IMI2: Cells of the innate immune system Flashcards
What is the purpose of the complement system?
To enhances the ability of phagocytic cells and antibodies to remove microbes and damaged cells.
What are the three main roles of the complement system?
- Tagging opsonised foreign surfaces
- Lysing membranes of foreign pathogens/cells
- Indicating presence of a foreign invader to the cellular immune system
Define opsonisation
The process by which bacteria are covered with substances that make them more visible to the immune system and more susceptible to phagocytosis (tagged)
What are the three stages of opsonisation?
- Pattern recognition trigger
- Protease cascade amplification/C3 convertase
- Inflammation, Phagocytosis and membrane attack
What components is the complement system made up of?
A group of serum proteins named C1-C9 and there are 3 pathways by which it acts
What are the pathways by which the complement system acts?
- Lectin
- Classical
- Alternative
Explain the Lectin pathway (long)
The Lectin pathway is triggered by PAMPs. Lectins bind specifically to carbohydrate molecules on the surfaces of pathogens. Mannose-Binding Lectins (MBLs) and ficolins bound to the bacterial surface are opsonised by MBL-Associated Serine Proteases (MASPs). MASPs can cleave C4 into C4a and C4b. This promotes the cleavage of C2 into C2a and C2b. C2a and C4b combine to form C3 convertase.
What is the lectin pathway triggered by?
PAMPs
What proteins are bound to the bacterial surface that are opsonised by MBL-Associated Serine Proteases (MASPs) in the lectin pathway?
- Mannose-binding lectins (MBLs)
- Ficolins
Describe the Classical pathway
The Classical pathway is activated by antibodies, and C1 (Recognition C1q and proteases C1s and C1r) binds to antibody-antigen complexes to activate it. Once active, C1 triggers the cleavage of C2 into C2a and C2b, and C4 into C4a and C4b. C2a and C4b combine to form C3 convertase.
What is the classical pathway activated by?
Antibodies
Explain the Alternative pathway
The Alternative pathway works by a different mechanism, as circulating C3 undergoes spontaneous cleavage into C3a and C3b. C3b reacts with Factor B, Factor D, and Properdin proteins to form the C3 convertase complex.
What does C3 cleave into spontaneously?
C3a and C3b
What does C3b react with? To form what?
Factor B
Factor D
Properdin
C3 convertase
What do all of the complement pathways have in common?
C3 convertase
What do C3a and C5a promote?
Inflammation
What does C3b bound to the bacterial surface promote? When?
Phagocytosis when C3b receptors on phagocytes’ surface bind to it.
How is the membrane attack Complex (MAC) formed?
When Properdin binds with C3 convertase, forming C5 convertase and C5 convertase cleaves C5 into C5a and C5b. C5b binds to C6, C7, C8 and C9, forming the MAC
What are anaphylatoxins made up of?
Discarded C3, C4 and C5 fragments
What do anaphylatoxins do?
They induce a local inflammatory response
What are C3a and C5a able to generate?
A chemotactic gradient, which promotes phagocytosis (recruit phagocytic cells to the site of infection)
How is anaphylactic shock triggered?
By systemic release of complement proteins
What does MAC do?
Completion of the membrane cascade leads to formation of MAC which disrupts the cell membrane causing cell-lysis
What are the three types of leukocytes in the body?
1) Granulocytes
2) Eosinophils
3) Neutrophils
Name the three types of granulocytes and their % proportions
i. Basophils – 0.4%
ii. Eosinophils – 2.3%
iii. Neutrophils – 62%
Name the three types of Lymphocytes
i. T cells
ii. B cells
iii. NK cells
What percentage do monocytes make up?
5.3%
What are the two types of monocytes?
Macrophages and Dendritic cells
What is the most common leukocyte?
Neutrophils (polymorphonuclear leukocytes)
What are neutrophils cytoplasmic granules like?
They have a low pH and have cytotoxic activity: MPO and PR3 are released when the neutrophil has engulfed or is in close proximity to a pathogen
What do neutrophils do?
