Immunology Flashcards
When would immunosuppression be utilitised?
Patients may be artificially immunosuppressed in the event of an autoimmune disease
Describe the properties of the skin as a physical barrier to infection
It is constantly renewed
It has a low pH
It has low oxygen tension
Sebaceous glands secrete hydrophobic oild whick make it hard for pathogens to bind
Mucous line all _____ ________ that come into contact with the ___________
Body cavities
Environment
Mucous contains many constitutes which can fight potential pathogens, what are these?
- Secretory IgA
- Lysozymes
- Defensins
- Antimicrobial peptides
- Lactoferrin - starve invading bacteria of iron
What are commensal bacteria?
Bacteria that reside in the body and on epithelial surfaces naturally.
They have a symbiotic relationship with the body and can eradicate most normally infections
They ensure there is no undefended ecological niche
The components of the immune system can be split into which two categories?
- Cells
- Humoral immunity (soluble factors)
Which 3 main groups of cells are involved in the immune system?
- Phagocytes
- Lymphocytes
- Granular
When a cell is infected with a virus what will it secrete?
Interferons (alpha and beta)
The antiviral state inititiated by interferons achieves what?
It down regulates protein synthesis which slows virus production
What is an antigen?
An substance able to stimulate an adaptive immune response - it can be protein, carbohydrate, nucleic acid, lipid, metal etc
Where are T and B cells formed?
Bone marrow
Where do B cells mature?
Bone marrow
Where do T cells mature?
Thymus gland
In response to an infection B cells will produce what?
Antibodies and memory cells
What are the two types of T cell?
Helper T cell (CD4+)
Cytotoxic T cell (CD8+)
How does a virus evade the immune system?
It will usually hide within body cells
How can cytotoxic T cells discover viruses hiding in body cells?
The host cell constantly samples its cytoplasm and displays proteins on its surface - this is mediated by MHC class 1 proteins
These displayed proteins can “show” cytotoxic T cells which cells are infected
How do viruses evade the process of cytoplasm sampling mediated by MHC class I proteins?
They downregulate the production of MHC class I proteins
This reduced cytoplasm sampling
How do natural killer (NK) cells retaliate to viruses that downregulate MHC class I production?
NK cells can detect a lack of MHC class I proteins on a cell surface
They can then attack and destroy such cells
How are parastitic works (helminths) attacked by the immune system?
Antibodies and mast cells
What is the complement system and where is it produced?
Family of around 30 different proteins produced in the liver
How does the complement system function?
When activated, the proteins activate eachother in a cascade fashion
This involves great amplification and playes a role in inflammation
When do monocytes differentitate into macrophages?
When they exit the blood and migrate to peripheral tissues
What are Kupffer cells?
Macrophages of the liver
What are mesangial cells?
Macrophages of the kidney
What are macrophages of the nervous sytem called?
Microglia
How can neutrophils be differentiated from macrophages?
Their multi-lobed nucleus
What is the role of dendritic cells?
They engulf pathogens, phagoytose and then present antigens on their surface to T cells
What are the main functions of neutrophils?
Killing and degredation
What are the main functions of macrophages?
Killing, degregation, wound healing, anti-inflammatory and antigen presentation
What is the main fucntion of dendritic cells?
Antigen presentation
What is lymphodema and why may it result in infection?
It a condition characterised by a lack of draining of tissue fluid by the lymphatic system
The fluid builds up and is not cleaned as effectively leading, potentially, to infection
The immune system itself is composed of two halves - what are these halves and how are they connected?
- Innate immune system
- Adaptive immune system
Joined through the action of dendritic cells
What is meant by “direct contact” between immune cells and pathogens?
A receptor/ligand interaction
What is meant by “indirect contact” in the immune system?
Communication between cells and pathogens through the use of cytokines
What are autocrine signals?
Signals produced by a cell that lead to self-activation
Interferons have the role of activating an _______ ______
Antiviral state
Which cells may secrete interferons?
Infected cells
Release of interferons has two main outcomes, what are they?
- Protein synthesis is downregulated
- Employment of particlular mlcules into the cell membrane is upregulated such as MHC class I - allows for detection
Interferons can also instruct cells to undergo apoptosis
What are the signs of acute infammation?
- Redness - vasodilation
- Swelling - vascualr permeability
- Heat - high metabolic function
- Pain
- Loss of function
What are the three phases of the innate response?
