Week 1 - Immunology Flashcards
What are the functions of the immune system?
- Protection from microbial pathogens
- Protection from “foreign” cells that may have malignant potential
- Detection of damaged tissue and facilitates regeneration of those tissues
- Permits microflora to aid in: protection and provision of nutrients
Allergy and autoimmune disease are ____ diseases, whereas acute and chronic inflammatory states are ____ diseases
immune-mediated
outside of immune-mediated
A “bystander” is damage that happens when attacking a ____
pathogen
The components of the immune system contribute to 3 things:
1) Recognizing foreign molecules, microbes, or cells
2) Destroying foreign molecules, microbes, or cells (cell membrane disruption, cellular damage from free radicals, catalyzing degradation of cellular components)
3) Communicating between these two activities
What are the 2 major functional divisions of the immune system?
- Innate immunity - “1st line of defense”
- Adaptive immunity - activated when innate
defenses are breached (delayed)
What are the features of innate immunity?
less specific - each cell or molecule recognizes a range of targets
genetically “hard-wired” - cells and molecular effectors
don’t change during the lifespan of the organism
What are the features of adaptive immunity?
highly specific - each cell or molecule recognizes a particular target
genetically “changeable” - cells and molecular effectors change their germline DNA to produce unique receptors/effectors during the lifespan of the organism
When is adaptive immunity activated?
when innate defenses are breached (delayed)
What is the response time for innate and adaptive immunity?
innate: hours to days
adaptive: days to 2 weeks
The innate immune system has no ____
memory
- fixed responses with repeated exposures (to antigen)
In adaptive immunity ____ is present and response can improve in specificity and rapidity of response with repeated exposures
memory
The innate immune system often recognizes ____
patterns
The adaptive immune system recognizes very ____
specific entities
What is the difference in diversity between the innate and adaptive immune system?
Innate: limited (though large) repertoire of entities that can be recognized and neutralized/destroyed
Adaptive: Extremely large number of entities can be recognized and neutralized/destroyed
Recognition of a foreign molecule by high-affinity binding to a receptor occurs in ____
adaptive immunity
True or False: In adaptive immunity, the affinity can increase as the receptor is modified over time
True
True or false: In adaptive immunity, receptors are generated by genetic recombination (gene shuffling)
True
An ____ is a substance that can bind to a receptor of the adaptive immune system
antigen
Receptors include:
B-cell and T-cell receptors
____ receptors can be released from a ____ into the ECF forming an antibody
B-cell
B-cell
An ____ is a substance that can generate an adaptive immune response
immunogen
The molecular entity that binds to the receptor is called a:
epitope
A substance that can bind to an antibody, but CANNOT generate an immune response is called a:
hapten
True or false: no two naive T or B cells are activated by the same molecule
true
In adaptive immunity, diversity is accomplished by randomly “shuffling” portions of genes for lymphocyte receptors and selecting receptors that are___ and ______
functional
do not recognize self
The set of antigen (Ag) receptors in a given individual’s immune system is known as:
lymphocyte receptor repertoire
True or false: Clonal Selection Theory is a part of innate immunity
False
Clonal Selection Theory is a part of adaptive immunity
In Clonal Selection Theory, each lymphocyte bears a single type of ____ with a ______
receptor
unique specificity
In Clonal Selection Theory, receptor binding is required for _____
cell activation
In Clonal Selection Theory, the differentiated effector cells derived from an _______ bear receptors of identical specificity as the ________
activated lymphocyte
parent cell
(they are clones of the parent cell - exact genetic copies with the same receptor)
In Clonal Selection Theory, lymphocytes bearing receptors for self molecules are ______ at an early stage
destroyed
- we select functional receptors that do not bind to self
Naive B cells express ____ on their surface, where they are called _____
antibodies
B-cell receptors
Once naive B cells are activated, they secrete _____ into the blood
antibodies
B cell receptors are made up of:
2 light chains and 2 heavy chains - each with variable and constant regions
The ____ regions of a B cell receptor are the portions that are “shuffled” and that can bind to an antigen
variable
True or false: some antigens can be bound by many different antibodies
true
- different epitopes on the same antigen
Most antibodies bind to ____ antigens
protein
- distinct sequences of amino acids
A recognized amino acid sequence can be either _____ or ______
Continuous (aka linear)
Discontinuous (aka conformational)
True or false: antibodies can also bind to lipid, nucleic acid, and carbohydrate moieties
true
- a wide range of molecules can be recognized
T cell receptors are composed of 2 chains, they are:
1 alpha, 1 beta - each with a variable region and a constant region
T cell receptors are best at recognizing _____
protein antigens
T cell receptors are never _____ , they always stay attached to the membrane
secreted
T cell receptors only recognize antigens by close communication with molecules on other cells, this is called _______
antigen presentation
Exposure of the adaptive immune system to an antigen _____ its ability to respond to the same or closely related antigen following ______
increases
re-exposure
Secondary immune responses are generally faster, larger, qualitatively different and often involve _______
high-affinity B-cell receptors
Control and down-regulation of the _______ is quite specific, as it activation
adaptive immune system
Immune responses to self can result in ______ , and immunological unresponsiveness to self can result in ______
autoimmunity
tolerance
A cell that has not reached a point where it can become activated –
usually refers to cells of the adaptive immune system, is called:
an immature cell
A mature cell that has not yet been activated – always refers to the adaptive
immune system, is called:
a naive cell
A cell (or group of cells) that is currently an active
participant in an immune response is called:
an activated or effector cell
A cell that responds to receptor binding by deactivation of the cell – it
“goes to sleep”, is called:
an anergic cell
A group of effector T/B cells that express the same antigen receptor and are
derived from the same parent cell, is called:
a clone
What are the 2 groups of hematopoietic stem cells?
