IAH theme 2 Flashcards
What are the immediate defences ?
Physical and chemical barriers
complement
phagocytosis
What are the induced defences ?
neutrophil chemotaxis
cytokines
interferon response
What are the adaptive defences ?
antibodies
cell mediated immunity
memory
What is the role of the adaptive immune response in an infection ?
to clear the infection
Describe the course of an infection ?
establishment of infection threshold reached to activate adaptive response induction of adaptive response adaptive response memory cells
What are the charactersitics of the immune response to an infection ?
dynamic- intensity changes with time
organised-in time and location- multiple secondary lymphoid locations
improved- increased affinity of BCRs, isotype switch
What is the isotype switch ?
IgM to IgA
What does the success of an infection depend on ?
properties of pathogen
dose of innoculation
route and mode of transmission
host properties
How do pathogen properties influence success of an infection ?
method of infection
extracellular/intracellular
How does the dose of innoculation influence the success of an infection ?
large dose needs to overcome innate immunity
multiple exposures mean more likely to get infected
How does the route and mode of transmission infleuce the success of an infection ?
mucosal surfaces more likely to get infected
dirty injection
How do host properties influence the success of an infection ?
health, age, chornic conditions
chronic disease mean immune system is already burdened
smoking and drugs can effect CNS and host defences
Describe the stages of the immune response after a skin breach ?
skin breach
complement, AMP and phagocytosis try to eradicate
dendritic cells migrate to lymoh nodes to present antigen
NK cells made
cytokines
chemokines made
adaptive immunity initiated
via efferent lymphatics- T, B and antibodies transported to site
infection cleared by antibodies, activated macrophages and CD8 cells
What is a primary infection ?
pathogen estbalishes at an initial site
adhere, colonise and penetrate
What is the job of the innate immunity in an infection ?
contain the infection
What are obligate intracellular pathogens ?
spread from cell to cell
How do extracellular bacteria sprea ?
blood
lymphatics
How do pathogens that dont enter tissues causes disease ?
toxin activity
Which bacteria produce neurotoxins ?
clostridium botulinum
clostridium tetani
cholera
What happens without innate immunity ?
high duration of infection
What is SCID ?
no RAG enzyme
no T/B cell development - no adaptive response
innate immunity still present so lower number of microorganisms
infection contained but cant be cleared by adaptive
What is TLR3 ?
viral PRR in innate system
What to TLR3 mutations lead to ?
lead to HSV induced encephalitits
HSV Is normally just cold sores
highlights importance of innate immuntiy
What is SCID ?
Severe combined immunodeficiency
RAG mutation in T cell development
lack of cell mediated and antibody immunity- no activated macrophages or B cells
susceptible to wide range of infections
What does establishment of a bacterial infection trigger ?
complement activation
activation of dendritic cells
innate signalling by macrophages for neutrophils
What happens in a cytokine milieu ?
cytokines made by T cells
specific TFs amde
differentiation of CD4 into effector cells
What are the different types of CD4 cells ?
Th17 Treg Th1 Th2 Tfh
What are the features of the cytokine milieu that allow T cell differnetiation into effector T cells?
mutual regualtion- positive/negative feedback
phenotypic plasticitiy- can change into different types
What is the role of the Th17 cell ?
reinforce innate immunity
What is the role of the Treg cell ?
supression of the immune system
What is the role of the Th1 cell ?
macrophage activation
What is the role of the Th2 cell ?
B cell activation
Mast cell activation
What is the role of the Tfh cell ?
B cell activation in lymph nodes
What does HIV do ?
take out CD4 cells
How are pathogen destruction mechnanisms tailored ?
tailored to the type of pathogen and its mechanism of pathogenicity
Bacteria that produce toxins require what type of destruction ?
antibodies to neutralise the toxin
eg. C.tetani
What type of destruction mechanism do extracellular bacteria require ?
antibodies
eg. strep pneumoniae in pneumonia
What type of destruction mechanism do intracellular bacteria require ?
cant be reached by antibodies infected cell has to die use macrophages activated by Th1 cells CD8 cells eg. Mycobacterium
How does Mycobacterium Tb infect ?
infects macrophages - intracellular
macrophages present antigen via MHC Class II to Th1 cell
co receptor recognition too - CD40 on macrophage and CD40 receptor on Th1 cell
Th1 cell activates macrophage
signal 3- IFN gamma released by macrophages- type II interferon- activates macrophages
Fas ligand pathway for death if bacteria are resistant to digestion
Th1 cells also recruit macrophages from monocytes in blood
What happens if Myco TB resists macrophage digestion ?
chronic inflammation develops
What are the 2 types of infections manifested by Mycobacterium leprae ?
tuberculoid leprosy
lepromatous leprosy
What are the characteristics of tuberculoid leprosy ?
low infectivity
local inflammation and peripheral nerve damage
normal serium Immunoglobulin levels
Normal T cell responsiveness allowing macrophage activation via Th1 and IFN gamma
What are the characteristics of lepromatous leprosy ?
high infectivity boen, cartilage and nerve damage hypergammaglobuminemia low or absent T cell responsiveness to antigens failed Th1 response Th2 respone activated instead
What is the consequence of activating the Th2 resposne instead of Th1 in lepromatous leprosy ?
Th2 response triggered
trigger B cell activation
produces antibodies
no effect on intracellular mycobacterium
Why is there no Th1 response in lepromatous leprosy ?
Th2 response activated
IL4/IL10 reciprocal inhibition means Th1 cells are supressed
no activation of macrophages to clear infection
What causes an imbalance between the Th1.Th2 resposne ?
peptide amount
MHC dnesitiy
cytokine milieu
What does an abundance of peptide lead to ?
MHC complexes drive Th1 response
What does a limited amount of peptide lead to ?
