MedEd Immuno 1 Flashcards
cells of innate immunity (6)
neutrophils
basophils
eosinophils
macrophages
natural killer cells
dendritic cells
cells of adaptive immunity (2)
B and T cells
which type of immunity is fast vs slow
innate = fast
adaptive = slow
soluble components of the innate immune system
complement
acute phase proteins
cytokines / chemokines
describe activation of the innate immune system
produce phagocytes and release them into blood
endothelial cells express adhesion molecules - allows cells to stick and migrate
phagocytosis
oxidative / non oxidative killing
macrophages communicate to t cells
neutrophils die and form pus
which immune cells is pus mainly composed of
neutrophils
what is the point of dendritic cells in terms of the 2 types of immunity
mediate the transition from innate to adaptive immunity
what type of cell is a dendritic cell
phagocyte
what do dendritic cells do after phagocytosis (3)
upregulate expression of HLA
express costimulatory molecules
migrate via lymphatics to lymph nodes
what receptor do dendritic cells use to migrate to lymph nodes
CCR7 receptor
what do B and T cells do in primary vs secondary lymphoid organs
primary - developed and mature
secondary - interaction with pathogens
which organs are primary vs secondary lymphoid organs
primary - bone marrow and thymus
secondary - spleen, lymph nodes, MALT
what is humoral vs cellular immunity
humoral = deals with antigens from freely circulating pathogens (outside cell)
cellular = deals with clearing the infected cell
lifecycle of a T cell
pre T cells made in thymus
selection in thymus
CD4 or CD8 T cells made
lifecycle of B cell
produced in BM: pro B cell –> pre B cell
develop into IgM secreting B cells
then develop into plasma cells or undergo class switching to make IgG / IgE / IgA
how does T cell selection work in the thymus
low affinity for HLA –> not selected (inadequate reactivity)
intermediate affinity for HLA –> selected
high afifnity for HLA –> not selected (autoreactivity)
what % of produced T cells are selected in the thymus
10%
which T cells go on to make CD4 t cells and which go on to make Cd8 T cells
cd4 = affinity for HLA II
cd8 = affinity for HLA I
what are cd4 T cells aka
T helper cells
what are cd8 T cells aka
T killer cells
3 functions of cd 4 / t helper cells
recognise extracellular protein peptides presented on HLA2
help development of full B cell response
help development of some cd8 t cell response
3 functions of cd8 / t killer cells
reconise intraceullar protein peptides presented on HLA1
kill cells
2 ways cd8 / t killer cells can kill
via perforin / granzyme
via Fas ligand expression
describe B cell selection in the BM
no recognition of self = survive
recognition of self = not selected
what are the 2 fates of a B cell selected in the BM
become IgM secreting plasma cell
undergo class switching to become IgG/A/E B cell
which pathway of the B Cell (IgM or class switching) requires T cells and which is T cell independent
IgM = T cell independent
class switching = T cell dependent
what reaction do B cells undergo to become IgG/A/E B cells
germinal centre reaction
describe the germinal centre reaction
dendritic ells prime CD4+ T cells
CD4+ T cells help B cell differentiation
B cell proliferation with somatic hypermutation isotype switching
what do CD4+ T cells require to help B cell differentiation
CD40L:CD40
2 roles of ABs
identification of pathogens and toxins
interaction with and activation of other immune componnets to remove pathogens
which part of the AB is needed to identify pathogens
Fab
which part of the AB is needed to activate other immune components and remove the pathogen
Fc
which cell exists in immature form in periphery where they recognize pathogens, then mature and become adapted for presenting antigens to T cells in lymph nodes?
dendritic cells
what is the complement cascade
sequence of reactions that enhances the rest of the immune system
what is the starting point of the complement cascade
inactive circulating proteins
what is the activation stage of the complement cascade
proteases cleave the protein and initiate the cascade
what is the end point of the complement cascade
membrane attack complex (MAC) - attacks the pathogen cell membrane
fragments released during the complement cascade have 4 other effects, what are they?
