The immune system Flashcards
What is immunology
The study of the immune system,• Integrated system of cells and molecules that defends against disease and reacts against infectious pathogens
What are malfunctions of the immune system
immunodeficiency
allergy
autoimmune disease
graft rejection
What is the innate immune system
Broad specificity, not improved by repeat infection (no memory), Rapid response (hrs)
Leucocytes - Phagocytes, natural killer cells
Soluble factors - Lysozyme, complement and interferons
What is the adaptive immune system
Adaptive - Highly specific, Improved by repeat infection (memory), Slower response (days)
Leucocytes - B lymphocytes and T lymphocytes
Soluble factors - antibody
What are leukocytes
White blood cells
What are the 2 main lineages of WBC
Myeloid cells - mast cell, myoblast
lymphoid cells - Plasma cell and Natural killer cell
What was the first immunity to evolve
Innate
What are the external barriers to infection
Keratinized skin (Keratin)
Secretions (Sebum, fatty acids, lactic acid, lysozyme)
Mucous (cilia)
Low pH (stomach)
Commensals (natural bacteria)
What is a neutrophil
Main phagocyte in the blood
Short lived, fast moving
Lysosomes release enzymes (H2O2)
Faintly green
Where are monocytes found
In the blood
Where are macrophages found
In the tissues - big eater - 1 macrophage eats 100 bacteria
Long - lived
Help initiate adaptive responses
What does a monocyte turn into
Macrophage
What are NK cells
Type of lymphocyte
Kill virally infected cells non-specifically
Important in self and non self recognition
Kill cancer cells
What do phagocytes PRRs (pathogen-recognition receptors) recognise
Microbe-associated molecular patterns (MAMPs)
What do natural killer cells reconise
Kill targets unless the recognise self proteins (MHC) that are present on all nucleated cells
What is the complement system
around 20 proteins in blood which are activated on infection cause bacteria cell lysis
What are defensins
- positively charged peptides made by neutrophils
* disrupt bacterial membranes
What are interferons
Produced by virally infected cells
• protect uninfected cells
• activate macrophages and NK cells
What are cytokines (interleukins)
hormones of the immune response
Produced by cells of the innate and adaptive immune system for cell - cell communication
Short distance
What are examples of inflammatory mediators
Histamine, prostaglandins
What is the integrated response to infection/injury
Heat
Redness
Swelling
Pain
What does infection/damage do to the body
induces the release of
INFLAMMATORY MEDIATORS (e.g. prostaglandins,
histamine) & production of CYTOKINES
What are the integrated responses to infection
INFLAMMATION • localised response to infection/damage • dilation of blood vessels (redness) • increased capillary permeability (swelling) - complement can access injury • phagocytes migrate into tissues
TEMPERATURE
On infection, macrophages may release cytokines e.g.
interleukin 1 (IL-1)
• acts on hypothalamus
• raises temperature
• stimulates phagocytosis
• reduces level of iron in blood - less iron for bacteria growth
What are the 4 types of pathogen
Bacteria (1-5um)
Viruses (20-400nm)
Fungi (2-20um)
Parasites (1um - 10m)
What are features of the adaptive immunity
Specific
Slower
Has memory
What recognises the antigen
Receptors on T and B lymphocytes
Where do B cells mature
In Bone marrow
Receptor - Antibody
Where do T cells mature
in the Thymus
What does maturation do
Allows for the Cell receptor to form
What is antigen independent differentiation
Lymphocyte turning into a B or T cell
What is antigen dependent differentiation
A T or B cell binding to an antigen and differentiating in the lymph nodes, spleen… B cells then secrete soluble antibodies, whereas T cells kill infected host cells or make cytokines
What do T cells work against
What do B cells work against
T - Viral, intracellular bacterial and intracellular parasitic
B - extracellular bacterial, secondary viral
When are antibodies produced
In response to antigens
What is the clonal selection hypothesis
Body produces millions of different B cells each with a specific different receptor and then the B cell which can bind to the antigen undergoes clonal selection à rapid division and differentiation à clone of cells called plasma cells à secrete soluble antibody proteins