MHC complexes drive Th2 response
What are the characteristics of mucosal surfaces ?
thin and permeable
route of infection
no keratin
What is present on each mucosal surface ?
natural, commensal, non pathogenic commensal microbiota
disticnt immune defences like peyers patches
What are the anatomical features of the mucosal immune system ?
comaprtments of lymphoid tissue- tonsils and peyers
specialised antigen uptake cells- M cell
What are the effector mechanisms of the mucosal immune system ?
Memory T cell
regulatory T cell
secretory igA
microbiotia
What are the immunoregulatory features of the mucosal immune system ?
down regulate immune responses to food/non harmful antigens
What is the micorbiotia like across different mucosal surface ?
varies in composition and diversity
different phyla
What can the composition of the microbiotia influence ?
immune system development and disease susceptibiliity
success of immumotherapy
What is the role of the microbiota on mucosal surfaces ?
synthesis AMPs
stimulate epithelial cells to make AMPs
compete with pathgoens for niches
What are the signs of inflammtion ?
heat due to increased blood flow
Redness due to increased blood flow- vasodialtion
Swelling due to neutrophil influx and tissue fluid influx
pain due to oedema, pressure, pus and chemical pain mediators like bradykinin and prostaglandind
loss of function due to chronic inflammation
What does “itis” refer to ?
inflamamtion
What is acute inflammation ?
the initial tissue response to a number of inflammatory agents
What are agents of acute inflammation ?
infections physical agents - trauma chemicals tissue necrosis immunological disease
How does tissue necrosis lead to inflammation ?
ischaemic infarction - blockage in blood vessel leads to death of blood vessel- cells burst open stimulating inflammation
What are the vascular changes in the early stages of inflammation ?
oedema, neutrophil and fibrin accumualtion in extracellualr spaces
increased vascular permeability to allow proteins to enter
How is neutrophil chemotaxis stimulated ?
IL8 release from macrophages
What are the benefits of acute inflamamtion ?
toxin dilution due to tissue fluid accumulation
entry of immune system elements- neutrophils and monocytes
transport of drugs
fibrin accumulation- blood clotting
delivery of oxygen and nutrients for neutrophils - high metabolic activity - divert energy to specific site
What are the 2 types of acute inflammation ?
membranous
suppurative
What is suppurative inflamamtion ?
production of pus
can be walled off by fibrotic tissue in repair forming an abscess
pus formed by pyogenic bacteria
What is an example of pyogenic bacteria ?
Staph aureus
What is it called when pus accumulates in a lumen ?
empyma
What is membranous inflammation ?
of mucosal surfaces
neutrophil chemotaxis, epithelium is coated in fibrin, desquamted
What are the consequences of untreated dental abscess ?
spread to fascial layers and spaces
cellulitis
press on carotid artery
septicaemia
What is the objective of acute inflammation ?
reduction in infection
What is fibrosis ?
due to chronic inflammation
attempt to repair damaged tissue
What does persistence of the causal agent lead to ?
chronic inflammation
What are the diseases Mycobacterium can cause by infecting macrophages ?
tuberculosis
leprosy
How do Th1 cells attempt to activate macrophages ?
Th1 cells are presented with antigen on class II
Th1 cells are activated and recognise
release IFN gamma
this activates macrophages to try to digest the infected cells
What happens in TB ?
pathogen persists
activated macrophages dont work
infection is contained but not cleared
leads to granuloma formation
What are granulomas ?
macrophages fuse into multinuclear giant cells
surrounded by epithelioid cells
surrounded by Th1 cells - CD4
What is the structure of granulomas ?
middle has few cells- large macrophages
outside has specs- densely stained - H&E stained T cells
Pink as middle is necrotic due to lack of oxygen
When are granulomas formed ?
bacteria resist the microbicidal effects of activated macrophages
How do Th1 cells activate macrophages ?
macrophage presents antogen via MHC class II
engagement with Th1 cell
Th1 cell proliferates via IL2
Th1 cell release IFN gamma to activate macrophages
What happens when the centre of the granuloma is cut off from oxygen ?
cut off from blood supply
cells die by anoxia and lytic macrophage enzymes
How does a necrotic granuloma manifest ?
caseation necrosis leads to caesation
cottage cheese appearance
What does caeseation of adrenal gland lead to ?
due to TB
lead to adrenal insufficirncy
What are the other manifestations of caeseation necrosis ?
confluent granulomas- pulmonary TB
lymoh node caeseation
miliary TB
Ghon complex
What is associated with the Ghon complex ?
anthracasis
tissue blackening
What can inflammation lead to ?
diseases with a loss of function
What happens in arthritis ?
loss of joint function
What happens in periodontal disease ?
loss of tooth function
What are the systemic effects of inflammation ?
fever
acute phase response
shock
What happens in fever ?
raising of temperature - not preferable for microbes
adaptive immunity becomes more potent
How does the body raise temperature ?
act on hypothalamus temperature control sites
physiologic response is to act on muscle and fat- altering metabolism to generate heat
How is the systemic fever effect triggered ?
pro inflammatory cytokines
IL6 IL1 TNF- alpha
What is the acute phase response ?
bacteria induce macrophages to produce IL6
acts on hepatocytes
induce synthesis of acute phase proteins- C reactive protein, fibrinogen and mannose binding lectin
What is the role of CRP ?
binds to phosphocholine on bacterial surfaces and opsinises bacteria to activate complement
What is the role of mannose binding lectin ?
binds to carbohydrates on bacteria
opsinisation
What can CRP be used in ?
