Innate Immunity Flashcards
Is innate immunity specific or non-specific? Fast or slow?
Non-specific, fast
Is adaptive immunity immediate or later? Specific or not?
Slow, specific
What are the cells that are involved in innate immunity?
- Phagocytes
- Neutrophils
- Natural killer T cells
What are the cells that are involved in adaptive immunity?
T and B lymphocytes
What are the cell receptors in innate immunity?
Fc & complement receptors, lectins (Non-polymorphic), Pattern recognition receptors
What are the cell receptors in adaptive immunity?
B and T cell receptors (diverse)
What are the circulating molecules in innate immunity?
Complement (non- polymorphic)
What are the circulating molecules in adaptive immunity?
Immunoglobulins (diverse)
What are the soluble mediators of innate immunity?
Macrophage-derived cytokines, other acute phase reactants, systemic effects, inflammation
What are the soluble mediators of adaptive immunity?
Lymphocyte-derived factors (local growth and regulation)
What is the recruitment mechanism in innate immunity?
Recruitment
What is the recruitment mechanism in adaptive immunity?
Clonal expansion
Which type of immunity has memory?
Adaptive
Which type of immunity it variable within indiiduals?
Adaptive–innate response is largely the same
What are PAMPs?
pathogen-associated molecular patterns (e.g single stranded DNA, RNA etc).
What is lipopolysaccharide (LPS, endotoxin)?
A pattern expressed by gram negative bacteria
What are damage associated molecular patterns?
endogenous molecules that are produced by, or released from damaged and dying cells, activating the innate immunity
What are toll-like receptors?
A subset of pattern recognition receptors
What is TLR4?
Toll-like receptor that binds to LPS, a gram negative protein
Where are PRRs found?
in different cellular locations; some are on the cell membrane, others in endosomes, and others in the cytoplasm
What does PAMP/TLR activate?
NFkB and IRFs which leads to inflammation antiviral state
What are inflammasomes?
Hyperactivation of the inflammasome results in autoinflammatory syndromes which can be treated with IL-1 antagonists.
True or false: The receptors of the innate immune system are encoded in germline DNA and recognize conserved patterns on pathogens
True
What is the complement system?
a system of non-polymorphic soluble proteins that form a proteolytic cascade important in clearance of a variety of pathogens
What are cytokines?
soluble molecules that form a mechanism for communication in the immune system. They can facilitate innate and adaptive immunity.
How does recruitment of lymphcytes occur? Leukocytes?
Lymphocytes - clonal expansion of specific lymphocyte populations
Leukocytes - Recruitment of leukocytes to sites of infection
Which type of immunity improves over time?
Adaptive
What are pattern recognition patterns (PRRs)?
Structures that a on leukocytes that recognize microbial pathogens
What are Pathogen-associated molecular patterns (PAMPs)?
molecular structures that are produced by microbial pathogens
PAMPs are ligands for what?
PRRs
What is the example of a PAMP used in class?
Lipopolysaccharide (LPS, endotoxin), which is on Gram-negative bacteria
What allows the innate immune system to recognize damaged self cells?
Damage associated molecular patterns (DAMPs). These are expressed by cells consitutively, so long as there is no damage to the cell
What are Toll-like receptors?
A protein recognition receptor on leukocytes that enables recognize specific PAMPs
What is the function of TLR4?
Recognizes the LPS molecule on Gram-negative bacteria, resulting in production of pro-inflammatory cytokines from monocytes and macrophages.
Where are PRRs found? Why is this significant?
some are on the cell membrane, others in endosomes, and others in the cytoplasm.
This is significant because both intracellular and extracellular pathogens can activate PRR.
What are NOD-like receptors?
Cytosolic PRR that trigger activation of innate immunity
What is the NLRP family
a subfamily of NLR that are important in generation of the proinflammatory cytokine IL-1 via activation of the inflammasome
What are inflammasomes?
Proteins that are responsible for activation of the inflammatory process
What are the three mechanical barriers the body has to prevent infection?
- Epithelial cells
- Longitudinal flow of air
- Movement of mucus
What type of junctions are between epithelial cells?
Tight junctions
What are the two families of antimicrobial peptides that epithelial cells produce?
- Defensins
2. Cathelicidins
What is the mechanism of action of Defensins/cathelocidins?
These molecules are directly toxic to microbes and also activate leukocytes to promote inflammation
What prevent colonization of microbes in the GI and GU tract?
Low pH
What are lysozomes?
antimicrobial enzymes that break down bacterial cell walls
What is the commensal bacteria that normally reside in/on epithelial barriers
The microbiome
What is the benefit of the presence of a microbiome on human epithelial cells?
