IAH theme 2 Flashcards
(404 cards)
1
Q
What are the immediate defences ?
A
Physical and chemical barriers
complement
phagocytosis
2
Q
What are the induced defences ?
A
neutrophil chemotaxis
cytokines
interferon response
3
Q
What are the adaptive defences ?
A
antibodies
cell mediated immunity
memory
4
Q
What is the role of the adaptive immune response in an infection ?
A
to clear the infection
5
Q
Describe the course of an infection ?
A
establishment of infection threshold reached to activate adaptive response induction of adaptive response adaptive response memory cells
6
Q
What are the charactersitics of the immune response to an infection ?
A
dynamic- intensity changes with time
organised-in time and location- multiple secondary lymphoid locations
improved- increased affinity of BCRs, isotype switch
7
Q
What is the isotype switch ?
A
IgM to IgA
8
Q
What does the success of an infection depend on ?
A
properties of pathogen
dose of innoculation
route and mode of transmission
host properties
9
Q
How do pathogen properties influence success of an infection ?
A
method of infection
extracellular/intracellular
10
Q
How does the dose of innoculation influence the success of an infection ?
A
large dose needs to overcome innate immunity
multiple exposures mean more likely to get infected
11
Q
How does the route and mode of transmission infleuce the success of an infection ?
A
mucosal surfaces more likely to get infected
dirty injection
12
Q
How do host properties influence the success of an infection ?
A
health, age, chornic conditions
chronic disease mean immune system is already burdened
smoking and drugs can effect CNS and host defences
13
Q
Describe the stages of the immune response after a skin breach ?
A
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
14
Q
What is a primary infection ?
A
pathogen estbalishes at an initial site
adhere, colonise and penetrate
15
Q
What is the job of the innate immunity in an infection ?
A
contain the infection
16
Q
What are obligate intracellular pathogens ?
A
spread from cell to cell
17
Q
How do extracellular bacteria sprea ?
A
blood
lymphatics
18
Q
How do pathogens that dont enter tissues causes disease ?
A
toxin activity
19
Q
Which bacteria produce neurotoxins ?
A
clostridium botulinum
clostridium tetani
cholera
20
Q
What happens without innate immunity ?
A
high duration of infection
21
Q
What is SCID ?
A
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
22
Q
What is TLR3 ?
A
viral PRR in innate system
23
Q
What to TLR3 mutations lead to ?
A
lead to HSV induced encephalitits
HSV Is normally just cold sores
highlights importance of innate immuntiy
24
Q
What is SCID ?
A
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
25
What does establishment of a bacterial infection trigger ?
complement activation
activation of dendritic cells
innate signalling by macrophages for neutrophils
26
What happens in a cytokine milieu ?
cytokines made by T cells
specific TFs amde
differentiation of CD4 into effector cells
27
What are the different types of CD4 cells ?
```
Th17
Treg
Th1
Th2
Tfh
```
28
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
29
What is the role of the Th17 cell ?
reinforce innate immunity
30
What is the role of the Treg cell ?
supression of the immune system
31
What is the role of the Th1 cell ?
macrophage activation
32
What is the role of the Th2 cell ?
B cell activation
| Mast cell activation
33
What is the role of the Tfh cell ?
B cell activation in lymph nodes
34
What does HIV do ?
take out CD4 cells
35
How are pathogen destruction mechnanisms tailored ?
tailored to the type of pathogen and its mechanism of pathogenicity
36
Bacteria that produce toxins require what type of destruction ?
antibodies to neutralise the toxin
| eg. C.tetani
37
What type of destruction mechanism do extracellular bacteria require ?
antibodies
| eg. strep pneumoniae in pneumonia
38
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
```
39
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
40
What happens if Myco TB resists macrophage digestion ?
chronic inflammation develops
41
What are the 2 types of infections manifested by Mycobacterium leprae ?
tuberculoid leprosy
| lepromatous leprosy
42
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
43
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
```
44
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
45
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
46
What causes an imbalance between the Th1.Th2 resposne ?
peptide amount
MHC dnesitiy
cytokine milieu
47
What does an abundance of peptide lead to ?
