Immunology Flashcards
list some of the consequences of immune system malfunction
immunodeficiency
allergy
autoimmune disease
graft rejection
what are the cells of the innate immune system?
phagocytes
NK cells
antigen presenting cells (dendritic cells, macrophages)
what are the cells of the adaptive immune system?
B lymphocytes
T lymphocytes
what are the features of the innate immune system?
broad specificity, resistance not improved by repeat infection. rapid response (hrs).
what are the features of the adaptive immune system?
SPECIFICITY + MEMORY.
highly specific. resistance improved by repeat infection.
slower response (days-weeks)
describe the main differences between the innate and adaptive immune system
innate = broad specificity, adaptive is highly specific. adaptive resistance is improved by repeat infection. adaptive takes days-weeks, innate is rapid.
what are the external barriers to infection?
keratinized skin; secretions; mucous; low pH; commensals
what soluble factors are involved in innate immunity?
lysosome,
complement,
interferons etc
what soluble factors are involved in adaptive immunity?
antibody
what is the purpose of pattern-recognition receptors?
to discriminate self from non-self by recognising unchanging patterns of microbes
how do pattern recognition receptors work?
recognise conserved polysaccharide molecular patterns on microbes - patterns that are constant across a group of bacteria for eg.
what do pattern recognition receptors activate?
innate immune system.
damage recognition receptors on dendritic cells.
what are cell-associated PRRs?
receptors present on cell membrane/in cytosol. recognise broad range of molecular patterns.
name some membrane-bound PRRs
TLRs are main family.
mannose receptor on macrophages - fungi
dectin-1 - phagocytes, beta glycans in fungal walls.
scavenger receptors on macrophages.
what does TLR4 bind to?
lipopolysaccharide in bacterial walls.
pneumolysin, viral proteins.
what do TLRs do, once activated?
induce signal transduction and cellular events, leading to induction of pro-inflammatory cytokines.
what causes a hyperacute rejection of a transplanted organ?
when there are preformed cytotoxic antibodies against the MHC class I antigens in graft (e.g. previous pregnancy that generated antibodies, or blood-group incompatibility)
describe acute rejection of a transplant
occurs weeks-months after. T lymphocyte mediated reaction against donor HLA, or can be antibody mediated.
febrile, tenderness, declining renal function.
describe chronic rejection (chronic allograft injury)
after 6m of transplant - progressive decline of renal function. proteinuria. hypertension.
immune and non-immune mechanisms.
how can we prevent transplant rejection?
tissue typing.
cross match.
immunosuppressive agents.
paired exchanges.
why are immunosuppressants given to transplant patients?
preventing rejection. must be taken indefinitely (non-compliance).
what gene codes for human leucocyte antigens (HLAs)?
MHC (major histocompatibility complex) on chromosome 6
describe the process of hyperacute rejection
preformed cytotoxic antibody reacts with MHC class I antigens. activation of complement. influx of PMN leukocytes. platelet aggregation. obstruction of blood vessels - ischaemia. microvasculature plugged with leukocytes/platelets - infarction.
how is acute rejection treated?
IV methylprednisolone, anti-CD3 antibody, or increase other immunosuppressive drugs
what are the two phases of transplant rejection?
afferent phase - initiation or sensitising component.
efferent phase - effector component.
what occurs in the afferent phase of transplant rejection?
donor MHC molecules in the graft are recognised by CD4+ T cells - allorecognition
what occurs in the efferent phase of graft rejection?
CD4+ T cells recruit macrophages/CD8 T cells/NK cells/B lymphocytes to graft - tissue damage.
describe the structure of a typical antibody molecule
two Fab regions attached to an Fc region by a hinge.
Fab = variable sequence
Fc = constant.
