1 - Innate immunity Flashcards
What is immunology?
The study of all aspects of host defense against infection and of adverse consequences of immune responses
What are some examples of immunodeficiency?
Genetic immunodeficiency and AIDS
What is the central role of the immune system?
Protection against microbial infection - evolutionary pressure has shaped the immune system so that it can best function against the microbial world
What does the immune system fight off?
Fight off the following:
- Viruses (must be intracellular)
- Bacteria (extracellular and intracellular)
- Parasites (unicellular and multicellular, intracellular and extracellular)
- Note that you need different mechanisms to fight off the three different types of infections listed above
What does the immune system target?
The immune system…
- Destroys a diversity of pathogens
- Attacks cancer cells
- Eliminates toxins
There are two types or “arms” of immunity. What are they?
Which type of immunity is an immediate response? Which type will take days or weeks to occur?
Innate
- Immediate response
- Hours to 1-2 days
Specific
- Later
- 7-10 days to weeks
Which type of immunity utilizes T and B lymphocytes? Which type utilizes phagocytes, neutrophils and natural killer cells? Are they always differentiated?
Specific
- T and B lymphocytes
- These cells are further differentiated by activation and selected amplification
Innate
- Phagocytes (macrophages), neutrophils and natural killer cells
- These cells are terminally differentiated
Which type of immunity involves non-polymorphic complement as the circulating molecule? Which type involves a diverse population of immunoglobulins as the circulating molecule?
Innate
- Complement (non-polymorphic)
Specific
- Immunoglobulins (diverse)
Which type of immunity involves lymphocyte-derived factors as the soluble mediators? Which type involves macrophage-derived cytokines?
Specific - soluble mediators
- Lymphocyte-derived factors (local growth and regulation)
Innate - soluble mediators
- Macrophage-derived cytokines
- Other acute phase reactants
- Systemic effects
- Inflammation
How is inate immunity amplified? How is specific immunity amplified?
Innate
- Recruitment
Specific
- Clonal expansion
Which type of immunity involves a memory?
ONLY specific (aquired) immunity, NOT innate (natural) immunity
__________ immunity is the initial response to mcrobes that prevents, controls or eliminates infection of the host by many pathogens.
Innate
There are three types of components of the innate immune system. What are they?
- Cell associated components
- Cellular components
- Soluble components
What types of cell associated components will you find in the innate immune system?
Cell associated components
- There are pattern recogntition receptors and sensors
- Toll-like receptors
- Cytosolic receptors
What types of cellular components are part of the innate immune system?
Cellular components of the innate immune system
- Epithelial barriers
- Phagocytes
- NK cells
What type of soluble components are part of the innate immune system?
Soluble recognition molecules and soluble effector molecules
- Complement
- Cytokines
What are the two types of pattern recognition receptors (PRRs)?
PAMPs = pathogen-associated molecular patterns
DAMPs = damage associated molecular patterns
What are the molecular structures that are produced by microbial pathogens and recognized by the innate immune system?
PAMPs
- Pathogen-associated molecular patterns
- These microbial products are often essential for the survival of microbes and include:
- ssRNA (virus)
- dsRNA (virus)
- Flagellin (bacteria)
- Libopolysaccharide (LPS, endotoxin) (gram-negative bacteria)
- Lipoteichoic acid (gram-positive bacteria)
What is lipopolysaccharide?
What are DAMPs?
Damage associate molecular patterns
- Not as important to know
- Endogenous molecules that are produced by or released from damaged and dying cells
- HMGB1 and HSPs are examples
What does toll-like receptor 4 (TLR4) bind to?
Lipopolysaccharides
- TLR4 is a PRR or pattern recognition receptor
- It binds to LPS, which, as you recall, is a PAMP that is common in almost all gram-negative bacteria
- TLR4 will therefore be active in gram-negative bacteria
***
What does TLR4 result in?
The production of proinflammatory cytokines from monocytes and macrophages
Are toll like receptors expressed on the surface of cells or as endosomes?
Can be either
Are TLRs found in the homodimer or heterodimer state?
Can be either
When a toll-like receptor (TLR) recognizes a microbial ligand, what results?
