IMI4: Integration of innate and adaptive branches of the immune system Flashcards
Name the cell types from the myeloid lineage
- Neutrophil
- Basophil
- Mast Cell
- Dendritic cell
- Macrophage
Name the cell types from the lymphoid lineage
Natural killer cell
What do phagocytes detect? With what?
- Pathogen Associated Molecular Patterns (PAMPs) using pattern recognition receptors e.g. TLRs
- Complements using complement receptors (CR)
- Antibodies using Fc receptors
What are PAMPs?
Molecular structures that are present in microorganisms but not on vertebrates
What enables the immune system to attack pathogens but not self-cells?
Different TLR expression patterns
What 3 components do Basophils release? To what effect?
- Histamine, a vasodilator that increases blood vessel permeability and smooth muscle contraction and which is responsible for many symptoms during allergic reactions;
- Serotonin, which stimulates monocytes and lymphocytes thereby modulating which cytokines get produced during a given immune response;
- Heparin an anti-coagulant that prevents blood clotting too quickly.
What do granuloctyes release and what does this do?
cannot perform phagocytosis. Instead, they are granulocytes that fight parasites, particularly helminths, by releasing contents in their granules.
What are NK cells able to identify? - To what effect?
cells that have started to behave abnormally, rather than detecting pathogens directly. This triggers the NK cell to kill the misbehaving cell
How many proteins are there in the compliment system?
> 30
What can the compliment system do?
- Enhance phagocytosis
- Attract neutrophils
- Initiate inflammation
- Kill microbes
Can NK cells express TLR?
Yes they do
Do mice express TLRs?
No
Name all the phagocytic cells, and thus eliminate pathogens directly
Macrophages
Neutrophils
Dendritic cells
Mast cells
What is the role of Cb3?
Tagging pathogens - promoting opsonisation
Where do B and T lymphocytes mature?
B - Bone marrow
T - Thymus
Briefly describe humoral immunity
Involves antibodies that circulate in the plasma, lymph and tissue fluids, and it can protect us against extracellular bacteria and foreign molecules (danger signals)
Briefly describe cell-mediated immunity
Mediated by antigen-specific T cells, and it can protects us against intracellular pathogens, cancer and non-self cells
Cell-mediated immunity is a type of immunity directed against what type of pathogens?
- have evaded the innate immune responses and
2. are replicating inside cells, away from antibodies, which circulate in the blood or are found in extracellular spaces
What are the two main players of cellular immunity?
- Cytotoxic T cells (TC), which generally express CD8 on their cell surface
- Helper T cells (TH), which generally display CD4 on their cell surface
What is an antigen?
a molecule capable of stimulating an immune response.
When can T-cells only recognise pathogens’ antigens?
If they are presented to them in association with proteins known as the Major Histocompatibility Complex (MHC)
What is Major Histocompatibility Complex also known as in humans?
Human Leukocyte Antigen (HLA) system
What are the two signals required to activate the T-cell?
MHC
CD80/86
Which proteins do Cytotoxic T Cells recognise?
Recognise antigens presented on MHC Class I complexes, which are present on all nucleated cells. But they also require interaction of CD8 (On T-cell surface)
What three things can helper T cells do?
- Stimulate B cells to secrete antibodies to attack extracellular pathogens
- Activate macrophages to destroy ingested microbes
- Trigger cytotoxic T cells to kill infected target cells
What proteins do helper T cells recognise?
Antigens presented on MHC II complexes, that are found on antigen-presenting cells (APCs) such as dendritic cells, macrophages and B cells
T cells express what protein on their cell surface?
CD4
When activated for the first time, the helper T cells can differentiate into what?
helper T cells 1 (TH1) or helper T cells 2 (TH2)
What are helper T cells 1 (TH1)?
TH1 cells primarily activate macrophages and cytotoxic T (TC) cells (cell mediate response)
What are helper T cells 2 (TH2)?
TH2 cells activate B cells (humoral response)
Describe initiation of TH1 response
An intracellular pathogen such as a virus will be detected by a PRR such as TLR-3. This then triggers a signalling cascade which starts with a DC producing cytokines such as IL-12. IL12 then binds to its receptors on T cells and activates kinases such as JAKs and the signal transducer and activator of transcription STAT4. STAT4 binds to the DNA and induces the transcription of the master regulator T-bet which then leads to the production of IFN-γ, an effector cytokine that defines a TH1 response.
Describe initiation of TH2 response
Extracellular pathogens such as a parasitic worm will be detected by PRRs such as TLR-2 and TLR-4. This then triggers a signalling cascade which starts with an immune cell such as mast cells, basophils or germinal centre B cells producing cytokines such as IL-4. IL-4 then binds to its receptors on T cells and activates kinases such as JAKs and the signal transducer and activator of transcription STAT6. STAT6 binds to the DNA and upregulates the expression the transcriptional regulator GATA-3 which then leads to the production of effector cytokines such as IL-4, IL-4 and IL-13, which define a TH2 response.
What does PRR stand for
Pattern recognition receptor
What happens following phagocytosis of a pathogen?
APCs engulf and digest a pathogen into hundreds of antigen fragments. These fragments are then transported to the surface of the APC, where they are presented on the MHC Class II. Helper T cells become activated and start secreting cytokines, which in turn will activate B and T cells.
Show the order of action of cell mediated immunity
CD8 T-cells (cytotoxic) have TCRs that bind to antigen of pathogen on MHC I (plus CD28-CF8-/86 interaction) > release of cytokines
CD4 T-cells (helper) have TCRs that bind to antigen on MHC II on APC (DC, macrophages, B cells) as well as CD4 interaction > Either become TH1 or TH2
TH1: release cytokines to activate macrophages and cytotoxic T (TC) cells > Cell-mediated response
TH2: release cytokines to activate B cells > clone themselves > humoral response
How is it ensured by dendritic cells that the correct type of T-cells differentiate?