2 light chains and 2 heavy chains
what do the Fab regions of antibodies bind?
antigens - specific
what does the Fc region of antibodies bind to?
complement, Fc receptors on phagocytes, NK cells etc
list the five classes of immunoglobulin
IgG IgM IgA IgD IgE
what is the function of IgG immunoglobulins?
important in secondary/memory responses.
main effector of humoral immunity. binds complement. can cross placenta.
what is the function of IgM?
low affinity and specificty. important in primary response - first line defence. fixes complement well.
what is the function of IgA?
protects mucosal surfaces.
is found in serum and secretions.
what is the function of IgE?
present a very low levels.
involved in allergy and response to parasitic infection.
describe how the specific binding properties of antibodies (Fab) help protect against infection
neutralize toxins
immobilise motile microbes
prevent binding to host cells.
form complexes - (each Ig can bind 2 pathogens).
how do antibodies enhance innate mechanisms to protect against infection (Fc)?
Activate complement
bind Fc receptors on:
phagocytes - enhanced phagocytosis.
mast cells - inflammatory mediator release.
NK cells - enhance killing of infected cells.
give some uses of antibodies in research, diagnostics and therapy
- identify and label molecules in complex mixtures.
- serotyping of pathogens.
- identifying cell types.
- “humanized” antibodies are used in therapy
where do T cells mature?
the thymus
what are the major T cell subtypes?
T helper cells (CD4+).
cytotoxic T cells (CD8+)
T regulatory cells (CD4+)
what are the roles of T helper cells?
help B cells make antibody.
activate macrophages and NK cells.
help development of cytotoxic T cells.
what is the role of cytotoxic T cells?
recognise and kill infected host cells
what is the role of T regulatory cells?
suppress immune responses
describe the structure of the T cell receptor
a heterodimer of either alpha/beta or gamma/delta chains.
similar to Fab arm of antibody.
each one is specific to an antigen.
how do T cell receptors recognise antigens?
as processed, cell-associated antigen. recognise antigen peptides in context of MHC class I and II antigens.
which MHC classes do T helper and cytotoxic T cells recognise respectively?
T helper cells = MHC class II, use CD4 to enhance binding/signalling. cytotoxic T cells = MHC class I, use CD8.
which cells are MHC I and MHC II expressed by?
MHC I = all nucleated cells.
MHC II = macrophages, dendritic cells, B cells
which T cells do MHC I and MHC II display antigens to, respectively?
MHC I displays them to CD8+ (cytotoxic) T cells.
MHC II = CD4+ (helper) T cells.
briefly describe the process of antigen presentation to cytotoxic T cells
- virus infects cell
- viral proteins are broken down in cytosol.
- peptides transported to ER, bind MHC I
- transported to cell surface
- activated cytotoxic T cells kill infected cell by inducing apoptosis
briefly describe the process of antigen presentation to T helper cells
- macrophage/dendritic cell/B cell internalises and breaks down foreign material
- peptides bind to MHC II in endosomes
- transported to cell surface
- activated T helper cells help B cells make antibody, and produce cytokines that activate/regulate other leukocytes
what are cytokines?
small secreted proteins involved in communication between cells of the immune response.
produced/act locally.
how do cytokines act?
by binding to specific receptors on surface of target cells
list some of the main groups of cytokines, and their general action
interleukins - made by T cells
interferons - respond to viral infections
chemokines - chemotaxis, e.g. IL-8
colony stimulating factors (CSFs) - leukocyte production
what do TH1 cells do?
activate macrophages, cause inflammation.
promote production of cytotoxic T cells (cell-mediated immunity)
important in intracellular infections.
induce B cells to make IgG antibodies.
what do TH2 cells do?
activate eosinophils and mast cells.
important in helminth infections and allergy.
induce B cells to make IgE - promotes release of inflammatory mediators e.g. histamine from mast cells.
describe the properties and roles of T memory cells
survive after infection, in greater numbers than naive cells. respond to antigens rapidly.
what two things are needed for T cell activation?
antigen presentation in the form of a peptide presented on MHC.
a costimulatory signal.
what is the “epitope” of an antigen?
the portion of the antigen that is bound by antibody
list the types of bonds that may form between antibody and antigen?
charge interactions.
hydrophobicity.
van der waals.
hydrogen bonds.
what are the main effector functions of antibodies?
opsonisation.
complement activation.
