Immunodefiency Flashcards
What factors can cause immunodeficiency (adaptive and innate)
Innate - NP, PRR, complement, NK, splenectomy
Adaptive - antibody deficiency, b/t cell defects
NP defects
Adhesion problems
Production problems
Killing problem (respiratory burst enzymes)
Df. Of neutropenia
< 0.5 x 10^9 /L
Tx for neutropenia
G-CSF to stimulate NP production (rare)
Treat underlying septicaemia by giving antifungals or antibiotics (TAZocin)
Cause of Neutropenia
Myelodepression due to chemo (drugs), leukaemia
NP enzyme defects
Chronic granulomas disease
Classical sign of NP enzyme defect
Recurrent fungal and Staph infection
No respiratory burst formation
Granulomas due to activation of MPs (IFNgamma response due to NETOsis activation)
Susceptible to TB
NP adhesion defect (e.g. LFA1)
No pus (pus normally produced due to NP apoptosis) High serum NP because they can't get into the cell
Types of complement defects
C3 def.
Classical def. (C1qrsC4C2) defect
C5-C9 def.
What does C3 def affect in the complement pathway and bacteria killing?
Defect in pathogen opsonisation and further activation of the classical and alternative pathways (MBL not affected)
Seen in pyogenic infections
Classical defect will affect what part of the complement pathway
Defective clearance of apoptotic cells
Immunogenic compounds remain (antibody:antigen complex clearance)
Immune complex disease
SLE
Cannot activate c3 convertase causing downstream effect
C5-C9 deficiency cAuses what defect in the complement pathway
MAC complex formation defect and cannot result in cell lysis
Characterised by neisseria and gonorrhoea infections
NK deficiency makes patient susceptible to what types of infections
HSV (zoster,EBV, CMV)
NK cells normally target virally infected cells and cancer cell via MHCI presentation, which is commonly downregulated by virus
How does splenectomy impair immunity
Spleen is a secondary lymphoid organ that is essential in adaptive immune response
Many encapsulated bacteria can evade innate response but are eventually killed via adaptive immunity due to IgM/G opisonisation
If remove - more likely to have septicaemia caused by malaria and meningococci
T cell defect can cause
Lymphopenia
Lymphopenia can be caused by
Defect T/B cell production
How does T cell defect causes defective antibody response?
T cell can stimulate B cell antibody production via TD Th2) It can also help class switch of B cells in the GC (Tfh)
Genetic B cell defect is not seen until
Mothers passive immunity (antibody received through placenta and milk) IgG, wanes off after 6 months time
CD40L defect of B cells will have high IgG/A and low IgM
True or false
False CD40L defect result in difficult of B cell class switch therefore there will be high IgM in serum with low IgA/G
BTK defect results in
No B. Cells in the peripheral blood due to delayed development
What does antibody normally do in the sense of combating infections
Binds to toxins and neutralise them (GC dependent)
Binds to C3b which is present on the pathogen to mark for opsonisation
Hypersensitivity type I is mediated or characterised by
Presence of IgE
What is hypersensitivity
Body reacting to harmless objects due to loss of tolerance. Exaggerated inappropriate immune response which can be detrimental to host
Process of sensitisation
First exposure - (no allergic symptoms)
T dependent B cell activation to produce Ab against the object but no cross link (classswitch) had occur yet. However patient is sensitised due to production of Ab
Second exposure
Cross linking of IgE Ab onto FceRI on mast cell - facilitate degranulation when antigen bind and hence symptom shown
Symptoms of anaphylaxis
Tachycardia
Hypovolaemia
Bronchoconstriction
Systemic vasodilatation and oedema
Immediate Tx for anaphylaxis
Adrenaline (epipen)
Decrease vascular permeability by increasing vasoconstriction
Does all IgE+ results indicate allergy and why
No, you can have IgE but no symptoms and hence patient is sensitised but not allergic
Histamine irritates nerve ending is the body’s reAction to do what