Prevents the colonization of the epithelial tissue by other microbials
What are the three professional phagocytic cells?
Neutrophils
Monocytes/macrophages
Dendritic cells
Where do the professional phagocytes originate from?
Bone marrow
What are the first cells that are present in the sites of infection?
Neutrophils
What percent of circulating leukocytes are neutrophils?
59%
How long do neutrophils live for?
24-48 hours
What differentiates monocytes from macrophages?
Monocytes are circulating cells, whereas macrophages are the cells when they are present in tissues, where they differentiate
How long do macrophages live for?
Months
Where are macrophages found?
In all tissues
How are macrophages named?
Based on their location (microglia, alveolar macrophages etc)
What is the first step in the generation of an immune response?
Phagocytosis of an antigen by professional phagocytes
What are intraepithelial lymphocytes?
lymphocytes found in the epithelial layer of mucosal linings, such as the gastrointestinal (GI) tract and reproductive tract. However, unlike other T cells, IELs do not need priming. Upon encountering antigens, they immediately release cytokines and cause killing of infected target cells. In the GI tract, they are components of gut-associated lymphoid tissue (GALT)
What is phagocytosis needed for, beside the immune system?
Development and tissue homeostasis
Also eat dead neutrophils
What are polymorphonuclear-leukocytes (PMNs)?
Neutrophils
Where are sinusoidal macrophages found?
In the spleen
What happens after microbes bind to phagocyte receptors?
Actin is rearranged to engulf microbe
What are dendritic cells? What is their function?
Phagocytic cells that exists in tissues.
Their main function is to process antigen material, and present it on the cell surface to the T cells of the immune system in lymph nodes. They act as messengers between the innate and the adaptive immune systems.
What are opsonins?
Soluble proteins that recognize phagocytic targets and are then recognized by specific receptors on phagocytics cells
What are the two major classes of opsins?
Complement and antibodiy
What are the two specific opsins discussed in class?
C3 -complement
IgG - antibody
What is the receptor molecule for IgG?
Fc(gamma)RI
What is the intracellular vesicle formed following engulfment of a particle ?
Phagosome
What happens to the phagosome once it is inside the cytoplasm?
Fuses with a lysosome
What is the pH of lysosomes?
3.5-4.5
How is TB able to survive the acidic phagosome?
prevent fusion of the phagosome and lysosome and inhibit acidification of the phagosome
What are the ROS that the body uses in defense?
superoxide hydrogen peroxide singlet oxygen hydroxyl radical Hypohalite (OCl)
How have bacteria evolved to avoid the ROS that the body produces?
expression of enzymes like catalase
How is superoxide produced in the body?
Via NADPH oxidase
What happens when individuals lack NADPH oxidase?
Developed chronic granulomatous disease (CGD), where they are more susceptible to bacterial infections
What type of cells express NADPH oxidase?
PMNs (neutrophils)
How are toxic nitrogen oxides produced?
from activated macrophages especially following macrophage activation with proinflammatory cytokines such as TNF.
What is the enzyme that is produced by both macrophages and epithelial cells that breaks down bacterial cell walls?
Lysozyme
What are cytokines? What is the effect on macrophages?
Cell signalling molecules
Upregulates NO production, and the killing capacity of macrophages
What is IL-12?
a cytokine released by macrophages that activates otherc ells types, such and lymphocytes
What are natural killer cells?
Large granular lymphocytes that are important in killing of virally infected cells and tumor cells
When are natural killer cells particularly important?
early stages of viral infection prior to induction of adaptive immune response
NK cell inhibitory receptors bind to what molecules?
MHC class I
What are MHC Class I molecules?
A molecule that is expressed on all healthy nucleated cells, and prevents killing by natural killer cells
What happens to MHC Class I molecules as a cell becomes infected?
Downregulated, leading the virally infected cell or tumor cell susceptible to killing by NK cells
What is Fcγ receptor III (CD16)?
A receptor for natural killer cells that binds to antibody (IgG) that binds to target cells
What is the process through which natural killer cells kill infected cells?
antibody dependent cell mediated cytotoxicity (ADCC)
What is perforin?
A protein found in NK cell granules that is released when prompted, and kills target cells
What are granzymes?
Granule proteins that translocate into the cytosol of a NK cell’s target, and cause programmed cell death
What is cytokine IL-2?
A cytokine that activated NK cells to kill, turning them into lymphocyte activated killer cells (LAK)
What are lymphocyte activated killer cells (LAK)?
NK cells that have been activated by IL-2, and kill tumor cells
What is cytokine IL-12?
