Immunodeficiencies I: Primary Deficiencies of Innate Immunity Flashcards
it’s very unusual to see a t cell def. that doesn’t also present as
combined immunodeficiency
primary immune deficiency, most molecular defects are
known
if someone has history of repeated infections, suggest diagnosis of
immunodeficiency
primary immunodeficiency are generally caused by
inherited gene defect
immunodeficiency disease only treatable by
Hematopoietic stem cell transplantation or gene therapy can be useful to correct genetic defects.
primary immunodeficiency are very
rare
secondary immunodefieicncies are very
common - major cause of infection and death
pure Immunodeficiencies
like x linked amanoglobinemia
clinical presentation is pretty similar
complex Immunodeficiencies
clinical presentation varies a lot
signifiance of Immunodeficiencies
increased risk of opportunistic infections and tumors
what are more common, primary or secondary Immunodeficiencies
secondary
primray or secondary can result in lesionsoutside of immune system
secondary Immunodeficiencies
X linked SCID is example of
inherited primary Immunodeficiencies
in SCID pt does not have
T cells
polymorphisms in primary Immunodeficiencies are much more common than
the mutations that give rise to the primary Immunodeficiencies
three causes of primary Immunodeficiencies
mutations
polymorphisms
polygenic disorders
selective IgA def. is most common of
primary Immunodeficiencies
notecard pg 8
8 - only do the ones he has gone through
asplenia is very
rare
APCEd defieicney in
AIRE
IPEX deficiency in
FOXP3
name some things that would cause you to suspect Immunodeficiencies
family history of it need IV antibodiotics or hospitalization to clear infection 2 or more infections of pneumonia per year 2 or more sepsis or meningitis recurrent or resistant candidiasis recurrent tissue or organ absecesses infection w/ opportunistic organism live vaccine complications non-healing wounds, chronic diarrhea
review pg 13
13
if there are recurrent infectiosn indictation there may be problem with
complement, phagocytes, or immunoglobulins
recurrent viral/fungal/opportunisitic infections may be problem with
T cell (cell mediated)
bacterial infections are
extracellular
intracellular pathogens are
intracellular
defects in phagocytes permit
widespread bacterial infections
defects in complement permit
widespread bacterial infections
LAD stands for
leukocyte adhesion deficiency
LAD1 prevents
adhesion ofphagocytes to actiated endothelium
LAD2
leukoctyes cannot adhere to endothelium
LAD3
defect in CD15, no rolling
all LAD result in neutrophils :
they can’t get to site of infection
CGD stands for
chronic granulomatous disease
CGD results in mutation in
NADPH oxidase complex
if you can’t assemple NADPH you lack
oxidative pathway
what is morst important killing of phagocytes
oxidative pathway
clinical effect of CGD
chronic bacterial and fungal infections
granulomas
CHS stands for
chediak higashi syndrome
defect in CHS
lysosomal trafficking regulator protein
functional effect in CHS
defective fusion of endosomes and lysosomes
defective phagocytosis
clinical effect of CHS
recurrenta nd presistant bacterial infections
granulomas
damage organs
how would you diagnose Immunodeficiencies
complete blood count/differential
if you find abnormal neutrophil counts what will you then look at
CD11/CD18 assay
LAD results in profound
leukocytosis
leukocytosis
electaed leukocyte numbers in peripheral blood
LAD1 defect?