The activation of several signaling pathways
- Ultimately transcription factors will induce the transcription of certain factors which will then induce the expression of genes that are important for the inflammatory and antiviral responses
What is the role of the transcription factors NFkB and IRF?
NFκB and IRFs…
- Both are activated in response to PRR ligation
- NFκB results in induction of an inflammatory state
- IRF results in induction of an antiviral state
What drives inflammation?
Inflammation is driven by cytokines such as TNF, IL-1 and IL-6
So, what is the innate immune response that is triggered by TLR (toll-linked receptors)?
PAMP/TLR → NFkB and IRFs → Inflammation and Antiviral state
What do toll-linked receptors (TLRs) detect when they are located on the cell surface?
Extracellular pathogens - they recognize the pathogen associated molecular pattern (PAMP)
What do toll-linked receptors (TLRs) recognize when they are found on the endosomal membrane?
Well, we know that they can’t detect PAMPs of extracullular pathogens because they are found within the cell and not on the surface.
Instead, they recognize nucleic acids of microbes that have already been phagocytosed by the cell
What are cytosolic sensors of microbial infection?
These receptors are found within the cytosol and detect microbial infections. Examples include…
- NOD-like receptors family (NLR)
- RIG-like receptor family (RLRs)
- Cytosolic DNA sensors (CDS)
What are inflammasomes?
Inflammasomes are the cells that are responsible for inducing the inflammatory response
What do inflammasomes activate?
IL-1 and IL-18
What happens when there is a dysregulated activation of the inflammasome?
Autoinflammatory syndromes
- Caused by a gain-of-function maturation in inflammasome components
- Leads to excess IL-1
What happens when excess IL-1 is present?
Response
- Recurrent attacks of fever
- Localized inflammation (joints and intestines)
How do you treat a autoinflammatory syndrome?
IL-1 antagonists
What property of epithelial cells allows them to provide protection from external pathogens? Where is this type of tissue found?
Epithelial cells joined by tight junctions
- Skin
- Gut
- Lungs
- Eyes/nose
What barriers exist in the skin
Mechanical barriers
- Epithelial cells joined by tight junctions
- Longitudinal flow of air or fluid
Chemical barriers
- Fatty acids
- Antibacterial peptides
Microbiological barriers
- Normal flora
What barriers exist in the gut?
Mechanical barriers
- Epithelial cells joined by tight junctions
- Longitudinal flow of air or fluid
Chemical barriers
- Low pH
- Enzymes, such as pepsin
- Antibacterial peptides
Microbiological barriers
- Normal flora
What barriers exist in the lungs?
Mechanical barriers
- Epitherlial cells joined by tight junctions
- Movement of mucus by cilia
Chemical barriers
- Antibacterial peptides
Microbial barriers
- No microbial barriers exist
What barriers exist in the eyes and nose?
Mechanical barriers
- Epithelial cells joined by tight junctions
Chemical barriers
- Salivary enzymes (lysosozyme)
Microbiological barriers
- No microbiological barriers exist
How does the epithelium act as a physical barrier?
In the skin…
- The outer layer of the skin, keratin, accumulates as dead keratinocytes on the skin surface
- This blocks microbial penetration into the deep epidermis
On mucus-covered surfaces…
- Physically impairs microbial invasion
- This function is enhanced by ciliary action in the bronchial tree
- Also enhanced by peristalsis in the gut
On top of the epithelium acting as a physical barrier to infection, what else does it do to accomplish this?
Prevent infection by…
- Killing of microbes by locally produced antibiotics
- Defensins
- Cathelicidins
- Killing of microbes and infected cells by intraepithelial lymphocytes
What is the initial step in the generation of an immune response?
Phagocytosis
Define phagocytosis
Cellular ingestion of large particles (0.5 micrometers)
What is phagocytosis required for?
Development and maintenacne of normal tissue homeostasis
Where are phagocytic cells located?
Right below the skin bariers so they can eat what they find there (i.e. bacteria) and take it to the nearby lymph nodes
What are some professional phagocytes?
Professional phagocytes
- Neutrophils
- Macrophages
Their primary function is to ingest and destroy microbes and get rid of damaged tissues
What is a polymorphonuclear leukocyte?