Myeloid cells and lymphoid cells
What are the myeloid cells?
granulocytes
- neutrophils
- basophils
- eosinophils
- mast cells
monocytes
- macrophages
dendritic cells
What additional cells are derived from myeloid cells?
RBCs and platelets
What are the lymphoid cells?
T cells
B cells
NK cells
dendritic cells
What is the most abundant cell type?
neutrophils
What is the least abundant cell type?
basophils
Monocytes circulate in the blood & differentiate into _____ upon migration into tissue (long-lived)
macrophages
Macrophages are phagocytic, and are the mature form of a ______
monocyte
Macrophages often produce soluble ______ that help orchestrate
a wide range of adaptive and innate immune responses
messengers
What cells present antigens to T cells?
monocytes/macrophages
dendritic cells
True or false: dendritic cells are resident in the body’s tissues
true
During infection _____ cells recognize infection and transports antigens to lymphoid organs
dendritic
Antigen presentation to T-cells is important in T-cell activation during ______ responses
adaptive immune
_______ are phagocytic and short-lived, enter sites of infection and die in infected tissues which forms pus
neutrophils
_____ defend against parasites and are involved in hypersensitivity responses
eosinophils
_____ along with mast cells, protect mucosal body surfaces & release histamine in hypersensitivity responses
basophils
______ reside in all connective tissues and orchestrate hypersensitivity responses (i.e., seasonal allergies), important in mucosal immune responses
mast cells
Mast cells participate in the expulsion of parasites from the body through the release of _____ containing histamine and other active agents
granules
Neutrophils kill microorganisms through _______
phagocytosis
Eosinophils kill antibody-coated parasites through the release of ______
granule contents
B-cells are derived from ______ , and upon activation differentiate into ______
bone marrow
antibody-secreting plasma cells
T-cells are derived from the _______ (though they originate in bone marrow)
thymus
What type of cells can T cells can become?
helper T cells (Th)
cytotoxic T lymphocytes (CTL)
What type of T cell activates other cells like macrophages and B cells?
helper T cells (Th)
What type of T cell kill cells that express foreign molecules?
cytotoxic T cells
True or false: T and B lymphocytes look alike, each having receptors for specific antigen
true
_________ are important in the innate immune system, lack antigen-specific receptors and kill infected/altered cells
Natural killer (NK) cells
What cells are absolutely key in presenting antigens to T-lymphocytes?
dendritic cells and macrophages
Many innate immune cells produce _____ that inform helper T-cells about how to help other immune cells
cytokines
True or false: certain subsets of helper T-cells are dedicated to ONLY aiding
innate immune responses
true
What cells are
important at helping to clear antigens that are bound by
antibody
Mast cells, neutrophils, eosinophils, and macrophages
Lymphoid tissues are organized tissues where lymphocytes interacts with ______ cells
non-lymphoid
true or false: lymphoid tissues are important in the initiation/maturation of adaptive immune
responses
true
What are the 2 types of lymphoid tissues?
1) primary (central) lymphoid organs
2) secondary (peripheral) lymphoid organs
Primary lymphoid organs where lymphocytes are generated and mature include:
bone marrow and thymus
Both B and T cells are generated in the bone marrow, however B cells mature in the ____ and T cells mature in the ____
bone marrow
thymus
For B cells, additional maturation steps can occur in the ____
spleen
Once lymphocytes mature, they leave primary lymphoid organs and are capable of responding to an ____
antigen
Secondary lymphoid organs are where adaptive immune responses are _____
initiated
- antigens and B/T Cell receptors encounter each other
Secondary lymphoid organs exist to bring antigen and lymphocytes together and include:
lymph nodes, spleen and MALT
Lymph nodes lie at junctions of ______ , collect _____ and return it to the blood via lymphatics
lymphatic vessels
ECF/lymph
Afferent lymphatics drain _____ and _____ from tissues, carrying it to the nodes where antigen is _____
lymph
antigens
trapped
The ____ filters for blood, collects blood-borne antigens and destroys aged RBCs
spleen
B-cells in the ____ produce large quantities of ____ and secrete them into the bloodstream
spleen
antibodies
The spleen organ is divided into _____ and _____
red pulp
white pulp
What division of the spleen does the destruction of RBCs take place?
