(05) Innate Immunity Flashcards
What is the time table for innate immune responses to a pathogen?
Initial Innate Response:
- 0-4 hours after exposure
Induced Innate Response:
- 4-96 hours post exposure
***Will remain on until the infection is cleared
What happens if we lack an acquired immune system?
- innate?
- which is worse?
SCID is the lack of an acquired immune system, infections will be normal for the first 96 hours but will take off after than when the acquired system is supposed to kick in (pt. ends up dying)
Lack of innate system the disease takes off immediately and ACQUIRED IMMUNITY CANNOT RECOVER.
**Lack of Innate Immunity leads to more rapid death
What type of innate immunity is involved in the 1st four hours of an infection?
- Ubiquitous responses that are always available and recognize non-specific targets that are common to pathogens (PRRs)
What are the most important mechanical barriers to microorganisms?
- tissues?
Epithelial Cells Joined by Tight junctions
- Skin, Gut, Lungs, Eyes/nose
Longitudinal Flow of air or Fluid
- skin, gut
Movement of mucous by cilia
- lungs
What are the most important chemical barriers that work against microorganisms?
Waxy Coat:
- Skin
Acid/Enzymes:
- Stomach
Antibacterial Peptides:
- Skin, Gut, Lungs
Salivary Enzymes:
- Lysozyme in eyes and Nose
What are the most important microbiological barriers to infection?
Skin, Gut
- NORMAL FLORA
What is the main role of defensins?
- The increase the minimum infectious dose needed
Dermacidins
- what category of innate responders?
- Structure and function?
- What is their function similar to?
- Defensins
Structure:
- 35-40 residues that make an amphipathic helix that can combine with other helicies to penetrate bacterial membranes and cause osmotic dysregulation
- Function similar to MAC
**What is the primary source of defensins in the gut?
Paneth Cells
Cathelicidins
- what broad class do they belong to?
- Where are they made?
- Antimicrobial Peptide
Made:
- Produced in lysosomes of MACROPHAGES, NEUTROPHILS, and EPITHELIAL CELLS
Alteranative Complement
- where are the proteins made?
- When?
- Speed?
- Proteins made in liver
when:
- Constitutively
Speed:
- almost immediately following encounter of microbe with host
What is the MAC most efficient at destroying?
- when does it kick in?
Gram (-) bacteria, this is because of the lipid outer layer rather than the peptidoglycan cell wall
- Kicks in in the 1st 0-4 hours
What happens if an infection last more than 4 hours?
Inflammatory Response leades to recruitment of macrophages
- Neutrophils (1st present, MOST ABUNDANT) and macrophages come in and and recognize pathogens with their PRRs
- They then begin to produce inflammatory cytokines
In initiation of the inflammatory response, which cytokines are used?
IL-1
IL-6
TNF-alpha
How does the inflammatory response initiate acquired response?
- Fluid and APCs (macs) move into extravascular space
- Lymphatic that drain these spaces carry Macrophages to 2˚ lymph tissues
- Antigen is presented to naive T cells
T or F: often the innate phagocyte mediated response is enough to clear the infection.
True, if this doesn’t work then the amplified innate response will be produced to hold the infection down in the meantime
What are the steps in neutrophil extravasation?
- Neutrophil is recruited by inflammatory mediator
- Neutrophil has CD34 and GlyCam-1 that bind P and E selectins and starts rolling
- Chemokine receptors on endothelial cells also bind to chemokines and neutrophil - CD31 (PECAM-1) on neutrophil bind CD31 on the endothelial cell TIGHT JUNCTION and gets pulled through
What is the primary way that phagocytes kill bacteria and fungi?
- bacterial defense
Respiratory Burst
- Phagosome enters and is bound by azurophilic granules
- Lysosome binds
- During this processes their is a transient increase in oxygen consumption that leads to ROS being produced
**Bacteria that produce catalase may be resistant to Respiratory burst
What is NETosis?
- cell type?
- what exactly are they made of?
