Immunology (Liz - Cytokines) Flashcards
What is a cytokine and what is its action?
- A group of low molecular weight regulatory proteins
- Secreted mainly by immune cells in response to a signal
- Bind to specific receptors, resulting in signal transduction and alter gene expression
What is pleiotrophy?
When a single cytokine has different effects on different cell types
What is redundancy?
When different cytokines have the same effect on a target cell
What is synergy?
When combinations of cytokines together have a stimulatory effect
What is antagonism?
When combinations of cytokines together have inhibitory effect
To clarify how cytokines differ from endocrine hormones, explain each in terms of their:
- site of production
- cellular targets
- biological role
- redundancy
- pleiotrophy
- sphere of incluence
- inducing stimulus
Hormones:
- Few
- Many
- Homeostasis
- Low
- Low
- Widespread
- Physiological change
Cytokines:
- Many
- Few
- Fighting infection
- High
- High
- Local
- Infection, tissue damage
Describe the general crystal structure of cytokines
- 4 alpha-helical regions (A-D) in which the A/B and C/d pairings run roughly parallel to each other in alternating directions
- Little or no beta-sheet structure
What are the approx size of cytokines?
25 kDa
Cytokines are grouped into families based on what?
Structure
How many members are there of the IL-1 family and what is their role? Give examples
IL-1 family has 11 members
e.g IL-1alpha, IL-1beta IL-18 and IL-33
Role: inflammatory mediators
What non immune and immune proteins are in the haematopoeitin family (Class I cytokine family)?
Non immune proteins e.g. erythropoetin and growth hormone
Immune cytokines e.g IL-2,3,4,5&6 and GM-CSF
What cytokines are in the interferon (class II) family?
IFN-alpha IFN-beta IFN-gamma IL-10 IL-19
What is the role of class II cytokines?
Mainly antiviral in action
Some control immune responses
E.g. IFN-gamma upregulates MHC class II expression
What are included in the TNF family? What are their roles?
More than 17 cytokines including TNF-alpha and TNF-beta
Many functions in immune cell development and function
Give some examples of the general roles of cytokines
1) Up or down-regulate enzyme activity in target cell
2) Change level of transcription of particular genes in a receptor bearing cell
3) Can instruct cell survival or death
‘Immune cell messangers’
What is a chemokine and what is its role?
- A sub class of cytokine
- Lower molecular weight than a cytokine
- Causes chemotaxis (movement of pre-activated WBC) from one area to another
How do leukocytes move to infected tissue and at what speed?
Move up a chemokine concentration gradient towards infected tissue
Can move up to 30µm/min
Do immune cells always have chemokine and cytokine receptors?
No, only when they’re activated by an antigen do they express the receptors
What are the properties of cytokines?
- Work by binding to membrane receptors on target cells
- Bind with high affinity
- Extremely low concentrations of cytokine are able to mediate its effect (picomolar = 10^-12 M)
- Very similar or identical functions
Cytokines secreted by a single Th cell following antigen specific activation can influence the activity of what cell types?
- B cells
- Cytotoxic T cells
- NK cells
- Macrophages
- Granulocytes
- Haematopoietic stem cells
What 5 cytokines/chemokines are produced by macrophages in response to an infection? What do all of the effects have in common?
IL-1beta TNF-alpha IL-6 CXCL8 IL-12
All have pro-inflammatory effects
Differentiation of CD4+ Th cells into Th1 or Th2 cells depends on what?
The type of pathogen they encounter
CD4+ Th cells that encounter bacteria or viruses usually become what and why?
Th1 cells
Because these pathogens cause DCs to produce IL-12 and NK cells to produce IFN-gamma
Causes differentiation to Th1 cells
CD4+ Th cells that encounter worms and some other pathogens usually become what and why?
Th2 cells
Worms cause NK cells to secrete IL-4
Causes differentiation to Th2 cells
What are the main functions of Th1 and Th2 cells?
Th1: Helping cells which are fighting intracellular viral infections e.g. cytotoxic T cells
Th2: helping cells fighting bacteria, protozoa, fungi and parasites e.g. B cells (via antibodies), eosinophils and mast cells
What is linked recognition?
A B cell can only be activated by a Th2 cell that responds to the same antigen
How does a Th2 cell cause a B cell to become a plasma cell?
Production of the cytokines IL-4, IL-5 and IL-6 which cause proliferation and differentiation into plasma cells
Describe the interaction between a Th cell and a B cell
1) T cell receptor binds to MHC and CD4 on B cell
2) This induces the CD40 ligand on the T cell which binds to CD40 on the B cell
3) The integrin LFA-1 on the T cell binds to the adhesion molecule ICAM-1 on the B cell
4) The cytoskeletal protein talin becomes relocated to the point of cell/cell contact
5) The golgi also becomes re-orientated by the cytoskeleton to the point of B cell contact
6) Cytokines e.g IL-4 are released at the point of contact
Cytokines play an essential role in what generative process?
Generation of all blood cells from the bone marrrow
Give some examples of cytokines involved in blood cell production
1) SCF - stem cell factor
2) GM-CSF - granulocyte-macrophage colony-stimulating factor
3) G-CSF - Granulocyte-colony stimulating factor
4) M-CSF - Macrophage-colony stimulating factor
What is the structure of the moderate affinity and high affinity IL-2 receptor?