increase vascular permeability
opsonise immune complexes and pathogens
activate phagocytes
promote mast cell and basophil degranulation
name the pathways of the complement cascade
classical or alternative or MBL
–> C3
–> final common pathway
–> MAC
what are the components of the classical pathway
C1 / C2 / C4
what are the components of the MBL pathway
C4 / C2
what are the components of the final common pathway
C5 / C9
how does the classical pathway kill pathogens
Ag-AB complexes
how does the alternative pathway kill pathogens
bacterial cell wall attack
how does the MBL pathway kill pathogens
attacks microbial cell surface and carbs
name 3 broad classes of immunodeficiencies
primary
secondary
physiological
3 classes of primary immune deficiencies
innate
adaptive
complement
4 classes of causes of secondary immune deficiencies and 2 examples of each
infections - HIV, measles
biochemical disorders - malnutrition, renal impairment
malignancy - leuakaemia, lymphoma
drugs - steroids, cytotoxics
3 physiological states of immune deficiency
neonates
pregnancy
old age
name 3 PIDs of failure to produce neutrophils
reticular dysgenesis
kostmann syndrome
cyclical neutropaenia
inheritance pattern of reticular dysgenesis
AR
inheritance pattern of kostmann
AR
inheritance pattern of cyclical neutropaenia
AD
mutation in kostmann
HAX1 protein
mutation in cyclical neutropaenia
ELA-2
PC of cyclical neutropaenia
episodic neutropaenia every 4-6 weeks
Tx for PIDs of failure to produce neutrophils
G-CSF
PID of defect of phagocyte migration
leukocyte adhesion deficiency
3 PC of leukocyte adhesion deficiency
high neutrophil count
absent pus formation
delayed umbilical cord sloughing
pathogenesis of leucocyte adhesion deficiency
deficient in CD11a/18 (expressed on neutrophils, binds to ICAM-1 on endothelial cells)
deficiency = neutrophils can’t exit bloodstream
Tx of leukocyte adhesion deficiency
haematopoietic stem cell transplant
PID of defect of oxidative killing
chronic granulomatous disease
pathogenesis of chronic granulomatous disease
deficiency of NADPH oxidase complex –> impaired killing
4 clinical signs of chronic granulomatous disease
granulomas
lymphadenopathy
hepatosplenomegaly
pus
what organisms are chronic granulomatous disease pts susceptible to
catalase positive organisms eg pseudomonas, listeria, aspergillus, candida, e coli, s.aureus, serratia
test for chronic granulomatous disease
nitroblue tetrazolium test
dihydrorhodamine flow cytometry test
result of nitroblue tetrazolium test in CGD
NO colour change from yellow to blue
result of dihydrorhodamine flow cytometry test in CGD
DHR oxidised to fluroescent rhodamine
Tx of CGD
IFNy
what cytokine deficiencies can cause issues
IL12 or IFNy
(both the cytokine or the receptor)
what are IL12 / IFNy deficient pts susceptible to
intracellular organisms eg mycobacteria or salmonella
child presents with recurrent bacterial and fungal infections. the nitroblue tetrazolium test is performed where the mixture remains yellow. Dx?
chronic granulomatous disease
3 PIDs with failure to produce lymphoid progenitors
reticular dysgenesis
X linked SCID
ADA deficiency
when do pts with failure to produce lymphoid progenitors present and why
after first 3 months of life, as maternal IgG protection wears off
pathogenesis of reticular dysgenesis
mutation of adenylate kinase 2 (AK2)
pathogenesis of X linked SCID
mutation of y-chain on IL2R
- poor cytokine response
what cells are absent in reticular dysgenesis
lymphocytes / neutrophils / macrophages / platelets
which cells are absent / weird in X linked SCID
no T cells or NK cells
B cells are IMMATURE
pathogenesis of ADA deficiency
adenosine deaminase deficiency
- needed for lymphocyte metabolism
which cells are present in low quantities in ADA deficiency
B, T, NK cells
Tx for failure to produce lymphoid progenitors PIDs
haematopoeitic stem cell transplant
Tx for ADA deficiency
Peg - ADA
which PID has a failure of T cell maturation
Di George syndrome
pathogenesis of Di george syndrome
deletion of 22q11.2
Sx / signs of Di George syndrome
CATCH22
cardiac abnormalities
abnormal facies
thymis aplasia
cleft palate
hypocalcaemia
22q11.2 deletion
cellular level abnormalities in di george syndrome
reduced T cells
normal B cells but reduced IgG
how does di george syndrome progress
gets better with age
Tx of di george syndrome
thymic transplant
what PID has failure of Cd4/8 selection
bare lymphocyte syndromes
how are bare lymphocyte syndromes type 1 and 2 different
1 = defect in gene expression of MHC1 –> deficiency of cd8
2 = defect in gene expression of MHC2 –> deficiency of cd4
what Igs are low in bare lymphocyte syndrome type 2
IgG,A,E (no cd4 help with class switching)
what PID has a failure of B cell development
bruton’s x linked alpha gammaglobulinaemia
pathogenesis of bruton’s x linked alpha gammaglobulinaemia
defective b cell tyrosine kinase gene
–> pre B cells can’t develop into mature B cells
–> no circulating IgG after 3 months of life
clinical sign of bruton’s x linked alpha gammaglobulinaemia
absent lymph nodes and tonsils
Tx of bruton’s x linked alpha gammaglobulinaemia
IV Ig
PID of failure to produce immunoglobulins
selective IgA deficiency
combined variable immune deficiency
prevelance of selective IgA deficiency
1/600
PC of selective IgA deficiency with %s
66% asymptomatic
33% recurrent respiratory tract infections
what Igs are low in CVID
A,G,E
PC of CVID
recurrent resp / GI infections
- AID
- granulomatous disease
what PID has failure of class switching
hyper IgM syndrome
pathogenesis of hyper IgM syndrome
T cell defect
- mutation in CD40L expressed by T cells
- encoded on Xq26
–> no class switching
Ig levels in hyper IgM syndrome
high IgM
no Ig A / G / E
Ix for adaptive immunodeficiencies
WBC
lymphocyte subsets inc cd4 / cd8
serum Ig / protein electrophoresis
child with recurrent infections who had seizures as a baby. Dx?
di george syndrome
what is the main clinical consequence of complement deficiency
increased susceptibility to encapsulated organisms eg s.pneumoniae, h.influenzae, n.meningitidis
which failure of the classical pathway is most common
c2
PC of classical pathway deficiency
recurrent infections
severe skin disease
all patients with C2 deficiency will have which AID?
