Page 350 - Clinical Immunology_ Principles and Practice ( PDFDrive )

330 Part two Host Defense Mechanisms and Inflammation

A B

FIG 22.10 Thoracic Pathology in Hyper-IgE Recurrent Infection Syndrome (HIES). (A) Chest
X-ray of a patient with scoliosis. (B) Computed tomography (CT) scan of the lungs in the same
patient demonstrates multiple pneumatoceles caused by prior infections.

Mutations in STAT3 lead to disruption of cytokine signaling, 7. Diagnosis is suspected on the basis of the infections and the
including IL-6, IL-10, IL-11, and IL-17. Signal transducer and abnormal results on hemography. Since most routine hematologi-
activator of transcription 3 (STAT3) deficiency leads to elevated cal laboratory studies allow quite low ranges of normal monocyte
tumor necrosis factor-α (TNF-α) and IFN-γ, but reduced IL-17 percentages, it is necessary to look at absolute monocyte numbers.
producing T cells (Th17 cells). This latter defect may explain the Other presentations of this syndrome include aplastic anemia,
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predisposition to mucocutaneous candidiasis. Memory B and acute myelogenous leukemia, lymphedema, and chronic myelo-
T cells are low. Shingles vesicles are increased in Job’s syndrome monocytic leukemia. Sequencing of GATA2 is required for
despite the fact that primary varicella-zoster virus (VZV) infec- diagnosis.
tions are normally eliminated. Lymphomas, but not epithelial
malignancies, are increased in STAT3 deficiency. ASSESSMENT OF NEUTROPHIL FUNCTION
Recently gain-of-function mutations in STAT3 associated with
high IL-6 response have been identified in children characterized Discrete abnormalities in neutrophil function lead to recurrent
by failure to thrive, arthritis, livedo, and lung disease. bacterial or fungal infections. Assays have been developed to
interrogate those functions. However, since neutrophils cannot
DOCK8 Deficiency (Autosomal Recessive be viably stored or frozen, samples are usually examined fresh
Hyper-IgE Syndrome) with simultaneous normal volunteer controls. The techniques
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Several distinct diseases have elevated IgE, eczema, and eosino- discussed here are reviewed in detail by Elloumi et al. and in
philia. Dedicator of cytokinesis 8 (DOCK8, located at 9p24) Chapter 94.
deficiency includes food allergies, asthma, herpesvirus infections,
human papilloma virus (HPV), and molluscum contagiosum Isolation of Neutrophils
infections, which are not part of dominant negative STAT3 Most assays require neutrophils to be purified away from other
deficiency. In addition to the infection susceptibility, patients leukocytes and blood components. Blood is usually anticoagulated
with DOCK8 deficiency are predisposed to cutaneous and using either citrate or heparin (10 units/mL) tubes and maintained
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lymphoid malignancies. Although Th17 cells are markedly at 20–25°C (room temperature) in polypropylene containers.
diminished in patients with STAT3 deficiency, they are less severely Most protocols use differences in the cell density as the basis for
reduced in those with DOCK8 deficiency (patients with HIES-like the separation by sedimentation or centrifugation, or both.
6
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disease ). The specific contributions of these relatively IL-17– Typically, 1–2 × 10 neutrophils can be isolated per milliliter of
deficient states are areas of active investigation. whole blood.
GATA2 Deficiency (Monomac Syndrome) Neutrophil Adherence
GATA2 (located at 3q21.3) is an early hematopoietic transcription The adhesive function of phagocytes is commonly assessed by
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factor most active in myeloid development. The syndrome passage of 1 mL of whole blood through a column filled with
of monocytopenia and mycobacterial disease (monoMAC) is nylon wool. Adherence is measured as the difference in the
characterized by late childhood or adult-onset disseminated absolute neutrophil count of the precolumn sample and of the
nontuberculous mycobacterial disease or disseminated fungal sample after passage through the nylon wool column. Alternatively,
disease. Patients have absolute circulating monocytopenia, NK-cell isolated neutrophils can be induced to bind to plastic using a
cytopenia, and B-cell lymphopenia. Despite these circulating 96-well plate either uncoated or coated with fetal bovine serum,
cytopenias, there are tissue macrophages and plasma cells, and a ligand like ICAM-1, or a specific ECM protein, such as fibrinogen
Ig levels are normal to elevated. Neutrophils are variably affected. or fibronectin. Endothelial cell monolayers harvested from human
Other infections in this syndrome include HPV infection, mol- umbilical veins can serve as a more physiological substrate for
luscum contagiosum, histoplasmosis, and aspergillosis. Progressive the measurement of cell adhesion. Isolated neutrophils are
pulmonary alveolar proteinosis is common, as are cytogenetic preloaded with the cell permeant, acetoxymethyl ester derivative
abnormalities of bone marrow, such as trisomy 8 and monosomy of the fluorescent dye, calcein (calcein-AM). Nonspecific esterases