- Recognition
- Activation
- Effector
Describe recognition as a phase in the innate response
Innate immune cells recognise pathogens due to the expression of PAMPs which bind to PRRs on innate immune cells
What are PAMPs?
Pathogen associated molecular patterns
These are ligands expressed on the surface of pathogens which allow them to be detected by immune cells
What are PRRs?
Pattern recognition receptors
Found on innate imune cells that are receptors for PAMPs found on pathogens
How do macrophages differentiate between apoptotic cells and normal cells?
Normally phospholids called phosphatidlyserine are held facing inward to the cytoplasm by the enzyme flippase
In the event of apoptosis, phosphatidlyserine is fliiped to face outwards by the acion of the enzyme scramblase
These outward facing phosphatidlyserine lipids act as signals for macrophageal engulfment
PAMPs have the ability to activate which three immune cells
- Macrophages
- Mast cells
- NK cells
Injured cells release which type of signals?
Danger signals
(e.g. IL 33)
What happens when macrophages cannot kill a pathogen?
Infected macrophages are walled off forming granulomas
The purpose of this is to prevent the spread of infection
What will be present on the surface of macrophages after engulfment of a pathogen?
Fragments of pathogen protein
This allows for recognition by antigen presentation
Interferon gamma can cause what change in a macrophage?
It will cause superactivation
This allows for expression of inducible nitric oxide synthase - an enzyme allowing for production of toxic oxygen and nitrogen species
The antigen presentation capacity of macrophages will also increase
Where are mast cells found most prominently?
Mucosal surfaces
Which two processes occur when a PRR on a mast cell is bound by a PAMP?
- Degranulation - release of pre-formed pro-inflammatory mediators are released allowing for acute inflammation
- Gene expression - production of new pro-inflammatory mediators commences within mast cells
Why do NK cells not kill normal helathy cells?
Normal cells have MHC class I protein on their surface which is bound to self proteins (antigens)
NK cells have a receptor on their surface that binds to the MHC class I protein and the antigen
When the antigen/MHC class I combination is of self-origin, inhibitory signals are sent to the NK cells
How do viruses evade cytotoxic T cell killing?
They cannot be detected by the antigen/MHC class I receptor system because they downregulate MHC class I production meaning it is more difficult for foreign antigens to be “seen”
How do NK cells kill cells in which viruses have downregulated MHC class I production?
If no ligand (MHC class I + antigen) is present, NK cells cannot be inhibited so the cell is killed regardless
NK cells take no chances
Upon activation NK cells secrete pro inflammatory mediators such as _________ gamma
Interferon
In what two ways are NK cells activated?
- Detection of no/foreign MHC class I
- Interferon alpha and beta released from infected cells
Which pro-inflammatory mediator acts upon macrophages to superactivate them?
Interferon gamma
(produced from NK cells)
Which cytokines act on the hypothalamus to increase prostaglandin production?
TNFalpha, IL-1 and IL-6
What is the function of prostaglandin production by the hypothalamus during an infection?
Induces fever
What effect do cytokines TNFalpha, IL-1 and IL-6 have on bone marrow?
Act on haematopoetic stem cells to drive production and differentiation of more neutrophils
What is increased production of neutrophils called?
Neutrophilia
Where is C reactive protein produced and what increases its production?
Liver
Pro-inflammatory mediators TNFalpha, IL-1 and IL-6
Clinically, why are CRP levels usefult to monitor?
They are very indicative of the level and severity of inflammation
CRP has which two functions in the immune system?
- Promotes phagocytosis
- Activates complement
What are the symptos of the local effects of inflammation?
- Rubor - redness
- Calor - heat
- Tumour - swelling
- Dolor - pain
- Loss of function
Pro-inflammatory mediators can cause systematic effects as well as local ones, what are these?
- Neutrophilia
- Fever
- Activation of complement
- Promotion of phagocytosis
How is vascular permeability brought about during acute inflammation?
- Macrophages - TNFalpha, IL-1, NO
- Mast cells - Histamine, TNFalpha, leukotrienes, prostaglandins
How is vasodilatation brought about during acute inflammation?
- TNFalpha - mast cells and macrophages
- Histamine - mast cells
During acute inflammation, what can cause endothelial cells within vessels to become activated?
- TNFalpha - macrophages
- IL-1 - Macrophages
- Chemokines - macrophages
- Histamines - mast cells
What does endothelial cell activation involve?
Expression of receptors (selectins) and ligands (ICAM-1 and VCAM-1)
Which cell types can undergo transendothelial migration?
