Neutrophil functional disorders Flashcards
What are the 5 main reaseons for functional disorder os neutrophils?
1) defects in oxidative burst
2) defects in migration
3) Defects associated with hyperpigmentation
4) cytoskeletal defects
5) specific granule deficiency
3 diseases that cause defects in respiratory burst?
CGD (NADPH oxidase)
glucose-6 phosphate dehydrogenase deficiency
myeloperoxidase deficiency
4 types of Leukocyte adhesion deficiencies
LAD type 1, 2, 3
LAD with abnormal E-selectin
2 immunodeficiencies associated with hypopigmentation?
Chediak higahsi syndrome
Griscelli syndrome
Cytoskeletal defects causing neutrophil dysfunction?
Rac2 deficiency
X-linked neutropenia (caused by WAS GOF)
What agonist is added in NBT and what is the colour change in response to?
PMA used, with yellow to blue colour change with oxidation of NBT.
What kind of organisms are CGD patients susceptible to?
catalse positive infections (they can break down residual myeloperoxidase).
Strep is catalase negative, but Staph is catalse positive (as is micrococci)
Why might you get a false positive for CGD with flow cytometry of DHR?
DHR oxidised to fluorescent rohadmine with H202 release.
Lack of this may also be because of a myeloperoxidase deficiency-fals positive.
What is the most common gene defect causing CGD?
X-linked gp91 phox, (CYBB gene).
what is second most conmon defect autosomal recessive cause of CGD?
p47 phox defect (NCF1 mutation).
p40phox (NCF4 mutation) also is AR.
Two AR causes of CGD which make up fewer than 5% OF CASES?
p67phox (NCF2) and p22phox (CYBA gene)
rarest cause of CGD?
glucose–phosphate dehydrogenase deficiency.
What molecules are recruited to gp91phox and P22phox upon NADPH oxidase activation?
p40, p47 and p67phox.
Signalling molecules Rac and Rho
Equations for ROS and NADPH oxidase?
NADPH + O2 —> NADP+ + 2O2 + H+
202 + 2H+ —(SOD)—> H202 +O2
H202+ Cl- —(myeloperoxidase)–> H20 + HOCl-
What sorts of treatments can be used for CGD?
prophylactic antibiotics and antifungals.
Also in AMerica, IFn-y administration
Immunisations (apart from BCG)
Severe cases then you can use HSCT.
What drug is myeloablative and used beofre HSCT? Drugs used to reduce GVHD?
Busulfan (used at reduced intensitiy conditioning in CGD)
and fludarabine and ATG (To deplete T cells and reduce GVHD
Why are CGD patients susceptible to catalse positive organisms?
Because they break down myeloperoxidase.
what autoimmune disase might Xlinked CGD carriers present with in some cases?
DLE- thought to be because NETosis is affected.
What moelcules are affected in LAD 1 2 and3 disorders?
type 1: B2 integrin (CD18). Usually combined with CD11a (B2 integrin), CD11b and 11c (CR3 and 4). (for adhesion to endothelial cells on ICAM-1)
type 2: sialyl-lewis X (is a golgi fucose transporter gene). So no fucosylated glycans for rolling (binding E-selectin).
type III: kindlin3 deficiency which is for signalling via the B2 integrin.
What are the genes affected in LAD I II and III
ITGB2
SLC35C1
FERMT3
What drug is used to treat dyregulated IL23 and IL17 inLAD1 deficiency (so lots of unresolved inflammation?)?
ustekinumabab (anti- p40 subunit of IL-23 (and IL-12) antibody).
What technique would you use to try and diagnose LAD type 1?
FACs to look at the levels of CD11 and CD18.
Look at this in context of whether it is augmented with PMA activation.
What are early and late presentations of LAD2 deficiency?
Lack of fycosylated glycans:
early: immunodeficiency
late: retarded growth and mental retardation.
What complcation is associated with LAD type III ?
platelet aggregation is impaired (Glanzman type bleeding)
