Chapter 69: Classification and Clinical Manifestations of Disorders of Monocytes and Macrophages

Classification of monocytic disorders is difficult because few abnormalities result solely in a disturbance of monocytes or macrophages. However, the presence of monocytopenia, monocytosis, histiocytosis, or qualitative disorders of monocytes may be an important diagnostic feature or contribute to the functional abnormality in the patient.

The terms histiocyte and macrophage are synonymous. The latter term is customary when discussing the biology of the cells of the mononuclear phagocyte system, which is the total pool of marrow, blood, and tissue monocytes and macrophages, formerly referred to as the reticuloendothelial system. In disease nosology, the terms histiocyte and histiocytosis continue to be used for diseases that principally involve cells derived from blood monocytes, that is, macrophages and monocyte-derived dendritic cells.

The physician should consider the absolute monocyte count and not the percent of cells that are monocytes when evaluating the differential blood cell count before concluding that there is an inappropriate content of blood monocytes (Chap. 70).

Table 69–1 lists a classification of monocyte and macrophage disorders of relevance to hematologists.

MONOCYTOPENIA

Table 69–1 contains several important causes of monocytopenia. Two notable examples of disorders accompanied by severe monocytopenia are aplastic anemia and hairy cell leukemia. Pancytopenia is usual in both conditions, but the predisposition to serious infection is heightened by the deficiency in monocyte production. In hairy cell leukemia, the severe monocytopenia represents an important diagnostic clue because of its constancy. A syndrome of profound monocytopenia, often amonocytosis, associated with susceptibility to mycobacterial avian complex, fungal, and disseminated papilloma virus infections, and subsequent development of myelodysplasia or acute myelogenous leukemia in some cases, was first described in 2010 (see Table 69–1). It is accompanied by blood B-cell lymphopenia and decreased circulating and tissue dendritic cells, but not by hypogammaglobulinemia or a deficiency of tissue macrophages or skin Langerhans (dendritic) cells. It is the result of mutations of GATA2 that impair transcription of its mRNA and is usually inherited as an autosomal recessive or can occur sporadically. The mutations of GATA2 were found in germline and hematopoietic tissues, adding it to the familial leukemia genes, as well as to a slow onset (sometimes decades), complex immunodeficiency state.

MONOCYTOSIS AND HISTIOCYTOSIS

Table 69–1 contains a comprehensive list of causes of monocytosis. Monocytosis is often the manifestation of an inflammatory or a neoplastic disease. Certain hematopoietic tumors, especially acute monocytic and chronic myelomonocytic leukemia, have as their principal manifestation a predominance of monocytic cells in marrow and blood. Occasionally, chronic monocytosis can precede the onset of acute myelogenous leukemia, representing an uncommon manifestation of the myelodysplastic syndromes. Dendritic cell variants of acute myelogenous leukemia have also been discovered since the advent of immunophenotyping and genotyping of acute leukemias. The precise derivation of these myeloid dendritic cells is uncertain (i.e., granulocytic or monocytic). In some cases of monocytic leukemia, the malignant clone does not appear to include progenitors of red cells and platelets. Such cases are not likely to be the result of a mutation of a multipotential hematopoietic cell. This type of progenitor cell monocytic leukemia and other histiocytic or dendritic cell tumors support the concept that primitive cells, committed to the monocyte-macrophage lineage, can undergo malignant transformation (Chaps. 83 and 88).