- Neutrophils
- Monocytes
- NK cells
- Basophils
- Eosinophils
- T cells
What is white cell margination and how does it come about?
Due to vasodilatation (induced by TNFalpha and histamines), there is slower blood flow (stasis) which causes white cells to move closer to the endges of vessels
Why do neutrophils roll along the endothelial walls after white cell margination?
They bind via carbohydrate ligands to selectins on the endothelial walls
This attraction has low affinity meaning bonds are continually made and broken so the white cells roll along the walls
What causes there to be strong attraction between neutrophils and the endothelial cell walls?
The release of chemokines from macrophages can activate neutrophils
This allows receptors on the neutrophil surface (integrins) to form strong bonds with the ICAM-1 and VCAM-1 on the endothelial cell walls
After binding between integrins and ICAM-1/VCAM-1 occurs what occurs next to the neutrophil?
It will come to a halt and undergo diapedesis - the process where neutrophils squeeze through the spaces between endothelial cells and into the extracellular space
How do neutrophils migrate to the site of inflammation after diapedesis?
Chemotaxis
Locomotion along a chemokine gradient
What are the two basic functions of neutrophils?
- Kill extracellular pathogens
- Produce pro-inflammatory cytokines
During phagocytosis, what are the two main ways that pathogens will be destroyed within a phagosome?
- Anti-microbial proteins
- NADPH oxidase dependent mechanisms
Describe how anti-microbial proteins will kill pathogens within a phagosome
The phagosome fuses with azurophilic granules raising pH
This activates the antimicrobial response - pH of the phagosome decreases, lysosomes fuse and acid hydrolases enter to break down bacteria
Describe how NADPH oxidase dependent mechanisms kill bacteria
Neutrophils can become activated by cytokines or PAMPs which forms the NADPH complex
This means that a highly reactive oxygen species (ROS) can now be produced and released into the phagolysosome
What is degranulation?
The release of anti-microbial proteins into the extracellular space instead of within a phagolysosome
What is the downside to degranulation an how is this negative aspect partly counteracted?
Release of anti-microbial proteins into extracellular space is damaging to surrounding tissues
This is counteracted by upregulation of proteinase inhibitors produced during the acute phase response
What are NETs?
Neutrophil extracellular traps
Intracellular structures release by neutrophils into extracellular spaces - they function as nets to prevent spread and facilitates phagcytosis
What is pus?
Collection of neutrophils, NETs, dead bacteria and cellualr debris
What is the term given to a collection of pus within an enclosed space?
Abscess
What is sepsis?
Blood poisoning brough about by infection
Uncontrolled inflammation causes sepsis and it can lead to septic shock due to a drop in blood pressure organ failure occurs
What are examples of complement proteins?
- Kinins
- Coagulation factors
- Fibrinolytic system
How many complement proteins are there and where are they produced?
30
Liver
In simple terms what activates complement?
Pathogens
(directly or indirectly)
What are the three pathways in which a cascade can occur involving complement?
- Mannose-binding lectin pathway
- The alternative pathway
- The classical pathway
Describe the classical pathway of complement activation
- C1 complex is activated upon binding to an immune complex involving either IgG or IgM
- C1 splits to C4 and C2
- C4 becomes C4a and C4b, whilst C2 becomes C2a and C2b
- Both C4b and C2a complex to form C4b2a (C3 convertase)
- This enzyme allows for C3 to be cleaved into C3a and C3b
Describe the mannose-binding lectin pathway for complement activation
Mannose - a bacterial carbohydrate
Mannose binding lectin is produced in the liver and binds to mannose
This initiates the breakdown of C3 to C3a and C3b
C3b contributes to an amplification loop
Describe the alternative pathway for complement activation
C3 spontaneously breaks down
C3b binds to the pathogen surface and acts in amplification of the response
How is the membrane attack complex formed and how is this achieved?
C3b causes breakdown of C5 into C5a and C5b
C5b binds to the surface of the pathogen
C6, 7, 8 and 9 assemble around C5b forming the membrane attack complex
This created a funnel shaped hole in the pathogen allowing for death by osmotic cell lysis
What is opsonisation?
The coating of pathogens by humoral factors (opsonins) to facilitate phagocytosis
Give some examples of opsonins
- C3b
- C-reactive protein
- IgG and IgM
C5a and C3a are _____________ which can act on which two things?
Anaphylatoxins
Acts on mast cells and blood vessels
What effects do the anaphylatoxins C3a and C5a have on mast cells and blood vessels?
