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Hilary week 4 > Neutrophil functional disorders > Flashcards

Neutrophil functional disorders Flashcards

1
Q

What are the 5 main reaseons for functional disorder os neutrophils?

A

1) defects in oxidative burst
2) defects in migration
3) Defects associated with hyperpigmentation
4) cytoskeletal defects
5) specific granule deficiency

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2
Q

3 diseases that cause defects in respiratory burst?

A

CGD (NADPH oxidase)

glucose-6 phosphate dehydrogenase deficiency

myeloperoxidase deficiency

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3
Q

4 types of Leukocyte adhesion deficiencies

A

LAD type 1, 2, 3

LAD with abnormal E-selectin

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4
Q

2 immunodeficiencies associated with hypopigmentation?

A

Chediak higahsi syndrome

Griscelli syndrome

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5
Q

Cytoskeletal defects causing neutrophil dysfunction?

A

Rac2 deficiency

X-linked neutropenia (caused by WAS GOF)

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6
Q

What agonist is added in NBT and what is the colour change in response to?

A

PMA used, with yellow to blue colour change with oxidation of NBT.

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7
Q

What kind of organisms are CGD patients susceptible to?

A

catalse positive infections (they can break down residual myeloperoxidase).

Strep is catalase negative, but Staph is catalse positive (as is micrococci)

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8
Q

Why might you get a false positive for CGD with flow cytometry of DHR?

A

DHR oxidised to fluorescent rohadmine with H202 release.

Lack of this may also be because of a myeloperoxidase deficiency-fals positive.

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9
Q

What is the most common gene defect causing CGD?

A

X-linked gp91 phox, (CYBB gene).

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10
Q

what is second most conmon defect autosomal recessive cause of CGD?

A

p47 phox defect (NCF1 mutation).

p40phox (NCF4 mutation) also is AR.

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11
Q

Two AR causes of CGD which make up fewer than 5% OF CASES?

A

p67phox (NCF2) and p22phox (CYBA gene)

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12
Q

rarest cause of CGD?

A

glucose–phosphate dehydrogenase deficiency.

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13
Q

What molecules are recruited to gp91phox and P22phox upon NADPH oxidase activation?

A

p40, p47 and p67phox.

Signalling molecules Rac and Rho

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14
Q

Equations for ROS and NADPH oxidase?

A

NADPH + O2 —> NADP+ + 2O2 + H+

202 + 2H+ —(SOD)—> H202 +O2

H202+ Cl- —(myeloperoxidase)–> H20 + HOCl-

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15
Q

What sorts of treatments can be used for CGD?

A

prophylactic antibiotics and antifungals.

Also in AMerica, IFn-y administration

Immunisations (apart from BCG)

Severe cases then you can use HSCT.

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16
Q

What drug is myeloablative and used beofre HSCT? Drugs used to reduce GVHD?

A

Busulfan (used at reduced intensitiy conditioning in CGD)

and fludarabine and ATG (To deplete T cells and reduce GVHD

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17
Q

Why are CGD patients susceptible to catalse positive organisms?

A

Because they break down myeloperoxidase.

18
Q

what autoimmune disase might Xlinked CGD carriers present with in some cases?

A

DLE- thought to be because NETosis is affected.

19
Q

What moelcules are affected in LAD 1 2 and3 disorders?

A

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.

20
Q

What are the genes affected in LAD I II and III

A

ITGB2

SLC35C1

FERMT3

21
Q

What drug is used to treat dyregulated IL23 and IL17 inLAD1 deficiency (so lots of unresolved inflammation?)?

A

ustekinumabab (anti- p40 subunit of IL-23 (and IL-12) antibody).

22
Q

What technique would you use to try and diagnose LAD type 1?

A

FACs to look at the levels of CD11 and CD18.

Look at this in context of whether it is augmented with PMA activation.

23
Q

What are early and late presentations of LAD2 deficiency?

A

Lack of fycosylated glycans:

early: immunodeficiency
late: retarded growth and mental retardation.

24
Q

What complcation is associated with LAD type III ?

A

platelet aggregation is impaired (Glanzman type bleeding)

25
Q

what is leucocytosis?

A

high WBC count.

26
Q

What are the two cytoskeletal defects assocaited with neutrophil defects?

A

Rac2 deficiency (affect actin) and WAS.

27
Q

how does Rac2 deficiency presetn?

A

similar to LAD (indication of LAD is umbilical sloughing difficulties and inability to form pus) (leukocytosis, defects in phagocytosis migration and oxidative burst)..

28
Q

What is X linked WAS mutations symptoms?

A

throombocytopenia, immune deficiency (bacterial and viral and fungi) and eczema.

Also may see lymphoma and autoimmune disease.

29
Q

What the immunological features of WAS?
T and B cell count?
Ig?

A

progressive decrease in T cells, but B cell count normal.

Decreased IgM, but increased IgA (IgA nephropathy) and IgE

30
Q

What is responsible for X-linked neutropenia?

A

WASp GOF mutation- only affects neutrophils- causes overactive actin cytoskeleton.

31
Q

what specific granule deficieny is there?

A

myeloperoxidase deficiency can’t generate HOCL.

32
Q

Who does myeloperoxidase deficiency present in? Why?

A

Moslty asymptomatic, compensated for by eosinophil peroxidase.
But diabetes mellitus can show candida infection.

33
Q

What mutation is seen in chediak higashi syndrome?

What is affected and seen under slide?

A

LYST gene, abnormal protein trafficking and granue fusion.
Forms giant cytplsamic granuleswithin neutrophils.

As well as severe neutropenia

34
Q

syndromic features of chediak higashi syndomre?

A

albinis,. (eyes) brittle hair, neurological impairment.

35
Q

What is seen in the accelereate phse of chediak higashi syndrome that occurs in 85% of people?

A

pancytopenia, hepatic and splenomegaly HLH (macrphages pahgoyctose RBCs) can be fatal.

36
Q

An example of a specific granul deficiceny?

A

C/EBP epsilon.- absenc of neutorphoil specific granule proteins.

37
Q

What do CEBP cells show defects in in vitro?

A

nuetrophil migation
phagocytosis
bactericidal activiay
affected platelts and eosinophils.

38
Q

When is C/EBPepsilon expressed?

What are proteins in primary (azurophili granules)

A

in myelocyte stage.

myeloperoxidase and neutrhophil elastase

39
Q

Proteins in secondary granules?

A

lactoferrin and NADPH oxidase

40
Q

Tertiary granule protein?

A

gelatinase

Hilary week 4 (7 decks)

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