Innate Immune Responses Flashcards
How does innate immunity act?
Immediately to effect removal of the pathogen without the development of disease in the host.
What happens if innate immune responses are overwhelmed/bypassed/evaded by a pathogen?
Adaptive immune responses are then required.
How does innate immunity recognize a pathogen?
Innate immunity has evolved over millions of years to distinguish “dangerous” things from “innocuous” things. Innate immunity involves the use of receptors that recognise parts of the most common pathogens we are likely to encounter. These proteins are known as Pattern Recognition Receptors (PRRs).
What are pathogen-associated molecular patterns?
Pattern recognition receptors (PRRs) recognise Pathogen-Associated Molecular Patterns (PAMPs).
Important features of PAMPs include:
- They are not produced by the multi-cellular host organism,
- are shared by large groups of pathogens,
- do not undergo frequent mutation,
- are often essential for pathogen’s survival, and
- are recognised by PRRs in the innate response.
Provide two examples of PAMPs.
- peptidoglycan in Gram-positive bacteria
- lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria.
Examples include: LPS, peptidooglycan, dsRNA (viruses).
What are two main groups of cell-assicated membrane PRRs?
The two main groups of cell-associated membrane PRRs include:
- phagocytosis receptors (that are used to bring the particle inside the phagocyte) and
- Toll-like Receptors (TLRs, to allow the phagocyte to determine if the particle is dangerous, i.e., a pathogen).
What are Toll and Toll-like Receptors (TLRs)?
They consist of an extracellular leucine-rich domain that recognises the PAMP, a transmembrane domain, and a cytoplasmic domain that is homologous to the IL-1 receptor (a receptor that binds the cytokine, interleukin-1 (IL-1).
What is the complement system?
The complement system is a set of plasma proteins that act together to attack extracellular pathogens.
The components of the complement system work in a set order (i.e., some act early in the cascade, whereas others act at a much later stage).
Describe the cascade activation of a complement component.
Activation of a complement component usually involves the cleavage of the protein to make two smaller proteins. The complement system is activated in a series of reactions, where the product of one reaction catalyzes the next reaction, which catalyzes the next reaction, and so on.
What is the classical pathway?
Complement proteins are activated when antibodies made during a previous adaptive immune response bind to the pathogen surface.
What are antibodies?
Antibodies are a type of plasma protein produced by B cells.
What is the alternative complement pathway?
The alternative C’ pathway is when complement proteins bind directly to the bacteria and initiate the complement activation cascade directly (thereby eliminating the need for antibody recognition to start the cascade).
There is a lot of the complement protein C3 in blood and small amounts spontaneously undergo hydrolysis to result in a form of C3b that binds to the pathogen surface. Additional proteins bind to form an enzyme complex called the C3 convertase.
Describe the alternative complement pathway from complement protein C3 (in the blood) to the formation of the membrane attack complex.
- Complement protein C3 (in the blood) spontaneously breaks down to form C3a and C3b.
- C3b binds to the pathogen surface and recruits other complement proteins to form a C3 convertase (left panel).
- This results in the formation of additional C3b protein.
- Some of the C3b is used to form additional C3 convertases (left panel), some C3b is used as an opsonin, and some C3b is used to form the C5 convertase.
- The C5 convertase cleaves complement protein C5 into C5a and C5b (right panel).
- C5b is then used to form the membrane attack complex
What are the three important consequences of the formation of the C3 convertase?
Activation of the inflammatory response
Opsonisation and enhancement of phagocytosis
Formation of the membrane attack complex and bacterial cell lysis
What happens if C3a and C5a are produced in large amounts?
When produced in large amounts, the effect of C3a and C5a on blood vessel permeability can induce a generalized circulatory collapse, producing a shock-like syndrome known as anaphylactic shock.
These small complement fragments are therefore often referred to as anaphylatoxins.
How does the formation of the C3 convertase activate the inflammatory response?