ADCC (antibody dependent cell mediated cytotoxicity).
allergic responses and IgE.
what is opsonisation?
coating of pathogens by antibody, leading to increased phagocytosis.
describe the process of B cell development
arise from lymphoid progenitor cells in fetal spleen/liver.
produced in bone marrow in adults.
what is active immunisation?
challenge subjects immune system to induce immunity. production of high affinity antibodies against immunogen. induction of immunological memory.
what is passive immunisation?
transfer of preformed antibodies to the circulation.
can be natural or artificial.
what is natural passive immunity? what does it protect against?
transfer of maternal antibodies across placenta to foetus.
diptheria/tetanus/strep/rubella/mumps/poliovirus
what are the indications for use of artificial passive immunity?
individuals with agammaglobulinaemias (B cell defects) - given normal human IgG.
exposure to disease at risk of complication.
when there’s no time for active immunisation to give protection - pathogen with short incubation period.
acute danger of infection.
how do anti-toxins work?
give passive immunity, as for some pathogens the main hazard is not the primary infection, but the toxins released by the pathogen.
e.g. tetanus, botulinum, diptheria.
what are anti-venins?
substances that provide passive immunity to venoms
e.g. snake bite, insects, jellyfish
what are some disadvantages of passive immunisation?
doesn’t active immunological memory - no long term protection.
may react to anti-sera used.
define inoculation
vaccination involving introduction of a viable microorganism into the subject
what are the aims of a “perfect” vaccine?
- achieve long term protection from a small number of immunisations (compliance)
- stimulate B and T cells
- induce memory B and T cells
- stimulate protective high affinity IgG production
describe the primary immune response
relies on innate immune system.
IgM predominates.
low affinity.
describe the secondary immune reponse
rapid and large reaction.
high affinity IgG.
T cell help.
doesn’t rely on innate immune system.
name some different types of vaccine
whole organism - live attenuated pathogen; killed, inactivated pathogen.
subunit - toxoids; antigenic extracts; recombinant proteins
peptides
DNA vaccines
engineered virus
what are some advantages of live attenuated vaccines?
sets up a transient infection. full immune response activated. prolonged contact with immune system. stimulation of B and T cell memory.
often single immunization.
what are some disadvantages of live attenuated vaccines?
can cause infection in immunocompromised patients.
complications.
can occasional revert to a virulent form, can cause a serious outbreak in poor sanitation.
refrigeration and transport are issues.
what are some advantages of whole inactivated pathogen vaccines?
no risk of infection.
storage less critical than a live vaccine.
good immune response possible.
what are some disadvantages of whole inactivated pathogen vaccines?
tend to just activate humoral response - lack of T cell response.
immune response can be quite weak - booster vaccinations needed, compliance can be a problem.
what are some advantages of subunit vaccines?
safer than live/inactivated pathogens.
no risk of infection.
easier to store/preserve
name some types of subunit vaccine?
toxoids.
capsular polysaccharides
purified proteins
recombinant proteins
what are some disadvantages of subunit vaccines?
immune response less powerful than to live attenuated vaccines.
repeat vaccinations/adjuvants needed.
give examples of adjuvants that could be added to a vaccine to stimulate the immune system?
whole killed organisms.
toxoids.
proteins
chemicals - aluminium salts, paraffin oil.
how do DNA vaccines work?
transiently express genes from pathogens in host cells. generates immune response - T and B cell memory.
what are some advantages/disadvantages of DNA vaccines?
easy to store/transport
simple delivery (DNA gun).
BUT - no transient infection, likely to produce mild response and require boosters.
how do recombinant vector vaccines work?
imitate effects of transient infection with pathogen, but using a non-pathogenic organism.
genes for pathogen antigens introduced into non-pathogenic microorganism and introduced to host.
what are some advantages/disadvantages of recombinant vector vaccines?
can create ideal stimulus to immune system - memory.
flexible and safe.