Eliminate pathogen
Late phase release of inflammatory mediators
Leukotrienes, prostaglandins, 5-HT
Process of class switch recombination
B cell migrate to GC from LN
B cells receive signals from Th cells and cytokines in response to the antigen binding VDJ rearrangement on heavy chain
Type II hypersensitivity is classified as what type of disease and characterised by presence of what Ig
Cytotoxic autoimmune IgG
Autoimmune disease
E.g autoimmune haemolytic anaemia
What T cell subtype is responsible for allergy
Absence of germs - Th2
Killing of parasite is mediated by what cell and how
Eosinophils
Parasites are recog. By eosinophils and binds to IgE via FceRI - eosinophils will release toxic granules to kill parasites (ROS, MBP, ribonuclease,peroxidase)
Route of entry for surface bacteria
Anthropod vectors - direct access to blood steam
Wounds/punctures/trauma - exposure to environment allows access
Active infection/invasion
Arthropod vectors invasion example
Lyme disease (tick)
Typhus (louse)
Plague (flea)
Staph aureus normally is the cause of septic complications after major surgery, why
Surgery increase wounds and puncture therefore increase chances of exporesure to pathogen. Most dangerous Staphylococcus aureus is known for being drug resistant (MRS
Local spread of disease can be via
Bacteria secreting degrading enzymes
Cellulitis and necrotising factor is a feature of what type of infection spread
Local spread
Difference between necrotising fasciitis and cellulitis
Cellulitis spreads within surface tissue whilst necrotising fasciitis spreads into deeper subcutaneous tissues
How does TB spread and avoid immune activation
Trojan horse - exploit alveolar MP to travel in bloodstream to avoid immune detection and disseminate in blood
Can we cure TB
No but immune system will suppress
- formation of granuloma
- MP surrounds TB
DIC (disseminated intravascar coagulation) is the phenomenon of
Systemic Micro-thrombosis accompanied with severe bleeding which results in single or multiple organ failure
HSV1 and HSV2 latency area and which one deactivates more frequently
HSV1- in the DRG of trigeminal nerve
HSV2- sacral sensory nerves
HSV2 > HSV1 reactivatig frequency
What is herpes neonatrum
When babies contract heroes due to presence of virus in the vaginal tract
Local manifestation disseminated illness
How does bacteria control transcription
Alter sigma factor - change polymerase binding site
Regulatory proteins - directly block RNAP to regulon (groups of similar genes)
What is the sigma factor
Part of RNAP that binds to the promotor region of the gene that is upstream (determines what genes to transcribe and also known as a scanner
Bacterial genome
Circular densely packed genome
Can have plasmid
Core and accessory genome
Difference between core and accessory genome
Core genome is more conserved and more important in function and survival (house keeping
Accessory genome depends on strains and can show other properties such as antibiotic resistance
Why do we need to control gene expression
Good housekeeping
Response to environment
Duplication of Effort (many metabolic pathway are redundant
Coordinate gene expression of related genes
Ways of Changing gene expression in bacteria
1) structural change to DNA (mutation in promoters, programmed mutations, epigenetics change)
2) change accessibility of DNA by RNAP (change sigma factor or regulatory protein availability
How is Treg generated
TTreg via medullary selection
PTreg when T cells in PNS respond to low levels of costimulation in a immunosuppressive rich environment (TGFb, IL10)
Or just switch on foxp3 to become regulators themselves
Genome loading ways in envelopes and naked viruses
Enveloped - psi signal that is encoded in the newly made viral genome makes virus capsid pick up the newly made sequence
Naked - accumulation of genome made drives packaging into capsule
Does genome loading require energy
No, spontaneous
Pathogenesis of virus is determined by
Viral release (Not host viral interaction).