CRP assay for suspected fever
What is septicaemia
infection of blood
might be via an endoxtoxin from gram negative bacteria like in a dental abscess untreatd
What happens in septic shock ?
circulatroy collapse causing hypoperfusion of organs
systemic inflammation means blood leaves circulation to enter tissues
What can lead to septic shock ?
haemorrhage
generalised vascular permeability
dilution
What does localised TNF lead to ?
macrophages are activated to release TNF alpha
release of plasma proteins into tissue
increased phaocyte/lymphocyte migration to tissue
phagocytosis of bacteria - contains infection
What does systemic TNF lead to ?
macrophages in liver/spleen activated secrete TNF alpha into blood systemic oedema reduced blood volume collapse of vessels multiple organ failure as hypoperfused septic shock
What are the pathways to inflamamtion ?
hypersenstivity immunodeficneciy autoimmunity infecton metabolic disroders
Different classes of viral pathogen require what ?
different effector mechanisms
What type of immunity do viruses require ?
cell mediated
humoral
What are the role of CD8 cells in viral infections ?
clear infection
recognise infected cells
antigen specific
What is the role of antibodies in viral infections ?
contain infection
stop spreading
Are NK cells antigen specific ?
no
they are innate lymphoid cells
How are NK cells activated ?
IFN alpha and beta
type one IFN
released from virally infected cells
IL-12
How do NK cells ensure the cell is virally infected ?
have complex array of receptors
KIR receptor
What does the KIR receptor detect ?
increased MHC class I expression infected cells make more MHC class I
What are KIR genes like ?
highly polymorphic
What do NK cells release ?
IFN gamma
type II IFN
activates macrophages, this leads to CD8 activation
How are cytotoxic CD8 cells activated ?
Naive T cell stimulated to proliferate by APC
Naive T cell releases IL2 - growth factor allows T cell proliferation
naive differnetiate into cytotoxic
Effector T cell kill virally infected cell
How do cytotoxic CD8 cells kill ?
CD8 cells recognise virally infected cells via TCR
and MHC class I
signal 2 and 3 not needed
CD8 induces apoptosus
How do CD8 cells carry out apoptosis ?
infected cells are killed by action of lytic grnaules that contain cyttoxic molecules such as perforin and granzymes
IFN gamma secreted by CD8 cells promotes antigen presentation and dead cell scavenging
successively kill others and jump to other cells
How do IgA protect against viral infections ?
bind to virus and prevent it entering cells
How do CD4 cells help CD8 cell sin viral infections ?
CD4 helps CD8 to fully funtion
What happens to CD4 cells in HIV ?
massive depletion
What happens to cellular immunity in AIDS ?
no CD4 cells to help CD8 cells in viral infections
no B cell help- no antibodies
What are the characteristics of AIDS ?
severe reduction in CD4 cells
severe infections by pathogens that dont normally infect healthy people
aggressive forms of karposis sarcoma and B cell lymphoma
fatal
What causes AIDS ?
HIV-1/HIV-2
How is HIV spread ?
from primates
How does HIV enter cells ?
CD4 receptor
CCR5 coreceptor
What is the CCR5 receptor ?
a chemokine receptor on memory T cells
HIV blocks out the receptor so memory to infection is wiped out
Which other cells is the CCR5 Co receptor also present on ?
macrophaes
dendritic cells
virus switches between cell types
What are the first cells to be infected with HIV ?
T cells
How does HIV affect T cells ?
virus swithces to T cells later on in the infection
causing a rapid decline in T cell numbers and progression to AIDS
What are the phases of a HIV infection ?
flu like symptoms
asymptomatic
symptomatic
AIDS
Describe the immune response to HIV ?
initial infection is asymomatic or might have like flu like symptoms
acute viraemia abundant virus circulates after infection and leads to depletion in CD4 T cells
activation of anti-HIV specific response - cytotoxic T cells and seroconversion antibodies
Virus load decreases and CD4 cells recover
Asymptomatic phase starts as CD4 cells recover - clinical latency od 2-15 years
high mutation rates in HIV- evasion from immune system
persistent infection and replication of HIV in T cells
rate of decline overtakes the rate of haematopoietic cells
immunodeficnecy ensures
AIDS progression
Which region do fungal infections target ?
oropharyngeal area
What are some predisposing conditions to fungal infections ?
immunodeficiency from HIV, chemotherapy, haematological malignancies
How many species of candida are there in the mouth ?
12
What can aspergillus cause ?
aspergillosis
What is 80% of oral candida ?
is candida albicans
What type of pathogen is candida ?
commensal
What are the candida morphologies ?
budding yeast
hypahe
pseudohyphae
What are the immune responses to candida ?
inhibition of adhesion and growth by IgA and lactoferrin
AMPs
neutrophils and macrophages
mucosal dendritic cells uptake yeast
How is candida recognised ?
TLR 2
TLR4
TLR9
on myeloid cells
What is the cell mediated immunity response to candid a?
IL-12
IFN gamma from NK cells which favours differentiation of Th1 cells
What are some predisposing factors to candidiasis ?
broad spectrum antibiotics - lead to thrush
corticosteroid inhalers in asthma
salivary abnromalities
smoking
chemotherapy can lead to xerostomia and neutropenia
HIV
ill fiting dentures
What is pseudomembranous candidiases characterised ?
plaques can be scraped off
How is chronic hyperplastic candidiasis characterised ?
plaques cant be scraped off
has penetrated tissues
What is erythematous candidiasis ?
poorly fitted dentures
What is pneumocystis jirovecii ?
opportunistic fungal pathogen
common in environment
causes pneumonia in AIDS and other immunosupressed
lack of CD4 Th1 cells leads to impaired alveolar macrophage function (not activated by IFN gamma) and infection
What is the evolution of pathogens like ?
in parallel to evolution of the human immune system
Which part of the immune system has evolved ?
adaptive immunity
How do we know pathgoens evade the immune system ?
from genomics
Why is evasion of the immune system necessary for pathogens ?
exploit habitat and compete in it
What is immune system evasion aided by ?
short life cycles
rapid mutation rate
What are social factors affecting spread of infectious diseases ?
poverty
agricultural techniques have lead to increased malaria incidence
migration
global circulation of blood and tissues
How do the large number of serotypes of Strep pneumoniae differ ?
in their capsular polysaccharide
What does each different serotype do ?
elicit a different serotype antibody response
Protective immunity is ?
serotype specific
What does serotype variety allow ?
bacteria to prosper
How is genetic variation defined ?
different serotypes require different serotype specific antibodies
Having specifc antibodies to one serotype does not ensure…..
immunity and antibodies to other different serotypes
How many serotypes does Strep Pneumoniae have ?