- Activate mast cells to produce pro-inflammatory mediators and chemokines to increase vascular permeability and increase recruitment of macrophages, neutrophils and lymphocytes
- Act directly on blood vessles to have the same effect as activated mast cells - increased vascular permeability and immune cell recruitment
Why does a small signal from the complement system result in a large effect?
The amplification loop
How is the amplification loop controlled in the complement system?
- Only cleaved proteins are active
- Active proteins have a short half life
- Some complement proteins cannot bind to human cells
- Complement inhibitors and regulatory proteins can limit the effects of complement where necessary
In the mature state, what do dendritic cells do?
Enter secondary lymphoid tissues and play a role in antigen presentation to CD4+ cells
Which “arm” of the immune system is rapid, non-specific and inborn
Innate
Which “arm” of the immune system is slow, specific and acquired?
Adaptive
Which cells can communicate between both “arms” of the immune system?
Dendritic cells
What are the types of cells in the aquired immune system?
- B cells
- CD4+ T cells (helper)
- CD8+ T cells (cytotoxic)
- Memory T cells
- Memory B cells
How is the interaction between PAMPs and PRRs different from the interaction between antigens and antibodies?
The interaction between antigen and antibody is far more specific and they are not at all interchangable
How are T cells recognised?
Membrane bound heterodimer (composed of alpha and beta chains)
How are B cells recognised?
Membrane bound antibody (IgM or IgD)
What are antibodies composed of?
Two heavy and two light polypeptide chains which are held together by di sulphide bridges
How do heavy and light chains confer variability?
Each heavy and light chain has a variable region at the end and a constant domain on the rest of the chain
What type of heavy chain does IgM have?
μ heavy chain
What type of heavy chain does IgG have?
γ heavy chain
What type of heavy chain does IgA have?
α heavy chain
What type of heavy chain does IgE have?
ε heavy chain
What type of heavy chain does IgD have?
𝛿 heavy chain
In an antibody, what is the antigen binding site composed of?
The hypervariabe regions Ig light and heavy chains
How is it possible that there are more antibodies than genes in the body?
The light and heavy chain are coded for by segmented genes in the germline genome of haematopoetic stem cells
How are the segmented genes from the germline genome of haematopoetic stem cells arranged within B cells as they go through development?
They are randomly rearranged
How is genertic material arranged during the development of T cells?
It is randomly rearranged
The gene arrangement process in the development of both T and B cells gives rise to which two importnt factors?
- Populations of B cells and T cells are hugely diverse
- There is potential for generation of autoreactive cells
How do naive T cells and B cells enter lymph nodes from high endothelial venules (HEVs)?
Transendothelial migration
What is the function list of an immature dendritic cell?
Ability to phagocytose antigens, cell debris and particles
Where do mature dendritic cells migrate to and what do they do there?
Secondary lymphoid tissues (lymph nodes)
Display antigens to T cells
Which cytokine will activate immature dendritic cells?
TNFalpha
Induces expression of co-stimulatory molecules (B7)
(dendritic cells mature)
How do dendritic cells present antigens?
In complex with MHC class I proteins on their cell surface
Where do dendritic cells go that are presenting foreign antigens?
Local lymph nodes
T cells can easily recognise the foreign antigens here
Stromal cells have what function in lymph nodes?
They are connective tissue cells that can bind to opsonised antigens
For B cells to be activated, how many signals do they require?
2
What signals can activate B cells?
The B cell receptor + antigen must always be one signal
The other signal can be any of the following:
- TFH (helper T cell)
- PRR + PAMP
- Multiple BCR + antigens - repetitive antigens with multiple epitopes (areas antibodies can bind to antigen)
What are the two classes of MHC proteins and their functions?
Class 1 - expressed on all nucleated cells - present peptide antigens to CD8+ T cells
Class 2 - only expressed on professional antigen presenting cells (APCs) such as dendritic cells, macrophages and B cells - they present the peptide antigen to CD4+ T cells
What two signals do T cells require to become activated?
- Antigen + MHC protein
- B7 - peripheral membrane protein on APCs for co-stimulation, and CD28 - protein expressed on T cells that provides co-stimulatory signals for T cell activation (B7 and CD28 bind)
What happens upon cell (T/B) activation?
Undergoes clonal expansion and differentiation into effector or memory cells
Plasma cells are characterised by which physical feature?
Huge amounts of endoplasmic reticulum for protein (antibody) production
How and why does antibody affinity for antigens vary over time after production?
