Disorders of Granulocyte Function (complete)

Question 1

How does neutrophil function affect leukocyte adhesion deficiency (LAD) I? (Clinical, functional defect, molecular defect)

Answer 1

ADHERENCE DISORDER

C: Recurrent soft tissue infections, gingivitis, abscesses. Delayed separation of umbilical cord — poor wound healing (BIG ASS WHOLE IN ABDOMEN)

FD: Neutrophils can’t enter tissues — decreased adherence to endothelial surface leads to defect in neutrophil movement

MD: Complete/partial deficiency of CD18 (no expression of protein) — auto recessive

Question 2

How does neutrophil function affect actin dysfunction? (Clinical, functional defect, molecular defect)

Answer 2

CHEMOTACTIC DISORDER

C: Recurrent, severe infections — poor wound healing

FD: Decreased chemotaxis and ingestion

MD: decreased actin assembly

Question 3

How does neutrophil function affect myeloperoxidase deficiency?(Clinical, functional defect, molecular defect)

Answer 3

GRANULE DEFECT DISORDER

C: general healthy — ^ fungal infections associated w/ diabetes

FD: complete/partial deficiency of myeloperoxidase — mild defect in killing bacteria, major w/ candida

MD: Post-translational mod defect in processing protein – auto rec

Question 4

How does neutrophil function affect Chediak-Higashi syndrome? (Clinical, functional defect, molecular defect)

Answer 4

GRANULE DEFECT DISORDER

C: Oculocutaneous albinism, photophobia, recurrent infections of skin/mucous membranes — neurodegenerative

FD: Neutropenia, giant granules in leuk, abnormal granulation – movement defects

MD: creates giant leaky granules b/c of membrane fusion problems — MT assembly probs

Question 5

How does neutrophil function affect chronic granulomatous disease (CGD)?

Answer 5

BACTERICIDAL ACTIVITY/O2 RADIAL PRODUCTION DISORDER

C: recurrent infections w/ catalase, bacteria and fungi — granulomas

FD: Neutrophilia, normal adherence, chemotaxis, ingestion, degranulation. No toxic oxygen metabolites produced — defect in oxidase enzyme system

MD: defects in 1 of 4 oxidase components, absent cytb558 (aut rec and x linked)

Question 6

Describe the NADPH oxidase enzyme system

Answer 6

Membrane-bound enzyme complex

When active:

• generates superoxide by xferring e-s from NADPH inside cell across membrane
• couples w/ molecular O2 to make superoxide
• superoxide is used in phagosomes

Question 7

What are techniques used to determine the activity of the NADPH oxidase enzyme system?

Answer 7

1) Nitro blue tetrazolium chloride:
- neutrophil can’t make ROS/radicals needed for killing bacteria; therefore can’t reduce dye (no blue)

2) Dihydrorhodamine (DHR):
- whole blood stained w/DHR, incubated, stimulated to produce radicals —»> reduces DHR to rhodamine in cells w/ normal function

Question 8

What are the consequences of a defect in one of the components in the NADPH oxidase enzyme system?

Answer 8

• Chronic granulomatous diseases

- low capacity to phagocytose —»> recurrent infections

Question 9

Characterize the types of infections you might see w/ defects of phagocyte function

Answer 9

• High rates of bacterial/fungal infections (w/ atypical microorgs)
• Infections of catalase+ orgs in pts w/ CGD
• Peridontal disease in children (severe infections)

Question 10

What are screening tests that characterize a phagocytic problems?

Answer 10

1) CBC differential
2) morphology review
3) bacterial activity
4) chemotaxis assay
5) CD11b/CD18 expression
6) NBT dye reduction/DHR oxidation

Question 11

What are confirmatory tests that characterize phagocytic problems?

Answer 11

1) Adherence to inert surface/endo cells – measure CD18 prod.
2) Response to chemoattractants
3) ingestion of labels particles/bacteria — watch for degranulation of specific/azurophilc components
4) Bactericidal/candicidal activity (O2, H2O2 prod)
5) MD in oxidase or other cells

Question 12

Discuss management strategies for pts w/ innate immune disorders

Answer 12

1) Anticipate infections, find cause
2) Potential surgical procedures
3) Proper antibiotics (first broad, then specific)
4) G-CSF if severe neutropenia
5) HSC transplant
6) Gene therapy (prelim study phase)

Question 13

Characterize the types of infections you might see w/ defects of complement

Answer 13

• similar bacteria infections as those w/ Ab deficiency

- terminal complement deficiencies (C5-C9)

Question 14

What are screening tests that characterize complement problems?

Answer 14

1) C3, CH50
2) Quantitative IgS
3) Lymphocyte numbers

Question 15

What are confirmatory tests that characterize complement problems?

Answer 15

1) measure specific complement components in alternative/classical pathway
2) Perform a detailed evaluation of adaptive immune response

Question 16

Describe the general normal function of neutrophils. (LONG ANSWER)

Answer 16

• First immune response
• Move in laminar blood flow but are pulled to infected areas when needed — interact w/ endo cells in rolling motion (adhesion mediated by adhesion proteins)
• cells pass through endo junctions — move towards bad orgs
• at infection site, microbe enveloped by pseudopods — phagosome encases bad org
• granules fuse w/ phagolysosome —- oxidase system assembled
• respiratory burst initiated (generates ROSs) —–»> kill bad org!