Innate Immunity (Lecture 2) Flashcards by J L

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

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Innate lymphoid cells (ILCs) cont

• Different groups of ILCs express distinct sets of ____ and thus are responsible for ____ functions.

cytokines

specialized

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Cardinal signs of inflammation (inflammare: latin for set on fire)

Characterized by:
Increase in temperature \_\_\_\_
\_\_\_\_
\_\_\_\_
\_\_\_\_
Loss of \_\_\_\_

heat
redness
swelling
pain
function

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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

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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