MHC complexes drive Th1 response
48
What does a limited amount of peptide lead to ?
MHC complexes drive Th2 response
49
What are the characteristics of mucosal surfaces ?
thin and permeable
route of infection
no keratin
50
What is present on each mucosal surface ?
natural, commensal, non pathogenic commensal microbiota
| disticnt immune defences like peyers patches
51
What are the anatomical features of the mucosal immune system ?
comaprtments of lymphoid tissue- tonsils and peyers
| specialised antigen uptake cells- M cell
52
What are the effector mechanisms of the mucosal immune system ?
Memory T cell
regulatory T cell
secretory igA
microbiotia
53
What are the immunoregulatory features of the mucosal immune system ?
down regulate immune responses to food/non harmful antigens
54
What is the micorbiotia like across different mucosal surface ?
varies in composition and diversity
| different phyla
55
What can the composition of the microbiotia influence ?
immune system development and disease susceptibiliity
| success of immumotherapy
56
What is the role of the microbiota on mucosal surfaces ?
synthesis AMPs
stimulate epithelial cells to make AMPs
compete with pathgoens for niches
57
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
58
What does "itis" refer to ?
inflamamtion
59
What is acute inflammation ?
the initial tissue response to a number of inflammatory agents
60
What are agents of acute inflammation ?
```
infections
physical agents - trauma
chemicals
tissue necrosis
immunological disease
```
61
How does tissue necrosis lead to inflammation ?
ischaemic infarction - blockage in blood vessel leads to death of blood vessel- cells burst open stimulating inflammation
62
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
63
How is neutrophil chemotaxis stimulated ?
IL8 release from macrophages
64
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
65
What are the 2 types of acute inflammation ?
membranous
| suppurative
66
What is suppurative inflamamtion ?
production of pus
can be walled off by fibrotic tissue in repair forming an abscess
pus formed by pyogenic bacteria
67
What is an example of pyogenic bacteria ?
Staph aureus
68
What is it called when pus accumulates in a lumen ?
empyma
69
What is membranous inflammation ?
of mucosal surfaces
| neutrophil chemotaxis, epithelium is coated in fibrin, desquamted
70
What are the consequences of untreated dental abscess ?
spread to fascial layers and spaces
cellulitis
press on carotid artery
septicaemia
71
What is the objective of acute inflammation ?
reduction in infection
72
What is fibrosis ?
due to chronic inflammation
| attempt to repair damaged tissue
73
What does persistence of the causal agent lead to ?
chronic inflammation
74
What are the diseases Mycobacterium can cause by infecting macrophages ?
tuberculosis
| leprosy
75
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
76
What happens in TB ?
pathogen persists
activated macrophages dont work
infection is contained but not cleared
leads to granuloma formation
77
What are granulomas ?
macrophages fuse into multinuclear giant cells
surrounded by epithelioid cells
surrounded by Th1 cells - CD4
78
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
79
When are granulomas formed ?
bacteria resist the microbicidal effects of activated macrophages
80
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
81
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
82
How does a necrotic granuloma manifest ?
caseation necrosis leads to caesation
| cottage cheese appearance
83
What does caeseation of adrenal gland lead to ?
due to TB
| lead to adrenal insufficirncy
84
What are the other manifestations of caeseation necrosis ?
confluent granulomas- pulmonary TB
lymoh node caeseation
miliary TB
Ghon complex
85
What is associated with the Ghon complex ?
anthracasis
| tissue blackening
86
What can inflammation lead to ?
diseases with a loss of function
87
What happens in arthritis ?
loss of joint function
88
What happens in periodontal disease ?
loss of tooth function
89
What are the systemic effects of inflammation ?
fever
acute phase response
shock
90
What happens in fever ?
raising of temperature - not preferable for microbes
| adaptive immunity becomes more potent
91
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
92
How is the systemic fever effect triggered ?
pro inflammatory cytokines
| IL6 IL1 TNF- alpha
93
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
94
What is the role of CRP ?
binds to phosphocholine on bacterial surfaces and opsinises bacteria to activate complement
95
What is the role of mannose binding lectin ?
binds to carbohydrates on bacteria
| opsinisation
96
What can CRP be used in ?
