32.3 Effector Mechanisms in Immunity to Infection Flashcards
How do antibodies aid in elimination of infection?
Opsonization and initiation of acute inflammation.
What is opsonization?
Opsonins (e.g. Ab) are used to tag foreign pathogens for elimination by phagocytes.
*Antibody is bound to microorganisms and the Fc portion binds to the Fc receptors of phagocytes
How can Abs initiate acute inflammation?
*Complement activation (IgM/G) –> inflammation
*Abs on phagocytes –? phagocytosis –> initiation of acute inflammation
How do antibodies provide resistance against infection?
Prevent pathogen binding to and entering host cells
What can antibodies neutralize?
Viruses and bacterial products, such as toxins.
How do antibodies neutralize?
By binding to surface structures (antigens) and preventing it from interacting with other cells (e.g. host cells)
What is the role of Fc in the immune response?
While Fab is bound to the target cell, Fc binds to FcRs on leukocytes
–> triggers signalling pathway and release of lytic enzymes, perforin, granzymes, TNF
–> destroys target cell
Give examples of an Fc receptor-mediated Ab function.
*Antibody-dependent cell-mediated cytotoxicity (ADCC)
*Ab-dependent cellular phagocytosis (opsonise pathogen to tag for ingestion + destruction)
*Complement-dependent cytotoxicity
What happens in Complement-dependent cytotoxicity?
Abs activate complement system –> lysis of the pathogen or infected system.
What is antibody-dependent cellular cytotoxicity?
A mechanism of cell-mediated immune defense where an effector cell of the immune system actively lyses a target cell, whose membrane-surface antigens have been bound by specific antibodies.
Which cells are Fcreceptor-expressing?
monocytes, macrophages, NK cells.
What is the mucosae in terms of pathogen entry?
It is the major site of pathogen entry
How is mucosal immunity achieved?
Through MALT (mucous-associated lymphoid tissue) underlying mucosa
Throughout body, known as the common mucosal immune system.
What are the Peyer’s patches?
MALT lining the small intestine. Here antigens are samples and it is a SLO able to initiation of the immune response begins with the activation of lymphocytes.
What does MALT contain?
- T cells, B cells
- Plasma cells
- Macrophages
- Intestine: M cells, which sample antigen from the lumen
What are the functions of IgA antibodies?
The first line of defence in the mucosae in the resistance against infection, via inhibiting bacterial and viral adhesion to epithelial cells and by neutralisation of bacterial toxins and virus, both extra- and intracellularly.
Which MHC class do CD8+ T-cells recognise?
peptide-MHC class I complexes (recognised by CD8)
What is required for CD8 activation?
MHC class I:peptide binding with TCR receptor and CD8 molecule
Costimulation with B7 (CD80) on APC interacting with CD28 on T cell
Cytokines IL-1 and IL-2
What does IL-2 stimulate in T cells?
Stimulates T cell proliferation (clonal proliferation) of antigen specific T cells
What is CD8+ T-cells cytotoxic role?
induction of apoptosis in target cell: killing the virally infected cells to abort the infection and potentially killing tumour cells.
How do CTLs detect tumour cells in the body?
When malignant cells accumulate somatic mutations, they generate novel (non self) proteins which are expressed by MHC class I molecules
CTLs are activated by dendritic cells that present the neoantigens and infiltrate and kill the tumour cells
Why do CD8+ T cells need to be highly regulated?
All nucelated cells express MHC class I so all cells are potential APCs
Require IL-2 for their activation produced by nearby Th CD4+ cells
What are CD8+ T-cells mechanisms of lysis?
perforin/ granzyme and FasL killing.
What is the perforin/ granzyme mechanism of lysis?
Secretion of perforin/ protease filled granules by CD8+ T-cells:
*Perforin monomers form transmembrane channels in target cells → leak.
*Proteases can enter cell cytosol (e.g. granzyme B → cleaves procaspases into caspases to initiate cell apoptosis).
What is the FasL killing mechanism?
Fas-FasL interactions
Induce IC signalling → activate caspases → cell apoptosis
Secrete TNF-alpha → TNF Rs on target cells → apoptosis.
What do Tfh cells express and secrete to aid CD8+ T cells?
Express CD40L which interacts with dendritic cells to increase the expression of costimulatory molecules (CD80/B7) to ensure activation of T cells
Secrete IL-2 needed for T cell clonal proliferation
How do some viruses and tumours try to evade the adaptive immune system and how is this combatted?
- Some viruses and tumours avoid immune surveillance by down-regulating or inhibiting MHC class I expression and becoming invisible to CTL
- In order to avoid this scenario, natural killer (NK) cells are deployed which actively kill somatic cells devoid of MHC class I
What is the lineage of natural killer (NK) cells?
- NK cells derive from the common lymphoid progenitor and are closely allied to T and B cells
- However, they are considered components of the innate immune system, so they are frequently called ‘innate lymphoid cells’, which seems like somewhat of an oxymoron
Which immune system are natural killer (NK) cells part of?
They are part of the innate immune system, but they are activated by the adaptive immune system.
Which cytokines activate NK cells?
IL-12
IL-2
IFN -gamma
How do natural killer cells know whether to kill a cell?
- Natural killer cells lack either a TCR or surface Ig for antigen recognition
- Killing of target cells does not require prior priming
- The decision of whether to kill a target cell depends on the balance between activating and inhibitory receptor signaling
- Killing occurs only if the activating signal is dominant: dominant inhibitory signals pacify the cell
Which receptor is found on NK cells that prevents apoptosis
Killer inhibitor receptor which normally binds to MHC class I to stop apoptosis of target cells
Why is it important to kill cells not displaying MHC class I molecules?
Many cells loose their ability to synthesise MHC class I molecules after infection with a virus
Why are NK cells generally thought of as being part of the innate immune system?
Despite being derived from common lymphoid progenitor cells, they do not recognise their target by detecting antigens presented by MHC, have no memory and are not enhanced upon exposure to pathogens
They are non specific
Give an example of an activating and inhibitory stimulus for natural killer cells.
Activating:
- NK cells express CD16, which is a receptor for the Fc region of immunoglobulins.
- Therefore, although NK cells are part of the innate immune response, they are stimulated by the adaptive immune response.
Inhibitory:
- NK cells express KIRs (Killer Cell Immunoglobulin-like Receptors)
- They bind specifically to MHC class I, regardless of the peptide presented
- Stimulation of the KIRs inhibits the NK cell
- Failure to do so results in NK cell activation and killing of the target cell -> Thus this protects against certain virus infections or tumours that inhibit MHC class I expression
What are some functions of natural killer cells?
- Killing virally-infected/tumour cells.
- Activation of macrophages early in response
What do natural killer cells secrete to stimulate macrophages?
[IMPORTANT]
IFN-γ
How do NK cells kill target cells?
Secrete cytotoxins (perforins and granzymes) which make a hole in the membrane to release the contents of the cells
What is the function of macrophages in the innate immune response?
*Phagocytosis
*Antigen presentation (interplay with specific immune response)
*Secrete CKs that initiate/ regulate inflammation
*Wound healing + repair
*ROS secretion to kill phagocytosed bacteria.
*Granuloma formation (wall of infections body is unable to eliminate)
How do macrophages aid the specific immune response?
Once they have phagocytosed and digested the pathogen, they will display peptides on MHC class II molecules for interaction with T helper cells
