Innate Immunity (Lecture 2) Flashcards
Immunity:
Protection from pathogens and disease
• Mechanical Barriers
– ____
– ____ surfaces
• Innate and Acquired (adaptive) defense mechanisms
skin
mechanical
Pathogens cause tissue damage directly or indirectly
• Direct Mechanisms
- ____
- Degradative ____
• Indirect Mechanisms (host-mediated damage to host) - Destructive \_\_\_\_ (locally or systemically) - \_\_\_\_ (Ag-Ab; blood vessel damage) - \_\_\_\_ (cross-reactive with microbes)
toxins
enzymes
inflammation
immune complexes
anti-host antibody
The immune system protects against four classes of pathogen
Bacteria > salmonella enteritidis > ____
Viruses > influenza > ____
Fungi > candida albicans > ____, systemic ____
Parasites > protozoa > plasmodium falciparum > ____
food poising flue thrush candidiasis malaria
Self vs Non-self
• The immune system needs to distinguish foreign (‘non-self’) material from self–tissues and –cells.
• Moreover, the immune system needs to neutralize or eliminate ____ while sparing ____ from immune attack.
• The latter concept is known as ____, in that the body needs to ‘tolerate’ its own tissues.
• If immune tolerance breaks down, the resulting aberrant immune response against self-tissues may cause disorders known as autoimmune diseases.
non-self
self
immune tolerance
Self vs Non-self cont.
• The self/non-self paradigm provided a useful conceptual framework on how the immune system responds to exogenous pathogens (non-self).
• However, it could not explain immunity to all types of ‘threats’.
• For instance, immunity to cancer could not readily fit into the self/non-self concept because ____ are not actually ‘non- self’ but rather represent ‘altered self’.
• Furthermore, immune responses are activated also to cope with tissue damage that is caused by ____ (____ damage).
tumor cells
mechanical injury
sterile
Detecting Danger
• The immune system has primarily evolved to discriminate between ____ and ____ rather than between ‘self’ and ‘non-self’.
• According to the so-called ____ model,the immune system is alarmed by signals released from ____ cells (due to injury or infection), such as nucleic acids, heat-shock proteins and other intracellular molecules, collectively known as ____.
safe dangerous danger damaged alarmins
Examples of self and non-self entities and possible outcomes of the immune response or lack thereof
Take a look at table
respond to normal self > don’t want to respond > ____
____ > altered self > want to respond
damaged self > want to respond
symbiotic microbes > don’t want to respond to commensal bacteria > if you do, there will be a lot of ____ (unncessary)
food antigens (innocuous substances) > do not want to respond > can develop into ____
self-tolerance
tumors
inflammation
allergies
The immune players
Innate
- ____ barriers
- ____
- ____ cells
- ____
- ____ cells
innate > VERY ____, deployed hours/minutes
adaptive > ____, days/weeks
epithelial phagocytes dendritic complement NK
fast
slow
Two arms of immunity
When preformed or constitutive defense mechanisms are not adequate to control an invading pathogen, the innate immune system needs to mobilize ____.
Initially, this involves only innate immune cells but, if necessary, ____ immune cells will also be recruited in a few days
0-4 hours: ____ responses of ____ immunity
4-96 hours: ____ responses of ____ immunity
>= 96 hours: ____ response
reinforcements
adaptive
ubiquitous innate induced innate adaptive
Innate vs. adaptive immunity
Innate
- ____ response (hours)
- ____
- ____ number of specificites
- ____ during response
Adaptive
- ____ response (days to weeks)
- ____
- ____ highly selective specifities
- ____ during response
rapid
fixed
limited
constant
slow
variable
numerous
improve
All innate and adaptive immune cells are derived from ____ cells in the ____
common myeloid progenitor and lymphoid progenitor
lymphoid pro > T cells and B cells and ____ cells
myeloid pro> ____ pro, or the ____ pro
hematopoietic stem
bone marrow
innate lymphoid
megakaryocyte/erythroid
granulocyte/macrophage
The players in innate and adaptive immunity
NEUTROPHIL > 3 ____, they arrive ____ than macro’s, ____
eosinophil > killing of ____ through release of granule contents
macrophages > ____, activation of ____ cells and initiation of immune responses
basophil > role in ____ infections
dendritic > activating ____ cells and activating ____ immune response
lobes faster antibody-coated parasites phagocytosis T parasitic T adaptive
How does innate immunity recognize microbial targets?