Moderate:
- only the beta and gamma chain
- requires very high concentrations of IL-2
High:
- beta, gamma and alpha chain
- only needs very low concentrations of IL-2
When do both receptor types exist?
Resting (i.e naive) T cells and NK cells express the moderate affinity receptor
One activated, T cells produce about 50,000 low affinity (alpha chain only) receptors and 5,000 high affinity
After activation, what are T cells able to do?
Secrete IL-2
- Binds to its own receptors on the T cell
- Induces proliferation
What is the common gamma chain (gamma-c)?
A component of many vital cytokine receptors
What occurs if the common gamma chain is missing is certain cytokine receptors?
- The receptor cannot bind the intracellular JAK 3 tyrosine kinase domain
- No signal transduction (STAT signalling) to nuclues
- No transcription therefore no cytokine effect
Individuals born with no common gamma chain have what disease?
X-linked severe combined immunodeficiency disease
How do some APCs recognise virally produced dsRNA or ssRNA?
ssRNA recognised by TLR-7 and dsRNA recognised by TLR-3
- Found on endosomes
- Viral RNA binds to these TLRs after viral uptake and processing via the endosomic pathway
What occurs in the cell when viral DNA binds to TLRs?
- Induced production of type 1 interferons (alpha and beta)
- Membrane protein UNC93B essential for signalling via these receptors
Describe the signalling pathway from TLR-3
- First, membrane protein UNC93B
- TLR-3 signalling dependant on a pathway of the adaptor TRIF and primarily activates interferon-regulatory factors IRF3 and IRF7
Describe the signalling pathway from TLR-7
- First, membrane protein UNC93B
- TLR-7 signals through a pathway dependant on the adaptor MyD88 that involves IRAKs and primarily activates the classical NFkB pathway
What happens to the produced IFN-a/B?
- Secreted by DCs
- Bind to alpha and beta interferon receptors on neigbouring cells
- Binding activates kinases JAK1 and TYK2
- These activate transcription factor ISGF3
- This drives expression of type I IFN-dependant genes in the nucleus
- These genes encode proteins that mediate antiviral response
What anti-viral genes are turned on by IFN alpha and beta?
1) Protein kinase R (PKR) - binds to dsRNA, inhibiting its translation
2) 2,5, oligo A synthetase - leads to mRNA degradation
3) Mx protein - inhibit viral replication
What are the 3 main roles of IFN alpha and beta? (summary)
1) Induce resistance to viral replication in uninfected cells by activating genes that cause mRNA destruction and inhibit translation of viral proteins
2) May increase sysnthesis of MHC class I in viral infected cells, making them more susceptible to killing by cytotoxic T cells
3) Activate NK cells, which are capable of selectively killing virus infected cells
Name 4 examples of diseases caused by altered cytokine secretion or altered cytokine receptor subunit expression?
1) Bacterial superantigens (septic shock)
2) X-linked SCID
3) Chagas’ disease
4) Lymphoid and myeloid cancers
How do bacterial superantigens cause septic shock?
- Bind to the outside of T cell receptors, causing non specific T cell activation
- Causes huge release of cytokines such as TNF-alpha and IL-1beta
Give an example of a bacterial superantigen
TSST-1 toxin produced by staphylococcus aureus
What is Chagas’ disease?
The protozoan Trypanosome worm (T.cruzi) causes a drastic reduction in the expression of the IL-2R alpha subunit needed to produce the high affinity IL-2 receptor
What is X-linked SCID?
Mutation in the common gamma chain subunit of IL-2 and other cytokine receptors
- No T and B cell activation via IL-2/IL2R interaction
What is the most common way to reverse primary immunodeficiencies?
Bone marrow transplants
What is a problem with bone marrow transplants?
Rejection
- Mature T cells that contaminate the bone marrow graft attack host cells causing graft versus human disease (GvHD)
Describe how lymphoid and myeloid cancers may occur from altered cytokine expression
Infection with HTLV-1 virus (Human T-lymphotropic virus) causes constitutive high expression of IL-2 and IL-2R
- Results in uncontrolled proliferation of the leukocyte-derived cancers cells
- Leads to development of adult leukemia and lymphoma diseases
Name some ways in which viruses can mediate immune mechanisms to evade cytokines
1) Interfere with cytokine production
2) Produce copies of cytokines the body normally uses to stop anti-viral response e.g. IL-10
3) Produce soluble cytokine receptors
4) Interfere with the action of interferon alpha and beta
Summary of the roles of cytokines (no question, just read)
- Cytokines act as intercellular messengers that evoke particular biological activities after binding to a receptor on a responsive target cell.
- Helper T cells and macrophages produce the most cytokines, although many other cell types are also capable of producing them.
- The physiological responses that cytokines control are:
The Inflammatory response to infection - The proliferation, differentiation and control of both innate (e.g. macrophage, NK cell) and adaptive (B and T lymphocyte) immune cells (survival or death!).
- Haematopoiesis (the formation of new blood cells)
- The induction of wound healing.