Where does viral envelope come from
From host cell as they bud out of the cell (pick up each type of envelope)
Group 7 virus is
DsDNA virus with RNA intermediate that uses RdDP
When does the reverse transcription occur for group 6/7 viruses during the vital life cycle
Group 6 - RT during entry
Group 7 - RT during exit
Most group 3/5 viruses encode for a RdDP, why
Humans uses DdDP system hence they often code for their own machinery
Human translational system is ____-dependent
Cap-dependent
4 steps of viral assembly
Attachment
Replication
Assembly
Release
Receptor entrance ways (4 dif ways
1) one virus target only one receptor
2) multiple viruses can target one receptor (e.g. ICAM-1 is targeted by 91 serotype of rhinovirus
3) anyreceptor in the body will allow entry (HSV, Ebola- often cause multiple organ infection
4) every receptor must be bound to before entry - ensure specificity and chronic infection - HCV
VECHS methods
Total host cell shut down
Subtle control of host cell machinery
Mechanism of VECHS
1) Hijack CAP-dependent translation system
2) attack polyadenylation signals
3) cap stealing
How do viruses hijack the cap system (or inactivate it)
1) cleave elF-4G via viral protease 2A which prevents eIF-4E activation (cap)
2) dephosphorylation of eIF-4E - can’t bind to eIF-4G
3) dephosphorylation eIF4bp can bind to and inactivate eIF-4E
How do viruses utilises the machinery when the cap pathway is inactivated
They have IRES (internal ribosome entry site) at 5’ end which allows ribosome to directly bind and initiate translation
How do virus attack the poly A tail to mess up initiation of translation
nsP3 (eIF4G binding protein) of the virus (part of transcript) displaces Pab1p (poly A tail binding protein) due to higher affinity and allow rotaRNA to bind to nsP3 and hijack the translation system
Cap stealing of the virus is utilised by flu, how does it work
The virus chop of the first 20bp of mRNA transcript (contains cap) which is later glued in front of the virus RNA
Picovirus structure
Long 5’ UTR (600-1200 nt) - contains clover leaf structure (IRES) - important in translation, virulence and encapsulation
Genome encore for a single polyprotein
Short 3’ UTR (50-100nt) - necessary for antistrand synthesis
Ig classes
IgM/G/D/E/A
IgM characteristics
900kDa, pentamer form in blood, first Ab secreted in response to infection
Low affinity, does not travel efficiently in tissue
Activate complement but poor toxin and viral neutralisation
IgG properties
Smallest Ab, present everywhere in serum (highest concentration), can transfer to foetus via placenta
Opsonin, activate NK cell for ADCC, neutralise viral proteins and form immune complexes
Cause type II/III hypersensitivity
IgDproperties
A marker for mature B cells along with IgM
We don’t know why it’s there
Membrane Bound
IgE properties
Related to type I sensitivity
Binds to FceRI on mast cells/eosinophils/basophils
In serum and plasma
High affinity
IgA properties
High concentration/main in mucosal surfaces
Can transfer to babies via breast milk
165 KDA
Secreted as dimer or monomer (dimer in mucosal system)
Does not activate complement
Antiviral capacity
How is IgA secreted to the mucosal durfaces
Via plgR - captures IgA and transport it to the surface
Complement activating Ig
IgG/M
Neutralisation Ig
IgA/G
NK cell sensitisation Ig
IgG
Function of Ab (TAICON)
Type I-III hypersensitivity
ADCC (Ab-dependent cellular cytotoxicity)
Immune complexes formation - complement activation
Neutralisation - prevent viral entry/bacteria adherence to cell/toxin binding to host cell
Opsonisation - IgG mainly with C3B
How is B cell attracted to LN for maturation
Express. CCR7 which sense chemokines secreted by follicular cells (CCL21/19)
How does super antigen work
Binds to Vb region of TCR and bypass specificity to activate random CD4 T cells
Constitutive proteasome is what dependent
Threorinine dependent
What stimulates constitutive proteasome to become immunoproteasome
IFNGamma
Causes change in beta 1,2,5 subunit
Intracellular signal transduction for TCR and BCR is via
TCR - CD3 complex
BCR- CD79/CD21
Tdt (terminal deoxynucleotidyltransferase function)
Important for adding 1-3 random nucleotides at junction sites during VDJ recombination to increase diversity
Alleic exclusion is the process whereby
Alleic exclusion is the process whereby further chromosomal rearrangement is prevented once a functional combination has occurred from one chromosome
Why does baby respond poorly to capsid polysaccharide derived chromosome? And how do you bypass this?
