and energy mobilization to increase body temp to decrease viral and bacterial replication and to increase antigen processing
What do systemic cytokines do to dendritic cells?
TNF-alpha stimulates the migration to lymph nodes to promote initiation of the adaptive immune system
What do cells of the innate immune system sense on pathogenic microbes?
PAMPs (pathogen-associated molecular patterns)
What on the innate immune system cell senses PAMPs?
PRRs (pattern recognition receptors)
What is mannose binding lectin (MBL)?
A PRR in plasma that recognizes bacterial pathogens by specifically binding to mannose and fucose on the bacterial cell wall
When a PRR is recognizing a PAMP, what two factors are crucial for recognition and binding?
- chemical structure
2. spatial organization of the PAMP
What family of receptors is responsible for recognizing extracellular microbial pathogens?
Where are these receptors typically located?
Toll-like receptor family (TLR) typically located on macrophages?
When a TLR binds to a PAMP, what occurs?
Triggers the secretion of cytokines and chemokines
How many genes are there for TLR? What does each gene encodE?
there are 10 that each encode a receptor that recognizes a specific PAMP that is characteristic of a pathogenic microorganism
Even though there are only a small number of TLR, how are they able to recognize a vast set of microbes?
The receptors detect components that are common to most pathogens like Gram -, gram +, mycobacteria, yeast, nucleic acid
This allows a generalized response despite limited diversity in receptor type
What is the TLR4 receptor able to detect?
- Gram - LPS
- Fungal mannans (mannoproteins)
- Parasite phospholipids
- viral envelope proteins
- host heat shock proteins
After a TLR recognizes a PAMP, what is the sequence of events?
- Recruitment of adapter proteins
- Activation of protein kinases
- Activation of trans. factors
- gene transcription of cytokines
Why does the innate immune system need to develop a different response to viruses than bacteria?
Most bacteria are extracellular so TLR and PRRs can recognize them.
Viruses replicate inside the host, and spread extracellularly to infect more cells.
What two phases of the viral life cycle does the innate immune system need to be prepared for?
- Intracellular phase where the virus is using the cells machinery to make more virus
- Extracellular phase where the virus is moving to infect more cells
What are the two viruses that usually cause the common cold?
- Rhinovirus
2. Coronavirus
To what does the virus normally attach in order to gain access to the host cell?
ICAM-1 which is an adhesion molecule expressed by many cells in the body
What causes all the classic symptoms associated with a cold?
Immune response (not the virus itself)
Congestion- local inflammation
Fever- systemic cytokine effect
What structures are able to recognize dsRNA to induce action against the virus?
- TLRs on endosomes
2. RIG-1, MDA-5 in the cytosol
When RIG-1, MDA-5 or TLR recognize dsRNA, what do they do?
They phosphorylate IRF3 and IRF7 which move into the nucleus of the cell to synthesize type 1 interferon
What do interferons do?
They inhibit viral spread and replication in cells adjacent to the one that was infected
What four things do INFalpha and INFbeta do?
- induce resistance to viral replication in adjacent cells
- Increase MHC-1 expression and antigen presentation
- Activate dedritic cells and macrophages
- Activate NK cells to kill virally infected cells
What does an MHC class 1 molecule do?
enhance recognition of the virally infected cell and initiate killing by CD8 cytotoxic T cells
What would interferons activate dendritic cells in response to viral infection?
Dendritic cells present antigens to lymph nodes to stimulate the adaptive immune system
What do viruses do to the cell that they have infected as a subversion technique?
Reduce the MHC class 1 molecules to avoid being killed by a cytotoxic T cell (CD8)
Where do NK cells develop and from what cell lineage?
They develop in bone marrow from the lymphoid cell lineage
What activates a NK cell?
Interferons and a few other macrophage induced cytokines
NK cells are always circulating but activation by interferon increases their capacity to kill virally infected cells by __________.
20-100 fold
How do NK cells recognize virally infected cells?
Virally infected cells fail to express normal levels of MHC1 molecules
What type of receptors are present on the NK cells?
What does this allow the NK cell to do?
The majority are killer-cell inhibitor receptors (KIR) which recognize MHC1.
If MHC1 is normal, the killer cell will be inhibited.
Other receptors can be activating and stimulate lysis of the host cell
The two types of receptors allows the NK cell to have a “signalling balance” to not kill normal cells but kill abnormal cells
What is the general function of a CD8 cytotoxic T cell?
To recognize peices of intracellular pathogens being presented by MHC1 molecules on the surface of infected cells and to lyse the cell.
What is the time frame for production of interferona, interferonb, TNFa, and IL-12?
1-5 days with a sharp peak around 2
What is the time frame for NK mediated killing of infected cells?
1-6 days with a peak around 3-4
What is the time frame for T-cell mediated killing of virally infected cells?
3-the end of infection (or chronic)
What happens to the virus titer over the course of a viral infection?
It increases with the production of IFNa,b, TNFa, IL-12
As soon as T-cell killing begins the virus titer starts to die off.
The initial response stops the spread of infection, but the adaptive response is necessary to stop the infection and reduce the viral titer