CRP assay for suspected fever
97
What is septicaemia
infection of blood
| might be via an endoxtoxin from gram negative bacteria like in a dental abscess untreatd
98
What happens in septic shock ?
circulatroy collapse causing hypoperfusion of organs
| systemic inflammation means blood leaves circulation to enter tissues
99
What can lead to septic shock ?
haemorrhage
generalised vascular permeability
dilution
100
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
101
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
```
102
What are the pathways to inflamamtion ?
```
hypersenstivity
immunodeficneciy
autoimmunity
infecton
metabolic disroders
```
103
Different classes of viral pathogen require what ?
different effector mechanisms
104
What type of immunity do viruses require ?
cell mediated
| humoral
105
What are the role of CD8 cells in viral infections ?
clear infection
recognise infected cells
antigen specific
106
What is the role of antibodies in viral infections ?
contain infection
| stop spreading
107
Are NK cells antigen specific ?
no
| they are innate lymphoid cells
108
How are NK cells activated ?
IFN alpha and beta
type one IFN
released from virally infected cells
IL-12
109
How do NK cells ensure the cell is virally infected ?
have complex array of receptors
| KIR receptor
110
What does the KIR receptor detect ?
```
increased MHC class I expression
infected cells make more MHC class I
```
111
What are KIR genes like ?
highly polymorphic
112
What do NK cells release ?
IFN gamma
type II IFN
activates macrophages, this leads to CD8 activation
113
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
114
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
115
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
116
How do IgA protect against viral infections ?
bind to virus and prevent it entering cells
117
How do CD4 cells help CD8 cell sin viral infections ?
CD4 helps CD8 to fully funtion
118
What happens to CD4 cells in HIV ?
massive depletion
119
What happens to cellular immunity in AIDS ?
no CD4 cells to help CD8 cells in viral infections
| no B cell help- no antibodies
120
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
121
What causes AIDS ?
HIV-1/HIV-2
122
How is HIV spread ?
from primates
123
How does HIV enter cells ?
CD4 receptor
| CCR5 coreceptor
124
What is the CCR5 receptor ?
a chemokine receptor on memory T cells
| HIV blocks out the receptor so memory to infection is wiped out
125
Which other cells is the CCR5 Co receptor also present on ?
macrophaes
dendritic cells
virus switches between cell types
126
What are the first cells to be infected with HIV ?
T cells
127
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
128
What are the phases of a HIV infection ?
flu like symptoms
asymptomatic
symptomatic
AIDS
129
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
130
Which region do fungal infections target ?
oropharyngeal area
131
What are some predisposing conditions to fungal infections ?
immunodeficiency from HIV, chemotherapy, haematological malignancies
132
How many species of candida are there in the mouth ?
12
133
What can aspergillus cause ?
aspergillosis
134
What is 80% of oral candida ?
is candida albicans
135
What type of pathogen is candida ?
commensal
136
What are the candida morphologies ?
budding yeast
hypahe
pseudohyphae
137
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
138
How is candida recognised ?
TLR 2
TLR4
TLR9
on myeloid cells
139
What is the cell mediated immunity response to candid a?
IL-12
| IFN gamma from NK cells which favours differentiation of Th1 cells
140
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
141
What is pseudomembranous candidiases characterised ?
plaques can be scraped off
142
How is chronic hyperplastic candidiasis characterised ?
plaques cant be scraped off
| has penetrated tissues
143
What is erythematous candidiasis ?
poorly fitted dentures
144
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
145
What is the evolution of pathogens like ?
in parallel to evolution of the human immune system
146
Which part of the immune system has evolved ?
adaptive immunity
147
How do we know pathgoens evade the immune system ?
from genomics
148
Why is evasion of the immune system necessary for pathogens ?
exploit habitat and compete in it
149
What is immune system evasion aided by ?
short life cycles
| rapid mutation rate
150
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
151
How do the large number of serotypes of Strep pneumoniae differ ?
in their capsular polysaccharide
152
What does each different serotype do ?
elicit a different serotype antibody response
153
Protective immunity is ?
serotype specific
154
What does serotype variety allow ?
bacteria to prosper
155
How is genetic variation defined ?
different serotypes require different serotype specific antibodies
156
Having specifc antibodies to one serotype does not ensure.....
immunity and antibodies to other different serotypes
157
How many serotypes does Strep Pneumoniae have ?