BUT - need refrigeration. can cause illness in immmunocompromised.
what is cancer immunosurveillance?
idea that immune system can recognise and destroy newly transforming/transformed cells
what is cancer immmunoediting?
immune system can protect you from cancer by killing tumour cells. but they’re very genetically unstable - so immune responses to tumours can cause changes in tumour cells, allowing tumour escape and recurrence
what are tumour specific antigens?
found only on tumours. result of point mutations/gene rearrangement. derive from viral antigens.
what are tumour associated antigens?
found on normal and tumour cells - overexpressed on cancer cells.
what are two methods by which tumours can “escape” the immune system?
- immune responses change tumours so tumours are no longer “seen” by immune system - tumour escape
- tumours change immune response by promoting immune suppressor cells - immune evasion
what type of immunoglobulin is typically involved in allergy?
IgE
what are the cells involved in allergy?
mast cells, eosinophils, lymphocytes, dendritic cells.
effectors of allergic response - smooth muscle, fibroblasts, epithelia
what cells express low-affinity IgE receptors?
B cells, T cells, monocytes, eosinophils, platelets, neutrophils
what cells express high-affinity IgE receptors?
MAST CELLS
basophils, eosinophils
describe the development of mast cells
derived from specific cell lineage. require c-kit protein to develop. immature mast cells circulate, mature in tissues
what activates mast cells?
indirect activators act via IgE - allergens, some bacterial/viral antigens.
phagocytosis.
direct activators - cold. aspirin, NO2, proteases, C3a, C5a
describe anaphylaxis
occurs within mins-hrs.
mast cell or basophil activation - IgE or direct activation.
histamine and tryptase are elevated.
vasodilation, vascular permeability, low BP, bronchoconstriction, rash, swelling, GI pain, vomiting etc.
what is a type I hypersensitivity reaction?
immediate hypersensitivity (‘allergy’) - due to activation of IgE antibody on mast cells or basophils.
what is a type II hypersensitivity reaction?
antibody to cell-bound antigen - triggered by antibodies reacting with antigenic determinants on cell membrane of target tissue. often involves drugs/their metabolites binding to RBC.
what is a type III hypersensitivity reaction?
immune complex hypersensitivity - results from deposition/formation of immune complexes in tissues
what is a type IV hypersensitivity reaction?
delayed-type hypersensitivity. mediated by T lymphocytes reacting with antigen - sensitisation. secondary challenge results in delayed-type reaction - local inflammation taking 2-3d to develop.
what causes primary immunodeficiency?
an intrinsic defect in the immune system
what causes secondary immunodeficiency?
an underlying condition - much more common than primary.
occurs when synthesis of key immune components is suppressed or their loss accelerated.
how would a patient with an antibody deficiency present?
recurrent bacterial infections of resp tract
how would a patient with defects in cellular immunity present?
invasive and disseminated viral, fungal and opportunistic bacterial infections involving any organ
what is panhypogammaglobulinaemia?
a silly word.
also, defects in antibody synthesis that involves different classes of Igs
what is selective antibody deficiency?
defects in antibody synthesis involving only one class/subclass of Ig
what are the presentations of primary antibody deficiencies?
recurrent infections of upper and lower resp tract. congenital forms present between 4m-2yrs due to passive protection provided by maternal IgG. skin sepsis gut infection meningitis arthritis splenomegaly purpura
what are the most common infecting organisms in antibody deficiency?
pyogenic bacteria:
staph
H influenzae
strep pneumoniae
why aren’t patients with primary antibody deficiency unduly susceptible to viral/fungal infections?
cell mediated (T cell) immunity is preserved
describe the features of X-linked agammaglobulinaemia (XLA) - bruton’s disease
boys present w/ recurrent pyogenic infection between 4m-2yo.
infections similar to other antibody deficiency + enteroviruses.
no mature B cells circulating.
very low serum Ig.
gene found on long arm of x chromosome, produces Bruton’s tyrosin kinase (Btk) - cytoplasmic enzyme - which is needed for B cell development. mutations = XLA.
describe the features of hyper-IgM syndrome
normal/high serum IgM in absence of other types.