Several uncommon types of histiocytosis are serious systemic diseases that may masquerade as malignant disease. However, in such cases the cytopathologic changes in monocytes or macrophages do not constitute a malignant transformation and are not monoclonal. Familial and sporadic hemophagocytic lymphohistiocytosis, infection-induced hemophagocytic syndromes, and sinus histiocytosis with massive lymphadenopathy are among such disorders (Chap. 71). Infectious hemophagocytic histiocytosis caused by Epstein-Barr virus may be a hybrid disease because of the association with an underlying monoclonal or oligoclonal proliferation of virus-infected lymphocytes. The striking activation of macrophages and the resulting cytokine elaboration and organ pathology seen in some patients with juvenile rheumatoid arthritis, referred to as the “macrophage-activation syndrome,” is closely related to other types of hemophagocytic syndromes (Chap. 71). Pediatric rheumatologists refer to the hemophagocytic syndrome in patients with juvenile rheumatoid arthritis as the “macrophage activation syndrome,” but the clinical expression is closely analogous to other acquired hemophagocytic lymphohistiocytic syndromes. In these hemophagocytic syndromes, it is currently thought that the inherited or acquired inability of natural killer cells and cytotoxic T lymphocytes to modulate and, eventually, abrogate the immune response is responsible for the pathologic events of cytokine storm, fever, intravascular coagulation, organ dysfunction, and intense hemophagocytosis. Tumors of histiocytes (or dendritic cells) are rare, but can be classified into several groups with a combination of morphologic and immunophenotypic markers (Chap. 71).

Inherited abnormalities can result in dysfunctional macrophages (see Table 69–1). In these situations the abnormality is usually shared by other leukocytes, as in chronic granulomatous disease, which results from a defect in oxygen-dependent microbial killing. In Chédiak-Higashi disease, defective macrophages result from an abnormality in their cell and granule membranes (Chap. 66). An indomethacin-sensitive monocyte-killing defect in children is associated with a predisposition to atypical mycobacterial disease. Also, inherited or enzyme deficiencies in macrophages can result in accumulation of undegraded macromolecules, leading to various types of storage diseases. A classic example is Gaucher disease, a disorder that results from an inherited deficiency of the enzyme glucocerebrosidase, in which tissue damage results from the engorgement of macrophages with the enzyme substrate. Recombinant glucocerebrosidase, which enters macrophage lysosomes by endocytosis, can ameliorate this macrophagic disease (Chap. 72).

Acquired functional abnormalities of monocytes occur in a variety of diseases and circumstances (see “VII. Monocyte and Macrophage Dysfunction” in Table 69–1). Monocyte dysfunction occurs after severe trauma, sepsis, in other critically ill patients, and in patients with metastatic cancer. Monocyte production of interleukin (IL)-12 or maturation to dendritic cells also can be impaired in cases of severe trauma, critical illness, or metastatic cancer.

Some factors, such as IL-10, impair monocyte functions. A viral IL-10–like molecule encoded by the Epstein-Barr virus BCRF1 gene also might play a role in the pathogenesis of that virus infection, and may act, in part, by inhibiting monocyte function. Tobacco smoking and marijuana smoking can result in impairment of alveolar macrophage function. In several diseases, including chronic lymphocytic leukemia, Kawasaki disease, Whipple disease, and malakoplakia, specific abnormalities of monocyte function play a significant role in the immune impairment in each disorder.

MONOCYTOPENIA OR MONOCYTE DYSFUNCTION

Isolated monocytopenia in the absence of any other blood cell deficiency or immune deficiency has not been reported. The manifestations of such a clinical state (pure amonocytosis) must be inferred. Neutrophils, endothelial cells, and other cell types can substitute, in part, for some monocyte functions. Monocytes have antibacterial, antiviral, antifungal, and antiparasitic capabilities. They are effective phagocytes that are involved in the ingestion and inactivation of microbes, such as mycobacteria, Listeria, Brucella, trypanosomes, and other granuloma-producing organisms. Thus, their deficiency or functional abnormality predisposes to such infections. In association with the amonocytosis of the MonoMAC (monocytopenia and mycobacterial infections) syndrome, opportunistic infections with mycobacteria, fungi, and viral organisms are characteristic. Macrophages can serve as a reservoir for the human immunodeficiency virus and are the principal locus for the virus in the brain and in neural tissue.