defect in beta chin ofintegrin
beta chain is present where
LFA-1
CR3 CR4
CR3 and 4 are involve din
complement -b ind to opsinized bacteria
review pg 20, draw out the effect LAD on leukocyte adhesion cascade
pg 20
will pts with LAD gorm pus
no
when does LAD present
1-2 months of age
LAD is characterized by extreme
leukocytosis
why is LAD characterized by extreme leukocytosis
they can’t get through endothelium to site of infection
what happens very early on to signal LAD
Umbilical Cord - Delayed separation at birth, postnatal redness and swelling (omphalitis)
describe Rebuck skin window
mild abrasion on skin and cover slip applied, abrasion of skin induces mild inflamatory response so neutrophils are attracted. normal individuals: neutrophils will attach to cover slip. individuals with LAD, no neutrophil attachment
flow cytometry for LAD
to analyze fi pt has it
treatment for LAD
BMT
BMT stands for
bone marrow transplantation
CD15 is
sialyl lewis
draw out flow cytometry of normal individual compared to CD18 and CD15
pg 23
draw out flow cytometry of pt with LAD II
pg 23
draw out flow cytometry of pt with LAD I
pg 23
what is defective step in LAD II
rolling
what step is defective in LAD I
tight binding step
NBT test looks at
ability of neutrophils to kill what they have inside them
CGD are compromised in
oxidative killing pathways
most common mutation in CGD
gp91
gp91 is encoded on
x chromosome
catalase breaks down
hydrogen peroxide
in absence of hydrogen peroxide, if pacteria are catalase negative there will still be
some to make superoxide anion
symptoms of CGD
recurrent infections with catalase-positive bacteria, fungi (normal flora)
susceptible infections of CGD
extracellular pathogens and fungi (neutrophils)
to test CGD/functionality of NADPH oxidase
NBT test
flow cytometry
NBT test assess
assess function of NADPH oxidase
negative NBT indictivei of
defective NADPH oxidase
if neutrophils are functional they reudce
NBT and blue crystals of reduced NBT
NBT stands for
Nitro Blue Tetrazolium
DHR stands for
Dihydrorhodamine
DHR test, describe
flow cytometry - resting neutrophils will not reduce the DHR
if you expose the neutrophils from healthy individuals to formil ester then the activated neutrophils will (IN DHR TEST)
reduce DHR - increased fluerescence
individuals with CGD, when you expose them to formil ester they do not
reduce DHR - non-functional
what woudl you see in carrier of CGD on DHR?
review pg 27
CHS results from
mutation in lysosomal trafficking regulator gene, LYST
lysosomal traficking is impaired in CHS so ther will be
giant granules in lysosomes
what else is impaired besides lysosomal trafficking in CHS
impaired chemotaxis, and abnormal NK cell activity
symptosm of CHS besides impaired chemotaxis, and abnormal NK cell activity
albinism, neurological abnormalities
LAD1 deficient in
CD18
LAD2 deficient in
CD15
CGD defect in
NADPH oxidase
most common form of CGD is
x linked
CHS results in mutation f what gene
LYST
LYST controls
trafficking of lysosomes
A50 tests for
alternative pathway activity
CH50 tests for
deficiencies in the classic pathway by measuring the ability of the patient’s serum to lyse antibody-coated sheep erythrocytes.
review my complement pathway thing
:D see also his pg 31
can soluble be opsinized by complement
no
deficiencies in components of early classical pathway lead to increase susceptibility of
immune-complex disease
defects in alternative pathway
C3b which is required for opsinization of pathogens so susceptibility of
why not imune compleex disease if you’re not generating C3d
you still have c4b
what is most serious deficieny oc fomplenet
C3
deficiency of C3 leads to susceptibility of
encapsulated bacteria
without C5-9 can’t generate
MAC
no C5-9 you are susceptible to
Neisseria
Neisseria meningitidtis is
encapsulated
Neisseria gonorrhoeae is
not encapsulated
DAF and CD59 are anchored to
membrane
neisseria species handeled by
MAC
most people with neisseria disease have what form
encapsulated - so neisseria meningiditis
deficiency in enzyme PIGA means that
DAF and CD59 cannot be anchored to membrane
what does PIGA do
makes the GPi anchor to anchor DAF and CD59 to the membrane
what does DAF do
displaces c2a from c4b (dissociation of c3 convertase)
in absence of membrane associated DAF and CD59 we will get
complement activation on cell surface
if we have deficiency of DAF and CD59 what disease do we get
Paroxysmal Nocturnal Hemoglobinuria (hemoglobin in urine)
CD55 is
DAF
DAF stands for
decay accelerating factor
CD59 is
protectin & HRF
C1 inhibitor deficiency gives rise to what disease
Hereditary Angioedema (HAE)
most people with HAE have what type
type I
HAE type I is classified by
low serum levels of normal C1-INH
so C1 inhibitor is not defective but there isn’t enough of it
HAE type II is classifeid by
normal level of C1 inhibitor but it is not functional
function of C1 inhibitor
displaces c1r and c1s from c1
displaces masp 1 and masp2 from MBL or ficolins
important in kinin and coagulation cascade
why do you have edema in HAE
c1 inhibitor isn’t functioning well and it is important in kinin cascade, like braadykinin, so you get fluid into tissues