Initially affinity of antibodies is low
After entering the germinal centre (secondary centre within B-cell area of lymph nodes) the plasma cells become long life plasma cells
They now excrete high affinity antibodies
Antibodies are classified by the type of _______ chain they use
Heavy
How many binding sites does IgM have?
10
Which pathway for complement activation does IgM activate?
Classical
How does IgM aid in the activation of the classical pathway of complement?
Upon binding to antigens of the pathogen surface it will undergo conformational change
This change provides a binding site for C1 the first component of the pathway
As well as IgM which other antibody class can activate the classical complement activation pathway?
IgG
What is the first antibody produced?
IgM
What is the most abundant antibody?
IgG
Which maternal antibody class will protect a growing foetus and why is this important?
IgG
The foetus does not have a fully developed immune system
Describe how IgG antibodies make good opsonins and aid phagocytic cells and their detection of pathogens
Phagocytic cells express a Fc gamma receptor on their surface for the gamma heavy chain
This can make pathogens visible to neutrophils
IgG antibodies are good activators of NK cells - why?
NK cells have receptors on their surface that interact with the gamma heavy chain of the IgG antibody
This interaction can instruct NK cells to destroy pathogens attached to IgG
Where is IgD commonly found?
- On the surface of B cells
- In the circulatory system
What is the role of IgD thought to be?
Recruitment of basophils into areas of inflammation
What is the second most abundant antibody type?
IgA
Secretory IgA is what form of IgA?
Dimeric form
Secretory IgA is involved in which two main areas?
- Neonatal defence - in breast milk
- Neutralisation - at muscosal sites such as GI tract and in tears
Which antibody class is involved in allergic responses?
IgE
How does IgE trigger allergic responses?
Activates mast cells which then release pro-inflammatory mediators
Why can mast cells and basophils be activated by IgE?
They have FcE receptrs for IgE on their surfaces
Why does the level of antibodies remain elevated for an extended period of time after an encounter with a pathogen?
In case the body re-encounters this pathogen
Cytokine environments can cause B cells to switch what?
Heavy chains
Based on the pathoehn experienced
Which factors influence the type of helper T cell that differentiates from a CD4+ T cell?
Cytokines present that dendritic cells secrete
The cytokines released by dendritic cells is influeced by the type of PAMP, danger and inflammatory signals
Effector TH cells can stimulate which other immune cells?
- B cells (TFH)
- Macrophages (TH1)
- CD8+
- CD4+
Antigen activated CD4+ T cells secrete what cytokine when they proliferate in reponse to the antigen and co-stimulation?
IL-2
IL-2 can stimulate which type of immune cell to do what?
CD8+ to differentiate into cytotoxic T cells
How do TH1 cells enter inflamed tissue?
Trans-endothelial migration
TH1 cells will express what cytokine in inflamed tissue and what is its purpose?
Interferon gamma
(as well as other co-stimulatory molecules)
This is to induce expression of nitrous oxide synthase in the macropage allowing the pathogen to be destroyed
This is superactivation of macrophages - similar to how NK cells do this
What is the full process of B cell activation involving TFH cells?
- Initially B cells encounter opsonised antigen and become partially activated
- The antigen/antibody complex is internalised
- The antigen is presented by MHC class II on the surface
- T cells complex with the MHC class II/antigen complex which allows B cells to become fully activated
How do TFH cells stimulate B cells to clonally proliferate?
Via CD40L (on TFH cell) and CD40 interactions
Effector TFH cells secrete cytokines the further activate B cells and stimulate the germinal centre response
What does the germinal response entail?
- B cell proliferation
- Antibody heavy chain switching
- Generation of high affinity antibodies
- Differentiation into plasma cells
- Differentiation into memory B cells
What is the overall aim within the germinal centre and how is it brought about?
To produce high affinity antibodies by inducing mutations into heavy and light Ig chains
This is mediated by activation induced deaminase (AID) which can mutate antibodies
The downside to this is that it can cause lymphoma
Cytotoxic T cells bind to what on infected cells?
MHC class I and the presenting antigen
What do cytotoxic T cells do to infected cells?
Introduce pore-like structures causing osmotic lysis or by initiating apoptosis
They can express Fas ligand whcih results in the release of cytochrome c - a pro-apoptotic protein
When there is no longer inflammation, what cytokine is released from macrophages?
IL-10
This stops the inflammatory respons eand initiates tissue repair