90
How many serotypes does the gneus salmonella have ?
2500 types
How are serotypes discovered ?
with assays
What can a species with a high serotype variety do ?
evade the immune system
Give an example of antigenic drift ?
neutralising antibodies can usually bind to infleunza antigen haemaglutinin
prevent cellular invasion
mutation occurs in haemaglutinin to produce a new version
neutralising antibodies can no longer bind- cellular invasion
What is antigenic drift ?
gradual change in genome due to point mutation in genes
different strains are prodcued
subtle changes in genes and vaccines
Which genes in the influenza virus undergo antigenic drift ?
genes for viral envelope proteins
haemaglutinin and neuraminidase
How do individuals become effected with antigenic drift variations ?
based on previous exposure to straisn
different degress of immunity
can be used to predict specific vaccines
Does antigenic drift diseases cause epifemics ?
no - limited epidemics
What is the characteristic of small pox ?
small pox has no antigenic variability
eradicated successfully with vaccine
Give an example of antigenic shift ?
human infected with human virus and avian virus strains
recombination of viral RNA in human host produces new novel haemaglutinin
no existing immunity to novel haemaglutinin
What does antigenic shift lead to ?
acute radical change in virus and new strain not ever seen before
radically different strain appears suddenly
What is the infectivity like of antigenic shit pathogens ?
infects large numbers of people
severe disease and pandemics
What are the genetic chnanges in antigenic shift ?
recombiantion of genomes between avian and human virus
Why do avain viruses infect humans ?
culture of animal husbandry
Viruses dividing rapidly allows what ?
large numbers of MHC class I expression with antigen by cell activate CD8
What type of state can viruses adopt ?
a quiescent state
low replication rates
doesnt produce enough antigen for presentation
no recognition
How do viruses also evade the immune system ?
immunosurveillance
What happens to viruses in the quiscent state ?
they are reactivated and causes disease
Where does herpes simplex live ?
nervous system- trigeminal tract - persists
manifests as cold spores
Where does HSV infect ?
epithelial cells
leading to pathology
Why does HSV persist in Nervous system ?
immune system has small amount of MHC class I expression avoid immune attack as it cant be activated
How is HSV reactivated ?
times of stress sunlight bacterial infection hormonal changes HSV reactivated and infects epithelial cells causing spores
What are examples of latent viral infections ?
Lentivirus group- HIV
EBV
How does EBV cause glandular fever ?
infecting B cells
remaining dormant in a small number in B cells
swollen lymph nodes
Which individuals are likely to be reinfected with EBV ?
immunosupressed individuals
Reactivated EBV can lead to what ?
disseminated EBV and infected B cells can become malignant - B cell lymphoma
What does reactivation of varicella zoster lead to ?
shingles in adult life
Why is sabotage and subversion of the immune system the greatest in viruses ?
greatest variety of mechanisms in their life cycle
life cycle depends on interactions with host cell metabolic and synthetic processes
What are the mechanisms of Herpes simplex ?
blocks normal antigen presntation by MHC class I lives in nervous system where there isnt much MHC class I anyway
What are the consequences of no MHC class I expression ?
no recognition of virally infected cells by cytotoxic cells
mechanism of herpes simplex and cytomegalovirus
How does treponema pallidium evade antibody recognition ?
coats in fibronectine- evade antibody recognition
What does P.gingivalis do to digest antibodies ?
secrete proteases
How does Mycobacterium TB evade phagocytosis ?
prevents fusion of lysosome and phagosome
What are bacteria superantigens ?
staphylococcal enterotoxins
What do bacterial superantigens do ?
link TCRs and MHC class I independent of the antigen stimualtes excessive polyclonal response of T cells
What is the consequence of excessive T cell cytokine release ?
toxic shock syndrome
What is an example of toxic shock syndrome ?
staph aureus contaminated vaccines
What happens to T cells in toxic shock after being overstimualted ?
undergo apoptosis
leaves few clones in circualtion
What happen in toxic shock syndrome ?
toxin shock dissemianted infection systemic inflamamtion loss of blood loss to the tissue organ hypoperfusion
What are the causes of Primary immunodeficiencies ?
affect immune cell development
gene mutation
What are the consequences of primary immunodeficienciencies ?
innate/adaptive immune deficiency manifesting as recurrent infections
What do T cell deficincies lead to ?
candida infections
viral infections
intracellular pathogens as no CD8
What do complement, B cell and phagocyte deficiencies lead to ?
extracellular pathogen infections
pyogenic infections
What are examples of Primary immunodeficincies ?
SCID
XLA
CVIDs
What are many primary immunodeficnecies due to ?
x linked recessive mutations
What happens in SCID ?
T cell deficnecy
leads to severe immunodeficnecy
no T cells, no help for B cells and no memory cells as no T cell cytokines mase
What is X linked SCID caused by ?
mutations in genes for cyotkine signalling molecules
genes for IL-2 receptor and Jak3
lack of cells that need these cytokines for development- T cells, NK cells and B cells
What is Jak3 ?
protein kinase
What are other causes of SCID ?