90
158
How many serotypes does the gneus salmonella have ?
2500 types
159
How are serotypes discovered ?
with assays
160
What can a species with a high serotype variety do ?
evade the immune system
161
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
162
What is antigenic drift ?
gradual change in genome due to point mutation in genes
different strains are prodcued
subtle changes in genes and vaccines
163
Which genes in the influenza virus undergo antigenic drift ?
genes for viral envelope proteins
| haemaglutinin and neuraminidase
164
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
165
Does antigenic drift diseases cause epifemics ?
no - limited epidemics
166
What is the characteristic of small pox ?
small pox has no antigenic variability
| eradicated successfully with vaccine
167
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
168
What does antigenic shift lead to ?
acute radical change in virus and new strain not ever seen before
radically different strain appears suddenly
169
What is the infectivity like of antigenic shit pathogens ?
infects large numbers of people
| severe disease and pandemics
170
What are the genetic chnanges in antigenic shift ?
recombiantion of genomes between avian and human virus
171
Why do avain viruses infect humans ?
culture of animal husbandry
172
Viruses dividing rapidly allows what ?
```
large numbers of MHC class I expression with antigen by cell
activate CD8
```
173
What type of state can viruses adopt ?
a quiescent state
low replication rates
doesnt produce enough antigen for presentation
no recognition
174
How do viruses also evade the immune system ?
immunosurveillance
175
What happens to viruses in the quiscent state ?
they are reactivated and causes disease
176
Where does herpes simplex live ?
nervous system- trigeminal tract - persists
| manifests as cold spores
177
Where does HSV infect ?
epithelial cells
| leading to pathology
178
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
```
179
How is HSV reactivated ?
```
times of stress
sunlight
bacterial infection
hormonal changes
HSV reactivated and infects epithelial cells causing spores
```
180
What are examples of latent viral infections ?
Lentivirus group- HIV
| EBV
181
How does EBV cause glandular fever ?
infecting B cells
remaining dormant in a small number in B cells
swollen lymph nodes
182
Which individuals are likely to be reinfected with EBV ?
immunosupressed individuals
183
Reactivated EBV can lead to what ?
disseminated EBV and infected B cells can become malignant - B cell lymphoma
184
What does reactivation of varicella zoster lead to ?
shingles in adult life
185
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
186
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
```
187
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
188
How does treponema pallidium evade antibody recognition ?
coats in fibronectine- evade antibody recognition
189
What does P.gingivalis do to digest antibodies ?
secrete proteases
190
How does Mycobacterium TB evade phagocytosis ?
prevents fusion of lysosome and phagosome
191
What are bacteria superantigens ?
staphylococcal enterotoxins
192
What do bacterial superantigens do ?
```
link TCRs and MHC class I independent of the antigen
stimualtes excessive polyclonal response of T cells
```
193
What is the consequence of excessive T cell cytokine release ?
toxic shock syndrome
194
What is an example of toxic shock syndrome ?
staph aureus contaminated vaccines
195
What happens to T cells in toxic shock after being overstimualted ?
undergo apoptosis
| leaves few clones in circualtion
196
What happen in toxic shock syndrome ?
```
toxin shock
dissemianted infection
systemic inflamamtion
loss of blood loss to the tissue
organ hypoperfusion
```
197
What are the causes of Primary immunodeficiencies ?
affect immune cell development
| gene mutation
198
What are the consequences of primary immunodeficienciencies ?
innate/adaptive immune deficiency manifesting as recurrent infections
199
What do T cell deficincies lead to ?
candida infections
viral infections
intracellular pathogens as no CD8
200
What do complement, B cell and phagocyte deficiencies lead to ?
extracellular pathogen infections
| pyogenic infections
201
What are examples of Primary immunodeficincies ?