Some B cells don’t differentiate into plasma cells but instead memory cells à come across same pathogen again à divide and differentiate to destroy pathogen
What happens to faulty lymphocytes
Lymphocytes that recognise self are depleted early in development
What do T cells recognise
T cells can only recognise antigen bound to host cells
What do B cells recognise
B cells can recognise soluble antigen on the surface
How do T cells create an immune response
Millions of T cells à different T cell receptors recognise different antigen, and these T cells differentiate into T cells that can kill infected cells or produce cytokinesis à development of memory t cells
How is lymphoid tissue organised
Primary lymphoid tissue: lymphocytes reach maturity,
acquire their specific receptors (thymus and Bone marrow)
Secondary lymphoid tissue: mature lymphocytes are
stimulated by antigen
What is humoral immunity
Antigen forms B lymphocytes forms plasma cells forms a soluble antibody
What does humoral (antibody) immunity allow
Defense against extracellular bacteria and secondary
viral infections
What are FAB regions
Regions of the antibody which can bind different antigens specifically
What is the FC region
Tail of the Y
What does the hinge do
Move to antigen molecules at different distances
What is the dual role of immune response
Antigen recognition - FAB regions bind to different antigens specifically
Antigen elimination - Fc region binds to complement, Fc receptors on phagocytes
What is the structure of an antibody
Light chain - 25kD
Heavy chain - 50kD
Immunoglobulin G = L2H2 = 150kD
Immunoglobulin domain
What does papain do
Cleaves the molecules and gives two fragments - FAB and FC
FAB - Fragment antigen binding
FC - Fragment crystallizable
What is the ratio of FAB to Fc
2:1
What is the variable and constant regions
Variable regions – bind antigens. Differ between antigens with different specificities
Constant regions – same for antibodies of a given H or L chain type
How can V region exons create different antibody specificities
RECOMBINE and MUTATE
during B cell differentiation
What are the different classes of immunoglobulin
IgG y - main class in serum and tissues, important in secondary/memory responses crosses the placenta
IgM u - Important in primary response
IgA a - In serum and secretions protects muscosal surfaces
IgD d - Unknown
IgE e - Present at very low levels, protective against parasites, involved in allergy
What are the 2 types of light chain
Kappa and lambda. Not class restrictive. Can have IgGk or IgG lambda
How many antigens can bind to IgA and IgM
IgA is secreted as a dimer so can bind to 4 antigens at once
IgM is a pentamer in serum – Can bind to 10 antigens at once
When is IgM used (primary or secondary)
IgM is more used in primary response as it can bind 5 different antigens so more likely to bind to pathogens whereas IgG is used in secondary response as it is highly specific
What is serum
blood which has been allowed to clot. Clear fluid
What antibodies are used in secondary response
IgG (and other classes)
How do the immunoglobulins differ
Five classes of immunoglobulins differ in the amino acid sequence of their heavy chains
What are antibodies made of
made up of two longer (heavy) chains and two smaller (light)
chains, each made up of compact, globular domains.
How do antibodies protect against infection
Specific binding proteins (FAB) Neutralise toxins (IgG, IgA)
Immobilise – motile microbes (IgM)
Prevent binding to and infection of host cells
Form complexes
Effector functions (Fc)
Effect removal and destruction of pathogen
Activate complement - (IgG, IgM)
Bind Fc receptors
Phagocytes - (IgG, IgA)
Mast cells - (IgE)
Natural killer cells - (IgG) `
What does complement do
Complements the activity of antibodies in destroying bacterial cells
Induces inflammation
Beneficial in the early stages of an immune response
How is complement activated
20 serum proteins are activated via an enzyme cascade
Activated specifically by antigen/antibody complexes
(CLASSICAL pathway) or non-specifically by e.g. certain
bacteria (MB-LECTIN or ALTERNATIVE pathway).