The C3 convertase cleaves additional C3 into C3a and C3b; after binding, C3b recruits additional proteins to form the enzyme complex C5 convertase that cleaves C5 into C5a and C5b.
How do C3a and C5a activate an inflammatory response?
C3a and C5a are small fragments that bind to specific receptors on blood vessels. This results in an increased permeability of the blood vessels and induces the expression of adhesion molecules that allow leukocytes such as neutrophils and monocytes to attach to the blood vessels.
C5a and C3a also bind to receptors on the resident mast cells and resident macrophages to release additional histamine and TNF-α, respectively.
In addition, C5a also is a powerful chemoattractant for neutrophils and monocytes.
Define: Opsonisation
Opsonisation is defined as the alteration of the pathogen surface or particle surface so that phagocytic cells can engulf it more efficiently.
How does C3b bound to the pathogen surface function as an opsonin?
The coating of a pathogen with C3b enhances phagocytosis by neutrophils and macrophages.
C3b binds to a receptor on the surface of the phagocytic cell. This results in an increase number of contact points between the phagocytic cell and the pathogen.
Phagocytic cells have receptors that can bind to C3b on to the pathogen surface
How is the membrane attack complex formed?
After C5b binds to the pathogen surface, other proteins are recruited to form a membrane attack complex (assembly of the late (“terminal”) complement components) that results in the formation of a pore in the pathogen’s cytoplasmic membrane, causing bacterial cell lysis and death of the pathogen.
Describe basic characteristics of the innate immune response.
The innate immune response is fast, non-specific, and triggered by components of the pathogen.
How are pathogens recognized as ‘foreign’?
Pathogens are recognised as “foreign” or “non-self” by pathogen-associated molecular patterns (PAMPs).
PAMPs bind to pattern recognition receptors (PRRs) on the innate immune cells, causing phagocytosis of the pathogen and cytokine production by the immune cell.
When does inflammation begin?
Inflammation begins after damage to the tissue.
Where is histamine released?
Mast cells release histamine.
What does histamine do?
After damage to tissue, inflammation begins. Mast cells release histamine that increases the permeability of blood vessels.
Cells, proteins, and fluid leak into the tissues, causing swelling.
Pathogens activate macrophages, which release alarm cytokines and recruit more cells from the blood.
Macrophages and neutrophils phagocytose and destroy pathogens.
Coagulation proteins seal off the inflamed area, and complement activation increases recruitment, phagocytosis, and pathogen destruction.
How can the complement system be activated?
Via the classical pathway or the alternate pathway
How are the classical and alternative pathways different?
The classical pathway uses antibodies generated by a previous adaptive immune response to the pathogen.
The alternate pathway is spontaneous and requires no previous exposure.
Reiterate the three important consequences of the complement cascade?
The complement cascade has three important consequences: it activates the inflammatory response, it allows opsonisation of the pathogen, and it can cause pathogen lysis through formation of the membrane attack complex.
What does activation of dendritic cells do?
Initiates the adaptive response.
What does the ability to mount an adaptive immune response depend on?
Dendritic cells link the innate and adaptive immune systems since the activation of dendritic cells initiates the adaptive response.
The ability to mount an adaptive response is dependent on the ability to mount an effective innate immune response.
What are some examples of barriers in our bodies, and how do barriers function to exclude invading microbes?
Natural barriers include the skin, mucous membranes, tears, earwax, mucus, and stomach acid.
Skin and mucosa provide an effective immune barrier between the internal and external environment.
What molecules do phagocytes use to identify an invading microbe versus a host cell?
Recognition often takes place by the use of phagocyte receptors that bind molecules commonly found on pathogens, known as pathogen-associated molecular patterns (PAMPs).
What are the functions of cell-membrane associated Pattern Recognition Receptors (PRRs)?
Pattern Recognition Receptors (PRRs) are proteins capable of recognizing molecules frequently found in pathogens (Pathogen-Associated Molecular Patterns—PAMPs), or molecules released by damaged cells (Damage-Associated Molecular Patterns—DAMPs).