Baby’s have immature marginal zone, where the M2 T cells develop and hence they don’t respond to CP vaccines well - bypass by conjugating to peptide TK activate immune response via TD
Ways of NP killing
1) phagosome activation
- respiratory burst
- granules secretion
2) netosis
3) NO production from iNOS
Assembly of NADPH oxidase on phagolysosome membrane is activated when what binds
When p47/67 bind and assemble to the p21/91 complex
Process of respiratory Burst
NADPH oxidase convert 02 to superoxide anions (O2-)
O2- can be converted to H2O2 via SOD (superoxide dismutase)
H2O2 can be further converted to HOCl (bleach ) by MPO (myeloperoxidase)
All of which can act on microbe and impair microorganism and cause death
Granules inNP
1) azurophilic granules - contains antimicrobial proteins
2) specific granules
Avidity and affinity definition
Affinity - defines the FIT between a receptor and it’s ligand (how well it binds)
Avidity - determined by how many numbers of receptors engaged with the ligand (if too high -> may produce dif magnitude of signal or different signals
Cytotoxic T cells contains what to kill virally infected/cancer cells
Contains granules which consist of granzyme B and perforin
How does Tc kill
Via FAS ligand binding or granzyme B induced apoptosis by inducing granules into cells
Th1 production stimulate by
IL12
Peripheral tolerance mechanisms
Ignorance
Anergy
Deletion
Immune regulation
How does ignorance work in peripheral tolerance
Naive T cells have strict circulation pattern through blood and secondary lymphoid tissues and they don’t enter nonlymphoid tissues unless activated
Low concentration also be insufficient to activate T cells
Immune privilege mechanism
Some tissues such as eyes brains and testes are isolated and inaccessible to lymphocytes
They also express immunosuppressants to prevent activation
T cell checkpoint involves
PD1 receptor and CTLA4 on T cells
How does T cell checkpoint work
When T cell receive signal 1 and 2, they also transport CTLA4 to the cell surface. CTLA4 binds to B7 at higher affinity to prevent overstimulation of T cells. Tissue at inflammation site also express PD1 ligand which binds to PD1 on T cell to send negative signals to T cell to dampen response
Mechanism of Treg
1) express Il2 receptor (CD25) to take up IL2, prevent T cell use for division
2) express CTLA4 which binds to B7 and rip B7 off APCs cells so T cell don’t get signal 2 for activation
3) secrete immunosuppressive molecules (IDO) - breakdown tryptophan so T cells cannot proliferate
4) release soluble mediators (immunosuppressants) - adenosine, TGFb, IL10/35
5) directly kill cell by pumping cAMP into cells
Genetic risk of Rhematois arthritis
MHCII genes
PTPN22
5 ways in which autoantibodies can cause autoimmune disease
1) complement dependent cell lysis of target cell
2) opsonisation
3) formation of immune complexes
4) blockade of receptor for physiological ligand
5) stimulation of cell surface receptors
Systemic autoimmune disease
SLE (systemic lupus erythematous)
Rheumatoid arthritis
Scleroderma
Multiple sclerosis causes
T cell cause damage to neurones which result in demyelination
SLE causes
Loss of B cell tolerance
Autoantibodies form precipitate which leads to inflammation in vascualture
Evasion strategies of bacteria
Elicit minimum response - mycobacterium
Destroy host molecules - IgA1 protease by neisseria
Intracellular lifestyle - listeria (O chain that disrupt phagosomal membrane)
Superantigen - activated immune response
Antigenic variation - programmed mutation
Molecular mimicry
CCR7 expressed by Immature B cells responds to what chemokine to migrate to LN
CCL19/21
B cells can undergo somatic hyper mutation and class switch recombination after being activated, what is the process
The activated B cells in the LN can migrate into the dark zone where they undergo somatic hypermutation (point mutation induced by AID which change affinity of Fab region) - coined centroblast. They move to the light zone and become centrocyte and then undergo selection in the light zone by follicular DC and Th cells which presents the orignial antigen. The centroblasts outcompete each other and the one with the highest affinity will be selected. Selected cell will undergo class switch recombination (RAG) and further proliferate and form memory B or long live plasma cells
What is calnexins role in MHC processing
Stabilises the MHCI heavy chain until a peptide is delivered
Attenuated vaccine example
BCG, MMR, OPV
I activated vaccine example
Pertussis, IPV (polio)
Recombinant protein vaccine
HBV