Pattern-recognition receptors (PRRs) ‘The ____ of innate immunity’
- ____ encoded receptors
- Detect and respond to conserved microbial structures, such as bacterial ____ or ____ acid, known as ____.
eyes germ-line LPS LTA microbe-associated molecular patterns (MAMPs)
Is innate (inborn) immunity really ‘non-specific’?
Since this type of immunity appeared to provide a ____ defense against classes of microorganisms and without being directed at any one in particular, it was historically seen as ____; we now know that innate immunity has ____ recognition elements:
Different ____ recognize different classes of microbial molecules and activate the expression of appropriate immune-response genes.
____, an important PRR family, offers a good example (next slide).
general
non-specific
specific
pattern-recognition receptors (PRR)
toll-like receptors
Different toll-like receptors (TLR) recognize distinct classes of microbial molecules
TLR4 > ____ (common on gram-neg bacteria)
TLR2 > ____ (gram-pos); partners with other TLRs (with TLR1 it reognizes ____, and with TLR6 it recognizes ____ from ____)
TLR5 > ____
don’t know what ____ recognizes
also intracellular pathogens (viruses) there is a TLR for them, dsRNA > ____; ____ > ssRNA; CpG rich of DNA, ____ is much more likely
LPS LTA lipoproteins zymosan fungi
flagellin
TLR10
TLR3
TLR7/TLR8
TLR9
The innate immune response is a universal and ____ conserved mechanism of host defense against infection.
! Predates the ____ immune response
- –! Found in all ____ organisms
- –! Adaptive immunity only in ____
Lack of ____ expression in flies leads to death from fungal infection
evolutionarily
adaptive
multicellular
vertebrates
toll receptor
Pattern-recognition receptors: More than sensing microbes
! PRRs recognize conserved structural features of microbes, termed ____).
! The immune system needs to detect and respond to ____ in general rather than to non-self, which might not always entail danger.
! Besides infectious agents, danger can be represented by the presence of ____ or ____ host cells.
! Inflammation can be induced by ____ causes such as:
! Trauma,
! Inhalation of ____ and silica,
! ____ crystals (cause of gout, a form of arthritis)
! ____ formed in the central nervous system
(implicated in Alzheimer’s disease)

microbe-associated molecular patterns (MAMPs)
danger
damaged
stressed
non-infectious
asbestos
uric acid
amyloid-beta
Pattern-recognition receptors: More than sensing microbes (cont)
! Endogenous stress signals are called ____ or ____, and include:
! ____ acids,
! ____ proteins
! ____ proteins
! Once released in the extracellular space, DAMPs act as generic markers for cell damage or death by binding and activating ____.
! PRRs/DAMP receptors stimulate immunity to clear damaged/dead cells and promote ____.
damage-associated molecular patterns (DAMPs) alarmins nucleic histone heat-shock
PRRs
tissue repair
Soluble pattern-recognition molecules (PRMs)
- The humoral arm of innate immunity contains a ____ group of PRMs, such as, ____, collectins, and ____.
- PRMs collectively detect unique ____ motifs on bacteria, fungi, and viruses. Additionally, they can recognize ____ and ____ cells.
• PRMs perform diverse host-defense functions,
including:
– Microbial ____ and neutralization,
– ____,
– Control of inflammation
– ____ activation and regulation
– Interact with ____ receptors and activate phagocytosis and cytokine secretion (____).
