Page 1051 - Williams Hematology ( PDFDrive )

1026 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 66: Disorders of Neutrophil Function 1027

benefit from intermittent colchicine therapy are those who experience Drugs and Extrinsic Agents That Impair Neutrophil Motility
a recognizable prodrome before developing fever and clear-cut acute Although many pharmacologic agents can influence neutrophil func-
symptoms. tion, few drugs used in clinical medicine affect neutrophil behavior
Course and Prognosis The prognosis for normal longevity for in vivo. Ethanol, an inhibitor of PLD, in concentrations that occur in
patients has been excellent since the recognition that colchicine is an human blood can inhibit neutrophil locomotion and ingestion.
366
effective treatment of this disease. Most patients can be maintained Glucocorticoids, especially at high and sustained doses, inhibit neu-
almost entirely symptom-free. However, if amyloidosis develops, it may trophil locomotion, ingestion, and degranulation. Administration
367
be followed by the nephrotic syndrome or uremia. Unless the patient of glucocorticoids on alternate days does not interfere with neutrophil
receives a renal transplant, the likelihood of eventual death from renal movement. Epinephrine does not have a direct effect on neutrophil
368
failure is high. adhesion but cyclic adenosine monophosphate (cAMP), which is
released from endothelial cells following exposure to epinephrine, can
369
Other Disorders of Neutrophil Motility depress neutrophil adherence. Similarly, elevated cAMP levels follow-
The directed migration of neutrophils from the circulation to an inflam- ing epinephrine administration may impair neutrophil adherence, lead-
matory site is a consequence of chemotaxis and leads to the accumula- ing to diminished neutrophil margination and apparent neutrophilia.
tion of an exudate. For normal chemotaxis to occur, a complex series of Immune complexes, as seen in patients with rheumatoid arthritis or
events must be coordinated. Chemotactic factors must be generated in other autoimmune diseases, also can inhibit neutrophil movement by
sufficient quantities to establish a chemotactic gradient. The neutrophils binding to neutrophil Fc receptors.
must have receptors for the chemotactic agents and mechanisms for dis-
cerning the direction of the chemotactic gradient. Depressed neutrophil Hyperimmunoglobulin E Syndrome
chemotaxis has been observed in a wide variety of clinical conditions Definition and History Autosomal dominant hyperimmuno-
360
(see Table 66–2). These can be stratified as follows: (1) defects in the globulin E syndrome (HIES) is a disorder characterized by markedly
generation of chemotactic signals; (2) intrinsic defects of the neutrophil; elevated serum IgE levels, chronic dermatitis, and serious recur-
and (3) direct inhibitors of neutrophil motility in response to chemotac- rent bacterial infections. The skin infections in these patients are
370
tic factors. remarkable for their absence of surrounding erythema, leading to
Older patients with chemotactic disorders may be infected by the formation of “cold abscesses.” The neutrophils and monocytes
a variety of microorganisms, including fungi and Gram-positive from patients with this syndrome exhibit a variable, but at times pro-
or Gram-negative bacteria. S. aureus is the most frequent bacterial found, chemotactic defect that appears extrinsic to the neutrophil
offender. Typically, the skin, gingival mucosa, and regional lymph (see Table 66–2). 371
nodes are involved. Respiratory tract infections are frequent, but sepsis The syndrome was originally described in 1966 in two red-headed,
is rare. Delayed or inappropriate signs and symptoms of inflammation fair-skinned females who had “cold abscesses” and hyperextensible
370
are common. Although the cells move slowly in Boyden chambers or joints, which led to the appellation “Job’s syndrome.” Subsequently
other chemotactic assays, they do accumulate in sufficient numbers in Buckley and coworkers documented the association of levels of immu-
inflammatory sites to produce pus. However, detection of patients with noglobulin E with undue susceptibility to infection. 372
neutrophils that have profound defects in chemotaxis usually is accom- Epidemiology Reports of more than 200 cases have been docu-
plished through other phagocytic assays. mented. 372,373 HIES occurs in persons from diverse ethnic backgrounds
Patients with the hereditary deficiency of complement factors C3, and does not seem to be more common in any specific population.
C5, or properidin exhibit an increased incidence of bacterial infections Etiology and Pathogenesis Both males and females have been
361
because they are unable to form the chemotactic peptide C5a. The affected, as well as members of succeeding generations, indicating that
degree to which defective chemotaxis plays a role in C3 deficiency is the disorder is autosomal dominant with an incomplete penetrance
unclear because opsonization and ingestion rates also are abnormal in form of inheritance. STAT3 mutations cause most, if not all cases of
370
these disorders. Frequently, chemotactic disorders are associated with autosomal dominant HIES. All mutations have been missense mutations
other impaired neutrophil functions. For instance, both glycogen stor- or in-frame deletions, leading to the formation of full-length mutant
363
362
age disease type 1b and Shwachman-Diamond syndrome are che- STAT3 protein, which exerts a dominant negative effect. STAT3 is a
motactic disorders frequently associated with an absolute neutrophil major transduction protein affecting pathways involving wound healing
9
count below 0.5 × 10 /L. Following restoration of a normal neutrophil angiogenesis, immunity, and cancer. The more rare autosomal recessive
count with G-CSF, the patients no longer are predisposed to recurrent form is caused by mutations in dedicator of cytokinesis 8 (DOCK8), a
bacterial infections in spite of a persistent chemotactic defect. Thus, a guanine nucleotide exchange factor. 374
chemotactic defect observed in vitro does not correlate invariably with The mechanism of the immune deficiencies in HIES remains
decreased resistance to bacterial infections in vivo. clouded. Several reports with limited numbers of patients have con-
Among the impaired defense mechanisms of the neonate is neu- flicted results as to whether a chemotactic defect exists and whether
trophil adherence and chemotaxis, as demonstrated by the in vitro there is a T-helper 1/T-helper 2 cytokine imbalance.
response of neonatal neutrophils to a variety of chemotactic factors. Clinical Features HIES may begin as early as day 1 after birth.
372
322
The impaired motility of the neonatal neutrophils in part arises from The syndrome is characterized by chronic eczematoid rashes, which are
the diminished ability to mobilize neutrophil β integrins following typically papular and pruritic. The rash generally involves the face and
2
neutrophil activation. Additionally, the neonatal neutrophil may have extensor surfaces of arms and legs; skin lesions are frequently sharply
364
a qualitative defect in β -integrin function, resulting in impaired neu- demarcated and usually lack surrounding erythema. By 5 years of age
2
trophil transendothelial migration for up to 1 month after birth. all patients have had a history of recurrent skin abscess formation with
At the other end of the spectrum, neutrophils from elderly loose recurrent pneumonias, along with chronic otitis media and sinusitis.
focus during chemotaxis while their motility is unimpaired. This is Patients may also develop septic arthritis, cellulitis, or osteomyelitis.
caused by increased activity of PI3-K and results in less efficient bacte- The major offending pathogen is generally S. aureus. Other patho-
rial killing and enhanced release of tissue destructive proteases. Inhibi- gens commonly infecting patients are C. albicans, H. influenzae, and
tion of PI3K activity reverts this condition in vitro. 365 pneumococci. Other associated features include coarse facial features,

Kaushansky_chapter 66_p1005-1042.indd 1026 9/21/15 10:48 AM