RAG 1/2 mutation
ADA mutations
What is ADA ?
adenosine deaminase
What is the treatment for SCID ?
bone marrow transplantation
What is the most common primary immunodefcinecy ?
CVID
What are the characteristics of CVID ?
mild immunodeficiency
heterogeneous clinically
defects in immunoglobulin production- limited to one type
can cause recurrent infections but many people dont have symptoms
What are the forms of IgA deficiency ?
familial and sporadic
What is hyper IgE deficiency syndrome ?
high IgE levels
autosomal dominant
How does hyper IgE deficinecy syndrome manifest ?
recurrent infection with fungi and pyogenic bacteria
What is the cause of hyper IgE deficinecy syndrome ?
mutation in STAT TF pathway for Th17 regulation - depleted Th17
What are the dental abormalities in hyper IgE deficnecy syndrome ?
supernumerary teeth
fusion of primary teeth
retention of primary
delayed/ectopic eruption of permenant teeth
What is the technique used to assess Th17 cell deficinecy ?
flow cytometry
What is XLA ?
brutons x linked agammaglobulinemia
What happens in XLA ?
failure of BCR signalling
B cells are arrested at pre B Cell stage
leads to B cell deficiency
lack of antibodies
What is the consequence of XLA ?
recurrent infections with extracellular pyogenic bactiera like strep pneumoniae
chronic infections with poliovirus,Hep B and Hep C
What is the treatment for XLA ?
immunoglobulin infusion
antibiotics for bacterial infections
What do complement deficiencies lead to ?
recurrent infections with extracellular bacteria
What does C3 deficiency lead to ?
recurrent strep pneumoniae
pnuemococcus infection
What does C5 deficiency lead to ?
susceptibility to neissera menigitides
leads to meningococcus infectious
What other disroders can complement deficinecy lead to ?
congenital neutropenia
leukocyte adhesion deficiencies
Why do complement and Ig deficiencies overlap ?
they both work together
What are the causes of secondary acquired immunodeficinecies ?
immune senescnece- ageing and poor nutrition Burns- remove skin and vasculature immunosupressants tumours HIV
What is chronic lymphocytic leukaemia ?
make only one type of cell
die from infections
vaccines also become ineffective
Where is HIV prevalent ?
sub sahran africa
What was the HIV prevalence in 2018?
37.9 million
What was the daily HIV incidence in 2018 ?
5000 new cases a day
What are the properties of HIV ?
genetic variability is high due to high mutation rate
classified into 3 groups based on nucloetide sequencing -
M,O and N
What are the factors that influence AIDS progression ?
viral load when innoculated - high viral loads can lead to faster progression
Age
genetic host variation- some genotypes confer resistnace to AIDS progression
antiviral drug treatment- prolongs T cell recovery periof
What is the evidence of resistanct to AIDS progression ?
progression resistance in seroconverted individuals with low viral load
HIV negative individuals with high exposure dont get virus
What is the effect of age on AIDS preogression ?
younger HIV+ people are less likely to succumb to AIDS- slow progression
What are the host genetic variants that influence AIDS progression ?
KIR
HLA
CCR5
What do polymorphisms in HLA ans KIR do ?
different polymorphisms make some people more resistant and some more susceptible to AIDS
What is CCR5 ?
chemoline receptor on memory cells
What does HIV do to CCR5 ?
binds to it and blocks it
What happens in a CCR5 mutation ?
frameshift producing a truncated protein HIV no longer binds hetero- slow progression homo- progression halted
What does HIV do with reverse transcriptase ?
HIV converts RNA to cDNA
via reverse transcriptase
Why is reverse transcriptase targeted in HIV therapy ?
stops viral replication
How is Reverse transcriptase targeted
with nuceloside analogues and non-nucleoside analogues
What is the role of protease in HIV ?
cuts large proteins into smaller ones
uses this for viral assembly
How can protease be targeted in HIV therapy ?
protease inhibitors
What is the problem with HIV therapy ?
resistance to therapy is conferred in HIV quickly due to high mutation rate
How does drug resistance happen in HIV ?
drug initially given and RNA decreases, CD4 cells recover
mutation happens again and virus appears with resistance and CD4 cells deplete
How can HIV drug resistance be avoided ?
combinatorial drug therapy
What is HAART ?
highly active antiretroviral therapy
What does HAART do ?
reduces viral load
reducing morbidity and mortalit
What has an increase in HAART lead to ?
decrease in deaths
What are the disadvantages of HAART ?
Doesnt fully clear virus
lifelong treatment necessary
expensive
severe side effects
What is the definition of autoimmunity ?
responses to self antigen/commensal flora leading to tissue damage
What is the normal state of self tolerance ?
lymphocytes which react to self antigen are eliminated
What is autoimmuniy characterised by ?
breakdown in self tolerance
What is autoimmunity mediated by ?
autoreactive antibodies
autoreactive T cells
What is psoriasis ?
autoreactive T cells against skin antigens
skin inflammation
formation of scaly patches and plaques
What is rheumatoid arthritis ?
autoreactive T cells against joint synovium
joint destruction and inflammation
What is graves disease ?
autoantibodies agaisnt TSH receptor
leads to hyperthyroidism and overproduction of thyroid hormones
What is hashimoitos thyroiditis ?
Autoantibodes and autoreactive T cells to thyroid antigens
destruction of thyroid tissue
hypothyroidism
underproduction of thyroid hormones
What is Systemic lupus erythematosus ?
autoantibodies and autoreactive T cells against DNA and chromatin leads to glomerulonephritis
What is sjorgens syndrome ?
autoanitobodies and autoreactive T cells against ribonucleoprotein antigens
lymphocyte infiltrate of exocrine glands
What is crohns disease ?
