Partridge (Immune System) Flashcards
What is immunology?
- study of immune system
What is immune system?
- integrated system of cells and molecules that defend against disease, by reacting against infections
What is the medical importance of immunology?
- vaccination
Examples of malfunctions in immune system?
- immunodeficiency
- allergy
- autoimmune disease
- graft rejection
What are immunological techniques?
- research, diagnostics, therapeutics
How do bacteria carry out immune surveillance?
- restriction enzymes
How do invertebrates carry out immune surveillance?
- negative surveillance, cells marked w/ “self” protein labs, unlabelled non-self cells destroyed by phagocytes
How do vertebrates carry out immune surveillance?
- external barriers (skin)
- negative surveillance by major histocompatibility complexes, v polymorphic
- positive surveillance specific recognition of foreign cells (active immunity)
What is the difference between innate and adaptive immune system?
- innate has broad specificity and adaptive highly specific
- in innate resistance resistance not improved by repeat infection, but is in adaptive
- innate has rapid response (hrs) and adaptive has slower response (days-wks)
What does 2º contact w/ antigen result in?
- enhanced adaptive responses
What are the external barriers to infection?
- keratinised skin –> keratin difficult for bacteria to digest and must be damaged to infect
- secretions –> sebum, sweat, FAs, lactic acid, lysosyme = low pH, dry and salty
- mucous –> cilia in resp tract traps pathogens
- low pH of 2.5 in stomach
What is commensalism?
- 1 organism benefits from another
What are the 3 types of phagocytes?
- neutrophils
- mononuclear phagocytes
- mast cells
What are the characteristics and role of neutrophils?
- main phagocyte in blood
- short-lived
- fast moving
- lysosomes release enzymes (H2O2) etc.
- unusual shaped nucleus
What are the characteristics and role of mononuclear phagocytes?
- monocyte in blood/macrophage in tissue
- long lived (months-yrs)
- help initiate adaptive responses
What are the characteristics and role of mast cells?
- underlying mucosal surfaces in skin
- release inflammatory mediators (eg. histamine)
- important in parasite and allergy response
What are the characteristics of NK cells?
- type of lymphocyte
- kill virally infected cells non-specifically
- important in self/non self recognition and may kill cancer cells
How are pathogens recognised by phagocytes/mast cells? (innate)
- have general pathogen recognition receptors (PRRs)
- that recognise pathogen-assoc molecular pattern (PAMPs)
- eg. Toll-like receptor 4 recognises LPS
How are pathogens recognised by NK cells? (innate)
- kills target unless they recognise self protein (MHCI)
What are the integrated responses to infection/injury?
- inflammation (v beneficial), localised response to infection and damage (dilation of blood vessels, increase in capillary permeability, phagocytes migrate into tissue)
- PAMPS/DAMPS (pathogen/damage assoc mol pattern)
- induces release of inflammatory mediator and prod of cytokines
3 examples of soluble factors
- complement system
- defensins
- interferons
What is the complement system?
- approx 20 proteins in blood
- activated on infection
- bacterial cell lysis
What are defensins?
- positively charged peptides
- made by neutrophils
- disrupt bacterial membranes
What are interferons?
- prod by virally infected cells
- protect uninfected cells
- activate macrophages and NK cells
What are soluble factors also involved in?
- cell to cell communication
What are cytokines?
- ‘hormones of immune response’
- eg. interleukins (act between WBCs)
- prod by cells of innate and adaptive IS
Example of inflammatory mediator?
- histamine
How is temp response (fever) an example of an acute phase response?
- on infection, macrophages may release interleukin 1 (IL-1)
- acts on hypothalamus
- increases temp
- stimulates phagocytosis
- decreases Fe levels in blood
How are antigens recognised by adaptive IS?
- by specific receptors on T and B lymphocytes
Where do B and T lymphocytes mature and then move to?
- B mature in bone marrow
- T mature in thymus
- move to central lymphoid tissue (antigen independent differentiation)
What occurs during maturation of lymphocytes?
- acquire antigen receptors
What is the difference between the receptors of B and T lymphocytes?
- B are antibodies
- T are T cell receptors
What type of differentiation occurs in peripheral lymphoid tissue?
