Innate Immunity (Lecture 2) Flashcards
Innate lymphoid cells (ILCs)
• ILCs are the most recently identified family of innate immune cells.
• Although they belong to the ____ lineage (lymphocytes), they lack T- or B-cell antigen receptors and thus cannot respond in an ____ manner.
- ILCs are predominantly found at ____ surfaces (e.g., skin, airways, and intestine), where they regulate immunity, inflammation, and tissue repair.
- ILCs can additionally maintain immune tolerance toward the ____ in the gut.
lymphoid
antigen-specific
barrier
commensal microbiota
Innate lymphoid cells (ILCs) cont
• Different groups of ILCs express distinct sets of ____ and thus are responsible for ____ functions.
cytokines
specialized
ILCs are the innate counterparts of specific T cell subsets
NK (CD8+) > ____, ____
ILC1 (Th1) > ____
ILC2 (Th2) > ____, ____, ____, ____
ILC3 (Th17) > ____, ____
IFNgamma perforin IFNgamma IL-4 IL-5 IL-13 AREG IL-17 IL-22
ILCs are the innate counterparts of specific T cell subsets
NK/ILC1: Type I Defense against \_\_\_\_ pathogens and \_\_\_\_. Adverse outcomes: Inflammatory, \_\_\_\_ diseases.
ILC2: Type 2 Defense against \_\_\_\_ and \_\_\_\_. Homeostatic funcIon: \_\_\_\_ repair. Adverse outcomes: \_\_\_\_, \_\_\_\_.
ILC3:
Type 3
Defense against extracellular organisms (____ and extracellular ____). Homeostatic function: ____ maintenance.
Adverse outcomes: Inflammatory, ____ diseases.
intracellular
tumors
autoimmune
helminths venoms tissue asthma allergy
fungi
bacteria
epithelial barrier
autoimmune
Interferons
• Two types, produced in response to inflammation or infection
• Type1 or ____–produced by ____ cells and ____
• Type2 or ____–produced by mainly by ____.
• Responsible for much of host control of viral replication in ____ and other infections
alpha/beta epithelial fibroblasts gamma lymphocytes
colds
Interferons alpha/beta
induce resistacne in cells so they resist ____ synthesis, and increase ____ and activate ____ cells to kill virus-infected cells
viral
MHC class I
NK
Interferons alpha/beta induce antiviral proteins that suppress viral replication
cell infected with virus > leads to produce of ____ interferons; has been secreted and activated second cell (now prepared > induces production of antiviral proteins); virus wil not be able to esrtablish ____ like in first cell now
alpha/beta
infection
Time course of antiviral reaction
time course of antiviral response
first ____; and activation of ____ cells (from IFN); if NK cells are not enough, then induction of ____ immunity
as immmunity progresses, virus titer plateuas and goes down
alpha/beta IFN
NK cells
adaptive
Complement
• Group of proteins that circulate in the blood
• Important role in host defense but also implicated in inflammatory immunopathology (eg, ____).
– Help ____ phagocytes to site of inflammation and activate them
– ____ bacteria which are targeted to receptors on ____, for clearance
– Form ____ in targeted susceptible microbes
– Activate ____ to release histamine and other factors
sepsis
recruit opsonize phagocytes pores mast cells
Functions of Complement
lectin/alternative you don’t need ____
lectin > MBL (is PRM)
doesn’t matter which mechanism
everything goes through ____ (central complement compoentn) two products > ____ = opsonin; ____ = inflam molecule, binds to receptors on phaocytes/inflam cells > C5 is the same > helps inflam cells (macro’s neutros) to get to a tissue > leads to chemotaxis/vascular perm > ____
downstreamf rom C5 > complexes with 6, 7, 8 and 9 > ____ (membran-ettack complex); when binds bacterium > casues its ____
adaptive C3 C3B C3A inflammation
C5b-9
lysis
The complement system “complements” the ability of antibodies and phagocytic cells to clear pathogens
C5A > bring ____ > recognize bacteria that has been decorated by ____; if not opsonized doesn’t mean it can’t get phagocytosis
phagocytes
C3B
Cytokines
• Secreted ‘messenger’ proteins that mediate communication between cells and regulate immune and inflammatory responses.
• Induced during both ____ and ____ immune responses.
• Have many activities, either ____ or ____ inflammatory.
• Generally follow an ____ appearance, with important roles both in the ____ and ____ phases of the response.
innate adaptive pro- anti- ordered early late
Cytokines are messengers in the immune system
Induction and regulation of inflammatory responses
is just one of their functions.