Person A was born with a genetic defect that results in an inability to produce complement component C3. Person B was born with a different genetic defect and is unable to produce complement component C5. Who would have a more difficulty in eliminating a bacterial infection? Why?
The C3 complement immune deficiency is more severe since it is required to trigger opsonization and inflammation.
C5 is a late stage (‘terminal’) complement protein. Deficiency of C5 would mean no formation of a membrane attack complex.
What cells create inflammation?
Mast cells (via release of histamine)
Where do leukocytes not have open access?
The brain and spinal cord.
What are the most abundant type of white blood cell?
Neutrophils (~60% of WBCs)
Neutrophils consume the ‘foreign’ particle and then die, resulting in the formation of pus.
How many pathogens can macrophages consume before death?
Macrophages can consume ~100 pathogens before they die.
Where are dendritic cells found?
Dendritic cells are present in those tissues that are in contact with the external environment, such as the skin (where there is a specialized dendritic cell type called the Langerhans cell) and the inner lining of the nose, lungs, stomach and intestines. They can also be found in an immature state in the blood.
What is an antigen?
The immune system protects the body from possibly harmful substances by recognizing and responding to antigens.
Antigens are substances (usually proteins) on the surface of cells, viruses, fungi, or bacteria.
What is the most common complement deficiency?
C2
How many proteins make up the complement system?
20
What is the terminal pathway?
The terminal pathway is common to the classical, alternative, and lectin complement pathways.
Leads to formation of the membrane attack complex causing lysis.
What is the critical step of the complement system?
Activation of C3
Where are the complement proteins synthesized?
C1 - intestine
C2, C4 - macrophage
C5, C8 - spleen
C3, C6, C9 - liver
Which complement proteins are considered anaphylatoxins?
C3a, C4a, and C5a
C5-9 activate bacterial lysis. What are the consequences of deficiency of these complement proteins?
Recurrent infections by capsulated organisms (eg: Pneumococcus)
Which complement protein is responsible for chemotaxis?
C5a - activates lypooxygenase pathway
What is chemotaxis?
Chemotaxis is the movement of an organism in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment.
C3b promotes phagocytosis. What is the consequence of a C3b deficiency?
Recurrent pyogenic infections
Describe the inflammatory response.
There are five steps in the inflammatory response.
Bacterial infection initiates a series of responses through activation of the alternative complement pathway as well through stimulation of tissue-resident macrophages that detect bacterial-derived PAMPs.
This results in the recruitment of additional innate cells and proteins that work together to eliminate the infection.
Describe phagocytosis and the killing of pathogens.
Macrophages and neutrophils express many surface receptors that may bind microbes for subsequent phagocytosis; select examples of such receptors are shown.
Microbes are ingested into phagosomes that fuse with lysosomes to from phagolysosomes.
The microbes are killed by enzymes and several toxic substances produced in the phagolysosomes.
What takes place within a phagolysosome?
In the phagolysosome, the nitric oxide (NO), the superoxide anion (O2–), hydrogen peroxide (H2O2), cationic peptides (defensins) and proteases work together to kill the bacteria and degrade it into smaller fragments.
Describe the formation of a membrane attack complex.
- C5b binds C6 and C7
- C5b67 complexes bind to membrane via C7
- C8 binds to the complex and inserts into the cell membrane
- C9 molecules bind to the complex and polymerize
- 10-16 molecules of C9 bind to form a pore in the membrane.
What is the step in both the classical and alternative pathways that leads to the formation of C3 convertase?
Classical pathway - Binding of antibody (or soluble PRR) to pathogen, Recruit early component proteins
Alternative pathway - Spontaneous breakdown of C3 Deposit of C3b on pathogen surface
What do alarm cytokines do?
The alarm cytokines (IL-1, IL-6, TNF-α) act on the endothelial cells of the veins - this causes the vein to become slightly “leaky” and “sticky.”
This helps to recruit neutrophils and monocytes to the infection site, allows them to slow down and stop at the infection site