- antigen dependent differentiation
What is the role of B lymphocytes, type of immunity they provide and infections they work against?
- secrete antibodies
- humoral immunity
- for extracellular bacterial and 2º viral infection
What is the role of T lymphocytes, type of immunity they provide and infections they work against?
- kill infected host cells
- make cytokines
- cell mediated immunity
- for viral, intracellular bacterial and intracellular parasitic
What was the role of Jenner in immunology?
- developed vaccination principles
- showed infection w/ cowpox protected against smallpox
- as shared antigens
What does the cell mediated (T cell) immune response involve?
- clonal expansion, differentiation, memory
- T cells can only recognise antigen bound to host cell
What is the clonal selection hypothesis?
- millions of B cells prod
- when 1 w/ correct antibody binds to antigen, triggers clonal selection of this cell
- lymphocytes that recognise “self” deleted early in dev
What are the types of vaccine?
- subunit, eg. toxoid (from toxin)
- attenuated strains
How is lymphoid tissue organised?
- 1ºis where lymphocytes reach maturity
- 2º is where mature lymphocytes stimulated by antigen, clustered around places of entry
What is humoral (antibody) immunity?
- antigen –> B lymphocytes (antibody receptor) –> plasma cells –> soluble antibody
What class do antibodies belong to?
- class of soluble glycoproteins, called immunoglobulins
How does an antibody’s structure reflect its dual role in immune response?
- antigen recognition = Fab regions variable in seq and binds diff antigens specifically
- antigen elimination = Fc region constant seq, binds to component, Fc receptors on phagocytes and NK cells etc.
What is the role of antibodies?
- act as labels for infectious material
- labelled material “eliminated”
What do Fab and Fc mean?
- Fab = fragment antigen binding
- Fc = fragment crystallisable
How do the sizes vary between the light chain, heavy chain and total molecule?
- L = 25kD
- H = 50kD
- L2H2 (immunoglobulin G) = 150kD
What AA is the hinge range rich in, and why?
- Pro
- so flexible
- but susceptible to proteolytic digestion
What are the 5 immunoglobulin classes of H chain and how do they differ?
- IgG (γ)
- IgM (μ)
- IgA (α)
- IgD (δ)
- IgE (ε)
- differ in AA seq of H chains
What are the 2 types of L chain and are they class restricted?
- kappa (κ)
- lambda (λ)
- no, can have IgGκ or IgGλ antibodies
What is the variable region of an antibody?
- binds antigen
- differ between antibodies w/ diff specificities
What is the constant region of an antibody?
- same for all antibodies of given H chain class of L chain type
Are the variable and constant regions of an antibody encoded by the same exon?
- no, encoded by separate exons
How can multiple variable regions in genome give diff antibody specificities?
- regions can recombine and mutate during B cell differentiation
How do H chain classes differ in 2º response?
- can include IgA and IgE
- same amount of IgM
- much more IgG
How do antibodies use specific binding/valency to protect against infection, and what H chain classes do these involve?
- Fab region
- neutralise, eg. toxins (IgG, IgA)
- immobilise mobile MOs (IgM)
- prevent binding to and infection of host cells
- form complexes, cross link antigens on diff pathogens to clump them together, so easier to deal w/
How do antibodies use effector functions to protect against infection, and what H chain classes do these involve?
- Fc region
- activate complement (IgG, IgM)
- bind Fc receptors, phagocytes (IgG), mast cells (IgE), NK cells (IgG)
What does the complement induce?
- inducer of inflammation, can cause pathology
How are serum proteins activated in complement?
- 20 serum proteins activated via enzyme cascade
How is the complement activated?
- specifically by antigen/antibody complexes (classical pathway)
- or non-specifically, by eg. certain bacteria (MB-lectin or alternative pathway)
What are the 3 major biological activities of the complement?
- activation
- opsonisation
- cell lysis
What happens during activation by complement?
- phagocyte recruitment
- induces inflammation
- C5a (or C3a)
- chemoattractants (causes chemotaxis)
- anaphylatoxins (mast cells release lots of inflammatory mediators all over body)
What happens during opsonisation by complement?