What are the main components of the classical complement pathway
C1-9
C3 is the most abundant
What is the classical complement pathway
Classical requires 1xantigen and 2xantibodies
Complement 1,2,4 binds to Fc region
2 of the heads need to be bound to activate complement
Why IgM is more potent activator of complement as it’s a pentamer
Activation of C1, C4 and C2 leads to the generation of a C3 convertase
C3b joins the C3 convertase to make a C5 convertase
What are the main biological activities of complement
Activation - C5a, chemoattractant, anaphylatoxins, bind to mast cells which become activated and release histamine ,released in response to anaphylatoxins
Opsonization - C3b, increased binding and phagocytosis - “makes tasty”, Coats bacteria
Cell lysis - membrane attack complex - C5 - 9 –> hollow cylinders which form pores in bacterial membranes
What type of bacteria are not susceptible to membrane attack complex
Gram-positive
What types of antibodies can act as opsonins
IgG and IgA
How do antibodies enhance the recognition of microbes
binding to Fc receptors on the phagocyte surface.
How do phagocytes kill bacteria
Phagocytes create pseudopods to encapsulate bacteria –> Pseudopods fuse → phagosome → lyzosomes fuse with phagosome → phagolysosome –> bacteria killed
How do Fc receptors on NK cells cause apoptosis
Secrete perforin –> like complement membrane attack complex
NK uses perforin channel to secrete enzymes into target
Activates apoptotic pathway so target cell commits suicide
Mediated by IgG
What do mast cells do
Mediate allergy and defence against large parasites – bind with very high affinity for Fc regions of IgE
Where are mast cells found
Under mucosal layer
How can antibodies be used in medicine
Producing antisera
What do polyclonal B cells respond to
Antigen
May lack fine specificity
Difficult to standardise
What is the epitope
The shape of antigen
How are monoclonal antibodies made
B cells from animal immunised with Antigen A + tumour cell line fused together.
Cell now divides indefinitely and makes antibody A
What are humansied antibodies
antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans.
What are the 2 main subpopulations of T lymphocytes
T helper cells - CD4+ve
T cytotoxic cell - CD8+ve - 33% of T cells
What do Th cells do
Help B cells make antibody
Activate macrophages and natural killer cells
Help development of cytotoxic T cells
Cytokines
What do T cytotoxic cells do
Recognise and kill infected host cells
What is the TCR
The T cell receptor is very similar to the Fab arm of an antibody
Important in recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules.
How do T cells recognise antigen
B cells recognise soluble free native antigens
T cells recognise cell associated processed antigen
Where is the MHC found
Chromosome 6
What is the MHC for
Important in graft rejection
Very polymorphic
Major role in initiating T cell response
Where are MHCs found
Red blood cells don’t have MHC proteins
Organs do
What is MHC 1
Expressed by all nucleated cells – not RBC
Display antigen cytotoxic (CD8+ve) T cells
What is MHC 2
expressed by macrophages, dendritic cells, B cells
display antigen to CD4+ve (helper) T cells
What does cytotoxic T cell recognise
peptide bound to MHCI
How do cytoxic T cells become activated
Cytotoxic T cell recognises peptide bound to MHC1
Virus-infected cell creates viral proteins, broken down in cytosol (proteosomes)
Peptides transported to ER, bind MHC1 at cell surface
Activated cytotoxic T cells kill the infected cell (perforins) by inducing apoptosis
How do T helper cells become activated
Helper T cell recognise peptide bound to MHCII
Macrophage/dendritic cell/B cell internalise and breaks down foreign material
Peptides bind to MHC II in endosomes à cell surface
Activated T helper cells help B cells make antibody, produce cytokines that activate and regulate other leucocytes
What is thymic selection
T cells acquire their receptors and are educated in the thymus
Only T cells that recognise self MHC, but not self-peptides survive
How many T cells go to peripheral lymphoid tissue
5%
What are cytokines
Hormones of the immune response
Small (5-20kD) secreted proteins involved in communication between cells of the immune response
Usually produced and act locally
Bind to specific receptors which are present on target cell
What are the main groups of cytokines
