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1022 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 66: Disorders of Neutrophil Function 1023

infection-free periods, and impaired neutrophil chemotaxis. The Approximately half of patients exhibit a low level of CD11/CD18 cell
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molecular basis for LAD-1 was first suggested when neutrophils from surface molecules and moderate disease, with the remainder having
a patient with the disorder was found to lack a high-molecular-weight totally absent surface expression of these proteins, which accounts for
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membrane glycoprotein. This finding suggested that the lack of the a profound impairment of neutrophil and monocyte adherence and
membrane protein impaired the neutrophil’s functional responses. In adhesion-dependent functions in vitro, including cell migration, phago-
1982, another patient was evaluated and it was confirmed that the mem- cytosis, and complement- or antibody-dependent cytotoxicity. 315,316
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brane glycoprotein with a Mr of 150 kDa was missing. The normal The bulk of the neutrophil Mac-1 glycoprotein is stored inside
parents and siblings of the proband exhibited intermediate quantities the cell in the membrane of neutrophil specific and gelatinase granules
of the glycoprotein, which suggested the existence of a heterozygous and in secretory vesicles. 32,318 Exposure of neutrophils to degranulating
carrier state. The disorder then became known as LAD. Subsequently, stimuli results in a 5- to 10-fold increase in the number of Mac-1 mol-
in 1984, a glycoprotein 150 was identified as one subunit of a glycopro- ecules on the cell surface, which parallels the fusion of granules to the
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tein that had two subunits that served as a receptor for a plasma com- plasma membrane. Neutrophils from these patients fail to augment
plement component. This was followed by other investigations that their surface adhesive glycoproteins, as the defect in β-subunit synthesis
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found that two other related leukocyte membrane glycoproteins also affects both membrane and granule pools of Mac-1. In contrast to
were deficient. Each of the three glycoproteins was then determined to Mac-1 and p150,95, LFA-1 is predominantly confined to the neutrophil
be heterodimers with one common subunit and one subunit unique to plasma membrane. Consequently, the cell surface levels of LFA-1 are
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each glycoprotein. Synthesis of a defective subunit common to the not enhanced by neutrophil degranulation.
three glycoproteins of CD11/CD18 complex resulted in loss of expres- Lymphocytes deficient in CD11/CD18 are able to adhere to endo-
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sion of all heterodimers. This observation provided the molecular thelial surfaces via the expression on lymphocytes of very-late antigen-4
explanation for the cellular defect. In 1985, the extent of clinical severity (VLA-4) integrin (synonym: integrin α β ) receptors, which bind to the
4 1
and magnitude of the cellular abnormalities were correlated with the vascular cell adhesion molecule 1 (VCAM-1), found on the endothelial
degree of CD11/CD18 deficiency, thereby laying the groundwork for cells. This residual adhesion may account for the paucity of clinical
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the direct relationship between the glycoprotein deficiency and the clin- symptoms related to lymphocyte function. The patients are not unusu-
ical presentation. 315 ally susceptible to viral infection, although three patients had one or
Etiology and Pathogenesis Each of these molecules contains an more episodes of aseptic meningitis. 315
α and a β subunit noncovalently associated in an αβ structure. They The failure of the LAD-1 neutrophils to migrate to the sites of
all have the same β subunit and are distinguished by their α subunits, inflammation outside of the lung and peritoneum arises from their
which have different isoelectric points, molecular weights, and cell dis- inability to adhere firmly to surfaces and undergo transendothelial
tribution (see Table 66–3). The structure of CD11/CD18 has been migration from venules. 321–323 Failure of Mac-1–deficient neutrophils to
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deduced from molecular cloning of the various subunits. The x-ray undergo transendothelial migration occurs because β integrins bind
2
crystal structure and nuclear magnetic resonance analysis also reveal to ICAM-1 (CD54) and ICAM-2 expressed on inflamed endothelial
that activation signals lead to the separation of the α and β subunit cyto- cells. 309,324 LAD-1 neutrophils are able to accumulate in the lung, per-
plasmic tails, thereby converting the bent conformation of each integ- haps through a process of movement mediated by “chimneying,” which
rin with its headpiece near the plasma membrane into fully extended does not require functional integrins. Chemotaxis that occurs despite
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high-affinity structures in a switchblade-like movement. These stud- blockade of CD11/CD18 under special in vitro conditions has been
ies establish that the CD11/CD18 heterodimers are members of a large dubbed “chimneying.” The neutrophils that do arrive at inflammatory
gene family involved in cell–cell and cell–matrix adhesion (integrins). sites in the inflamed lung by CD11/CD18-independent processes fail to
Several subfamilies of integrins are described and classified according to recognize microorganisms coated with the opsonic complement frag-
the type of their highly homologous β subunits. The α subunits are also ment C3bi (an important stable opsonin formed by the cleavage of C3b
homologous to each other, but to a lesser degree than are the associated by C3b inactivator). 313,326 Other neutrophil functions, such as degranu-
β subunits. Within each subfamily, a single β subunit usually is shared lation and oxidative metabolism, normally triggered by C3bi binding
by several α subunits. Certain α subunits often share more than one β are also diminished and markedly compromised in neutrophils from
subunit, which alters their specificity for various ligands. The molec- LAD-1. Similarly, the urokinase-plasminogen activator-receptor
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ular defect involves all four members of the CD11 integrin subfamily. and the FcγRIII receptors, both phosphatidylinositol-linked proteins,
In patients with LAD-1 who have been evaluated at the molecular level, are defective in their functions because these receptors transduce their
absent, diminished, or structurally abnormal β subunits (CD18) were signals through CD11/CD18. 234,327 Monocyte function is also impaired.
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identified. A heterogeneous group of mutations that are confined to Monocytes of affected individuals have poor fibrinogen-binding func-
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the gene on chromosome 21q22.3 also was identified. Many patients tion, an activity promoted by the CD11/CD18 complex 309,328 ; con-
have point mutations that result in single amino acid substitutions sequently, such cells are not able to participate effectively in wound
in CD18, which predominantly reside between amino acids 111 and healing. Thus, impairment in neutrophil function underlies the pro-
361. This peptide domain is highly conserved among all β subunits pensity to recurrent infections, which is the clinical expression of this
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and appears to be important for interaction with the α subunit. Sev- disease. Similar genetic syndromes have been discovered in Irish Setter
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eral affected individuals are compound heterozygotes for two different dogs and Holstein cattle. A CD11/CD18-deficient mouse with 2 to 6
mutant alleles, whereas others are homozygotes for a single mutant percent of normal β -integrin expression has been produced by gene
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allele. Messenger RNA splicing abnormalities that have been described targeting. 321,329
in two kindreds can result in either deletion or insertion of amino acids Clinical Features Activated leukocytes of patients with the
in the conserved extracellular domain of CD18. Small deletions within most-severe clinical form express less than 0.3 percent of the normal
the coding sequences of the CD18 gene disrupting the reading frame amount of the β integrins, whereas those of patients with the moderate
2
or a nucleotide substitution resulting in a premature termination sig- phenotype may express 2 to 7 percent of normal numbers of β -integrin
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nal has been described. Mutations in CD18 disrupt the association in molecules. The severely affected patients suffer from recurrent and
the αβ subunits so that maturation, intracellular transport, and all cell chronic or even gangrenous soft-tissue infections (subcutaneous tissues
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surface assembly of functionally active αβ molecules fail to occur. or mucous membranes), generally by bacterial or fungal microorganisms

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