Autoreactive T cells against intestinal Flora antigens
intestinal epithelium inflammation and scarring
What is multiple sclerosis ?
autotoreactive T cells against brain antigens
formation of sclerotic plaues in brain and destruction of myelin sheath
leading to muscle weakness
What is type one DM ?
autoreactie T cells against pancreatic Beta cells
destruction of pancreatic beta cells
non production of insulin
What are the mechanisms of self tolerance ?
central tolerance
antigen segregation
What is central tolerance ?
deletion and editing of T cells that react to self antigen
happens in thymus gland
breakdown leads to autoimmunity
What is antigen segregation ?
physical barrier to self antigen and lymphoid system
in peripheral organs like pancreas
Is breakdown in self tolerance enough to trigger autimmunity ?
not sufficient
environmental triggers like infection and genetic triggers will also be needed
Can autoimmune cells that escape central tolerance be destroyed ?
yes- peripheral tolerance- Treg cells
What is the aetiology of autoimmunity ?
unknown
What is the effector mechanism of autoimmunity ?
autoreactive T cells
autoantibodies
What is the aim of the normal immune system ?
remove non self antigen
Can self antigen be eliminated ? What is the implication of this ?
self antigen cannot be destroyed hence a chronic infection ensues
What are the exceptions to the destruction of self antigen rule ?
hashimotos thyroiditis and type one DM - actually destroy the tissue
What are the ways in which autoimmune disease can be classified ?
organ specific
non specific- many tissues effected
inflammatory bowels disease
clustering in families
What are examples of organ specific autoimmune diseases ?
type one DM
goodpastures syndrome
crohns disease
graves diseasse
What is an examples of a sytemic autoimmune disease ?
rheumatoid arthritis
primary shorjens syndrome
systemic leupus erythematosus
What is the progress of autoimmune diseases ?
activation phase leads to a chronic phase
How are the chronic effects of autoimmune diseases mediated ?
autoantibodies
autoimmune T cells
What mediates the effects of myasthenia gravis ?
autoreactive antibodies
What is tissue breakdown mediated by in autoimmune diseases and what is the result ?
tissue breakdown mediated b integrated immune response
loss of tissue function
tissue breakdown replenishes self antigen
What is a type II autoimmune disease ?
antibodies against cell surface
What are examples of type II autoimmune diseases ?
goodpastures syndrome
pemphigus vulgaris
bullous pemphigoid
What is goodpastures syndrome ?
antibodies against collagen type IV in basement membrane
manifests as pulomonary haemorrhage and glomerulonephritis
What is pemphigus vulgaris ?
autoantibodies agaisnt epidermal cadherin joins epithelial cells
mainfests as skin blistering and heamorrhage
How can we identify pemphigus vulgaris ?
create antibodies complementary to antibodies that are autoimmune to cadherin
tag first antibody with fluorsence
What is bullous pemphigoid ?
autoimmune antibodies to basement membrane
What is a type III autoimmune disease ?
immune complex- complex of antigen an antibodies causing effects- large molecules that depsoit in tissue recruiting neutrophils leading to inflammation
What are the 2 examples of type III autoimmune disease ?
mixed essential cryoglobulinemia
rheumatoid arthritis
What is the complex in mixed essential cryoglobulinemia ?
rheumatoid facto igG complexes- systemic vasculitis
What is the complex in rheumatoid arthritis ?
rheumatoid factor IgG complexes
What is a type IV autoimmune disease ?
T cell mediated
What are examples of type IV autoimmune diseases ?
Type I DM
multiple sclerosis
What is type one DM ?
T cells cluster around B islets of langerhans and destroy - leading to non production of insulin
antigen is pancreatic beta cell
What is multiple sclerosis ?
myelin protein
destruction of myelin sheath by T cells
brain invasion by CD4 cells
muscle weakness
What are the cells of the pancreas ?
alpha cells- glucagon
beta cells- insulin
gamma cells- somatostatin- GHIH
How does type one DM selectively target beta cells ony ?
effector cytotoxic T cells recognise peptides of a beta cell specific protein- kill B cell- no insulin made
What classification is Rheumatoid arthritis ?
type III and IV
Myasthenia gravis and graves disease are examples of what ?
autoantibodies against cell surface receptors
What happens in myasthenia gravis ?
affects NMJ
antibodies to acetylcholine receptors which are degraded
no signalling between neurones and muscles
What is graves disease ?
autoimmune B cell makes antibodies against TSH receptor on thyroid gland, the antibodies also stimulate thyroid hormone production
autoimmune antibodies shut down TSH via negative feedback and thyroid hormone
trigger thyroid production- hyperthyroidism
What is SLE ?
antibodies to common antigens like DNA
widespread butterfly red patches
systemic
detected in immunofluoresence
What is the evidence for the genetic component of autoimmune diseases ?
family studies- it is in families
nearly 100% concordance in identical twins
mice clones have different susceptibility
What is the evidence for the environmental component of autoimmune diseases ?
lack of 100% concordance in identical twins
different age of onset in identical mice
What is the difficulty of analysing genes for autoimmune diseases ?
outbred popualtion
interindividual variation is great
What are the ways in which we can analyse genes to look at gene association ?
candidate gene studies look at association and linkage
GWAS
knock out genes to see if needed in pathogenesis
What is the conclusion from study of genes and autoimmune diseases ?
autoimmune diseases are polygenic being influenced by multiple alleles on numerous different gene loci
What is a gene loci ?
area of a chromosome
Which gene variants are associated with Autoimmune diseases ?
HLA variants- they are highly polymorphic
What do HLA genes do ?
encode MHC proteins - MHC has peptide groove where antigen sits
changing amino acid composition of peptide binding groove changes interaction between antigen and MHC
Variations in HLA genes can confer what ?
resistance to breakdown in self tolerance
suscpetibility
What is the role of MHC ?
antigen presentation
T cell development in thymus gland
Which polymorphism effects CD4 cells ?