X linked mutation in CD4+ T cell.
bacterial infections and Pneumocystis jirovecii neumonia.
replacement Ig therapy needed, bone marrow transplant is gold standard.
describe the features of selective IgA deficiency
normal IgG and IgM, no IgA.
IgA deficiency = asymptomatic. selective IgA deficiency predisposes to other disorders. prompt Abx therapy for infection, immunisation against respiratory pathogens.
describe the features of common variable immunodeficiency (CVID)
group of disorders presenting as antibody deficiency in late childhood/adults. recurrent bacterial infections, higher risk of autoimmune disease (purpura, pernicious anaemia etc). granulomas can cause end-organ damage.
replacement Ig therapy
name some primary antibody deficiencies
panhypogammalgobulinaemia. transient hypogammaglobulinaemia of infancy. XLA - bruton's disease. hyper-IgM syndrome. selective IgA deficiency. common variable immunodeficiency.
describe the features of severe combined immunodeficiency (SCID)
seen in infants - major failure of T cell (and variable B/NK cell) function.
genetic variables.
first few weeks/months - failure to thrive, chronic diarrhoea, respiratory infections. lymphopenia.
avoid live vaccines and blood transfusions.
SCID patients die before reach 2yo without haemopoietic stem cell transplants.
describe the features of primary C1, C4 or C2 deficiency
malar rash (facial rash), arthralgia, glomerulonephritis, fever or chronic vasculitis - immune complex deposition in tissues
describe the features of C3 deficiency
occurs as primary, or secondary to factor H or factor I deficiency.
increased susceptibility to life-threatening bacterial infections (pneumonia, septicaemia, meningitis)
describe the features of C5, C6, C7 or C8 deficiencies
recurrent bacterial infection.
what are some causes of secondary immunodeficiency?
nephrotic syndrome/protein-losing eteropathy - severe protein loss causing hypogammaglobulinaemia (seen in Crohn’s, ulcerative colitis).
malnutrition (protein, energy) - impaired synthesis of immune system components.
immunosuppressive drugs.
splenectomy.
some microorganisms - CMV, measles, rubella, viral hep, HIV.
what is autoimmunity?
immune response against a self-antigen.
what is autoimmune disease?
tissue damage resulting from an autoimmune response
what are the criteria to show a disease is caused by autoimmunity?
- demonstrate immunological reactivity to a self-antigen
- characterise/isolate the autoantigen
- induce immunological reaction against same antigen by immunisation of experimental animals
- show pathological changes in the organs/tissues of an actively sensitised animal
how does immunological tolerance ensure not everyone has autoimmune disease?
there will always be T cell receptors and Ig molecules produced that react to self-antigens - the T/B cells bearing these self-reactive molecules are eliminated/downregulated to make the immune system tolerant to self-antigens.
induction of specific tolerance occurs in or out of thymus (thymic tolerance/peripheral tolerance).
there must be a breakdown of tolerance for autoimmune disease to occur.
How does thymic tolerance work?
T cell development occurs in thymus - those bearing self-reactive molecules are negatively selected for. this is only partially successful.
how do regulation and suppression work in the context of peripheral tolerance?
self-reactive T cells may be actively suppressed by regulatory T cells recognising the same antigen
how does B cell tolerance (a peripheral tolerance) work?
production of self-reactive antibodies is limited by lack of T cell help for self-antigens
how might peripheral tolerance be overcome?
inappropriate access of self-antigens to APCs.
inappropriate/increased expression of co-stimulatory molecules.
alterations in way the self-molecules are presented to the immune system.
what makes peripheral tolerance more likely to be overcome, leading to autoimmune disease?
inflammation and/or tissue damage
how does “molecular mimicry” lead to a breakdown of tolerance?
structural similarity between self-proteins and microbial antigens, triggering an autoimmune response
what are some environmental triggers of autoimmunity?
hormones
infection
drugs
UV radiation
what are the mechanisms of tissue damage in autoimmune disease?
activation of macrophages/cytotoxic T cells.
or,
autoantibodies can also cause disease by binding to functional sites of self-antigens (e.g. hormone receptors, neurotransmitter receptors) - causing function abnormalities without damage/inflammation.
how are autoimmune diseases treated?
replacement of function of organ damaged.
suppression of autoimmune response - immunosuppression before irreversible tissue damage is vital (early detection is a challenge)
what is the complement system?
complex series of interacting plasma proteins acting as an enzymatic cascade - major effector system for antibody mediated immune reactions
what are the 3 pathways complement can be activated by?