red pulp
What division of the spleen is where lymphocytes surround arterioles entering the organ?
white pulp
White pulp can be further subdivided into _____ and _______
corona
periarteriolar lymphoid sheath (PALS)
Mucosa-associated lymphoid tissues (MALT) includes:
gut associated lymphoid tissues (GALT) and bronchial- associated lymphoid tissues
BALT
The purpose of MALT is to collect _____ from mucosal surfaces
antigens
______ is a specialized lymphoid tissue at the body’s “wet” surfaces required due to large surface area, and is rich with potential pathogens
MALT
______ includes tonsils, adenoids, appendix and Peyer’s Patches (PP)
GALT
______ collect antigens from epithelial surfaces of the GI tract via M cells
peyer’s patches
_______ are composed of distinct T and B cell areas
peyer’s patches
True or false: only when innate defenses are overwhelmed/bypassed/evaded is an adaptive immune response required
true
What are the 3 barriers of the immune system?
1) mechanical
2) chemical
3) microbiological
What are the mechanical, chemical and microbiological barriers of the skin?
mechanical
- epithelial cells joined by tight junctions
- flow of fluid, perspiration, sloughing off of skin
chemical
- antimicrobial peptides (defensins)
- sebum (fatty acids, lactic acid, lysozyme)
microbiological
- normal flora of the skin
What are the mechanical, chemical and microbiological barriers of the GI tract?
mechanical
- epithelial cells joined by tight junctions
- flow of fluid, mucus, food, and saliva
chemical
- antimicrobial peptides (defensins)
- acidity, enzymes (proteases)
microbiological
- normal flora of the GI tract
What are the mechanical, chemical and microbiological barriers of the respiratory tract?
mechanical
- epithelial cells joined by tight junctions
- flow of fluid and mucus e.g., by cilia, air flow
chemical
- antimicrobial peptides (defensins)
- lysozyme in nasal secretions
microbiological
- normal flora of the respiratory tract
What are the mechanical, chemical and microbiological barriers of the urogenital tract?
mechanical
- epithelial cells joined by tight junctions
- flow of fluid, urine, mucus, sperm
chemical
- antimicrobial peptides (defensins)
- acidity in vaginal secretions, spermine and zinc in semen
microbiological
- normal flora of the urogenital tract
What are the mechanical, chemical and microbiological barriers of the eyes?
mechanical
- epithelial cells joined by tight junctions
- flow of fluid, tears
chemical
- antimicrobial peptides (defensins)
- lysozyme in tears
microbiological
- normal flora of the eyes
Chemical barriers include _____ and ______
lysozymes
antimicrobial peptides - defensins
Lysozymes present in secretions and uses _____ to break apart the peptidoglycan wall, causing lysis of the bacterial cell wall
hydrolysis
Antimicrobial peptides/defensins are small, heterogenous, cationic peptides that kill _____ and _____ bacteria, some enveloped viruses and fungi
Gram-negative
Gram-positive
What are the antimicrobial effects of antimicrobial peptides/defensins?
- Destabilize membranes and Pore formation in bacterial cell walls
- Proteolytic degradation of bacterial proteins
- Inhibit viral binding and entry
- Inhibit virus particle assembly
Defensins are prototypical AMPs that can act as a chemical barrier when they are secreted by _______ in a variety of mucosal surfaces
epithelial cells
Defensins and other AMPs (i.e. cathelicidins) are also stored
in _______ and can be released within tissues in
response to inflammation
neutrophil granules
Defensins and other AMPs (i.e., cathelicidins) can kill microbes _____ when neutrophils die during inflammation, and _____ after a cell phagocytoses a pathogen
extracellularly
intracellularly
Phagocytes are a _____ of defense as they can recognize, ingest and destroy many pathogens without the aid of an adaptive immune response
first line
True or false: Phagocytosis can also occur after an antibody (signal) has bound to an antigen and triggers phagocytosis
true
What are the 2 major phagocytes in the body?
