Disorders of Monocyte Number

Question 1

Define adherance, chemotaxis, ingestion, and granulation as it relates to neutrophil function

Answer 1

Adherance: neutrophils roam the blood adhering to endothelial cells mediated by adhesion proteins

Chemotaxis: Neutrophils pass through endothelial cell junctions and move towards offending organisms

Ingestion: Microbes at infection site are enveloped by pseudopods and a phagosome is formed

Granulation/Microbicidal activity: Granules bind the phagosomelysosome initiating ROS-> binds with oxygen independent enzyme leading to microbe death

Question 2

How is neutrophil function affected in Leukocyte Adhesion Deficiency I (LAD I)?

Answer 2

Classification: Adherance disorder

Decreased adherance to endothelial surface leads to defect in neutrophil movement to infected tissue sites.

Complete or partial CD18 deficiency

Often presents with soft tissue infections, and poor wound healing.

Question 3

How is neutrophil function affected in Leukocyte Adhesion Deficiency II (LAD II)?

Answer 3

Classification: Adherance disorder

Decreased rolling on endothelial surfaces secondary to adherance being too tight

• Results from abnormal transferase
• Often results in recurrent infection, mental retardation, and short stature

Question 4

How is neutrophil function affected in Actin Dysfunction?

Answer 4

Classification: Chemotactic Disorder

Decreased chemotaxis ultimately leads to decreased ingestion (so neutrophils don’t kill the pathogen)

Question 5

How is neutrophil function affected in Specific Granule Deficiency?

Answer 5

Classification: Granule Defect Disorder

Decreased chemotaxis leading to decreased microbicidal activity

• Results from a defect in the transcription factor needed to produce specific granulocytes

Question 6

How is neutrophil function affected in Myeloperoxidase deficiency?

Answer 6

Classification: Granule Defect Disorder

Deficiency of myeloperoxidase leads to decreased ability to kill bacteria (e.g. Candida) in diabetic patients.

• Due to modification defect in processing protein

Question 7

How is neutrophil function affected in Chediak-Higashi syndrome?

Answer 7

Classification: Granule Defect Disorder

• Giant granules in all leukocytes. Abnormal degranulation. Major defect in movement, also decreased degranulation and microbicidal activity
• Alterations in membrane fusion with formation of giant, leaky granules.

Neurodegenerative as an adult, often presents with HSM (Hepatosplenomegaly)

Question 8

How is neutrophil function affected in Chronic Granulomatous disease?

Answer 8

Classification: Bacterial Activity/Oxygen Radical Production Disorder

• Defect in oxidase enzyme system. No toxic oxygen metabolites produced
  
  • Neutrophils do not produce reactive oxygen radicals.

Question 9

Describe the NADPH oxidase enzyme system

Answer 9

• Membrane bound enzyme system
• Transferring e- from NADPH inside cell across membrane and coupling these to molecular oxygen -> superoxide
• In phagosomes, superoxide can spontaneously form H2O2 that will undergo further reactions to generate ROS’

Question 10

What diagnostic tests can detect an NADPH oxidase abnormality?

Answer 10

Nitro blue tetrazolium (NBT) dye reduction test

• General mechanism: If oxidase is working properly the dye is reduced turning it visibly blue (defect is indicated by no blue)

Dihydrorhodamine (DHR)

• General mechanism: If oxidase is working properly, it produces ROS which reduces DHR forming rhodamine (a flourescent tracer dye)

Question 11

What type of infections would you expect in someone with a NADPH oxidase enzyme defect?

Answer 11

• Defects in Phagocyte Function:
  
  • Bacterial and fungal infections
  • Infections of catalase positive organisms
  • Peridontal disease
  • Recurrent infections in body areas where microbes are common
• Defects in Complement:
  
  • Bacteria infections as might be seen with antibody deficiency
  • Terminal complement deficiencies (C5-C9) see problems with Neisseria

Question 12

What are some of the main tests to identify a phagocyte problem?

(Discriminate between screening and confirmatory tests)

Answer 12

Screening

1. CBC, Differential
2. Review of morphology
3. Bactericidal Activity
4. Chemotaxis Assay
5. Expression of CD11b/CD18
6. NBT dye reduction or DHR oxidation

Everything else, that “sounds” more specific or detailed is a confirmatory test

e.g. - Test adherence to inert surface or endothelial cells. Measure CD11b/CD18, L-selection, Sialyl LeX

Question 13

What tests could you order to see a complement problem?

(Discriminate between screening and confirmatory tests)

Answer 13

Screening

1. C3, CH50
2. Quantitative Ig’s
3. Lymphocyte numbers

Confirmatory

1. Measure specific complement components in the alternative or classical pathway
2. Perform a detailed evaluation of the adaptive immune response

Question 14

What are some of the primary management strategies in people with innate immune disorders?

Answer 14

• AGGRESSIVE attempts to identify cause of infection
  
  • Initiation of broad spectrum antibiotics critical.
    
    • Specific abx once a microbial is known
• Surgical intervention
• IG-CSF can be used at a dose of 3 μg/kg/day to resolve neutropenia.
• Transplantation with hematopoietic stem cells
• Gene therapy - still being studied