SCID
XLA
CVIDs
202
What are many primary immunodeficnecies due to ?
x linked recessive mutations
203
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
204
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
205
What is Jak3 ?
protein kinase
206
What are other causes of SCID ?
RAG 1/2 mutation
| ADA mutations
207
What is ADA ?
adenosine deaminase
208
What is the treatment for SCID ?
bone marrow transplantation
209
What is the most common primary immunodefcinecy ?
CVID
210
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
211
What are the forms of IgA deficiency ?
familial and sporadic
212
What is hyper IgE deficiency syndrome ?
high IgE levels
| autosomal dominant
213
How does hyper IgE deficinecy syndrome manifest ?
recurrent infection with fungi and pyogenic bacteria
214
What is the cause of hyper IgE deficinecy syndrome ?
mutation in STAT TF pathway for Th17 regulation - depleted Th17
215
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
216
What is the technique used to assess Th17 cell deficinecy ?
flow cytometry
217
What is XLA ?
brutons x linked agammaglobulinemia
218
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
219
What is the consequence of XLA ?
recurrent infections with extracellular pyogenic bactiera like strep pneumoniae
chronic infections with poliovirus,Hep B and Hep C
220
What is the treatment for XLA ?
immunoglobulin infusion
| antibiotics for bacterial infections
221
What do complement deficiencies lead to ?
recurrent infections with extracellular bacteria
222
What does C3 deficiency lead to ?
recurrent strep pneumoniae
| pnuemococcus infection
223
What does C5 deficiency lead to ?
susceptibility to neissera menigitides
| leads to meningococcus infectious
224
What other disroders can complement deficinecy lead to ?
congenital neutropenia
| leukocyte adhesion deficiencies
225
Why do complement and Ig deficiencies overlap ?
they both work together
226
What are the causes of secondary acquired immunodeficinecies ?
```
immune senescnece- ageing and poor nutrition
Burns- remove skin and vasculature
immunosupressants
tumours
HIV
```
227
What is chronic lymphocytic leukaemia ?
make only one type of cell
die from infections
vaccines also become ineffective
228
Where is HIV prevalent ?
sub sahran africa
229
What was the HIV prevalence in 2018?
37.9 million
230
What was the daily HIV incidence in 2018 ?
5000 new cases a day
231
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
232
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
233
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
234
What is the effect of age on AIDS preogression ?
younger HIV+ people are less likely to succumb to AIDS- slow progression
235
What are the host genetic variants that influence AIDS progression ?
KIR
HLA
CCR5
236
What do polymorphisms in HLA ans KIR do ?
different polymorphisms make some people more resistant and some more susceptible to AIDS
237
What is CCR5 ?
chemoline receptor on memory cells
238
What does HIV do to CCR5 ?
binds to it and blocks it
239
What happens in a CCR5 mutation ?
```
frameshift
producing a truncated protein
HIV no longer binds
hetero- slow progression
homo- progression halted
```
240
What does HIV do with reverse transcriptase ?
HIV converts RNA to cDNA
| via reverse transcriptase
241
Why is reverse transcriptase targeted in HIV therapy ?
stops viral replication
242
How is Reverse transcriptase targeted
with nuceloside analogues and non-nucleoside analogues
243
What is the role of protease in HIV ?
cuts large proteins into smaller ones
| uses this for viral assembly
244
How can protease be targeted in HIV therapy ?
protease inhibitors
245
What is the problem with HIV therapy ?
resistance to therapy is conferred in HIV quickly due to high mutation rate
246
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
247
How can HIV drug resistance be avoided ?
combinatorial drug therapy
248
What is HAART ?
highly active antiretroviral therapy
249
What does HAART do ?
reduces viral load
| reducing morbidity and mortalit
250
What has an increase in HAART lead to ?
decrease in deaths
251
What are the disadvantages of HAART ?