macrophages and neutrophils
Pro-monocytes are found in the ____, monocytes are found in the ____ and macrophage/macrophage-like cells are found in the ____
bone marrow
blood
tissues
_____ are a non-dividing short-lived cell type in the blood (dominant WBC), and are derived from hematopoietic precursors in the bone marrow
neutrophils
Review the stages of phagocytosis:
1 - bacterium binds to pattern recognition receptors on membrane evaginations called pseudopodia
2 - bacterium is ingested, forming phagosome
3 - phagosome fuses with lysozyme
4 - bacterium is killed and then digested by low pH activated lysosomal enzymes
5 - digestion products are released from cell
Evolutionarily conserved mechanism for
recognizing common, conserved ‘signs’ of microbial
infection, physiological stress, or other damage is known as:
pattern recognition
True or false: Pattern recognition is immediate, does not require prior
recognition, and activates several arms of the
innate (and adaptive) immune response
true
Responses are elicited via the engagement of
Pattern Recognition Receptors (PRRs) found on
phagocytes, in response to:
- Pathogen Associated Molecular Patterns (PAMPs)
- Danger Associated Molecular Patterns (DAMPs)
Pattern recognition receptors include:
- Toll-like receptors
- Nod-like receptors
- Lectins
Pattern recognition receptors illicit responses such as:
phagocytosis and cytokine secretion
In step 1 of the phagocytosis process, a pattern-recognition-receptor (PRR) binds to a microbe or bit of
debris, OR an ____ created by
another cell binds to the microbe
opsonin
An opsonin is a
soluble, secreted PRR
that enhances the
effectiveness of
_____
phagocytosis
An opsonin coats a
microbe, the ____
has receptors for parts of
that opsonin
phagocyte
Lectin receptors (i.e., mannose receptor) recognize _____
carbohydrate patterns
Scavenger receptor examples are:
SR-A and SR-B
Complement receptors (i.e., CR3) binds to _____
complement opsonins
Fc receptors are receptors for the _____ region of an antibody
constant
In step 2 of the phagocytosis process (microbe engulfment), the PRR receptors signal the
________ to
approach, coat and
surround the sites where
the receptor is bound.
cell membrane
In step 2 of the phagocytosis process, we form a ____ , mediated by intracellular signaling events and actin polymerization
phagosome
PI3 kinase is important in which step of phagocytosis?
the 2nd step
In step 3 of the phagocytosis process (microbe killing), phagosomes fuse with _____ as well as primary and secondary ______
lysosomes
granules
Phagosomes have many molecules that are effective at cellular killing. Major groups include:
- Reactive oxygen species
- “pore”-forming proteins or peptides
- Hydrolytic enzymes
- pH changes – i.e. acidic
environment of the
lysozyme
In step 3 of the phagocytosis process (microbe killing), the microbe remnants are either _______ or can be excreted from the phagocyte
digested and used
After the microbe has been phagocytosed, the phagosome will
dock with a ____ and/or neutrophil granules
lysozyme
What are the characteristics of lysozymes?
- they can pretty much break down anything (acid hydrolases)
- they have a low pH of a lysozyme which is unpleasant for many bacteria
The NADPH oxidase complex becomes associated with the membrane of the ____ and uses a large amount of ____
phagolysosome
oxygen
True or false: If a particle is too large to phagocytose, macrophages will surround
it and “place” their NADPH oxidases close to it to try to kill it
true
Macrophages are also capable of killing cells by inducing the synthesis of ______ at high concentrations
nitric oxide
Neutrophils have a multitude of pore-forming molecules within their _____ , that will fuse with the phagosome
granules
Neutrophil granules include:
defensins
cathepsin
cathelicidins
lysozyme
lactoferrin
Defensins causes lysis and are very rich in ____
cysteine
Defensins form voltage-dependent pores in ____ that are permeable to water
bacteria
Cathepsin is a type of ___
protease
Cathelicidans are pore-forming molecules that causes ____
lysis
Lysozome is a glycoside hydrolase that doesn’t require an ____, is found in a variety of glandular secretions, and is great at killing gram ____
acidic pH
positive bacteria
Lactoferrin is an iron-binding protein that interferes with _____ in microbes
iron metabolism
When neutrophils are in an environment with many bacteria, they can lyse and release their ____ into the ___
DNA
ECF
NETs are neutrophil extracellular traps that are sticky and contain ____ where most bacteria are trapped
chromatin
True or false: histones are toxic to many bacteria
true
True or false: the granule contents will remain close to the NETs and
help with killing bacteria, even after the neutrophil itself is dead
true
LPS, dsRNA, ssRNA, DNA, and Flagellin are all examples of ____
toll-like receptor ligands
Cytokines secreted in response to TLR’s include:
inflammatory cytokines (IL-1b, IL-6, CXCL8, IL-12, TNFa) and interferons
What are the functions of inflammatory cytokines?
small protein messenger secreted by many cells that can:
- Influence the differentiation of a wide variety of cells,
including leukocytes
- Mediate – activate or inactivate – the activity of many cells, including leukocytes
- Increase or decrease the production of a wide variety of stem/hematopoietic cells
What are the types of interferons (IFN)?
alpha, beta, and lambda (IFNa, IFNb, IFNl)
Interferons are autocrine and paracrine signaling molecules that are effective in activating _____ and ____ cells, and inducing an _____ state
macrophages
NK
antiviral
MyD88 is an essential adaptor in ___ signaling
TLR
People with MyD88 deficiency suffer frequent and severe _____ infections, while antiviral responses are generally unaffected
bacterial
People with constitutively active MyD88 are prone to developing ____ and ____
blood disorders
blood cancers
- overproduction or dysregulated production of igM
- B cell lymphoma, marginal cell lymphoma
Nod-like receptors are a family of intracellular receptors found in the ____ that detect products derived from the intracellular degradation of phagocytosed pathogens
cytoplasm
True or false: Nod-like receptors can recognize DAMPs associated with cellular stress
true
Nod-like receptors activate expression of _______
inflammatory cytokines
What are the 3 steps of acute inflammation?