DR class II
Which polymorphism effects CD8 cells ?
B27 class I
What is the odds ratio ?
ratio of the chance of a disease developing in members of the population exposed to a certain factor compared to members who are not exposed
Which polymorphism is present in most AD diseases ?
DR polymorphism- class II
Which gender is more at risk for AD diseases ?
females
What is the role of infection in AD diseases ?
infection can trigger autoimmunity in hosts with the right genetic make up
Why does infection play a role in AD diseases ?
infection triggers MHC presentation and APC activation and cytokines - bystander effect of autoimmune cells
adaptive resposne more likely to be triggered
adjuvant effect demonstrated in animal models
What is molecular mimicry ?
cross reaction between microbial antigens and own antigens
stimulate autoimmune reaction to self antigens
Give an example of molecular mimicry ?
rheumatic fever
infection with strep antigen
cross react with cardiac muscle
degenerate cardiac muscle
What is an allergic response ?
hypersensitivity reaction to an otherwise harmless extrinsic antigen
What is the classification of allergic responses ?
same as autoimmune- type II.III and IV
but also have type I not seen in autoimmune
What are the shared effects of autoimmune and allergic responses ?
inflammation and tissue destruction
What are the environmental antigens in hypersensitivity ?
inhaled- plant pollen and dust mice faeces
injected- drugs and insect venom
ingested- peanuts and shellfish
contacted materials- plant oil and metal
What is a type I hypersensitive reaction ?
immediate type
What is the range of consequences in a type I hypersensitive reaction ?
mild attrition to anaphylaxis
What is atopy ?
an allergy with a genetic predisposition like hayfever
What are examples of atopic disorders ?
10-40% caucasians have one
asthma, eczema and uticaria
What is uticaria ?
hives
What mediates type I hypersensitivity reactions ?
IgE and mast cells
When do type I hypersensitivity reactions occur ?
immediately after exposure to allergen
What do mast cells do in hypersensitivity reactions ?
release inflamamatory mediators
cause pathological effects
What does the hygeine hypothesis state ?
early childhood exposure to particular micoorganisms like gut flora and helminth parasites protect against allergic diseases by contributing to immune development
explains why allergies are increasing as children are getting less exposure to these microbes
What is Der P I ?
common respiratroy allergen found in foecal pellets of house dust mite
What are the 2 phases that lead to type I hypersensiticity ?
sensitisation and reaction
What happens in the sensitisation phase of type I hypersensitivity ?
susceptible individuals present antigen to get a Th2 response
activates B cells and mast cells
plasma cells made which made IgE to the allergen
What happens in the reaction phase of type I hypersensitivity ?
allergen is encountered again
IgE binds to mast cells via Fc receptrors
releasing inflamamtory mediators
cause hypersensitivity
What does cross linking of IgE on mast cell surfaces lead to ?
on second exposure leads to release of mast cell granules containing inflammatory mediators
like histamine
What types of molecules can be released by mast cells in granules ?
histamine, heparin
TNF-alpha
What do histamine and heparin do ?
toxic to parasites
increase vascular permebaility
smooth muscle contraction
anticoagualant
What does TNF-alpha do ?
promotes inflamamtion via cytokines leads to swelling
What are the IgE mediated reactions to extrinsic antigens ?
systemic anaphlyaxis
acute uticaria
What happens in systemic anaphylaxis ?
stimuli- drugs, venom and peanutes
allergens enter via IV or after absorption
edema, increased vascular permeability, circulatory collapse and death
What is acute uticaria ?
animal hair, bee stings and allergy resting
allergens enter through skin
leads to wheal and flare
local increase in blood flow , vascular permeability and eedema
What are the phases of an allergic reaction ?
imemdiate reaction and late reaction
What is usually an imemdiate reaction in allergic situations ?
Wheal- raised area
flare- redness
What is a late reaction to allergic reactions ?
swelling spreads from site of injection
swelling leads to increased blood flow and tissue fluid to area.
What is systemic anaphylaxis ?
allergens reaching the bloodstream activating mast cells throughout the body
mast cell degranulation throughout the body
What are some of the systemic effects of systemic anaphylaxis ?
increased capillary permeability
smooth muscle contraction
wheezing
stomach cramps
Why has IgE evolved ?
to get rid of metazoan parasites
eg. ascaris and schistosoma - worms
conventional immune systems are not effective to get rid of
What are the effects of IgE ?
eject pathogen by physical force - coughing, sneezing and vomiting
invovles Th2 response- help B cells to produce IgE
What does IgE arm ?
arms mast cells, eosinophils and basophils to respond to parasite antigens by binding to Fc receptors on the cells
What are the other roles of mast cells ?
at mucosal surfaces express Fc receptors and TLRs
What is a type I hypersensitive reaction ?
Immune response at the cell surface
What is an example of a type II hypersensitive reaction ?
haemolytic anaemia
What are the causes of heamolytic anaemia ?
penicillin allergy
blood group incompatibility
autoimmune haemolytic anaemia
What happens in haemolytic anaemia ?
autoimmune Antibodies bind to RBCs
the antibodies also bind to Fc receptors on phagocytes leading to phagocytosis
complement fixation- RBC destruction and intravascular haemolysis
What happens in type III hypersensitivity ?
antigen.antibody complex deposition leads to inflammation
What is an example of type III hypersensitive reactions ?
serum sickness
in response to injected therapeutic antibody such as mouse antibody
in susceptible individuals the albumin proteins in serum also lead to an immune response - deposition of complexes in skin leads to rash
What is another cause of type III hypersensitivity ?
pencillin allergy
What happens in penicillin allergy ?
penicllin modifies protein on RBC
creates foreign epitopes
creates antibodies to penicillin modified proteins leading to other hypersensitivies
type I- anaphylaxis
type II- haemolytic anaemia
type III- serum sickness
What is a type IV hypersensitive reaction ?
delayed type T cell mediated
What happens in type IV hypersensitive reactions ?
activation of macrophages by Th1 cells
secretions lead to tissue necrosis
activation of CD8 cells - cytotoxic to cells
Where can type IV hypersensitivty be seen ?
allergic contact dermititis
graft rejection
poison ivy and nickel allergy
What happens in allergic contact dermititis ?
antigen is injected into subcutaenous tissue
processed by local APCs
Th1 cell recognises antigen
releases cytokines that act on vascular endothelium, recruit neutrophils casuing a visible lesion
How does allergic contact dermititis manifest ?
blisterng skin lesions
What happens in nickel allergy ?