A PMN or a neutrophil
Describe the action of neutrophils
Neutrophils
- Circulate in blood for hours or a few days
- Migrate to sites of infection rapidly after the entry of microbes
- After entering tissues, neutrophils function only for 1 to 2 days and then die
What is a mononuclear phagocyte? What does it become?
Mononuclear phagocytes are released from the bone marrow as monocytes which migrate into different tissues and further differentiate into macrophages
Where are macrophages found?
In all tissues
What is the role of a macrophage when there is no inflammation?
In the absence of inflammation, a major role for the tissue macrophage is to remove dead and damaged cells from the tissues
Macrophages have special names in special tissues… What is it called in the liver, lungs and brain?
- Kupfer cells - liver
- Alveolar macrophages - lung
- Microglia - brain
What is the role of dendritic cells?
Dendritic cells are specialized to present antigen to lymphocytes
Where are immature dendritic cells found? Mature dendritic cells?
- Immature DC are found in the tissues and are highly phagocytic.
- They mature and migrate from the periphery to the lymph nodes and become much less phagocytic.
What are the steps in the process of phagocytosis?
- Microbe binds to phagocyte receptors
- Phagocyte membrane “zips up” around the microbe
- The microbe is ingested in the phagosome
- The phagosome fuses with the lysosome
- The phagocyte becomes activated
- The microbe is destructed by ROS, NO and lysosomal enzymes in phagolysosomes
What is opsonin?
Opsonin
- Soluble proteins that recognize phagocytic targets and are in turn recognized by specific receptors on phagocytic cells
- In Greek, opson means “to prepare to eat”
What are the two classic opsonins in the plasma?
Complement and antibody
How do opsonins aid in the process of phagocytosis?
Opsonins
- Allow cells to recognize more microbes easier
- Creates a better signal for the removal of a microbe
- Creates a better signal for the destruction of a microbe
Will phagocytic cells “eat” more or less when complement is present?
MORE!
What are the chemical defenses used in killing microbes?
-
Acidification
- pH of 3.5 to 4.5 kills bacteria
-
Toxic oxygen-derived products
- Superoxide, hydrogen peroxide, singlet oxygen, hydroxyl radical, hypohalite
-
Toxic nitrogen oxides
- NO
-
Enzymes
- Lysozyme
What is chronic granulomatous disease?
Patients with chronic granulomatous disease (CGD) have a defective NADPH oxidase and are more susceptible to bacterial infection
What is the most important cytokine for activating macrophages?
IFNy (IFN-gamma)
What produces IFNy?
NK cells and T cells (mostly NK cells)
What is the function of cytokines?
Inflammation
What is the function of chemokines?
Chemotaxis - Trigger other cells to move to the site of infection
What are some characteristics of natural killer cells?
NK cells
- Largre granular lymphocytes
- They don’t specifically recognize antigens, they can just tell the difference between a health cell and a malignant/infected cell
- They kill virus-infected cells and certain tumor cells
What blocks the killing activity of natural killer cells?
NK cell killing activity is blocked when NK cells bind to MCH class I on normal cells - it can tell that this is a healthy cell so it will not kill it
Natural killer cells also mediate ADCC, what does that stand for and what does that mean?
ADCC
- Anti-body dependent cell-mediated cytotoxicity
- The NK cells are activated and kill the antibody-coated cells
What happens to NK cells when they are exposed to interleukin-2 or interferons?
They become highly activated
How could interleukin-2 possibly be used as a future cancer therapy?
Interleukin-2 can lead to lymphokine-activated killer cells (LAK)
- This provides enhanced tumor cell cytolytic capability
- Enhanced range of target cell recognition
- Could be effective in CA therapy
What is important to know about FcγRIII? What is it?
FcγRIII
- FcγRIII is a receptor that bind to the Fc portion of IgG antibodies which then activates the NK cell for ADCC (antibody-dependent cell-mediated cytotoxicity)
- Need to be familiar with this
- When you see FcγRIII, think NK cells and ADCC
How do NK cells respond to IL-12?
NK cells respond to IL-12 produced by macrophages and secrete interferon-gamma, which activates the macrophages to kill phagocytosed microbes.
There are three major subsets of innate lymphoid cells. What are they?
Subsets of innate lymphoid cells (ILCs)
- Defense against viruses
- Allergic inflammation
- Intestinal barrier function; lymphoid organogenesis
What do the three major subsets of innate lymphoid cells (ILCs) all develop from?