DCs send signals (cytokines) to naïve T cells which depend on the type of pathogen: it is the PAMP-PRR interaction that will determine which cytokines are secreted and these will skew differentiation of the T cells into particular T cell subsets
What is an antibody?
A large, Y-shaped protein used by the immune system to neutralise pathogens. The antibody recognises a unique pathogen’s antigen
What part of the antigen is recognised by the immune system?
Epitopes
Explain the maturation of B-cells
1) B cells develop from B-lymphocytes and originate and mature from the red bone marrow
2) Before they migrate the develop immunocompetance - the ability to carry out adaptive immune responses (the cell makes immunoglobulins that are inserted into the cell’s membrane
3) They then migrate to the lymph nodes or the spleen
Explain what happens to B cells and helper T cells whenever a pathogen invades
- Epitope binds to correct immunoglobulin on B-cell
- Pathogen is taken in by endocytosis
- Epitope is dislayed via MHCII complex on membrane
- Helper T cells recognise the antigen MHCII complex and deliver the co-stimulation needed to allow the B cell to proliferate and differentiate
- B cell becomes activate and starts to clone and specialise into memory B cells and effector B cells
What do memory B cells do?
Involved in the secondary immune response - initiate quick reaction, destroying the pathogen before any symptoms can occur.
What do effector B cells do?
Secrete millions of antibodies, which will only combine with the antigen that originally activated the B cells.They leave the lymph node of spleen and circulate the body humours
What way can antibodies kill pathogens
Agglutination Neutralisation Immobilisation Enhancing phagocytosis Activating the complement System
What can inappropriate cross-talk between innate and adaptive immune system lead to?
allergy, autoimmunity, and allograft rejection
Unlike other professional phagocytes, what is the major task of dendritic cells?
To enable the presentation of antigens to the immune system.
What happens to dendritic cells when they detect a pathogen? (very long) 5 steps
- When immature dendritic cells (DCs) detect a pathogen, they phagocytose it, degrade its proteins into pieces and present them at the cell surface associated with MHC Class II molecules.
- Simultaneously, they upregulate cell-surface receptors that act as co-receptors in T cell activation (such as CD80, CD86 and CD40).
- Dendritic cells (DCs) also upregulate chemotactic receptors, such as the chemokine CCR7, that induce them to travel to the spleen or to the lymph nodes where T cells reside and they act as antigen-presenting cells (APCs).
- Then, they activate helper T cells (TH) by presenting them with antigens derived from the pathogen, alongside non-antigen specific costimulatory signals.
- Finally, DCs can secrete a diversified panel of cytokinesthat provide a third signal that allows helper T cell to differentiate to the appropriate subtype (i.e. TH1, TH2)
What are the 2 distinct signals leading to activation of T cells?
- recognition of an antigen loaded onto the MHC Class II molecule by the TCR
- co-stimulatory signal provided by CD80/86 binding to CD28
What are the three signals required by T cells for activation?
Signal 1.The TCR/MHC-peptide interaction plus CD4 and CD8 coreceptors and adhesion molecules; Signal 2: Co-stimulation by additional proteins such as CD28 Signal 3: Activation of transcription factors and cytokine release as a result of signals 1 and 2
What type signalling of cytokines is carried out to cause T-cell proliferation following activation?
Autocrine
Induction of transcription factors leads to the secretion of other cytokines that act in a _______ manner to determine the polarisation of the T cells
paracrine
What are the 3 major functions of DCs?
1) They serve as sentinel cells and activate innate defences when needed
2) They process and present antigens, and therefore, initiate adaptive immune responses
3) They regulate adaptive immunity by determining whether an antigen will trigger an antibody (TH2) or a cell-mediated (TH1) response.
What do IL-1 and IL-6 do?
Stimulate T-cell proliferation and cause an increase in body temperature
What do IL-2, IL6 and IL-4 do?
Increase T cell proliferation
What do IL-1, IL-4 and IL-5 do?
Stimulate B cells to multiply
What do IL-2, IL-4 and IL-6 do?
Cause differentiation of B cells
How do antibodies get into the bloodstream?
Via lymphatic system
How do viral particles enter epithelial throat cells?
by receptor-mediated endocytosis
What does the virus do once it’s entered the endothelial cells? What happens next?
Releases fragments of genomic DNA into the cells. The infected cells start producing viral proteins which are displayed on their MHC I molecules and secrete IFN-alpha to alert surrounding cells of the viral infection. DCs present the antigens and T-helper cells secrete IL-2 as well as IL-4 and IL-5 to activate T and B cells.
How and where is the viral pathogen recognised? Once it has been recognised what happens?
Activated cytotoxic T Lymphocytes (CTLs) recognise the viral antigen on MHC I of infected cells and initiate apoptosis in these cells. They then attract phagocytes to the site via secretion of IFN-alpha and TNF. Thus, free viruses can be destroyed by antibody action and infected cells by cytotoxic T cells.
What does TNF stand for?
Necrosis Tumour factor
What are CTLs?
Cytotoxic T lymphocytes
What two ways do Cd4+ cells lead to the production of CD8+ cells?
- Producing cytokines that stimulate CTL differentiation
- Enhancing the ability of APCs to stimulate CTL differentiation
What class of MCH class do professional APC present?
MHC I and MHCII
All nucleated cells produce MHC I
What is presented on MHCI?
Viropeptides
Do follicular dendritic cells present through MHCII?
No, by complement or FC receptor (to B cells in germinal centre)
What determines whether a TH1 and TH2 is given?
- Type and load of antigen present
- The type of costimulatory molecules
- Dominant cytokine environment