T cell mediated response to foreign antigens or modified self antigens
nickel modifies peptides in allergy leading to a CD4 response
What happens in poison ivy allergy ?
chemical in ivy called pentadecatechol modfies self antigens leading to CD8 response
Why is type IV hypersensitivity delayed ?
requires development of T cells
unlike immediate type I- already sensitised
What considerations should be made with allergic rhinitis ?
mouthbreather and develop mild gingival hyperplasia
What considerations should be made with antihistamines ?
cause dry mouth
What is angiodema ?
rapid swelling of dermis and mucosa in response to allergen
What is oral allergy syndrome ?
food allergy from fruit and veg
leading to allergic reactions in the mouth
Where can latex allergies be found ?
gloves. dental dams and tubing
What are the histological features of coeliac disease ?
inflammatory filtrate
tissue damage
lengthening crypts
increased epithalial cell division
What are the clinical consequences of coeliac disease ?
abdmoinal distention malabsorption diarrhoea anaemia intestinal cancer
What is coeliac disease ?
inflamamtion of the jejunum due to a response to gluten
What is gluten ?
complex of proteins found in wheat, barley and oats
What is the management of coeliac disease ?
elimination from the diet
Why is the incidence of coeliac disease increasing in china and india ?
western diet increasing
What is the molecular basis of coeliac disease ?
normally gluten peptides dont bind to MHC class II
in coelaic disease, enzyme called trandglutaminase modifes peptides allowing them to be presented MHC class II - activates CD4 cells
activated CD4 cells kill mucosal epithelial cells via Fas pathway
activated T cells also secrete IFN gaamma to activate other inflamamtory cells like macrophages
is transglutaminase active in non coeliacs ?
no it is inactive in non coeliacs
What is the genetic predisposition to coeliac disease ?
95% of coeliacs have HLA-DQ2 allele
but this does not lead to coeliac disease, just more suscpetible to coeliac disease
80% concordance in identical twins
6x higher in downs syndrome
strong genetical element but also an environmental interaction
What are inflammatory bowel diseases ?
chronic inflammatory diseases with features of autoimmune disease
immune response to commensal gut flora
crohns disease and ulcerative colitis
antigens are from gut microflora
What are the manifestations of crohns disease ?
transmural inflammatory lesions - involve epithelium and lamina propia
chronic and episodic
thickened/fissured bowel
fistulation
What happens in normal immune gut regulation ?
mucus present in mucosal layers paneth cells make AMPs IgA also present M cell samples environment for antigen and presents to peyers patch activate T/B cells make IgA
What happens in crohns disease ?
cant secrete AMPs- cant tolerate normal microflora
What are the oral manifestations of crohns disease ?
cheilitis
oral ulceration
fissuring
glossitis
What are the genetic variants associated with crohns disease ?
NOD2
ARGM
IL23R
What happens to NOD2 in crohns disease ?
NOD2 is intracellular PRR
detects peptidoglycan and muramyl dipeptides
mutations means cells cant recognise bacteria
mutations in all mucosal cells- includig mouth
Immune dysfucntion means imparied AMP secretion
sustained bacterial exposure
What happens to IRGM in crohns disease ?
IRGM usually used in autophagy - tag with ubiquitin to recycle
immune dysfucntion means mutation leads to sustained cytokine secretion and inflammation
What happens to IL23R in crohns disease ?
usually IL23R activates Th17 cells and inhibits Treg cells
immune dysfucntion leads to sustained inflamamtions and supression of T reg cells
What is the pathogenesis of crohns disease ?
Failure of immunoregulatory mechanisms to toelrate commensal bacteria
failure of innate immunity- no AMPs leading to failure of the adaptive immunity- CD4 cells
microbial dysbiosis
Which metabolic disorders are involved with inflammation ?
gout and T2DM
Are gout and T2DM genetic ?
no- theyre acquired
mainly environmental
What other conditions can gout and diabetes be involved with ?
obesity and CVD
What is gout ?
inflammation of the digits, toes and joints
EG. metatarsal joint
What leads to gout ?
uric acid crystal deposition
leads to inflamamtion
activates the inflamamsome
What is the inflammasome ?
complex of proteins which drive IL-1 secretion
more inflamamtion
use anti IL-1 therapy
What are the forms of gout ?
primary gout- may be genetic
secodnary gout- due to chemotherapy/drugs
What is the pathway for gout ?
primary/secondary gout hyperuricemia crystal formation in periphery crystal depostion gout flares
What factors can exacerbate crystal deposition in gout ?
western diet
obesity
age
What is the link between diabetes type 2 and inflammation ?
hyperglycaemia
advanced glycation end products and oxidative stress
immune dysfucntion- cytokine imbalance- TNF alpha, IL-6 and IL-1
exacerbated by adipokines
inflamamtroy state
enhanced tissue destruction leading to rheumatoid arthritis, impaired tissue repair leading to CVD and periodontitis , pancreatic Beta cell destruction