1) alteration of vascular caliber - vasodilation
2) enhancement of vascular permeability
3) emigration and activation of leukocytes
Vasodilation leads to increases in blood flow at the capillary bed due to _____ dilation, dilation of precapillary sphincters
arteriolar
What components contribute to vasodilation in acute inflammation?
- Nitric oxide and histamine
- Prostaglandins (PGI2, PGE2, PGD2)
- Platelet activating factor (at low concentrations – higher
concentrations cause vasoconstriction) - Complement (C5a and C3a stimulate histamine release)
At low concentrations _____ is a potent vasodilator
nitric oxide
At high concentrations ____ is capable of destroying both microbes and host cells since it’s a _____
nitric oxide
free radical
In macrophages, higher concentrations of nitric oxide are produced by an inducible _____
nitric oxide synthase
Vasodilation and fluid loss due to increase permeability lead to slower blood flow known as ______ , which helps with margination of leukocytes
vascular congestion
Prostaglandins and leukotrienes are produced when PLA2
generates ______ from membrane phospholipids
arachidonic acid
Different types of cyclooxygenases produce different types
of prostaglandins from ______
arachidonic acid
What prostaglandins cause vasodilation and increase vascular permeability?
PGE2, PGD2, and PGI2
Different types of 5-lipoxygenase produce different types of leukotrienes from _____ that are
important in lung tissue
arachidonic acid
LTB4 is a leukotriene that is an important _____
chemotactic agent
Many leukotrienes increase vascular permeability and _______
smooth muscle constriction
Lipoxins are generated from arachidonic acid by 12-lipoxygenase and they decrease ____
inflammation
Capillaries and venules become more “leaky” with the release of numerous mediators:
- Histamine and serotonin (released by activated
platelets) - Prostaglandins (PGD2 and PGE2)
- Leukotrienes (LTC4, LTD4, LTE4)
- Platelet activating factor
- C3a and C5a
- Bradykinin
Increased vascular permeability is due to contraction of
_______ , which is often short-lived and occurs mainly in the ____
endothelial cells
venules
Vascular permeability can also occur through ______ caused by trauma, burns and microbial damage, or leukocyte-mediated damage to the _____ , which is longer-lived
endothelial damage
endothelium
Increased transcytosis can result in ____ of plasma components into the _____
leakage
interstitial space
Active, vesicle-mediated transport across the capillary endothelial cell is known as:
transcytosis
In transcytosis, larger molecules can move across the endothelium via _____ and _____
- Pinocytosis (caveolin
pathway) - Receptor-mediated
endocytosis
Mechanisms of increased vascular permeability:
Retraction of endothelial cells –> endothelial injury –> leukocyte-mediated vascular injury –> increased transcytosis
A interstitial fluid accumulates during inflammation, pressure increases in the interstitial space and _____ increases
lymphatic drainage
Excess fluid, microbes, debris, and leukocytes all migrate into the ____ during inflammation
lymph
When lymphatic vessels themselves become inflamed this is called:
lymphangitis
During emigration and activation of leukocytes, neutrophils, monocytes, eosinophils, and basophils will all migrate from the circulation into _____
inflamed tissue
What are the 5 steps of leukocyte migration?
1) Margination
2) Rolling (Mediated by binding of selectins and
cellular adhesion molecules to their respective ligands on leukocytes)
3) Adhesion (Mediated by binding of selectins and
cellular adhesion molecules to their respective ligands on leukocytes)
4) Diapedesis
5) Chemotaxis of leukocytes to sites of injury or infection
What are the functions of cytokines?
1) Influence the differentiation of a wide variety of cells, including leukocytes
2) Mediate – activate or inactivate – the activity of many cells,
including leukocytes
3) Increase or decrease the production of a wide variety of stem/hematopoietic cells
What are the functions of chemokines?
1) Bind to cell-surface receptors (usually leukocytes)
2) Induce movement of leukocytes along the chemokine concentration
gradient
3) Mediate adhesion of leukocytes for the purposes of:
* Differentiation
* Inflammation/migration
What are the 2 major chemokine families?