- C3b binding and phagocytosis
- C3b binds to bacterium membrane
- phagocytes have receptors, so can be bound w/ high affinity and destroyed more efficiently
What happens during cell lysis by complement?
- need activation of whole cascade
- membrane attack complex: C9 –> polymers –> hollow cylinders which form pores in bacterial membranes
What is involved in the classical pathway? (complement)
- req Ag/Ab2, C1, C2, C4
- 2 IgG molecules attached to bacterial cell surface
- C1 must interact w/ 2 Fc regions
- IgM more potent activator of complement (pentamer)
What is the role of Fc receptors on phagocytes?
- IgG and IgA most important
- some classes of antibodies can act as opsonins
- pseudopods fuse to form phagosome and release contents
- phagolysosome acid, peptides, toxic O derivatives, competitor enzymes
What is the role of Fc receptors on NK cells?
- only IgG has receptors on NK cells
- mediate antibody dependent cell-mediated cytotoxicity (ADCC)
- secrete perforin from granules, allows passage of particles to induce apoptosis
- target undergoes apoptosis, cell contents destroyed and “corpse” taken up by macrophages
What is the role of Fc receptors on mast cells?
- IgE
- mediate allergy and defence against large particles
- allergen binds to specific IgE, causing degranulation, which releases inflammatory mediators, eg. histamine, causing local inflammation
- beneficial in response to particles
What is an epitope?
- antibodies of similar structure
How is antisera production used in research and medicine?
- conventional antisera = polyclonal antisera
- used to give 2º response (IgG in animals)
- remove small amount of blood and allow to clot
- may lack fine specificity and difficult to standardise
How are monoclonal antibodies used in research and medicine?
- single specificity (binds 1 epitope)
- derived from single B lymphocyte
- B cells from animal immunised w/ antigen A and isolated
- B cells fused w/ tumour cell line (divide indefinitely)
- prod hybrid cells, make anti-A antibody
How are antibodies used in research, diagnostics and therapy?
- identifying and labelling molecules in complex mixtures
- serotyping pathogens
- characterising cell surface proteins, identifying cell types
- “humanised” antibodies, used in therapy, magic bullets to kill cancer cells
What are the 2 major sub pops of T cells and what are their roles?
- T helper cells –> help B cells make antibodies, activate macrophages and Nk cells, help dev of cytotoxic T cells
- T cytotoxic cells –> recognise and kill infected host cells
What is the structure of T lymphocyte receptor (TCR) and how does this relate to its function?
- v similar to Fab arm of antibody
- variable regions responsible for antigen recognition
What do B and T cells recognise?
- B recognise “soluble” free native antigens
- T recognise “cell-assoc” processed antigens
- cytotoxic T cells recognise peptide bound to MHCI
What happens during T cell recognition of antigen?
- viral proteins in a virus infected cell broken down in cytosol (proteasomes)
- peptides transported to ER, bind MHCI w/ cell surface
- activated cytotoxic T cells kill infected cell by inducing apoptosis
- helper T cells recognise protein bound to MHCII
- macrophage/dendritic cell/B cell internalises and breaks down foreign material
- peptides bind to MHCII in endosomes on cell surface
- activated T helper cells help B cells make antibody and prod cytokines that activate/reg other leucocytes
What is the problem w/ lymphocytes meeting antigen?
- lymphocyte w/ specific receptor must meet antigen
What is lymph?
- extracellular fluid that accum in tissues and carried by lymphatic vessels back through lymphatic system to thoracic duct and into blood
Where is adaptive immunity activated?
- in draining lymph node
What encodes major histocompatibility proteins?
- major histocompatibility gene complex (MHC)
- chromosome 6
What is the role of major histocompatibility proteins?
- initiating T cell responses
- important in graft rejection
Are major histocompatibility proteins polymorphic, and what does this mean?
- yes, v polymorphic
- most polymorphic proteins in man
- many diff alleles at each gene locus
Where are major histocompatibility proteins expressed?
- MHCI on all nucleated cells, displays antigen to CD8+ve (cytotoxic T cells)
- MHCII on macrophages, dendritic cells and B cells, displays antigen to CD4+ve (helper T cells)
What are cytokines and what is their role?