• PRMs appear to act as functional ____ of antibodies (‘ante-antibodies’).
heterogenous
pentraxins
ficolins
carbohydrate
damaged
apoptotic
agglutination opsonization complement Fcgamma pentraxins
predecessors
Antibody-mediated immune functions
- ____ activation
- ____ neutralization
- ____
- ____ cytotoxicity
- ____ mediated inflammation
- inhibition of bacterial ____
complement virus opsonization antibody-dependent cellular fc-receptor adherence
In contrast to PRMs, antibodies have ____ specificity
exquisite
The innate (inborn) immunity
• Barriers
- ____ (skin, hair, mucosae)
- ____ (sweat, tears, saliva, stomach acid)
- – For instance, tears and saliva contain antimicrobial ____ and ____ that attack bacterial cell walls
• Cellular response
– ____ (neutrophils, macrophages)
– NK (natural killer) and mast cell responses
• Soluble factors (e.g,____)
- microbiological barriers > commensal bacteria that are present in mouth/gut > do not allow pathogens to get established > ____ resistance
mechanical
chemical
peptides
lysozyme
phagocytosis
complement
complement
Antimicrobial peptides (____)
• Short, generally ____, ____ antimicrobial proteins
• Secreted by ____ cells, neutrophils, alveolar ____
• Found at ____ surfaces
– trachea, small intestine, female reproductive tract in mammals
– ____ secretions in fish and amphibians
They have ____
activity against targeted
pathogens
(microbial cell is punctured)
defensins cationic broad-spectrum epithelial macrophages mucosal skin
membranolytic
Cells of the innate immune system
Phagocytic cells: neutrophils monocytes/macrophages \_\_\_\_ cells immature \_\_\_\_ cells
Non-phagocytic cells:
____ cells
mature ____ cells
Most common leukocyte: ____ (____ are next most common)
mast
dendritic
NK
dendritic
neutrophil
monocyte
Phagocytic Cells
• Polymorphonuclear leukocytes(PMNs)/neutrophils
– Abundant, ____ lived
– Elevated numbers in blood indicate ____
• Professional antigen-presenting cells(APC)
– ____ lived, lower frequency
– Dendritic cells /Langerhans cells (____)
– Monocytes (____)
– Macrophages (motile or stationary), which can be ____ specific (i.e. alveolar – lung)
short
infection
longer
skin
blood
tissue
Macrophages are everywhere….
macrophages in lung > ____
macrophages; in brain > ____
also ____; found in intestine, lymph node
in liver > ____ cells
alveolar
microglia
osteoclasts
kupfer
Phago-lysosomal killing
• Phagosome-membrane bounded vesicle that becomes
____
• Lysosome-granules that contain products that damage or kill pathogens
– Enzymes
• ____ - dissolves cell walls of some bacteria
• ____ - digests bacteria
– Proteins
• ____ - binds and removes Fe++ needed for bacterial
growth
• ____-binding protein
– Peptides
• ____ and cationic proteins - direct antimicrobials
Phago-lysosome = phagosome that has fused with ____
acidified lysozyme acid hydrolase lactoferrin vitamin B12 defensins
lysosome
Phagocytic killing of microbes
• Oxygen-dependent: The respiratory burst and enzymes such as ____ produce multiple forms of ____ that are toxic to bacteria and other ingested microbes.
• The generation of reactive oxygen species (eg, superoxide anion) in the respiratory burst is mediated by the ____. Much of the superoxide anion formed is dismuted by superoxide dismutase (SOD) to produce oxygen and hydrogen peroxide, which is converted by ____(MPO) to hypochlorous acid and chloramines inside the phagosome.
- Oxygen-independent (____): Granules within phagocytes contain ____ enzymes that digest microbial components.
- Non-oxidative mechanisms to eliminate pathogens, such as granule proteases or antimicrobial peptides which can be delivered to the ____ or released to the ____.
myeloperoxidase
oxygen radicals
NADPH oxidase
myeloperoxidase
degranulation
lytic
phagosome
extracellular space
Neutrophils
neutrophils produced in ____ > move into circ > stay unless called to a tissue due to an infection (when they die they are degraded by ____)
CR3, CR4
glycan receptors
LPS receptor (____, not CD14)
bone marrow
macrophages
TLR4
How do circulating neutrophils know when to exit the blood and migrate to an infected tissue?
In response to infection, vascular endothelial cells express ____ molecules (selectins, ICAM-1) that interact with complementary adhesion molecules on neutrophils.