Interleukins (IL-1, IL-38?) – usually made by T cells
Interferons (IFNs) - viral infections e.g. IFNα, IFNβ; cell
activation (IFN γ)
Chemokines - cell movement or chemotaxis e.g. IL-8
Colony stimulating factors (CSFs) – leukocyte production
e.g. GM-CSF
What does the binding of a cytokine do
causes cell activation and changes in gene expression
What is an overview of the adaptive immune response
LONG LONG LONG LONG ANSWER HEHEHEHE
Infection caused by bacteria –> macrophages and dendritic cells recognise the infection –> enter the nearest lymph node from infected site –> macrophages and dendritic carry foreign material through lymphatics into the lymph node –> naïve T cells in lymph (haven’t seen antigens before)–> divide and differentiate via clonal selection –> macrophages and dendritic cells activate T cells which dive into Tk or Th cells –> Th cells can help B cells differentiae into plasma cells and secrete antibody –> b cells stay in lymph node –> T effector cells leave the lymph node and go to where they’re needed in the tissues
Who invented the vacine
Edward Jenner
What are the types of vaccine
Attenuated strains Killed pathogen Subunit e.g. toxoid (derived from toxin) Vaccination Engineered virus, RNA, DNA
When was aids first recognised
1981
When was HIV identified
1983
What is HIV (type of virus)
Retrovirus - has reverse transcrptase - Allows RNA to turn into DNA which enters host cell chromosome
Lentivirus - Slow virus - cause disease long time after infection
What is the lifecycle of HIV
Virus binds to cell receptor
Virus envelope fuses with plasma membrane
Nucleocapsid enters cytoplasm
Viral RNA reverse transcribed into double stranded DNA
Viral DNA transported to nucleus and integrates into host cell genome (provirus)
New viral genomic RNA and mRNA → cytoplasm
Viral mRNA → viral protein
New nucleocapsids forms and virus “buds” from cell, acquiring
lipid envelope
What are the types of retroviral infection
Latent - no virus shedding
Permissive - few particles, host cell doesnt die
Lytic - lots of virus particles –> kills host cell
What cell type is susceptible to HIV
CD4+ve (Th cell, Monocytes, macrophages and dendritic cells)
What happens to number of T cells through each round of replication
Increases with each round of
viral replication
What is needed for HIV infection
CD4 and Co-receptor - CCR5 required for virus fusion with host cell
How does the CNS become involved in HIV
Monocytes may traverse the blood/brain barrier → CNS
involvement
What causes AIDS
Th cell depletion
Direct lysis by virus, syncytium formation
Killed by cytotoxic T cells or other immune mechanisms
Apoptosis
Blood count CD4+veTcells < 200/mm^3
Where are infected Th cells
Lymphoid tissue (PCR discovered)
`What are symptoms associated with AIDS
Susceptible to pathogens that healthy people would fight off
o Opportunistic infections
o Reactivation of latent viruses
o Rare cancers
o CNS involvement, dementia
o Memory T cells lost
o All adaptive immune responses are compromised
Where did HIV-1 originate
Central Africa
Group M –> pandemic form
Related virus affecting subgroup of chimpanzees
Phylogenetic studies suggest cross-species
transmission 1910 – 1930
Where did HIV 2 originate
Origin West Africa
Pre-dates HIV-1.
Likely source - related virus
affecting sooty mangabees
Less virulent and less easily
transmitted
How many people are infected with HIV (2019)
38million
Total >70million with 33 million dead
How is HIV spread
unprotected sexual intercourse (~70%)
• blood/blood products (~28%, mainly i.v. drug use)
• breast-feeding
• mother to foetus
What are the prevention and therapy methods
blood testing
“safe sex”
decrease i.v. drug use/needle sharing
treat HIV+ve pregnant women
This is decreasing HIV by around 1million in last 10 years
Why is there no vaccine for HIV
high mutation rate of virus - 60x more rapid mutations than flu
- “humoral” immunity may not be protective
- need to induce cytotoxic T cells
What are the problems of drug therapy
- high mutation rate of virus
- toxicity
- viral latency
- cost
> 25 licensed drugs block HIV replication
What is combination therapy
- cocktail of drugs directed at different viral targets
What are the future treatments of HIV
Stem cell therapy (bone marrow cells lacking CCR5)
Immunisation of infected patients: “Kick and Kill”
“Passive immunisation” using human monoclonal antibodies or engineered T cells
Gene editing with CRISPR/Cas9?