- small (approx 5-20kD) secreted proteins
- involved in communication between cells of immune response
- can have autocrine or paracrine activity
- usually prod and act locally
- act by binding to specific receptors on target cell surface
What are the main groups on cytokines and their roles?
- interleukins (IL-1 - IL-38?) –> usually made by T cells
- interferons (IFNs) –> viral infections, cell activation
- chemokines –> cell movement or chemotaxis
- colony stimulating factors (CSFs) –> leucocyte prod
What cytokines do diff types of T helper cells prod?
- TH1 cells –> inflammatory intracellular infections, prod IL-2, γ-interferon and TNFβ
- TH2 cells (parasitic) –> prod range of interleukins
- TREGs, suppress other T cells
How does HIV infect cell?
- 2 copies ss RNA enter cyto
- RNA to DNA by reverse transcriptase
- takes part of host cell as it leaves, creating envelope, gp120 = viral receptor
- virus binds to cell receptor
- virus envelope fuses w/ plasma membrane
- nucleocapsid enters cyto
- viral RNA reverse transcribed into ds DNA
- viral DNA transported to nucleus and integrated into host cell genome (provirus)
- new viral genomic RNA and mRNA transported to cyto
- viral mRNA translated to viral protein
- new nucleocapsids form and virus “buds” from cell
- acquires lipid envelope
Which cells and how many are infected by HIV?
- CD4+ve cells susceptible to infection
- no. T cells infected increases w/ each round of viral rep
- monocytes, macrophages and dendritic cells also infected, as low levels CD4+ve
How does latent HIV infection progress?
- T cell stimulation activates HIV provirus transcrip
- T cell lysis
How do dendritic cells and monocytes respond to HIV infection?
- dendritic cells present antigen to T cells in lymphoid tissue
- monocytes may traverse blood/brain barrier, CNS involvement
How can CD4 expression affect HIV infection?
- not sufficient for HIV infection
- but may influence susceptibility to infection/disease progression
- progression slower if young and healthy
- some not susceptible as no chemokines
What are the co-receptors for the HIV virus?
- chemokine receptors
How do symptoms of HIV progress to AIDS?
- ‘flu-like’ symptoms
- (seroconversion occurs)
- asymptomatic
- symptomatic
- AIDS
- death
What is the immune response to HIV?
- high levels of virus in blood initially cleared (mainly by cytotoxic T cells)
- antibodies may not be detected for 3-6 months (seroconversion) –> B may not be helped by T helper cells
- IS mounts vigorous response against virus, CD8+ve cytotoxic T cells esp important
How does HIV avoid immune detection?
- mutates
What does T helper cell depletion lead to immune response against HIV?
- direct lysis by virus
- killed by cytotoxic T cells or other immune mechanisms
- infected cells in lymphoid tissue
What are the symptoms of AIDS?
- opportunistic infections, eg. Candida
- reactivation of latent infections
- rare cancers (caused by viruses)
- CNS involvement, dementia
- all adaptive immune response compromised
What do the symptoms of AIDS show about T helper cells and how?
- that they’re vital in IS
- as memory T cells lost
What are the differences between HIV-1 and HIV-2?
- HIV-2 slower to progress to AIDS
- HIV- 2 predates HIV-1
How is HIV transmitted?
- unprotected sex (approx 70%)
- blood/blood products (mainly IV drug use, approx 28%)
- breast feeding
- mother to foetus
How can HIV/AIDS be prevented through changes in behaviour?
- blood testing
- safe sex
- decrease in IV drug use/needle sharing
- treating HIV +ve pregnant women
What are the problems with preventing HIV/AIDS through vaccination?
- difficult due to high mutation rate
- humoral immunity may not be productive
- need to induce cytotoxic T cells (some people never progress to AIDS due to elite ones)
How can HIV/AIDS be prevented through drug therapy and what are the problems?
- problems = high mutation rate, toxicity, viral latency, cost
- combo therapy = 3+ drugs directed at diff viral targets
- no. infected hasn’t decreased much
What future treatments could be available for AIDS?
- gene editing
- immunisation of infected patients, “kick and kill”
- possible immunisation using human monoclonal antibodies