CXC and CC
CXC chemokines attract ____ and are ____
neutrophils
angiogenic
In CXC chemokines, the “X” indicates the location of a _____ bond
disulphide
CC chemokines act on/attract a wide variety of _____
leukocytes
Review the steps for emigration and activation of leukocytes:
a) Margination – leukocytes migrate towards vessel wall
b) Rolling – formation & dissociation of adhesion bonds between
leukocytes and endothelial cells
c) Stable/Tight Adhesion – Formation of tight/stable
adhesion bonds between leukocytes and endothelial cells
d) Diapedesis/Transmigration – leukocyte migrates through
endothelium
e) Chemotaxis of
leukocytes to sites of injury or infection
Activation by chemokines presented on endothelial cells is required before the leukocyte can form ______
stable adhesion
When an endothelial cell presents a chemokine that stimulates the activation of leukocytes, this increases the affinity of leukocyte integrin for it’s ____ , allowing _____ to form
ligand
stable/tight adhesion bonds
What are the 3 families of endothelial and leukocyte adhesion molecules?
selectin, integrin and Ig
How does histamine and thrombin increase the ability of leukocytes to migrate to a target?
rolling and selectin expression by endothelial cells
How does TNF and IL1 increase the ability of leukocytes to migrate to a target?
ICAM expression by endothelial cells
How do chemokines increase the ability of leukocytes to migrate to a target?
increased integrin affinity
Chemotactic agents are produced in higher concentrations at sites of _____
cellular damage/pathogen invasion
- i.e., leukotriene B4, bacterial products containing N-formyl-methionine, activated complement (C5a), chemokines (IL-8, RANTES, eotaxin)
Leukocytes can “follow the breadcrumbs” to the site of pathology via the _______
chemotactic agent concentration gradient
What is the complement system?
A blood-borne molecular defense system that “complements” the immunity provided by antibodies
What 3 functions does the complement system aid in?
1) phagocytosis - some complement components are opsonins
2) destruction of microorganisms - the end result of complement activation is formation of a large, antimicrobial protein complex
3) inflammation - some complement components are potent inflammatory mediators
How is the complement system activated?
Through a tightly-controlled enzyme-triggered cascade
- cascade = enzymatic reactions that activate protein effectors in a sequence
What are the 3 pathways of complement activation?
1) Alternative pathway
- complement component 3 (C3) acts as a PRR binding to the surface of a pathogen
2) Mannose-binding-lectin (MBL)
- triggered by binding of MBL, a PRR, to mannose-containing CHO on bacteria/viruses
3) Classical pathway
- when antibodies bind to a pathogen, C1q binds to the Fc portion of those antibodies
The _____ pathway and ______ pathway have a similar activation mechanism
mannose-binding-lectin
classical
C3 convertase cleaves C3 into ___ and ___
C3b
C3a
C3b is an important ____ , forms part of the _____ convertase, and causes progression through the rest of the complement cascade
opsonin
C5
C5 convertase cleaves C5 into ___ and ___
C5a
C5b
C5b becomes associated with the cell wall/membrane of the microbe and causes ____ as it activates other components of the complement system
lysis
What complement molecules all associate to form a large pore in the microbial membrane and cause lysis
C5b, C6, C7, C8, C9
True or false: C3a and C5a are incorporated into the microbes membrane and also mediate inflammation
true
The classical and lectin pathways have the same ___ and ___ convertases, and C1q and MBL look very similar
C3
C5
C3 forms C3a and C3b spontaneously in the bloodstream, but is ____ quickly under normal conditions
degraded
Factor B, a circulating proteins is spontaneously ____ to a protein known as ____
cleaved
Bb (complexes with C3b to form C3bBb)
C3bBb is a C3 convertase and can convert C3 into ___ and ___
C3a
C3b
C3bBb is rapidly inactivated in the ____. If an bacterium is present, then it will bind to the _____
uninfected host
bacterial membrane
C3Bb bound to the bacterial membrane is a stable _____
C3 convertase
As more C3b is generated, more ___ is formed
C3Bb
The circulating protein, properdin helps stabilize the alternative pathway complex to form the stable ___ and ___ convertases
C3 and C5
C3bBbC3b and properdin are components of the C5 convertase of the _____ pathway. They need to bind to the bacterial membrane to stay stable and keep converting C5 into ___ and ___
alternative
C5a
C5b
When C1q detects a bound antibody or MBL detects mannose on a membrane, they bind ______ proteins, and these proteins cleave ___ and ___
complement-activating
C2
C4
C4b2a is formed from the cleavage of ___ and ___ upon C1q or MBL activation
C4
C2
The membrane attack complex (MAC) generates a ___ in lipid bilayer membranes
pore
What is the sequence of events for cell lysis in the MAC?
