Page 805 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 50

DISORDERS OF PHAGOCYTE FUNCTION

Mary C. Dinauer and Thomas D. Coates

Phagocytic leukocytes are an essential component of the innate microbial killing—adhesion, chemotaxis, ingestion, degranulation,
immune system that has evolved to rapidly respond to the presence and production of microbicidal oxidants (Fig. 50.1). Patients with
of invading bacteria, fungi, and parasites. This first line of host inherited disorders typically present in infancy or childhood with
defense also includes natural killer (NK) lymphocytes, complement, recurrent, unusual, or recalcitrant bacterial and fungal infections,
and other plasma proteins. As reviewed in Chapters 27 and 48, and it is usually not difficult to determine that these are outside
phagocytes are responsible for ingesting, killing, and digesting the range of normal. The presentation of these different inherited
pathogens. Granulocytic phagocytes (neutrophils and eosinophils) disorders can overlap, so that a specific diagnosis cannot be made
circulate in the bloodstream until they sense chemotactic signals from on clinical grounds alone. Infections commonly seen include those
infected tissues, resulting in adhesion to the vascular endothelium of skin or mucosa, lung, lymph node, deep tissue abscesses, or child-
1
and subsequent migration into the site of infection. Mononuclear hood periodontitis. These can often have an indolent presentation
phagocytes (macrophages and their circulating precursor, the mono- with only low-grade fevers. Bacterial sepsis is an unusual initial
cyte), on the other hand, function primarily as resident cells in a symptom and usually reflects dissemination from an infected site.
variety of tissues such as the lungs, liver, peritoneal cavity, and spleen, Inherited defects in phagocyte function are rare and represent only
2
where they perform a surveillance role and also interact closely with about 20% of the primary immunodeficiencies. Thus, children
lymphocytes to promote specific immune responses. Microbial killing with suspected disorders of host defense should also be screened for
is accomplished by two types of mechanisms: (1) de novo synthesis defects in humoral, cellular, and complement-mediated immunity.
of highly toxic and often unstable derivatives of molecular oxygen An approach to evaluating the patient with significant recurrent
by an enzyme known as respiratory burst oxidase and (2) preformed infections is shown in Fig. 50.2. Patients in whom a defect is
polypeptide “antibiotics” and proteases stored within several types identified should be referred to a center specialized in care of such
of lysosomal granules that are delivered into phagocytic vacuoles patients.
containing the ingested microbes. In clinical practice, although nearly all patients with well-
This chapter reviews the major congenital and acquired disorders characterized phagocyte abnormalities have recurrent or unusual
of phagocyte function, which from the clinical standpoint largely infections, the majority of individuals with histories of persistent or
involve neutrophils. As would be predicted, these disorders manifest recurrent infections do not have identifiable phagocyte disorders or
clinically by recurrent bacterial and fungal infections, often with other immune defects. In some cases, these reflect another underlying
atypical pathogens or unusual presentations. Interestingly, the medical condition or nonimmunologic problem related to an ana-
converse of this is only rarely observed. Most patients with recur- tomic or obstructive defect. This chapter focuses largely on disorders
rent infections do not have any identifiable abnormality in their in which a good correlation exists between the clinical condition and
phagocytes. There are at least two explanations for the clinical rarity an identifiable defect in phagocyte function.
of phagocyte disorders. First, given their critical role in host defense,
nature may be quite intolerant of major abnormalities in phagocytes.
Before the modern antibiotic era, patients with severe disorders prob- DISORDERS OF THE RESPIRATORY BURST PATHWAY
ably did not survive into their childbearing years. Second, there
is a remarkable redundancy in the antimicrobial machinery of the Reactive oxygen species generated by the phagocyte respiratory burst
phagocytes that permits one system to compensate for a defect in are critical for microbial killing. The enzyme responsible for the
another. For example, the host does not rely on a single chemotactic initial reaction in this pathway is nicotinamide adenine dinucleotide
signal or neutrophil membrane receptor to ensure that phagocytes phosphate (NADPH) oxidase found in plasma and phagolysosomal
accumulate at sites of infection. Instead, multiple chemotactic signals membranes. Upon activation by inflammatory stimuli, NADPH
and receptors are used. A similar phenomenon is seen in the reac- oxidase catalyzes the transfer of an electron from NADPH to
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tions that kill microbes, as both oxidative and nonoxidative systems molecular oxygen, thereby forming superoxide (as the O 2 ion; Fig.
3–5
are used. 50.3, reaction 1). This NADPH oxidase, along with enzymes and
This chapter is organized according to the cellular functions reactions that are directly involved in the production or metabolism
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outlined above: disorders of the respiratory burst microbicidal of O 2 , constitutes the respiratory burst pathway as depicted in
pathway, abnormalities of phagocyte adhesion and chemotaxis, and Fig. 50.3. Superoxide is the precursor to numerous microbicidal
defects in the structure and function of lysosomal granules. This oxidants, including hydrogen peroxide and hypochlorous acid. Five
chapter is not meant to be an encyclopedic review of the numerous clinically significant defects have been identified in the respiratory
papers published on phagocyte abnormalities. It is important to burst, involving the following enzymes: NADPH oxidase (reaction
note that many of these reports describe marginal in vitro defects, 1), leukocyte glucose-6-phosphate dehydrogenase (G6PD; reaction
with little evidence that they are responsible for a clinical problem. 8), myeloperoxidase (MPO; reaction 4), glutathione reductase, and
Comprehensive reviews offering additional information on phagocyte glutathione synthetase (reaction 9). These reactions are involved in
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disorders are available. 2,3 the production of O 2 (reactions 8 and 1) in the conversion of O 2
and hydrogen peroxide to other toxic derivatives (reaction 4) or in
APPROACH TO DIAGNOSIS OF PHAGOCYTE the detoxification of excess hydrogen peroxide needed to protect the
phagocyte during the respiratory burst (reactions 7 and 9). Of note,
FUNCTION DISORDERS NOX homologues to the leukocyte NADPH oxidase are present
in the gut, vascular cells, and other tissues, which may generate
Inherited and acquired clinical disorders of phagocyte function oxidants for local host defense or for regulation of other cellular
result from defects in one or more of the major steps leading to functions. 6

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