NETS - Neutrophilic Extracellular Traps are secreted when NEUTROPHILS die
- They are made from intracellular contents like chomatin which are secreted in UNDIGESTED FORM
What are the receptors that allow them to bind common features of pathogens?
- what happens when they encounter them?
Pattern Recognition Receptor (PRRs) recognize Pathogen Associated Molecular Patterns (PAMPs) (aka danger signals)
PAMP recognition triggers:
- Phagocytosis
- Cytokine produciton
- B7 expression on APCs
What are the 3 types of PRRs?
- Endocytotic
- Signaling
- Secreted
Endocytotic PRRs
- what is their signal?
- what happens after they bind?
- What doesn’t have to happen?
Signal:
- Carbohydrates (mannose, glucan, scavenger receptor)
Phagocytosis is initiated on binding SIGNAL DOES NOT NEED TO TRANSMIT SIGNAL to NUCLEUS
**These are non-signaling receptors
Signaling PRRs
- what classes of receptor fall in this category
- What does each of them do?
**ALL initiate cytokine Production
Toll-like Receptors:
- recognize microbial constituents
NOD-like Receptors (NLRs):
- Cytoplasmic proteins that have affinity for BACTERIAL PRODUCTS
RIG-1-like Receptors:
- cytoplasmic proteins that serve as sensors for VIRAL RNAs
What are TLR2 and TLR6 and what do they do?
- Quaternary structure
Toll-like Receptors
Heterodimers that recognize:
1. lipoteichoic acid (from gram + bacteria)
- Zymosan (component of fungi)
TLR3 function
Bind to double stranded viral RNA
TLR4
- Quaternary Structure
- Function
- Homodimers
- Receptor for LPS of gram (-) bacteria
TLR-7 and TLR-8 function
recognize single-stranded viral RNAs
Secreted PRRs
- what are they?
- Examples
PRRs secreted from the host cell
e.g. complement receptors, collectins, C-reactive protein, mannose binding protein, peptidoglycan recognition proteins
What 2 functions does mannose binding protein serve?
- what other Secreted PRR serves the same two functions?
- Pattern Recognition Receptor (PRR)
- Acute Phase Protein (upregulated in liver during acute response)
* C-reactive Protein serves the same two functions
* Note that both activate the classical cascade
5 important cytokines secreted from macrophages.
- IL-6
- TNF-alpha
- IL-1beta
- CXCL8
- IL-12
What are the functions of IL-6, CXCL8, and IL-12.
- what cell type releases these?
- what do they do?
- Local or systemic?
*Released by Macrophages
IL-6
Systemic:
- fever
- induces acute phase protein production by hepatocytes
CXCL8
Local:
Chemotactic factor recruits neutrophils and basophils to site of infection
IL-12
Local:
- Activates NK-cells
What are the function of TNF-alpha and IL-1beta?
- what cell type releases these?
- what do they do?
- Local or systemic?
*Macrophage released
TNF-alpha
Local:
Activates endothelium and Blood vessel dilation and permeability increase allows fluid to drain to lymph nodes
Systemic:
- Fever
- Mobilization of Metabolites
- Shock
IL-1beta
Local:
Activates vascular endothelum and Local Tissue Destruction for easy access by effector cells
Systemic:
Fever Production of IL-6
How does a macrophage contribute to fever?
- Releases:
IL-1beta
IL-6
TNF-alpha
How does a macrophage contribute to inflammation?
TNF-alpha and IL-1beta are both strong mediators of inflammation
IL-1/IL-6/TNF-alpha work together on 4 main tissues.
- what are these tissues and what does it do?
Liver
- C-Reactive Protein (CRP)
- Mannose Binding Protein (MBP)
- activation of compelment opsonization
Bone marrow Endothelium
- Neutrophil mobilization
- increased phagocytosis
Hypothalmus
- Increased body temp.
- Decreased bacterial and viral replication
Fat
- Protein and energy mobilization to generate increased body temperature
- Decreased bacterial and viral replication
What is the acute phase response?
- Organ(s) involved
- when does it occur?
