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1090 Part VIII: Monocytes and Macrophages Chapter 69: Disorders of Monocytes 1091

hemophagocytic syndromes, it is currently thought that the inherited or or functional abnormality predisposes to such infections. In associ-
acquired inability of natural killer cells and cytotoxic T lymphocytes to ation with the amonocytosis of the MonoMAC (monocytopenia and
modulate and, eventually, abrogate the immune response is responsible mycobacterial infections) syndrome, opportunistic infections with
for the pathologic events of cytokine storm, fever, intravascular coag- mycobacteria, fungi, and viral organisms are characteristic. Macro-
ulation, organ dysfunction, and intense hemophagocytosis. Tumors of phages can serve as a reservoir for the human immunodeficiency
histiocytes (or dendritic cells) are rare, but can be classified into several virus and are the principal locus for the virus in the brain and in
groups with a combination of morphologic and immunophenotypic neural tissue.
markers (Chap. 71). Deficiency in a specific subset of macrophages, the osteoclasts,
results in osteopetrosis, an imbalance in bone metabolism that favors
accretion. Osteoclasts normally play a key role in the closely regulated
QUALITATIVE DISORDERS process of bone resorption and accretion, mediating the former pro-
OF MONOCYTES cess. Monocyte derivatives are, thereby, involved in the development of
osteoporosis and other metabolic bone diseases in which the balance
Inherited abnormalities can result in dysfunctional macrophages (see tips toward resorption. Bisphosphonates can inhibit osteoclast action
Table 69–1). In these situations the abnormality is usually shared by by interfering with its function of bone resorption and by inhibiting
other leukocytes, as in chronic granulomatous disease, which results the mevalonate pathway to geranylgeranyl diphosphate, which prevents
from a defect in oxygen-dependent microbial killing. In Chédiak- the transformation of monocytes to osteoclasts. Thus, the deleterious
Higashi disease, defective macrophages result from an abnormality in clinical manifestations of macrophages are being subdued by making
their cell and granule membranes (Chap. 66). An indomethacin- the monocyte a target of therapy, in this case the prevention and amelio-
sensitive monocyte-killing defect in children is associated with a pre- ration of postmenopausal osteoporosis, tumor-induced bone lysis, and
disposition to atypical mycobacterial disease. Also, inherited or enzyme Paget disease, as well as of others.
deficiencies in macrophages can result in accumulation of undegraded Macrophages and their derivatives, monocyte-derived dendritic
macromolecules, leading to various types of storage diseases. A classic cells, process and present antigens and play a role in immune regulation.
example is Gaucher disease, a disorder that results from an inherited In complex systems, such as that of antibody production, abnormal mac-
deficiency of the enzyme glucocerebrosidase, in which tissue dam- rophages might lead to defects in humoral immunity. Activated mono-
age results from the engorgement of macrophages with the enzyme cytes secrete more than 50 chemical mediators or monokines, which,
substrate. Recombinant glucocerebrosidase, which enters macrophage among other things, play a vital role in cellular immunity and inflamma-
lysosomes by endocytosis, can ameliorate this macrophagic disease tion. In effect, they are a critical endocrine (hormone-elaborating)
(Chap. 72). apparatus. The absence of monocytes from the inflammatory response
Acquired functional abnormalities of monocytes occur in a vari- and the failure to elaborate, or the inappropriate elaboration, of monok-
ety of diseases and circumstances (see “VII. Monocyte and Macrophage ines such as IL-1, α -proteinase inhibitor, prostaglandins, leukotrienes,
1
Dysfunction” in Table 69–1). Monocyte dysfunction occurs after severe plasminogen activator, elastase, tumor necrosis factor (TNF), IL-6,
trauma, sepsis, in other critically ill patients, and in patients with meta- IL-12, and other cytokines, may cause or contribute to disease manifes-
static cancer. Monocyte production of interleukin (IL)-12 or maturation tations. A deficiency or impairment of monocytes has the potential of
to dendritic cells also can be impaired in cases of severe trauma, critical influencing several functions and systems, because monocytes are such
illness, or metastatic cancer. important sources of inflammatory cytokines (Chap. 67). In contrast,
Some factors, such as IL-10, impair monocyte functions. A viral the unregulated activation of monocytes can lead to deleterious cytok-
IL-10–like molecule encoded by the Epstein-Barr virus BCRF1 gene ine elaboration. Central to this process is TNF. The monocyte is a major
also might play a role in the pathogenesis of that virus infection, and source of TNF, which is a principal proinflammatory cytokine, trigger-
may act, in part, by inhibiting monocyte function. Tobacco smoking ing the elaboration of IL-1, IL-6, and others. Monocyte-derived TNF is
and marijuana smoking can result in impairment of alveolar macro- also the primary chemical inducer of granuloma formation. The appre-
phage function. In several diseases, including chronic lymphocytic ciation of its latter roles resulted in therapy to sequester TNF by anti-
leukemia, Kawasaki disease, Whipple disease, and malakoplakia, spe- body neutralization or receptor blockade and has resulted in substantial
cific abnormalities of monocyte function play a significant role in the therapeutic effects in adult and juvenile rheumatoid arthritis, psoriasis,
immune impairment in each disorder. psoriatic arthritis, and Crohn disease. The side effects of such therapy
confirm the key role of TNF in suppression of intracellular pathogens,
such as Mycobacterium tuberculosis (potentiation of microbial diseases
CLINICAL MANIFESTATIONS by TNF sequestrants), and in the role of the monocyte in modulating
OF MONOCYTE DISORDERS demyelinization (exacerbation of multiple sclerosis in patients treated
with anti-TNF). The therapeutic administration of granulocyte-monocyte
MONOCYTOPENIA OR MONOCYTE colony-stimulating factor (GM-CSF) also activates monocytes to elab-
DYSFUNCTION orate cytokines, and this effect is being used to augment cancer vaccine
therapy.
Isolated monocytopenia in the absence of any other blood cell defi- Monocytopenia and decreased monocyte entry into inflammatory
ciency or immune deficiency has not been reported. The manifesta- sites occur after glucocorticoid administration. This may explain why
tions of such a clinical state (pure amonocytosis) must be inferred. patients treated with glucocorticoids are predisposed to infections in
Neutrophils, endothelial cells, and other cell types can substitute, in which monocytes play a protective role, such as those resulting from
part, for some monocyte functions. Monocytes have antibacterial, fungal, mycobacterial, and other opportunistic organisms. Dysfunc-
antiviral, antifungal, and antiparasitic capabilities. They are effec- tional monocytes, incapable of killing ingested microorganisms, are
tive phagocytes that are involved in the ingestion and inactivation present in chronic granulomatous disease (Chap. 66), as well as in
of microbes, such as mycobacteria, Listeria, Brucella, trypanosomes, hematopoietic stem cell diseases, such as monocytic variants of acute
and other granuloma-producing organisms. Thus, their deficiency myelogenous leukemia.

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