I - Immune Deficiencies Flashcards
list sensor cells
epithelial
dendritic
macrophages
mast
4 ways sensor cells produce a response to infection
- type 1 and 3 interferon production
- recruitment of circulating neutrophils and monocytes
- effector activity: phagocytosis and ROS
- release of mast cell granules
describe induction of the adaptive immune response
- pathogens are detected by dendritic cell subsets
- dendritic cell subtypes release cytokines
- type 1 interferons signal onto cytotoxic t cells –> lyse pathogens
- CD4 / Th1 cells sustain cytotoxic t cell response
- IL1B/6/23 and TGF-B signal to CD4 Th17 cells
- CD4 FTh signals to germinal cell B cells
what cytokines and effector cells do CD4 Th1 ILC1 lymphocytes signal to?
IFN gamma, TNF alpha and IL2
–> macrophages and cytotoxic t cells
what cytokines and effector cells doCD4 Th17 ILC3 lymphocytes signal to?
IL 17A and IL22
–> neutrophils and epithelial cells
what cytokines and effector cells do CD4 follicular lymphocytes signal to?
IFN gamma, IL17A, IL4, IL21
–> germinal centre b cells –> memory / plasma cells –> release IgG, IgA, IgE
what chains make up immunoglobulins
2 soluble heavy and light chains
give the 2 regions of an antibody
Fab - fragment antigen binding
Fc - fragment crystallisable / constant
which part of the antibody recognises the antigen
Fab of both heavy and light chains
what part of the antibody determines the effector function
Fc heavy chain
what part of the antibody specifies the antibody isotype
heavy chain
4 main effector functions of IgG
- activation of complement
- clearance and elimination of antibody coated pathogens
- transport and delivery of immunoglobulin to different body compartments
- regulation of immune responses
define inborn errors of immunity
heterogeneous group of genetic disorders resulting in immune dysfunction and ill health
how many single gene defects (roughly) impact the immune response
485
what discovery has lead to a massive increase in discovery of inborn errors of immunity
DNA sequencing tech
what is the commonest cause of inborn errors of immunity?
antibody deficiency 37%
what types of inborn errors of immunity make up the majority?
antibody deficiency 37%
syndromes with immunodeficiency 17%
complement deficiencies 16%
congenital defects of phagocytes 16%
cellular / humoral immunodeficiencies 10%
list clinical features of most immune deficiencies
increased susceptibility to infection
AI disease
allergy
auto-inflammatory disease
viral related cancers eg EBV, HPV
which cellular component is the most common cause of inborn errors of immunity
B cell
what are syndromic infectious diseases commonly known as
primary immune deficiencies
what infection risk does primary immune deficiencies incur
susceptible to multiple infections
a large number of infectious episodes
rare, but opportunistic infections
who is affected by primary immune deficiencies
kids more than adults
what cell type is most affected in primary immune deficiencies
leukocytes
how can primary immune deficiencies present?
AI, inflammatory, allergic disordes or cancer
give examples of primary immune deficiencies
SCID - severe combined immune deficiency syndromes
XLA - x linked agammaglobulinaemia
CGD - chronic granulomatous disease
genetic inheritance of primary immune deficiencies
X linked or autosomal recessive
person is susceptible to a single or few infection agents, with only a single or multiple episodes of infection. Dx?
familial infectious diseases
who is most affected by familial infectious diseases
kids more than adults
cell types affected in familial infectious diseases
leukocytes or epithelial cells
genetics of familial infectious diseases
X linked, AR or AD
examples of familial infectious diseases
mendelian susceptibility to mycobacterial disease
critical care influenza A pneumonia
what triggers mendelian susceptibility to mycobacterial disease
gene defects cause failure to produce IFN gamma so can’t fight weakly virulent mycobacteria and BCG
what gene defects cause mendelian susceptibility to mycobacterial disease
IFN gamma producing genes - IL12 / IL23
IFN gamma responding genes - IFN-gammaR and Tyk2
describe pathway in normal response to mycobacterial disease
infected macrophages stimulated to produce IL12 / IL23
this induces T cells to make IFN gamma
IFN gamma acts on macrophages and neutrophils to stimulate TNF alpha and NADPH oxidase to eliminate pathogen
what is wrong in mendelian susceptibility to mycobacterial disease
no generation or response to IFN gamma –> variable penetrance
what R recognises influenza
TLR3
what is made when influenza binds to receptor
type 1 interferons
promote interferon stimulated genes
how do interferon stimulated genes affect replication of influenza
they control replication
name a genetic susceptibility to TB
P1104A variant of tyk2
how does p1104a affect TB susceptibility
it impairs il23 but not il12 production of ifn gamma
–> 80% go on to develop TB
what mutation increases COVID19 mortality
type 1 interferon immune pathway mutation
some x linked TLR defects
what ABs did 10% of severely ill COVID 19 patients develop
type 1 interferon ABs therefore dampening the response
what errors of immunity lead to AID
t cell tolerance
t cell apoptosis
t reg function
also hypomorphic SCID gene
2 main categories of monogenic autoinflamm disorders
Il1 inflammasomopathies (FMF)
type 1 interferonopathies (aicardi goutiers syndrome)
what IEI causes allergic disorders
autosomal dominant (AD) STAT 3 loss of function (hyper IgE syndrome)
what symptoms does STAT3 patient present with
eczema
staph aureus / fungal infections of skin and lung
bone disease
elevated IgE
what can EBV cause in immune def patients
hodgkins
non hodgkins
smooth muscle cancers
what IEI cause EBV to cause cancer
impairment in cytotoxic function - perforin def, XLP/XIAP def
loss of proximal signalling molecules for T cell activation and expression of NKG2D on NK/CD8 cells
in which disease does a genetic mutation or AID cause between 10-20% of cases
severe SARS COV2 infection
which IEI gets minor symptoms only
selective IgA deficiency
which IEI has normal life expectancy
common variable immune deficiency
Mx of common variable immune deficiency
weekly / monthly IgG therapy
which IEI is life threatening
SCID
Mx of SCID
transplant or gene therapy
presentation of IEI infections
SPUR
severe- sepsis
persistent - multiple ABx needed to treat it
unusual infections - opportunistic eg PMJ, CMV
recurrent - 2+ pneumonias/yr or 8+ otitis media in a child
what are other key presentation features of IEI
early onset refractory AI cytopenias
early osnet IBD, HLH, skin disease
difficult to treat allergic skin disease
unexplained viral cancers in pt <40 yrs old
FH of immune def or consanguinity
Ix for immundeficiency
FISH
FBC - Hb, neuts, plats, lymphs
Ig - G/A/M/A
serum complement - C3,C4
HIV test
what % of immune deficiencies will get picked up with FISH Ix
85%
why is IgG important
key host defence in alevoli - in equilibrium with blood
function of secretory IgA and IgM
protect URT and LRT
where do secretory IgA/M come from
mucosal B cells rather than blood
2nd line Ix for immune deficiencies
measure conc of vaccine ABs - tetanus, pneumovax
analysis of lymphocyte subsets using flow cytometry (eg CD4, CD8 etc)
why is vaccine response important to determine
inappropriate vaccine response is diagnostic of primary AB deficiency syndromes