- classical pathway - by antibody
- alternative pathway - by bacterial cell walls
- lectin pathway - by mannose-binding lectin
what are the effects of complement activation?
increased vascular permeability.
chemoattraction of leukocytes.
enhanced phagocytosis.
cell lysis.
what letter is the major fragment of a complement component, and describe the functions of its active sites.
“b”.
2 active sites:
triggering complex - binds to cell membranes.
other is for enzymatic cleavage of the next complement component.
how is complement activation controlled?
spontaneous decay of any exposed attachment sites. inactivation by specific inhibitors.
what is the major purpose of the complement pathway?
remove/destroy antigen - by direct lysis or by opsonisation
what are the two sequential phases of complement activation?
- activation of C3 component
2. activation of the ‘attack’ or lytic pathway
what is the critical step of complement activation?
cleavage of C3 by complement-derived enzymes (C3 convertases).
C3b mediates vital activities, especially opsonisation.
C3 cleavage is achieved via 3 pathways, all generate C3 convertases but in response to different stimuli.
what activates the classical pathway of complement activation?
when binding of IgM/IgG to antigen causes conformational change in Fc of antibody, revealing C1 binding site
which types of Ig activate the classical pathway?
IgM and IgG
what occurs once C1 is activated in the classical pathway? what regulates this?
enzyme activity generated that splits C4 and C2 into a and b fragments.
regulated by C1 esterase inhibitor.
what complex is the classical pathway C3 convertase?
C4b2b
what is the action of C4b2b?
cleaves C3, with C3a being anaphylatoxic and chemotactic, and C3b binding to the initiating complex - C4b2b3b complex is a C5 convertase, initiating the final lytic pathway
what initiates the final lytic pathway following the classical pathway?
C4b2b3b - C5 convertase
what are the most important activators of the alternative pathway?
bacterial cell walls and endotoxin
what is responsible for innate defence against invading organisms?
the alternative pathway of the complement system
what causes initial cleavage of C3 in the alternative pathway?
occurs spontaneously, generating low levels of C3b
once formed, what does C3b do in the alternative pathway?
uses factors D and B to produce active enzyme C3bBb, which is stabilised by properdin
what is the action of C3bBb in alternative pathway? what stabilises it?
breaks down more C3, providing more C3b.
properdin.
what regulates the breakdown of C3 in the alternative pathway?
factor H and I
H competes with factor B for binding to C3b, then I cleaves and inactivates displaced C3b
what initiates the lectin pathway?
mannose-binding lectin - circulating protein, binds to carbohydrate of surface of some microorganisms
what are the two ways in which C5 convertase is produced?
in classical = C3b, C4b and C2b
in alternative = C3b, Bb and properdin
describe the final lytic pathway of complement?
once C5 convertase is produced, C5 is cleaved into C5a and C5b.
successive addition of C6/C7/C8/C9 forms the MEMBRANE ATTACK COMPLEX.
- lysis of cell via pore formation.
how does complement-dependent phagocytosis work?
microorganisms are coated with C3b - can then be bound by possessing complement receptors (CR1) - present on phagocytic cells
what pro-inflammatory mediators does complement activation release? what are their effects?
C5a, C4a and C3a.
act as anaphylatoxins.
increased vascular permeability, release vasoactive amines, induce smooth muscle spasm.
what is the action of C5a?
acts as anaphylatoxin.
also, a potent chemoattractant, and it stimulates neutrophils and macrophages to synthesise cytokines, undergo oxidative metabolism and release degradative enzymes.