- C5b triggers the assembly of complexes C5b, C6, C7 and C8
- Upon binding to C7, C8 inserts into the membrane
- Polymerization of C9, forming a pore in the membrane
True or false: The MAC and the pro-inflammatory effects of C5a and C3a can be extremely damaging to cells if they are not tightly regulated
true
___ and ___ both cause vasodilation, increased vascular permeability, smooth muscle contraction (i.e., bronchoconstriction) and histamine release from mast cells
C3a
C5a
____ is a chemotactic agent for a wide variety of cells (neutrophils & macrophages)
C5a
Inadequate complement proteins C2, C3, C4, C5, MBL, and MAC complex tend to make patients vulnerable to _____ infection
bacterial
Deficiencies in ___ highly predispose patients to systemic lupus erythematosus
C1q
C1q helps macrophages to clear _____ bodies and initiate the ____ pathway, as it recognizes phosphatidylserine
apoptotic
classical
The alternative pathway is the first responder, while the lectin/classical pathways are more effective later because ___ is always present in the bloodstream and is constantly being produced by the liver, cleaved and degraded
C3
Mannose-binding lectin does not circulate in high ____ unless it is secreted by the liver in response to pro-inflammatory signals
concentrations
What do toll-like receptors 1-4 detect?
TLR1 - can detect mycobacteria (like Tb) and gram-negative bacteria
TLR2 - can detect peptidoglycans (major component of cell wall of gram-positive bacteria)
TLR3 - can detect double stranded RNA (only found in viruses)
TLR4 - can detect lipopolysaccharide (LPS) (major component of gram-negative bacteria)
TLRs tend to recognize PAMPs in the ____ or in ___
ECF
endosomes
C-type lectin receptors detect ____ components of many microbes, and are found on the cell membrane of a wide variety of _____ cells
carbohydrate
immune
True or false: C-type lectin receptors are found on the cell membrane and detect pathogens in the cytosol
false
- they do NOT detect pathogens in the cytosol
NOD-like receptors (NLRs) are present in the ____ of a wide range of immune cells and non-immune cells (i.e., epithelial cells)
cytosol
Most NLRs detect ____ or parasite cell walls and some can also detect ____
bacteria
viruses
Activation of ____ leads to activation of NF-KB and AP-1
NLRs
RIG-like receptors (RLRs) are present in the ___ of many immune cells and non-immune cells. They detect viral ___ and activate NF-KB and transcriptions factors which leads to the production of antiviral ____
cytosol
RNA
cytokines (interferons)
DAMPs are molecular signals that are present when a cell is damaged but they can also present as crystals including:
cholesterol crystals (cellular damage or oxidized LDL)
uric acid crystal (gout)
When a DAMP activates NLRP3, it associated with caspase 1 and activates it by forming a large molecular complex known as an ____
inflammasome
What are the 2 major effects of caspase 1 activation?
1) activation of pro-IL-1-beta to IL-1-beta
2) insertion of a cell membrane pore - gasdermin - into the cell membrane
If enough gasdermin is produced, the cell will ____ , and release more ____
lyse/die (pyroptosis)
DAMPs
Inflammasomes are a molecular assembly that activates _____
caspase 1
IL-1 leaves the cell via ____
gasdermin pores
True or false: The release of DAMPs can lead to activation of neighboring cells
true
Review the 2-step process of IL-1 generation/release:
1) Priming - detection of PAMPs or DAMPs leading to synthesis and storage of pro-IL-1
2) release - continued or larger DAMP or PAMP stimuli, causing NLRP3 activation leading to caspase 1 activation and the conversion of pro-IL-1 to IL-1, releasing IL-1
What cells are cellular sentinels/important DAMP and PAMP detectors?
Resident macrophages, endothelial cells, epithelial cells
Il-1-beta is one of the most important _____, and is released in large quantities by macrophages in response to _____ or _____
pro-inflammatory cytokines
significant infection
tissue damage
What cells express most PAMP and DAMP receptors and can secrete large quantities of pro-inflammatory cytokines?
Langerhans cells - dermis and epidermis
Kupffer cell - liver
Alveolar macrophages - lung
Microglia - brain
Resident macrophages also found in connective tissue
Spleen (and other secondary lymphoid organs)
Endothelial cells in the blood and lymph vessels express TLRs and RLRs, and when they detect a PAMP they do 2 things:
1) increase the expression of ICAMs and selectins
2) increase the production of pro-inflammatory cytokines and chemokines
The PRRs in epithelial cells (found in skin and mucosal surfaces) tend to result in increased production of local ______ peptides
antimicrobial
Chemokines and cytokines in epithelial cells can be produced if more ____ need to be recruited from circulation
leukocytes
What are the major pro-inflammatory cytokines?
IL-1-beta, IL-6, IL-12, CXCL8, and TNF-alpha
What are the important cellular sources for IL-6?
Macrophages/monocytes, dendritic cells, NK cells, epithelial cells, endothelial cells
What are the important cellular sources for IL-1?
Macrophages/monocytes, dendritic cells, keratinocytes, epithelial cells, endothelial cells
What are the important cellular sources for TNF-alpha?
Macrophages/monocytes, dendritic cells, mast cells, NK cells, epithelial cells
Which 3 cytokines have redundant and pleiotropic effects?
IL-1, IL-6, TNF-alpha
IL-1-beta, IL-6 and TNF-alpha all act on the ____ to cause fever, participate in the synthesis and release of acute-phase proteins by the ____, and increase vascular permeability
hypothalamus
liver
IL-1-beta and TNF-alpha both increase ____ molecules on vascular endothelium, produce the chemokine ____, and IL-6
adhesion
CXCL8
What are the mechanisms of higher body temperature?