Doesnt fully clear virus
lifelong treatment necessary
expensive
severe side effects
252
What is the definition of autoimmunity ?
responses to self antigen/commensal flora leading to tissue damage
253
What is the normal state of self tolerance ?
lymphocytes which react to self antigen are eliminated
254
What is autoimmuniy characterised by ?
breakdown in self tolerance
255
What is autoimmunity mediated by ?
autoreactive antibodies
| autoreactive T cells
256
What is psoriasis ?
autoreactive T cells against skin antigens
skin inflammation
formation of scaly patches and plaques
257
What is rheumatoid arthritis ?
autoreactive T cells against joint synovium
| joint destruction and inflammation
258
What is graves disease ?
autoantibodies agaisnt TSH receptor
| leads to hyperthyroidism and overproduction of thyroid hormones
259
What is hashimoitos thyroiditis ?
Autoantibodes and autoreactive T cells to thyroid antigens
destruction of thyroid tissue
hypothyroidism
underproduction of thyroid hormones
260
What is Systemic lupus erythematosus ?
autoantibodies and autoreactive T cells against DNA and chromatin leads to glomerulonephritis
261
What is sjorgens syndrome ?
autoanitobodies and autoreactive T cells against ribonucleoprotein antigens
lymphocyte infiltrate of exocrine glands
262
What is crohns disease ?
Autoreactive T cells against intestinal Flora antigens
| intestinal epithelium inflammation and scarring
263
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
264
What is type one DM ?
autoreactie T cells against pancreatic Beta cells
destruction of pancreatic beta cells
non production of insulin
265
What are the mechanisms of self tolerance ?
central tolerance
| antigen segregation
266
What is central tolerance ?
deletion and editing of T cells that react to self antigen
happens in thymus gland
breakdown leads to autoimmunity
267
What is antigen segregation ?
physical barrier to self antigen and lymphoid system
| in peripheral organs like pancreas
268
Is breakdown in self tolerance enough to trigger autimmunity ?
not sufficient
| environmental triggers like infection and genetic triggers will also be needed
269
Can autoimmune cells that escape central tolerance be destroyed ?
yes- peripheral tolerance- Treg cells
270
What is the aetiology of autoimmunity ?
unknown
271
What is the effector mechanism of autoimmunity ?
autoreactive T cells
| autoantibodies
272
What is the aim of the normal immune system ?
remove non self antigen
273
Can self antigen be eliminated ? What is the implication of this ?
self antigen cannot be destroyed hence a chronic infection ensues
274
What are the exceptions to the destruction of self antigen rule ?
hashimotos thyroiditis and type one DM - actually destroy the tissue
275
What are the ways in which autoimmune disease can be classified ?
organ specific
non specific- many tissues effected
inflammatory bowels disease
clustering in families
276
What are examples of organ specific autoimmune diseases ?
type one DM
goodpastures syndrome
crohns disease
graves diseasse
277
What is an examples of a sytemic autoimmune disease ?
rheumatoid arthritis
primary shorjens syndrome
systemic leupus erythematosus
278
What is the progress of autoimmune diseases ?
activation phase leads to a chronic phase
279
How are the chronic effects of autoimmune diseases mediated ?
autoantibodies
| autoimmune T cells
280
What mediates the effects of myasthenia gravis ?
autoreactive antibodies
281
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
282
What is a type II autoimmune disease ?
antibodies against cell surface
283
What are examples of type II autoimmune diseases ?
goodpastures syndrome
pemphigus vulgaris
bullous pemphigoid
284
What is goodpastures syndrome ?
antibodies against collagen type IV in basement membrane
| manifests as pulomonary haemorrhage and glomerulonephritis
285
What is pemphigus vulgaris ?
autoantibodies agaisnt epidermal cadherin joins epithelial cells
mainfests as skin blistering and heamorrhage
286
How can we identify pemphigus vulgaris ?
create antibodies complementary to antibodies that are autoimmune to cadherin
tag first antibody with fluorsence
287
What is bullous pemphigoid ?
autoimmune antibodies to basement membrane
288
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
289
What are the 2 examples of type III autoimmune disease ?
mixed essential cryoglobulinemia
| rheumatoid arthritis
290
What is the complex in mixed essential cryoglobulinemia ?
rheumatoid facto igG complexes- systemic vasculitis
291
What is the complex in rheumatoid arthritis ?
rheumatoid factor IgG complexes
292
What is a type IV autoimmune disease ?