Other functions include the development, differentiation, and proliferation of ____ cells
Cytokine ____
Do not have to learn this! Just appreciate
the intricate complexity
(in fact, quite simplified here).
immune
networks
Inflammation
Homeostatic process aiming to:
• Isolate and destroy the initial insult (e.g., infectious agent)
• Mitigate tissue damage
• Remove necrotic cells and tissue, repair damage
• Restore normal function
Also a potentially harmful process
• Components of inflammation capable of destroying microbes may also cause ____ injury
• Serious consequences if not properly controlled and ____
bystander tissue
self-limited
Cardinal signs of inflammation (inflammare: latin for set on fire)
Characterized by: Increase in temperature \_\_\_\_ \_\_\_\_ \_\_\_\_ \_\_\_\_ Loss of \_\_\_\_
heat redness swelling pain function
when you have inflam; if persistent infection > ____ inflammation > common denimoator of ____, ____ loss (rheumatoid arthritis), ____ (neurological diseases), ____ diseases (artheroscleoris, stroke), ____ disease (asthma, COPD), ____ disorders (multiple sclerosis)
chornic periodontitis bone alzheimers cardiovascular pulmonary autoimmune
Example of inflammation (skin)
bacteria enter skin; through a wound; bacteria detected by local macro’s > ____ > activte endothelium > ____ and also ____ of junction bt endo cells > faciliate the recruitment of neutrophils/macro’s into the tissue
cytokines
vasodilation
loosening
Inflammation and associated symptoms at the molecular level
pain also occurs > ____and ____ (why you take NSAIDs, inhibit the function)
prostaglandins
histamines
Inflammation: Effects on Vascular Endothelium
- ____ – vessel enlarges and gets greater blood flow, but lower ____
- Expression of receptors – endothelial cells upregulate ____ proteins specific for interactions with leukocytes (e.g., selectins, ICAMs and VCAMs)
- Loosening of cell junctions – ____ open up to allow passage of leukocytes
- Clotting of microvessels – restricts exit of ____ agents from the area to prevent ____ dissemination
vasodilation
velocity
adhesion
tight junctions
infectious
systemic
Complement involvement in inflammation
The anaphylatoxin receptors ____ and ____ mediate most of complement’s inflammatory responses.
C3a and C5a contribute to ____ degranulation and inflammation during ____-dependent anaphylaxis.
C3aR
C5aR
mast cell
IgE
Complement is involved in the recruitment of ____, such as neutrophils
Complement amplifies the production of inflammatory ____ potentially leading to tissue damage
too much inflam > complement can be invovled in cytokine ____ > tissue damage, organ failure
inflammatory cells
cytokines
storm
Inflammatory Cytokines
All are produced by ____, IL-1 the only one also produced by ____. All the others are also produced by ____.
IL-8 > chemoattractant for ____
IL-12 > activated naive ____ to be activate
IL-1/6 > active in ____ and activate lymphocytes; activate ____ proteins
TNFalpha > acts on ____; induces changes
macrophages
keratinocytes
dendritic
neutrophils T cells liver acute-phase vasco endo
Inflammasomes
• Inflammasomes are multiprotein complexes that assemble in the ____ after exposure to certain PAMPs or DAMPs and result in the activation of ____, which cleaves the inactive cytoplasmic precursor pro-IL-1β to the mature form of proinflammatory ____, which can then be secreted.
• Inflammasome complexes typically consist of:
– ____ (NLR or ALR sensor protein)
– ____ (ASC)
– ____ (in inactive form prior to activation: pro-caspase-1)
• A number of distinct inflammasome complexes have been identified (different activation triggers and PRRs); the best characterized is the ____ complex.
cytosol
caspase-1
IL1B
cytosolic PRR
adaptor protein
caspase-1
NLRP3
NLRP3 inflammasome
The NLRP3 inflammasome is activated in a 2-step process:
– Signal 1 (priming step): ____ activation (e.g., by bacterial LPS) results in increased expression of ____ and ____.
– Signal 2: Activation of NLRP3 occurs by different triggers* that lead to the assembly of the complex and activation of ____.
Triggers: Whole pathogens; PAMPs/DAMPs; potassium efflux; lysosomal-damaging ____ factors [uric acid, silica, alum]; endogenous factors [amyloid-β, cholesterol crystals]; mitochondrial damage which releases ____.
NF-kB
NLRP3
prol-IL-1beta
caspase-1
environmental
reactive oxygen species
Anti-inflammatory Cytokines
____ and ____ are anti-inflammatory cytokines produced by several cell types including macrophages and ____ cells.
These cytokines act as ‘brakes’ to restrain the host inflammatory response. For instance, Treg-derived IL-10 and TGFβ can control inflammatory responses by ____, eosinophils or ____ effector cells.
IL-10
TGFbeta
regulatory T helper cells
basophils
T helper effector
Acute phase proteins
– Proteins in the ____ that increase during infection and inflammation
– Can be used ____ to give an indication of acute inflammation
produced in liver; activated by ____ and ____; icnrease in plasma during infect/inflam; cxn go VERY high during these
plasma
diagnostically
IL1
IL6
Acute Phase Proteins
IL6 acting liver cells (MBP [one of substances that activated complement]) > binds to residue on bacteria, activates ____ pathway and ____
C-reactive is similar; binds ____ on bacterial cells, acting as an opsonin and a complement activator
Also ____
complement
opsonization
phosphorylcholine
fibrinogen
Inflammation: Could protect or kill you
Although the inflammatory response contributes to immunity against infection, excessive and/or sustained inflammation contributes to ____ and ____.
immune pathology
disease
inflam must be regulated; helpful if ____
when systemic inflammation > systemic edema causes decreased ____; causes vessel to ____, and disseminated intravasculature ____ > can result in death (local clotting is good, but coagulation everywhere > bad news)
localized
blood flow
collapse
coagulation
Inflammation underlies the pathogenesis of many diseases
LOOK OVER THE IMAGE
\_\_\_\_ infection \_\_\_\_ \_\_\_\_ disease \_\_\_\_ arthritis \_\_\_\_
myocardial stroke chohn's or alzheimers rheumatoid periodontitis
Mast cells & allergy
mast cells > activated like basophils (with ____); pollen can activate receptors that have already bound IgE
antigens that activate mast > inhaled ____, or material (____), food (____), insect ____, and material we contact (____)
bacteria pollen peanuts venom poison ivy
Mast cells
• Found in tissues such as the skin, near ____.
