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1020 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 66: Disorders of Neutrophil Function 1021

lungs. S. aureus and Pseudomonas aeruginosa have been the most com- be observed in thermally injured patients or in individuals with myelo-
monly observed pathogens, although Candida albicans also has been dysplasia. 281,308 Treatment of SGD is symptomatic, with the administra-
isolated. Specific granule-deficient neutrophils lack gelatinolytic activity tion of parenteral antibiotics for acute infections and surgical drainage
in the tertiary granules; vitamin B -binding protein, lactoferrin, hCAP- of refractory infections. With aggressive medical management, patients
12
18, and collagenase in the specific granules; and defensins in the pri- may survive into their adult years.
mary granules. 301–303 This disorder also extends to eosinophils that lack
the characteristic eosinophil granule proteins: major basic protein, eos- Adhesion Abnormalities
inophilic cationic protein, and eosinophil-derived neurotoxin (Chap. Leukocyte Adhesion Deficiency
304
62). Thus, the disorder is a global defect in phagocytic granules rather Definition and History Leukocyte adhesion deficiency type I
than limited to specific granules, as suggested by its name. Neutrophils (LAD-1) is a rare autosomal recessive disorder of leukocyte function
from these patients are defective in chemotaxis, possibly related to the (see Table 66–2). More than 100 cases have been reported worldwide.
absence of the intracellular pool of leukocyte adhesion molecules that The disease is characterized clinically by recurrent soft-tissue infec-
normally reside in the tertiary and specific granules, and exhibit a mild tions, delayed wound healing, and severely impaired pus formation
defect in bactericidal activity, possibly related to the deficiency of the despite striking blood neutrophilia. Individuals with this disorder
309
granule constituents, lactoferrin and defensins. 301,305 The impairment in have decreased or absent expression of a family of structurally and
granule protein synthesis affecting the granulocytic cells appears sec- functionally related leukocyte surface glycoproteins designated CD11/
ondary to the functional loss of the myeloid transcription factor, C/ CD18 complex (also referred to as the β -integrin family of leukocyte
2
EBPε, which was identified in two patients. 109,306 In another case of SGD, adhesive proteins; Table 66–3). These proteins include LFA-1 (CD11a/
the expression of the transcription factor growth factor independence-1 CD18), Mo-1 or Mac-1 (CD11b/CD18), p150,95 (CD11c/CD18), and
(Gfi-1) was markedly reduced along with a heterozygous mutation of C/ p160,95 (CD11d/CD18). The CD11 subunits are integral membrane
309
EBPε gene. It was suggested that the combined abnormalities blocked glycoproteins, each spanning the plasma membrane only once. They are
307
specific granule expression leading to the expression of the SGD phe- approximately 40 percent homologous, suggesting that they arise from
notype. The defect is restricted to blood cells, as normal lactoferrin a common primordial gene. The three distinct genes encoding the α
309
secretion has been demonstrated in the nasal secretions of an SGD subunits occur in a cluster on chromosome 16, whereas the gene for the
302
patient despite the abnormality demonstrated in his neutrophils. The β subunit is located on chromosome 21. 310
diagnosis of SGD is suggested by the presence of neutrophils devoid The initial clinical description in 1979 described six children
of specific granules but containing azurophilic granules on the blood and two families with findings of delayed separation of the umbilical
film. The diagnosis can be confirmed by demonstrating a severe defi- cord and delayed healing at the site of detachment of the cord, recur-
281
ciency in either lactoferrin or hCAP-18. An acquired form of SGD can rent infections despite neutrophilia, neutrophilia persisting during

TABLE 66–3. Biologic and Clinical Features of Leukocyte Adherence Deficiencies 1 and 2
Leukocyte Functional
Genetic Defect Abnormalities Clinical Features Diagnosis
LAD-1 Molecular mutations Neutrophils; adherence spreading, Autosomal recessive; Flow cytometry for
affecting expression of homotypic aggregation, chemo- delayed umbilical cord sep- expression of CD11b/
the β -integrin CD18 taxis receptor CR3 activities: C3bi aration; neutrophilia; defec- CD18 (Mac-1)
2
binding affecting phagocytosis, tive neutrophil migration
respiratory burst, and degranula- into tissue; recurrent bac-
tion in response to C3bi-coated terial infections; impaired
particles* wound healing
Monocytes; adherence, CR3
activities
Lymphocytes; cytotoxic
T-lymphocyte activities; NK cyto-
toxic activities; blastogenesis
LAD-2 (CDG-IIc) Mutations affecting Neutrophils; rolling mediated by Autosomal recessive; recur- Flow cytometry for leu-
x
function of GDP-fucose sLe to endothelium; neutrophilia † rent bacterial infections, kocyte sLe (CD15)
x
transporter 1 resulting in periodontitis; growth
defective glycosylation retardation; developmental
expression at the α -po- retardation; Bombay red
1,3
sition of selectin ligands cell phenotype
x
including sLe and other
fucosylated proteins
requiring fucosylation
CDG-11c, congenital disorder of glycosylation type IIc; GDP, glucose diphosphate; NK, natural killer; sLe , sialyl Lewis X.
x
*These functional abnormalities and clinical features are a consequence of lack of the CD11b/CD18, which includes CD11a, CD11b, CD11c, and
CD11d markers of four different α chains and the common β -chain CD18 of Mr 95 kDa.
2
† These functional abnormalities and clinical features are a consequence of lack of sLe expression on leukocytes.
x

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