BL - Disorders of WBC Function

Question 1

Adherence

Answer 1

Neutrophils interact with adhesion molecules on epithelial cell layer, rolling down sites of inflammation into endothelial cells

Question 2

Chemotaxis

Answer 2

Cells move towards offending organisms

Question 3

Ingestion

Answer 3

Neutrophils ingest microbes after opsonization (with complement or Ab)

Question 4

Degranulation/microbicidal activity

Answer 4

Granules fuse with phagolysosome, oxidase enzyme system assembled in membrane initiating respiratory burst and generating reactive oxygen species

Question 5

*Leukocyte adhesion deficiency I

Answer 5

Presents with recurrent soft tissue infections, gingivitis, mucositis, periodontitis, cellulitis, abscesses, poor wound healing.
Neutrophilia.
Decreased adherence to endothelial surface leading to a defect in movement of neutrophils to infected tissue sites.
Complete or partial deficiency of CD18 resulting in lack of expression of CD11b/CD18.

Question 6

Leukocyte adhesion deficiency II

Answer 6

Autosomal recessive.
Presents with recurrent infections, mental retardation, short stature, craniofacial abnormalities.
Neutrophilia.
Decreased rolling on endothelial surfaces as a prelude to tight adherence. RBCs also affected, abnormal ABH antigens. Abnormal transferase resulting in altered fucosylation of adhesion molecules (e.g. Sialyl LeX) and poor interaction with selectins.

Question 7

Actin dysfunction

Answer 7

Maybe autosomal recessive
Presents with recurrent severe infections (skin, sepsis). Poor wound healing.
Decreased chemotaxis, ingestion, sometimes spreading. Decreased actin assembly.

Question 8

Specific granule deficiency

Answer 8

Autosomal recessive.
Presents with recurrent skin and deep tissue infections.
Decreased chemotaxis and microbicidal activity.
Mild neutropenia.
Failure to produce specific granules or their contents; defect in a TF (C/EBPe) results in decreased production of specific granule proteins.

Question 9

*Myeloperoxidase deficiency

Answer 9

Autosomal recessive.
Present generally healthy, increased fungal infections when associated with diabetes.
Partial or complete deficiency of myeloperoxidase; mild defect in killing bacteria, significant defect in killing Candida.
Post-translational modification defect in processing protein.

Question 10

*Chediak-Higashi syndrome

Answer 10

Autosomal recessive.
Presents with oculocutaneous albinism, nystagmus photophobia. Recurrent infections of skin, mucous membranes, and respiratory tract by bacteria. Lymphoproliferative phase associated with fever, hepatosplenomegaly, and hemophagocytic disorder. Neurodegenerative.
Neutropenia.
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. Other metabolic abnormalities, altered MT assembly.

Question 11

*Chronic granulomatous disease (CGD)

Answer 11

AR or XLR.
Present with recurrent purulent infections with catalase positive bacteria and fungi involving skin and mucous membranes; deep infections of lung, liver, spleen, lymph nodes, and bones.
Neutrophilia.
Normal adherence, chemotaxis, ingestion, degranulation; defect in oxidase enzyme system; no toxic oxygen metabolites produced; absent or reduced ability to kill coagulase positive bacteria and fungi.
Defects in 1 of 4 oxidase components; absent cytochrome b558 associated with gp91phox (XLR), p22phox (AR), p67phox (AR); mild X-linked variant: G6PD deficiency in PMNs.

Question 12

NADPH oxidase enyzme system

Answer 12

Granules fuse with phagolysosome, oxidative enzyme system assembled in membrane. Initiates respiratory burst and generates reactive oxygen species (O2-, H2O2, HClO, hydroxyl radical). Leads to death and dissolution of microbe.

Question 13

Infections seen in defects of phagocyte function

Answer 13

High rate of bacterial, fungal infections; infections with atypical pathogens (Aspergillus, Candida, Serratia, Klebsiella, S. aureus); catalase positive organisms for CGD patients. Infections of exceptional severity; periodontal disease in childhood; infections at interface areas (skin, sinopulmonary, perirectal).

Question 14

Infections seen in defects of complement function

Answer 14

Systemic lupus erythematosus, autoimmunity, inflammatory vascular disease (C1, C2, C4). Recurrent bacterial infections (C3). Severe infections with Neisseria (C5-C9).

Question 15

Tests to determine phagocyte problem

Answer 15

Screening: CBC, differential; review of morphology; bactericidal activity; chemotaxis assay; expression of CD11b/CD18; NBT dye reduction or DHR oxidation
Confirmatory: adherence to inert surface or endothelial cells; measurement of CD11b/CD18, L-selectin, Sialyl LeX; response to chemoattractants (shape change, change in direction, rate of movement); actin assembly; ingestion of labeled particles or bacteria; degranulation of specific and azurophilic components; bactericidal/candidicidal activity; production of O2-, H2O2, other oxidants; studies for specific molecular defects in oxidase or other cell constituents

Question 16

Tests to determine complement problem

Answer 16

Screening: C3 level, CH50, quantitative Ig’s, lymphocyte phenotype (B-cells, T-cells, subsets), proliferation in response to mitogens and antigens
Confirmatory: measurement of specific complement components, alternative and classical pathways; detailed evaluation of adaptive immune response

Question 17

Management strategies for patients with innate immune disorders

Answer 17

Anticipation/treatment of infections; surgical procedures (diagnostic and therapeutic); initial use of broad spectrum antibiotics followed by specific antibiotics when pathogen is known; G-CSF in severe quantitative disorders of neutrophils; CGD patients treated with INF-gamma or trimethoprim-sulfa. HSC transplantation for neutropenia and neutrophil dysfunction syndromes. Gene therapy for CGD and others.