. They are active phagocytes, so present in large numbers in infected wounds and they contribute to pus.
What is the problem with neutrophil’s granules being released?
Kill all surrounding cells indiscriminately and causes inflammation which is characterised by redness and swelling
Once neutrophils have performed their phagocytosis what happens?
They cannot renew their lysosomes, so die shortly after and are ‘mopped up’ by phagocytic macrophages
What cytotoxic granules do neutrophils release?
MPO and PR3
How do Neutrophils move?
Migration is performed by extending pseudopodia
Where are Eosinophils found?
Mainly in mucosal tissues, like the lungs and intestines
What do eosinophils secrete? To what effect?
biomolecules (toxins and enzymes) to deal with large parasites and allergic reactions by destroying them or mediating immune responses
What do basophils release and to what effect?
Histamines - to cause blood vessel dilation to help with allergy response
Heparin - prevent coagulation of blood and promote the movement of leukocytes to the infection site
Chemokines - To recruit neutrophils to the infection site
What are lymphocytes?
Mononuclear cells with a relatively small amount of cytoplasm
- B cells
- T cells
What are the two types of B cells?
- Plasma B
- Regulatory B
Describe Plasma B cells
long-lived, non-proliferating antibody-secreting cells
Describe Regulatory B cells
Immunosuppressive and secrete anti-inflammatory cytokines (IL-10) to prevent expansion of inflammatory lymphocytes.
What are the two types of T cells?
Helper T cells - CD4+
Cytotoxic T cells - CD8+
Why do monocytes have a longer lifespan than neutrophils?
They can replace their lysosomes
What do monocytes do?
- They are capable of releasing both pro-inflammatory and anti-inflammatory cytokines.
- Enter tissues and become polarised in order to differentiate into macrophages with potent phagocytic function.
How are dendritic cells derived?
- from precursors in the bone marrow
- from a subpopulation of circulating monocytes
What are dendritic cells?
Professional antigen presenting cells
Where are dendritic cells found?
They mainly reside in tissues patrolling
What do dendritic cells do?
- They grow branching ‘dendrites’ which make for efficient scanning of the surrounding environment
- They perform a more inefficient phagocytosis
How do dendritic cells function?
1) They internalise antigens, 2) process the antigen into peptides which can be displaced on their membrane-bound MHC Class II receptor
3) T-cells can become activated when they bind to and interact with this receptor-complex
4) When Dendritic cells are activated by chemokines, they migrate to the nearest lymph-node in order to interact with T- and B- cells
How are macrophages formed? What is this process called?
When monocytes migrate into infected tissues in response to cytokines (M-CSF) – this process is called chemotaxis.
How do macrophages work?
They possess one lobed nucleus and can form phagosomes when they engulf foreign particles
What is the spectrum of macrophages between? How do macrophages ‘decide’ which to differentiate into?
- M1 macrophages – pro-inflammatory cells that kill pathogens
- M2 macrophages – anti-inflammatory cells that clear apoptotic cells, tissue-resident
Macrophages can interconvert between types depending on the signals they receive from cytokines.
List the similarities between neutrophils and macrophages
- most phagocytes
- originate in the bone marrow
- initiate inflammation
- have the ability to dampen inflammation by secreting anti-inflammatory cytokines
If not originated from the bone marrow, where do some phagocytes come from?
Some tissue-resident macrophages are seeded during embryonic development, and do not originate in the bone marrow but from the yolk sac or foetal liver.
Why are neutrophils the first to reach site of infection?
The multilobed nucleus of neutrophils allows for easier migration from the blood circulation into tissues.
What are the three categories of granules in neutrophils? Describe them
- Primary/azurophilic – contain defensins and enzymes such as myeloperoxidase which are potent anti-microbials.
- Secondary – most common granule which contains anti-microbial compounds such as lysozyme (hydrolyses bacterial cell walls) and lactoferrin.
- Tertiary – either filled with metalloproteinases or phosphatases to degrade ECM to allow neutrophils to migrate through tissues.