- Acute-phase protein
- Important symptom?
- response to BACTERIAL infections that last more than a few days (often bacteria has disseminated into the blood)
- Synthesis of acute-phase proteins takes place in the LIVER
- occurs after a few days
- C-reactive Protein, Mannose-binding Protein, and fibrinogen?
- Produces Fever
What two pathways are activated by the proteins released from the acute-phase response?
CRP:
- Finds phosphocholine and activates the CLASSIC COMPLEMENT PATHWAY
MBP:
- Finds mannose and activate LECITHIN COMPLEMENT PATHWAY
What 3 cytokines are involved in the acute phase response?
- what cells are they derived form?
IL-1
TNF-alpha
IL-6
What cytokine is responsible for the acute phase response in the liver?
- What cells in the liver produce this?
IL-6 is released by KUPPFER cells in the liver (liver macrophages) leading to CRP, MBP, and fibrinogen production
How does TNF-alpha achieve a localization affect?
- Causes leakiness of vascular endothelium
- increased Diapedesis of phagocytes from circulation into tissues - Causes Platelets to adhere to vascular walls of small blood vessels
- Vessels are occluded and the bacteria cannot disseminate into the blood
What happens with TNF-alpha and its affects when a patient becomes septic?
All of the same processes of BV leakiness, macrophage invasion, platelet adherence and occlusion occur system wide
Result:
- occluded small BVs collapse from reduced blood volume and platelet adherence
- in organs this causes FAILURE –> SEPTIC SHOCK –> and death
B1 B cells
- Where are they found?
- Function
- acquired or innate immunity?
Where:
- Secondary Lymphoid Tissue
What?
- respond to T-independent type 2 antigens (typically composed of MULTIVALENT polysaccharides)
- Can produce antibody but CANNOT clonally expand, undergo affinity maturation or isotype switch
Innate Immune Cells:
- Any time these are activated the response will be the exact same
Are antibodies produced by B1 B cells? If so, what type?
- Mostly IgM
- Some IgG
T or F: B1 B cells can recognize capsular pathogens like capsular polysaccharide
True
Why do children under 5 respond so poorly to capsular vaccines?
- Their B1 B Cells have not been fully generated
- This system is important to recognizing capsular polysaccharide
What 2 cytokines (interferons) do virus infected cells produce?
- what 3 things do these do?
- IFN-alpha, IFN-beta
Functions:
1. Induces Resistance to Viral Replication in all cells
- Increases MHC I on virus infected cells (for T Cells), and ligands forreceptors on NK cells
- Activates NK cells to kill virus infected cells
T or F: NK cells have antigen specific receptors.
FALSE
How do IFN-alpha and beta induce other cells to protect themselves against viral infection?
- INF-alpha/beta is released from infected cell and bind to cytokine receptors on healthy cell
- Signaling makes cells more difficult to infect and causes MHC-1 upregulation
- THIS MAKES THEM LESS SENSITIVE TO NK Cells
Viral infected cell concentrations tend to be high until day 3-6 where they level off (but do not decrease). Explain this.
IFN-alpha, IFN-beta and (TNF-alpha, and IL-12) work to decrease viral spread
- IFN-alpha and beta induce NK cells which keep the infection leveled off until T cell response kicks in
NK cell receptors:
- what binds to activate?
- what binds to inhibit?
- when are these expressed?
2 types (immunoglobulin like, and lectin-like)
Activate:
- MIC-1 and MIC-2
- These are expressed on STRESSED (virus infected) cells
Inhibit:
- MHC class 1
- expressed on normal healthy cells and upregulated by INF-alpha and beta to protect healthy cells
T or F: if NK cells come into contact with MHC class 1 receptors they will refrain from degranulating regardless of what else it is bound to?
FALSE, if a cell is bound to MIC-1 or MIC-2 it is still possible for the NK cell to degranulate
**NOTE: a lack of MHC class 1 also calls for degraulation
What cytokine in sepsis is crucial to induction of septic shock?
- TNF-alpha