Cytokine produced by activated macrophages, and stimulates NK cells to produce interferon γ which is the most potent macrophage activating cytokine
How do NK cells cells facilitate macrophage activation and killing of phagocytosed micro-organisms?
Via interferon γ
What are the three types of innate lymphoid cells?
ILC1, 2, and 3
What is the function of innate lymphoid cells?
Produce specific cytokines
What are the three main effector functions of complement?
Opsonization
Leukocyte migration
Lysis of pathogens
(Therefore, when a microbe enters the body, the complement system facilitates clearance of the microbe by enhancing phagocytic clearance, recruiting additional leukocytes to the site of infection, and directly killing the pathogen. )
The complement opsonins are large proteolytic fragments of what?
complement components C3b and C4b
What is the function of C3b and C4b?
covalently attach to the surface of pathogens via a reactive thioester bond to opsinify it
Do NK cells specifically recognize antigen that causes disease?
No–only the virus infected cells
What stimulates keuocyte migration?
Chemicals called chemokines
What are the complement chemokines?
Anaphlyatoxins
What is C3a?
A chemokine that triggers leukocyte recruitment
What is C3b?
an opsonin that stimulate phagocytosis
What is C3?
Precursor to C3a/b, and is central to all complement pathways
What is the mechanism by which lysis of pathogens can be brought about?
The terminal components of complement: C5, C6, C7, C8 and C9 form a pore in the membrane of pathogens (mostly Gram-negative bacteria) resulting in lysis of pathogens
What are the three pathways through which complement is activated?
- Classical
- Alternative
- Lectin
What is the result of all three complement activation pathways?
- opsonization
- leukocyte recruitment
- pathogen lysis
Where do the three pathways of complement activation converge? What happens next?
At C3, which is cleaved by C3 convertase into C3a and C3b
C3b also associates with the C3 convertase to form what?
a C5 convertase which cleaves C5 into C5a and C5b
What is the function of C5b?
C5b remains associated with the microbial surface to form the membrane attack complex
What is the classical complement activation pathway?
Initiated by antibodies to produce C1.
What is C1?
The complement activating protein in the classical pathway,consisting of the recognition component, C1q, and two molecules each of the serine proteases C1r and C1s.
How it the lectin pathway initiated?
Sugar residues on microbes are recognized and start the pathway, leading to
Will free antibodies activate the complement cascade?
No
Which is more effective at activating the classical pathway, IgM or IgG?
IgM
What is the initiation component of the classical complement pathway?
C1
Where does the alternative complement pathway take place? When does it occur?
On the microbial surface
Happens constitutively, but the C3 will be degraded if there are no bacteria around
What is the effect of the regulator protein CD59?
prevents the binding of C9 such that the membrane attack complex cannot form
What is the effect f decay accelerating factor?
dissociates the C3 convertases to prevent all effector functions of complement
What is paroxysmal nocturnal hemoglobinuria? What causes it?
A condition where there is intravascular lysis of red blood cells by complement.
This is caused by deficiencies in either CD59, or decay accelerating factor
What is the inhibitor for the classical complement activation?
C1 inhibitor
What is the activator protein for the alternative pathway?
C3
What are the activator proteins for the lectin pathway?
MASP1 and 2
What is hereditary angioneurotic edema (HAE?) What causes it?
A condition where there is swelling of skin and larynx which can be potentially life threatening.
This is caused by a deficiency in C1 inhibitor
Deficiencies in C1, C2, C4 or other early classical complement pathway components leads to what?
Autoimmune diseases, like lupus
Deficiencies in early components of the lectin pathway results in what?
increased susceptibility to bacterial infection
Deficiency in Factor D and Factor P, early components of the alternative pathway leads to what?
increases susceptibility to infection with pyogenic bacteria and Neisseria
Deficiency in C3 affects all three complement pathways and leads to what?
increased susceptibility to pyogenic bacteria and Neisseria
Deficiency in the terminal components of complement, C5b- 9, results in what?
The inability to generate the membrane attack complex and increased susceptibility to Neisseria infection.
Can cytokines act at a distance?
Yes
What is the main method of communication in the immune system?
Cytokines
What is IFNγ?
Cytokine produced by activated T-cells to promote macrophage activation
What is IL-12?
A cytokine produced from activated macrophages that causes NK cells to make more IFNγ
Type 1 interferon (IFN) is composed of and IFN and is produced in response to viral infection. What are its effects? (3)
- Inhibit viral replication via a paracrine action.
- Enhance the cytolytic capability of NK cells
- Increase cellular expression of class I MHC molecules (Class I MCH is important for host defense against viral infection.)