• Activated after antigen binds to a specific type of antibody called ____ that is attached to receptors on the mast cell.
• When activated, mast cells release substances that contribute to inflammation, such as ____.
• Important in ____ responses but are also part of the ____ immune response, helping to protect against infection.
blood vessels IgE histamine allergic innate
Innate and Adaptive Immunity work together
good to know that both innate and adaptive wokr together, cannot fight separately
extra bac > present in interstitail spaces or epi surfaces > can be dealt with ____ and ____ > work together to better fight
complement activation > classical pathway, which is activated by ____ (complements antibody functions)
intercell bacteria > cyto or vesicular > both forms; ____ cells with ____ cells
complement (innate)
antibodies (adaptive)
antibodies
NK
cytotoxic T
Immunity is a double-edge sword: protection vs. harm
tumors and infectious agent you want a ____
3 cases where YOU DONT WANT HTE HOST TO RESPOND > ____, ____, or ____
reaction
innocuous substance (peanut)
grafted organ
self-organ
Innate:
____
____ recognition
____
First line of defense Necessary for proper function
of adaptive immunity
Adaptive:
Evolutionarily ____
Defined ____ target
____ & custom-made (____ upon repeated infection)
Second line of defense Reinforces innate immunity
primitive
pattern
invariant
recent
epitope
variable
improves
Innate Immunity
Cells: ____
Receptors for detection of microorganisms: ____: encoded in the ____
Receptor repertoire: ____
Specificity for microbial components: ____ > molecular patterns (shared by classes of microbes)
Adaptive Immunity
Cells: ____
Receptors for detection of microorganisms: ____: generated ____ by gene recombination
Receptor repertoire: ____
Specificity for microbial components: ____ > structural details (specific peptides)
monocytes/macrophages, neutrophils (PMN) and dendritic PRRs germline limited broad
T & B lymphocytes T cell receptors/B cell receptors randomly unlimited narrow
Beyond an initial obstacle to infections
! In recent years, it has been appreciated that innate immunity is not simply a physiological barrier or a set of immune responses aiming to ‘buy time’ until adaptive immunity becomes activated.
! Innate immunity is endowed with adequate ____ to distinguish between different classes of ____ as well as to detect ____ damage.
! Adaptive immunity can elicit a response only after it is informed by the ____ system that the recognized target is dangerous for the host.
! If lymphocytes are instructed that there is no danger, they become ____ to the recognized target.
specificity
microorganisms
host cell
innate
unresponsive (tolerant)
Beyond an initial obstacle to infections (cont)
! Dendritic cells (DCs) act as sophisticated mediators between detection of infection and induction of the appropriate adaptive immune response.
! This role requires a function known as ____, a process whereby DCs capture microbial antigens, degrade them into small peptides, and couple them with specialized cell surface proteins, termed ____ molecules, for presentation to and recognition by T cells.
! In addition to antigen presentation, DCs provide co-stimulatory signals to ____ cells, thereby activating them and instructing their development in a manner that is tailored to the nature of the infection.
! Antigen presentation alone (without co- stimulation) induces ____ (unresponsiveness).
antigen presentation
major histocompatability complex (MHC)
T
T cell tolerance
Properties of Adaptive Immune Responses
see same antigen a second time, you respond much ____ > in a more robust way
basis for vaccination; respond much ____ when encounter the infection later
faster
quicker
No memory in innate immunity?
- Although innate immune cells lack the exquisite antigen specificity, clonality, and longevity of adaptive lymphocytes, they can be ‘trained to ____’ following exposure to infection or vaccination.
- Designated ____, this capacity enables innate cells (e.g., monocytes, macrophages, and NK cells) to display enhanced ____ after secondary stimulation with microbial pathogens, which can thereby be eliminated more readily.
- The molecular basis of ‘trained immunity’ involves sustained changes in their transcriptional programs, known as ____ (as opposed to permanent genetic changes owing to mutations and recombination).
- Although innate immune memory is ____ lived and less ____ than classical adaptive immune memory, it can contribute to efficient control of many infections.
remember
trained immunity
responsiveness
epigenetic reprogramming
shorter
specific
What is the relative importance of the innate and adaptive immune systems in infection?
if only going to have one > no innate > ____ immediately > death
if you don’t have adaptive > in beginnign you’ll be okay (bc innate might be able to handle it) > but if it’s more challenging, you will lose control ____ on
uncontrolled infection
later