- peripheral vasoconstriction (blood flows away from the periphery to the core)
- shivering
- increased metabolic rate
What is the benefit to fever?
adaptive immune mechanisms in general are more effective at higher temperatures
The hypothalamic set-point is altered by increased levels of _____
pro-inflammatory cytokines
IL-1-beta and TNF-alpha can induce fever at low ____ , and IL-6 induces fever at higher (10X) ____
serum concentrations
concentrations
Pro-inflammatory cytokines cause elevation of ____ E2 production by cells in the 3rd ventricle, which leads to signaling that changes the _____ setpoint
Prostaglandin
hypothalamic
What are the 5 major acute phase proteins?
- C-reactive protein (CRP)
- Ferritin
- Hepcidin
- Mannose-binding lectin (MBL)
- Serum amyloid protein A (SAA)
Blockers of cyclooxygenase activity (i.e., tylenol) are effective _____
anti-pyretics
Elevated levels of inflammatory cytokines cause the ____ to increase the secretion of useful ___ into the bloodstream, known as acute _____
liver
proteins
phase proteins
C-reactive protein (CRP) includes ___ which binds to phosphorylcholine. CRP can activate ____ to trigger the classical complement cascade.
opsonin
C1q
True or false: CRP is a common lab measurement ordered to diagnose inflammatory disease
true
Ferritin binds to ____ with high affinity, and many microbes depend on ____ for their metabolism
serum iron
iron
Mannose-binding lectin is the PRR that initiates the ______ cascade
lectin complement
Hepcidin interferes with intestinal transport of ___ into the bloodstream
iron
Serum amyloid protein A modulates/increases the activation of the ____ and ____, and also opsonizes ____ bacteria
inflammasome
TLRs
gram-negative
IFN-alpha and IFN-beta are secreted by:
macrophages, dendritic cells and cells that have detected viruses via PRRs
What are the 2 major groups of interferons?
1) Group 1 - interferon-alpha (IFN-alpha) and interferon-beta (IFN-beta)
2) Group 2 - interferon-gamma (IFN-gamma)
The role of IFN-alpha and IFN-beta is to:
interfere with viral replication
IFN-gamma is secreted by ___ cells and ___ cells, and it activates ____to push the adaptive immune system to a cell-mediated response
Th
NK
macrophages
Type 1 interferons act in an ___ and ___ fashion to provide a rapid, innate protection to viral infection
autocrine
paracrine
If type-1 IFNs and the NK response is inadequate, then we rely on the ______
adaptive immune response
What are the 3 ways type 1 interferons protect against viral infection?
1) induce resistance to viral replication in all cells
2) increase MHC class I expression and antigen presentation in all cells
3) activate NK cells to kill virus-infected cells
How do interferons interfere with viral replication inside cells?
- they inhibit protein translation in the presence of viral RNA
- they degrade viral mRNA
- they inhibit viral protein assembly
Natural killer cells are specialized cells derived from the ____ lineage, and has a non-specific way of detecting cancer cells or virally-infected cells
lymphoid
Large lymphocytes that are activated by Type 1 IFNs and IL-12 do 2 things:
1) kill cells that are infected by viruses
2) secrete cytokines that predispose the adaptive immune system to adopt a response that relies on cellular effectors rather than antibodies
NK cells survey the body for ___ or ____ abnormal cells
infected
stressed
What are the two types of NK cell receptors?
1) NK activating receptors (NKARs)
2) NK inhibitory receptors (NKIRs)
_____ detect molecules expressed on the membrane of cells that are infected by viruses or have developed into cells that may be malignant, while ____ detect molecules that are typically expressed by normal cells
NKARs
NKIRs
NKG2D is an NKAR that detects _____ molecules on cells
strange MHC-I
KIR is an NKIR that detects -_____ molecules on a cell membrane
normal MHC-I
While normal MHC-I proteins can present intracellular ____, abnormal MHC-I proteins cannot and are typically expressed by virally-infected cells or cells with damaged genomes.
antigens
Before NK cells can be activated, they need to be licensed to make sure their ____ are functional. This is done by _____
NKIRs
dendritic cells (protect body from indiscriminate NK-killing and tissue damage)
Once NK cells are activated an licensed, they travel to areas of ____ and ___ the cells
damage/inflammation
survey
If a cell expresses mostly normal MHC-I proteins, ____ over-rule ____ and vice versa for abnormal MHC-I proteins
NKIRs
NKARs
When NKARs are activated, it kills the cell by:
1) receptor-mediated apoptosis via Fas-Fas ligand interaction
2) secretion of the proteins perforin and granzyme
- perforin pokes holes in membrane
- granzyme activated BH3-only apoptotic protein Bid and executioner caspase 3