SLE
when does failure of MBL pathway present and why
only if other precipitant eg prem / chemo / HIV / AB def
30% heterozygous for MBL def / 6-10% no circulating MBL
how does failure of alternative pathway present
encapsulated bacterial infections
how does failure of final common pathway present
encapsulated bacterial infections
which factors are deficient in final common pathway failure
c3 and c5-9
name 2 secondary complement deficiencies
SLE
nephritic factors
why does SLE cause a secondary complement deficiency
consumption of c3 and c4
why does nephritic factors cause secondary complement deficiency
auto ABs against complement
what 2 clinical features are nephritic factors associated with
glomerulonephritis
partial lipodystrophy
Ix for complement deficiencies
complement levels - c3/4 or c1 etc
CH50 - classical pathway activity
AP50 - alternative pathway activity
what condition has low c1 esterase inhibitor
hereditary angioedema
which condition has low c3 and c4
active lupus
Mx of primary complement deficiencies
screen family members
prophylactic vaccination / ABx
aggressive Tx of infections
severe childhood onset SLE with normal c3 and c4
c1q deficiency
mebranoproliferative nephritis with abnormal fat distribution
c3 deficiency with nephritic factor
meningococcal meningitis with FHx of sibling dying young
C7 deficiency
recurrent infections when neutropaenic following chemo, but previously well
MBL deficiency
is it auto inflamm or auto immune that has HLA associations
autoimmune
is it auto inflamm or auto immune that has auto ABs
autoimmune
name a rare monogenic autoinflamm condition
FMF - familial mediterranean fever
PC of FMF
periodic fevers and serositis
pathogenesis of FMF
abnormal TNFa / IL1 signalling due to MEFV mutatoin
what complex is involved in FMF
pyrin-marenostrin complex (controls activation of neutrophils)
Tx of FMF
colchicine
anakinra - IL1R antagonist
etanercept - TNFa inhibitor
name polygenic autoinflamm disorders
Crohns
UC
osteoarthritis
GCA
Takayasau’s arthritis
name some mixed pattern autoinflamm/autoimmune diseases
ankylosing spondylitis
psoriatic arthritis
Behcet’s
what HLA mutation does mixed pattern disease often have
HLA B27 mutation
what cells does the HLA B27 mutation affect
Cd8 and Th17 cells (adaptive)
NK cells (innate)
name some polygenic autoimmune conditions
RA
myasthenia gravis
pernicious anaemia
SLE
what mutations are present in polygenic autoimmune conditions
PTPN22 -‘ve T cell regulator
CTLA4 -‘ve T cell regulator
what is the HLA susceptibility allele of goodpastures
HLA DR15
what is the HLA susceptibility allele of graves / SLE
HLA DR3
what is the HLA susceptibility allele of T1DM
HLA DR3/4
what is the HLA susceptibility allele of RA
HLA DR4
name 3 monogenic autoimmune disorders
APECED
IPEX
ALPS
what is APECED
central tolerance breakdown
pathogenesis of APECED
mutation of TF AIRE - responsible for expression of self antigens in thymus to enable negative selection of autoreactive T cells
5 features of APECED
Autoimmune
polyendocrinopathy
candidiasis
ectodermal
dystrophy
what is IPEX
T reg abnormality
pathogenesis of IPEX
mutation in FoxP3 required for T reg cell development
Sx of IPEX
diarrhoea / diabetes / dermatitis
what does IPEX stand for
immune dysregulation
polyendocrinopathy
enteropathy
x linked
pathogenesis of ALPS
mutation in Fas pathway
T cells NOT killed in thymus –> dodgy T cells enter periphery
what does ALPS stand for
autoimmune
lymphoproliferative
syndrome
3 clinical features of ALPS
large spleen / lymph nodes
autoimmune cytopaenia
lymphoma
what is type 1 hypersensitivity
immediate - Ag cross links IgE on mast cells –> degranulation
what is type 2 hypersensitivity
AB dependent - ABs bind to surface Ag
what is type 3 hypersensitivity
immune complex - Ag-AB complexes form in blood and deposit in tissues
what is type 4 hypersensitivity
delayed - T cell mediated (Cd4 release cytokines, CD8 kill targeted cells)
example of type 1 hypersensitivity
atopic eczema
anaphylaxis
example of type 2 hypersensitivity
Graves
Myasthenia Gravis
example of type 3 hypersensitivity
SLE
serum sickness
example of type 4 hypersensitivity
T1DM
contact dermatitis