T cell mediated
293
What are examples of type IV autoimmune diseases ?
Type I DM
| multiple sclerosis
294
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
295
What is multiple sclerosis ?
myelin protein
destruction of myelin sheath by T cells
brain invasion by CD4 cells
muscle weakness
296
What are the cells of the pancreas ?
alpha cells- glucagon
beta cells- insulin
gamma cells- somatostatin- GHIH
297
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
298
What classification is Rheumatoid arthritis ?
type III and IV
299
Myasthenia gravis and graves disease are examples of what ?
autoantibodies against cell surface receptors
300
What happens in myasthenia gravis ?
affects NMJ
antibodies to acetylcholine receptors which are degraded
no signalling between neurones and muscles
301
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
302
What is SLE ?
antibodies to common antigens like DNA
widespread butterfly red patches
systemic
detected in immunofluoresence
303
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
304
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
305
What is the difficulty of analysing genes for autoimmune diseases ?
outbred popualtion
| interindividual variation is great
306
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
307
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
308
What is a gene loci ?
area of a chromosome
309
Which gene variants are associated with Autoimmune diseases ?
HLA variants- they are highly polymorphic
310
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
311
Variations in HLA genes can confer what ?
resistance to breakdown in self tolerance
| suscpetibility
312
What is the role of MHC ?
antigen presentation
| T cell development in thymus gland
313
Which polymorphism effects CD4 cells ?
DR class II
314
Which polymorphism effects CD8 cells ?
B27 class I
315
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
316
Which polymorphism is present in most AD diseases ?
DR polymorphism- class II
317
Which gender is more at risk for AD diseases ?
females
318
What is the role of infection in AD diseases ?
infection can trigger autoimmunity in hosts with the right genetic make up
319
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
320
What is molecular mimicry ?
cross reaction between microbial antigens and own antigens
| stimulate autoimmune reaction to self antigens
321
Give an example of molecular mimicry ?
rheumatic fever
infection with strep antigen
cross react with cardiac muscle
degenerate cardiac muscle
322
What is an allergic response ?
hypersensitivity reaction to an otherwise harmless extrinsic antigen
323
What is the classification of allergic responses ?
same as autoimmune- type II.III and IV
| but also have type I not seen in autoimmune
324
What are the shared effects of autoimmune and allergic responses ?
inflammation and tissue destruction
325
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
326
What is a type I hypersensitive reaction ?
immediate type
327
What is the range of consequences in a type I hypersensitive reaction ?
mild attrition to anaphylaxis
328
What is atopy ?
an allergy with a genetic predisposition like hayfever
329
What are examples of atopic disorders ?
10-40% caucasians have one
| asthma, eczema and uticaria
330
What is uticaria ?
hives
331
What mediates type I hypersensitivity reactions ?
IgE and mast cells
332
When do type I hypersensitivity reactions occur ?
immediately after exposure to allergen
333
What do mast cells do in hypersensitivity reactions ?
release inflamamatory mediators
| cause pathological effects
334
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
335
What is Der P I ?
common respiratroy allergen found in foecal pellets of house dust mite
336
What are the 2 phases that lead to type I hypersensiticity ?
sensitisation and reaction
337
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
338
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
339
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
340
What types of molecules can be released by mast cells in granules ?
histamine, heparin
| TNF-alpha
341
What do histamine and heparin do ?
toxic to parasites
increase vascular permebaility
smooth muscle contraction
anticoagualant
342
What does TNF-alpha do ?
promotes inflamamtion via cytokines leads to swelling
343
What are the IgE mediated reactions to extrinsic antigens ?
systemic anaphlyaxis
| acute uticaria
344
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
345
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
346
What are the phases of an allergic reaction ?
imemdiate reaction and late reaction
347
What is usually an imemdiate reaction in allergic situations ?
Wheal- raised area
| flare- redness
348
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.