These interactions initially slow down the neutrophils (“rolling”; mediated by ____) which then come to a complete stop (‘tight binding’; mediated by ____).
The neutrophils then exit through ____ into the tissue to fight an infection.
For tight binding (firm adhesion), ICAM-1 interacts with the integrin ____ on neutrophils.
Individuals with ____ mutations have ‘leukocyte adhesion deficiency’ and fail to recruit neutrophils to infected tissues.
adhesion
selectins
ICAM-1
diapedesis
LFA-1 (CD11a/CD18)
CD18
Neutrophil chemotaxis
Neutrophils recognize chemicals produced by bacteria or the host (e.g., ____ or ____) and migrate “toward the smell”.
Here, neutrophils were placed in a gradient of a chemical that is produced by bacteria.
The cells are seen to move in the right direction chasing the bacteria through a process known as ____.
FMLP peptide
chemokines
chemotaxis
Neutrophil killing yeast
One way that neutrophils kill is by producing an anti- bacterial compound called ____, through a process called ____ burst.
Here, a human neutrophil senses, moves toward, and ingests a yeast. Oxidation can be visualized by means of a ____.
superoxide anion
oxidative
dye
Neutrophil NETs Trap and Kill Bacteria
In response to certain pathogens, neutrophils release ____ and ____ from their granules. (The DNA is not ____)
These form the so-called ____ which trap and kill bacteria.
DNA
antimicrobial proteins
naked
neutrophil extracellular traps (NETs)
Macrophages
macro’s > bind to bacteria; which are opsonized; and they kill into phagosomes, fuse with lysosome, and killing in phagolysosome
can respond to isolated bacterial components > produce ____ (also produced via phagocytosis)
cytokines
Macrophage ingesting yeast
Macrophages, like the neutrophils, are professional ____ or eating cells (phago = “eating”, cyte = “cell”).
Here, a macrophage is eating Candida albicans. After ingestion, it must kill the yeast by some means, such as via the ____ burst.
phagocytes
oxidative (respiratory)
Summary: Antimicrobial mechanisms associated with phagocytosis
GO THROUGH TABLE
____ > in phagosome before fuses with lysosome; when phagolysosome you have oxygen-derived products that can come into play
NO > is good in ____ specifically
acidification
macrophages
Other Innate Immune Cells Specialists for some Pathogens
- Both eosinophils and NK cells attack by ____ means
- Eosinophils–specialized with granules of substances toxic to ____ and other pathogens – kill by release of Major Basic Protein, Eosinophil Cationic Protein and Eosinophil-derived Neurotoxin; partners with ____.
- NKcells–”Natural killer”-specialized large granulocytic lymphocyte (LGL) recognize “funny looking” cells - ____ or ____; partners with ____. Proliferate in response to ____.
- Both can perform ____
non-phagocytic
worms
IgE antibody
tumors
virus-infected
interferons
IL-15
antibody-dependent cell cytotoxicity (ADCC)
ADCC by Eosinophils
IgE act as an ____ antibody mediating the attachment of eosinophils to helminths for killing. The ____ portion of IgE reacts with antigenic epitopes on the helminth whereas the Fc portion binds to Fc receptors of activated ____. The lysosomal proteases of eosinophils are released and destroy the tough integument of helminths. Released major basic protein binds to and directly damages helminths. IgE also promotes ____ to recruit phagocytes.
opsonizing
Fab
eosinophils
inflammation
ADCC by natural killer cells (NK cells)
- Rather than attacking the invaders, they attack the body’s own cells that have become infected by ____.
- They also attack potential ____, often before they form tumors.
viruses
cancer cells
ADCC by NK cells
• NK cells bind to target cells using an ____, then kill it by secreting a chemical (perforin) that makes ____ in the cell membrane of the target cell. With enough holes, the cell will die, because water rushing inside the cell will induce ____, and an influx of calcium may trigger ____.
binds via ____ (not IgE)
antibody "bridge" holes osmotic swelling apoptosis IgG
Necrosis vs Apoptosis
In contrast to necrosis which may cause ____, apoptosis is a ____ mechanism for the disposal of dying cells
inflammation
safe