The three major subsets of innate lymphoid cells (ILCs) all develop from a common bone marrow precursor identified by the Id2 transcription factor
What are two types of T cells? Which is more abundant?
Types of T cells
-
vγδ T cells
- Less tan 5% of T cells
-
Natural killer T cells (NKT)
- Much more abundant
Where are vγδ T cells found?
vγδ T cells are found in monospecific populations of the skin and in the mucosa (so pretty much, they are found in the epithelial barriers)
What is a NKT cell?
NKT cells are a small subset of lymphocytes that express surface molecules characteristics of both NK cells and T cells
What is the role of NKT cells?
NKT cells
- Express TCRs with very little diversity
- Produce cytokines
- Some are also able to recognize lipid antigens
What is the complement? What is its purpose?
Complement
- A soluble serum protein that is sequentially activated
- They coat particles so that they can be recognized by phagosomes
- They also bring more cells into the site of infection
Descrie the functions of complement
- Produce chemokines which promote inflammation
- Cover antigens with opsonins, which helps them to become phagocytosed
- Create pores in the cell surface of microbes so they can die by osmotic lysis
What is the most highly concentrated component of complement that you would find in the serum?
C3
- Need to know this
- It is central to all the other complement pathways
C3 can be leived into C3a and C3b… What does each of these do?
C3 is cleaved into two smaller parts (C3a and C3b) by a C3 convertase
- C3a = bigger, a chemokine that triggers leukocyte recruitment
- C3b = smaller, an opsonin that stimulates phagocytosis
There are three pathways of complement activation… What constitutes an activated complement pathway?
There are three pathways of complement activation…
- These pathways generation a C3 convertase
- Cleaves complement protein C3 into C3a and C3b
- These pathways also generate a C5 convertase
- Cleaves complement protein C5 into C5a and C5b
What are the three pathways of complement activation? Once they are activated, do they all do the same thing?
Yes - they all do the same thing once activated
- Alternative pathway
- Classical pathway
- Lectin pathway
Describe the classical pathway
Two IgG’s appropriately spaced apart (or one IgM pentamer) are sufficient for classical pathway activation…
- IgM is more efficient than IgG in activating complement
- Free antibody will not activate complement
***So pretty much, the classical pathway is activated when an antibody is bound to a pathogen
Describe the alternate pathway of complement activation
General characteristics:
- Named after the discovery of the classical complement pathway
- Initiated in the absence of antibody; takes place directly on microbial surfaces
What types of regulators exist for the complement cascade?
Most regulators either dissociate complexes or catalyze degradation of complexes
What would happen if there was a failure in the regulation of complement activation?
Uncontrolled activation of the complement system would be detrimental
- Paroxysmal nocturnal hemoglobinuria (recurrent bouts of intravascular hemolysis)
- Hemolysis = abnormal breakdown of RBCs
- Leads to chronic hemolytic anemia and thrombosis
- Thrombosis = clot formation inside a blood vessel
What occurs when there is a C1 INH (C1 inhibitor) deficiency? This functions to regulate complement.
Hereditary angioneurotic edema (HAE)
- Emotional stress or trauma → complement activation + bradykinin production → edema in the skin and larynx → potentially life-threatening
- Bradykinin-induced edema produces the symptoms of edema
- C1 INH restricts the spontaneous activation of C1 in plasma and regulates Hageman factor, which gives rise to HAE in the absence of the inhibitor
Go look at the slide you printed on the complement cascade… She said you should spend your time memorizing this slide.
SO DO IT!
What are cytokines?
Proteins made by cells that affect the behavior of other cells
- Can act at a distance (soluble)
- It is a method of communication
- Example: IFNγ produced by activated T-cells to promote macrophage activation and killing of intracellular pathogens
What are interferons? What types are there?
Potent antivirals
- Type I
- Type II
What do Type I interferons (IFN)s do? What are they composed of?
Type I
- Type I interferon (IFN) is composed of a and b IFN.
- Biologic actions of type 1 IFN’s:
- Inhibit viral replication via a paracrine action
- Enhance the cytolytic capability of NK cells
- Increase cellular expression of class I MHC molecules
