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1024 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 66: Disorders of Neutrophil Function 1025

cells expressing E-selectin (see Table 66–3). Thus, the neutrophils from in a dog model. 338,339 Not only did the neutrophils express the inte-
the patients categorized as having a LAD-2 phenotype are unable to grins, but the cells demonstrated improvement in their functional
tether to inflamed venules, which is necessary for subsequent activation responses, such as adhesion and the respiratory burst when chal-
(Chap. 19). The LAD-2 can be explained by a congenital disorder of lenged with ligands for CD11/CD18. These results indicate that ex
fucosylation of ligands for selectins and other glycoconjugates. Each of vivo of the transfer gene for CD18 into LAD-1 CD34+ cells followed
the three selectins binds with variable affinity to sialylated and fuco- by reinfusion of the transfused cells may represent a therapeutic
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sylated oligosaccharides, including sLe , which is present on multiple approach for LAD.
specific glycolipids and glycoproteins on leukocytes and activated endo- The severity of infectious complications correlates with the degree
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thelial cells. Neutrophils from LAD-2 subjects lack sLe , which leads of β deficiency. Patients with severe deficiency may die in infancy, and
2
to impaired neutrophil rolling on endothelial cells. Other fucosylated those surviving infancy have a susceptibility to severe, life-threatening,
determinants, including the H, Lewis, and secretor blood group anti- systemic infections. In patients with moderate deficiency, life-threaten-
319
gens, are lacking as well, suggesting a global defect in fucosylation. The ing infections are infrequent and survival relatively long. LAD-1 can
diminished fucosylation arises from impaired transport of GDP-fucose be diagnosed by prenatal screening.
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from the cytoplasm to the Golgi lumen. A human GDP-fucose trans-
porter (GFTP) that localizes to the Golgi apparatus has been demon- Neutrophil Actin Dysfunction
strated to be defective secondary to distinct mutations in the SLC35C1 These patients, like patients with LAD, have recurrent pyogenic infec-
13
gene encoding the transporter. When fibroblasts and lymphoblastoid tions from birth as a result of defective chemotactic and phagocytic
cells derived from a LAD-2 patient were grown in the presence millimo- response (see Table 66–2). In one patient, actin isolated from blood and
lar concentrations of fucose, cell-surface fucosylation could be restored. neutrophils could not polymerize under conditions that fully polymer-
Following this observation oral administration of L-fucose to two Turk- ized the actin of neutrophils from normal individuals. Subsequent
340
ish patients led to normalization of neutrophil counts and functional studies on the index patient’s family confirmed that partial actin dys-
E- and P-selectin ligands on myeloid cells accompanied by abatement function was present in the parents and one sister. One of the par-
341
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of fevers and infections. Two Arab patients, in contrast to the Turkish ents was found to be a heterozygote for LAD, and the other was not,
patients who have different mutations of the gene encoding the putative but further studies established that LAD was not generally associated
GFTP, did not respond to oral fucose. A Brazilian LAD-2 patient, like with defective actin filament assembly. 342,343 The basis of the defective
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the Turkish patients, initially benefited from oral fucose; but, follow- polymerization of actin in the index patient remains unknown, but this
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ing expression of sLe on the myeloid cells, the patient developed auto- disorder of phagocytes is distinct from LAD.
immune neutropenia. The diagnosis of LAD-2 can be made by flow Defective actin polymerization has been described in a 2-month-
334
cytometry analysis of CD15s (sLe ) expression. old infant with severe recurrent bacterial infections associated with
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LAD-3, also known as LAD-1 variant syndrome, compromises impaired chemotaxis and phagocytic response. The patient’s neu-
344
two major hallmarks: a moderate LAD-1–like syndrome and severe trophils showed increased expression of CD11b, distinguishing the
Glanzmann-like bleeding diathesis (Chap. 120). Four patients have patient’s clinical problem from LAD-1. Morphologically, the neu-
been described in whom the inheritance appears to be autosomal trophils displayed thin, filamentous projections of membrane with an
recessive and is associated with functional defects of the leukocyte underlying abnormal cytoskeletal structure. Subsequently, a 47-kDa
and platelet integrins arising from intracellular signaling. The dis- protein was purified that inhibited actin polymerization in vitro.
335
345
ease initially presents in early childhood and consists of the inability Further biochemical studies revealed a markedly defective actin poly-
to form pus at sites of microbial infections, as well as a severe bleeding merization in the patient’s neutrophils along with a severe deficiency
tendency. The neutrophils from the patients display defective adhe- of an 89-kDa protein and an elevated level of the 47-kDa protein. The
sion and chemotaxis and are unable to undergo the respiratory burst 47-kDa protein was identified as LSP-1 (lymphocyte-specific protein-1),
when triggered by unopsonized zymosan. The molecular basis for which is an actin-binding protein present in normal neutrophils. Over-
LAD-3 arises from mutations in FERMT3, which encodes kindlin-3 expression of LSP-1 resulted in bundling of actin in cells, leading to an
in hematopoietic cells. Kindlin-3 binds to regions of the β-integrin abnormal cytoskeletal structure and motility defects. Neutrophils
346
tails and constitutes an essential element for transition of integrins from the patient’s parents revealed a partial defect in actin polymer-
from the bent and inactive to the extended an active conformation. ization accompanied by intermediate levels of LSP-1 and the 89-kDa
336
Marrow transplantation can be curative. protein. These observations suggest that the neutrophil actin dysfunc-
Another rare cause of neutrophilia and an inability to form pus tion (NAD) known as NAD47/89 is an autosomal recessive disorder.
was observed in a patient with a mutation in the Rac2 GTPase, which is Because actin dysfunction is lethal, treatment requires restoration of
discussed below. The neutrophils from the patient had defects in both normal neutrophil function by marrow replacement from a normal
adhesion and chemotaxis (see Table 66–2). donor. Marrow transplantation was successful. 347,344
Therapy, Course, and Prognosis Treatment of LAD-1 is largely
supportive. 309,315 Patients with a history of recurrent infections can be
maintained on prophylactic trimethoprim-sulfamethoxazole. Marrow
transplantation with human leukocyte antigen (HLA)-compatible sib- DISORDERS OF NEUTROPHIL MOTILITY
lings or parental donors has resulted in engraftment and restoration of Familial Mediterranean Fever
neutrophil function and remains the treatment of choice for patients Definition and History Familial Mediterranean fever (FMF) is an auto-
with a severe phenotype. 337 somal recessive disease that primarily affects populations surrounding
The restoration of CD11/CD18 expression in CD34 peripheral the Mediterranean basin. The disease is characterized by acute limited
stem cells from LAD-1 following transduction with a retrovirus bear- attacks of fever often accompanied by pleuritis, peritonitis, arthritis,
ing CD18 and induced to differentiate into neutrophils with growth pericarditis, inflammation of the tunica vaginalis of the testes, and
factors indicates that LAD-1 is caused by a defective CD18 gene and erysipelas-like skin disease (see Table 66–2). The initial description
provides a basis for somatic gene therapy, which was accomplished occurred in 1908, identifying a Jewish girl who had episodic abdominal

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