Disorders of Granulocyte Number & Function

Question 1

Monocytes/Macrophages

Answer 1

Develop in the bone marrow under stimulation of GM-CSF and M-CSF; move to peripheral blood

Functions: remove microbes & cell debris from sites of infection/inflammation; filter our microbes from blood (spleen); process and present antigens to adaptive immune system

Question 2

Neutrophils

Answer 2

Produced in the marrow under stimulation of GM-CSF and G-CSF; marrow storage pool contains metamyelocytes, bands, and segs

Function: Ingests & kills microbes at site of infection

Question 3

Eosinophils

Answer 3

Produced in the bone marrow under influence of IL-5; characterized by red/orange granules & bilobular nucleus

Functions: defense against parasitic infection, function in hypersensitivity reactions

Question 4

Basophils

Answer 4

Characterized by prominent blue-purple granules and receptors for IgE

Function: hypersensitivity reactions

Question 5

Neutropenia

Answer 5

Decrease in the absolute neutrophil count (bands and segs) < 1,500/uL

Presents increased risk for infection, especially by staph aureus and gram negative bacteria

Question 6

Causes of neutropenia - acquired

Answer 6

Chemotherapy - suppression of myelopoiesis

Aplastic anemia - stem cell failure in marrow

Viral infections

Nutritional deficiencies (folate, B12, copper, protein/calorie)

Drugs/Toxins, i.e. Penicillin, Cephalosporin - production of anti-neutrophil Ab

Question 7

Kostmann Syndrome

Answer 7

Congenital cause of neutropenia

Caused by elastase (ELA-2) gene mutations leading to early apoptosis of neutrophil precursors

Presents as severe neutropenia early in infancy; high risk for infection before 2 years of age

Treatment: G-CSF to keep ANC > 1,000/uL

Question 8

Shwachman-Diamond Syndrome

Answer 8

Congenital cause of neutropenia

Caused by FAS-associated apoptosis of neutrophil precursors in the marrow

Presents as a multi-system disease: neutropenia, pancreatic insufficiency, bony disease; 25% develop marrow aplasia, 25% develop MDS/AML

Question 9

Cyclic Neutropenia

Answer 9

Congenital cause of neutropenia

Caused by ELA-2 mutations leading to early apoptosis of myelow precursors

Characterized by severe neutropenia, fevers, and mouth ulcers for 5-7 days with specific periodicity; ANC is normal at other times

Question 10

Chronic benign neutropenia of childhood

Answer 10

Neutropenia with normal reserve but increased turnover; caused by production of antibodies that cross-react with neutrophils; usually resolves and is not associated with severe infection

Question 11

Autoimmune neutropenia

Answer 11

Caused by auto-antibodies to neutrophils; marrow production is normal but increased turnover of neutrophils occurs

May also see ITP, AIHA

Question 12

Alloimmune neutropenia

Answer 12

Caused by the passive transfer of neutrophil-specific IgG antibody from mother’s circulation to fetal circulation, where fetal neutrophils are attacked

Question 13

Left shift

Answer 13

Refers to a change in the WBC differential with an increase in segs and bands (neutrophilia) with possible presence of even more immature myeloid precursors (metamyelocytes, myelocytes) in the peripheral blood

Question 14

Basophilia

Answer 14

Increase in peripheral basophils, seen primarily in food or drug hypersensitivity

Question 15

Eosinophilia

Answer 15

Increase in peripheral eosinophils > 350/uL, seen primarily in the setting of allergies, parasitic infections, and drug hypersensitivity reactions

Question 16

Monocytosis

Answer 16

Increased peripheral monocytes > 500/uL, seen primarily in hematologic malignancy, granulomatous disease, and bacterial infection

Question 17

Leukocyte Adhesion Deficiency (LADI)

Answer 17

Autosomal recessive disorder caused by a deficiency of C18, an integrin that enables leukocyte adhesion to vascular endothelium

Characterized by plasma neutrophilia; neutrophils cannot diapedese into infected tissue sites; presents with recurrent soft tissue infections

Question 18

Myeloperoxidase deficiency

Answer 18

Caused by a defect in post-translational modification leading to deficiency of the myeloperoxidase enzyme; neutrophils are mildly defective in killing bacteria and are significantly defective in killing candida

Patients are usually healthy with increased frequency of fungal infections

Question 19

Chediak-Higashi Syndrome

Answer 19

Granule defect disorder caused by alterations in membrane fusion with formation of leaky granules; caused by defect in the CHS1 gene

Characterized by neutropenia with decreased granulation and microbicidal activity; recurrent infections of skin & mucous membranes

Clinical presentation: Oculocutaneous albinism, nystagmus, photophobia

Question 20

Chronic granulomatous disease (CGD)

Answer 20

Caused by molecular defects in one of the oxidase components; neutrophils are unable to produce toxic ROS

Characterized by recurrent purulent infections with fungi and catalase-positive bacteria (bacteria that can neutralize hydrogen peroxide) and fungi involving the skin and mucous membranes

Question 21

Deficiency of complement components

Answer 21

1q, 4, 2 - Associated with increased risk of SLE and other autoimmune / inflammatory vascular diseases

C3 - associated with inefficient opsonization of bacteria and recurrent bacterial infections

C5-C9 - associated with increased risk for Neisseria bacteria (meningitis, arthritis, sepsis)