349
What is systemic anaphylaxis ?
allergens reaching the bloodstream activating mast cells throughout the body
mast cell degranulation throughout the body
350
What are some of the systemic effects of systemic anaphylaxis ?
increased capillary permeability
smooth muscle contraction
wheezing
stomach cramps
351
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
352
What are the effects of IgE ?
eject pathogen by physical force - coughing, sneezing and vomiting
invovles Th2 response- help B cells to produce IgE
353
What does IgE arm ?
arms mast cells, eosinophils and basophils to respond to parasite antigens by binding to Fc receptors on the cells
354
What are the other roles of mast cells ?
at mucosal surfaces express Fc receptors and TLRs
355
What is a type I hypersensitive reaction ?
Immune response at the cell surface
356
What is an example of a type II hypersensitive reaction ?
haemolytic anaemia
357
What are the causes of heamolytic anaemia ?
penicillin allergy
blood group incompatibility
autoimmune haemolytic anaemia
358
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
359
What happens in type III hypersensitivity ?
antigen.antibody complex deposition leads to inflammation
360
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
361
What is another cause of type III hypersensitivity ?
pencillin allergy
362
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
363
What is a type IV hypersensitive reaction ?
delayed type T cell mediated
364
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
365
Where can type IV hypersensitivty be seen ?
allergic contact dermititis
graft rejection
poison ivy and nickel allergy
366
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
367
How does allergic contact dermititis manifest ?
blisterng skin lesions
368
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
369
What happens in poison ivy allergy ?
chemical in ivy called pentadecatechol modfies self antigens leading to CD8 response
370
Why is type IV hypersensitivity delayed ?
requires development of T cells
| unlike immediate type I- already sensitised
371
What considerations should be made with allergic rhinitis ?
mouthbreather and develop mild gingival hyperplasia
372
What considerations should be made with antihistamines ?
cause dry mouth
373
What is angiodema ?
rapid swelling of dermis and mucosa in response to allergen
374
What is oral allergy syndrome ?
food allergy from fruit and veg
| leading to allergic reactions in the mouth
375
Where can latex allergies be found ?
gloves. dental dams and tubing
376
What are the histological features of coeliac disease ?
inflammatory filtrate
tissue damage
lengthening crypts
increased epithalial cell division
377
What are the clinical consequences of coeliac disease ?
```
abdmoinal distention
malabsorption
diarrhoea
anaemia
intestinal cancer
```
378
What is coeliac disease ?
inflamamtion of the jejunum due to a response to gluten
379
What is gluten ?
complex of proteins found in wheat, barley and oats
380
What is the management of coeliac disease ?
elimination from the diet
381
Why is the incidence of coeliac disease increasing in china and india ?
western diet increasing
382
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
383
is transglutaminase active in non coeliacs ?
no it is inactive in non coeliacs
384
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
385
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
386
What are the manifestations of crohns disease ?
transmural inflammatory lesions - involve epithelium and lamina propia
chronic and episodic
thickened/fissured bowel
fistulation
387
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
```
388
What happens in crohns disease ?
cant secrete AMPs- cant tolerate normal microflora
389
What are the oral manifestations of crohns disease ?
cheilitis
oral ulceration
fissuring
glossitis
390
What are the genetic variants associated with crohns disease ?
NOD2
ARGM
IL23R
391
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
392
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
393
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
394
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
395
Which metabolic disorders are involved with inflammation ?
gout and T2DM
396
Are gout and T2DM genetic ?
no- theyre acquired
| mainly environmental
397
What other conditions can gout and diabetes be involved with ?
obesity and CVD
398
What is gout ?
inflammation of the digits, toes and joints
| EG. metatarsal joint
399
What leads to gout ?
uric acid crystal deposition
leads to inflamamtion
activates the inflamamsome
400
What is the inflammasome ?
complex of proteins which drive IL-1 secretion
more inflamamtion
use anti IL-1 therapy
401
What are the forms of gout ?
primary gout- may be genetic
| secodnary gout- due to chemotherapy/drugs
402
What is the pathway for gout ?
```
primary/secondary gout
hyperuricemia
crystal formation in periphery
crystal depostion
gout flares
```
403
What factors can exacerbate crystal deposition in gout ?
western diet
obesity
age
404
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