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 process of bone resorption and accretion, mediating the former process. Monocyte derivatives are, thereby, involved in the development of osteoporosis and other metabolic bone diseases in which the balance tips toward resorption. Bisphosphonates can inhibit osteoclast action by interfering with its function of bone resorption and by inhibiting the mevalonate pathway to geranylgeranyl diphosphate, which prevents the transformation of monocytes to osteoclasts. Thus, the deleterious clinical manifestations of macrophages are being subdued by making the monocyte a target of therapy, in this case the prevention and amelioration of postmenopausal osteoporosis, tumor-induced bone lysis, and Paget disease, as well as of others.

Macrophages and their derivatives, monocyte-derived dendritic cells, process and present antigens and play a role in immune regulation. In complex systems, such as that of antibody production, abnormal macrophages might lead to defects in humoral immunity. Activated monocytes secrete more than 50 chemical mediators or monokines, which, among other things, play a vital role in cellular immunity and inflammation. In effect, they are a critical endocrine (hormone-elaborating) apparatus. The absence of monocytes from the inflammatory response and the failure to elaborate, or the inappropriate elaboration, of monokines such as IL-1, α₁-proteinase inhibitor, prostaglandins, leukotrienes, plasminogen activator, elastase, tumor necrosis factor (TNF), IL-6, IL-12, and other cytokines, may cause or contribute to disease manifestations. A deficiency or impairment of monocytes has the potential of influencing several functions and systems, because monocytes are such important sources of inflammatory cytokines (Chap. 67). In contrast, the unregulated activation of monocytes can lead to deleterious cytokine elaboration. Central to this process is TNF. The monocyte is a major source of TNF, which is a principal proinflammatory cytokine, triggering the elaboration of IL-1, IL-6, and others. Monocyte-derived TNF is also the primary chemical inducer of granuloma formation. The appreciation of its latter roles resulted in therapy to sequester TNF by antibody neutralization or receptor blockade and has resulted in substantial therapeutic effects in adult and juvenile rheumatoid arthritis, psoriasis, 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 by TNF sequestrants), and in the role of the monocyte in modulating demyelinization (exacerbation of multiple sclerosis in patients treated with anti-TNF). The therapeutic administration of granulocyte-monocyte colony-stimulating factor (GM-CSF) also activates monocytes to elaborate cytokines, and this effect is being used to augment cancer vaccine therapy.

Monocytopenia and decreased monocyte entry into inflammatory sites occur after glucocorticoid administration. This may explain why patients treated with glucocorticoids are predisposed to infections in which monocytes play a protective role, such as those resulting from fungal, mycobacterial, and other opportunistic organisms. Dysfunctional monocytes, incapable of killing ingested microorganisms, are present in chronic granulomatous disease (Chap. 66), as well as in hematopoietic stem cell diseases, such as monocytic variants of acute myelogenous leukemia.

TISSUE EFFECTS OF MONOCYTOSIS

Benign monocytosis is not associated with specific clinical manifestations. All forms of myelogenous leukemia with a predominance of monocytes are associated with a predisposition to troublesome tissue infiltrates, especially in the skin, gingiva, lymph nodes, meninges, and anal canal. The higher the monocyte count and the higher the proportion of leukemic monocytes, the more prevalent is tissue infiltration. In some cases, the tissue infiltration of leukemic monocytes can produce symptoms: lung dysfunction, laryngeal obstruction, and intracranial vessel rupture, as well as others. Release of procoagulants leading to intravascular coagulation also occurs in myelogenous leukemia with a high proportion of monocytes. The hyperleukocytic syndrome can occur in acute monocytic leukemia with markedly elevated white cell counts (Chaps. 83 and 88).

EFFECTS OF HISTIOCYTOSIS

Hemophagocytic lymphohistiocytosis usually refers to the accumulation of activated macrophages (histiocytes) in tissue sites. The cells become intensely cytophagocytic; ingestion of red cells and occasionally of leukocytes, platelets, erythroblasts in marrow, or cells in other tissue sites is an important feature of these inflammatory histiocytoses (Chap. 71). Because morphology has been misleading, the diagnosis of histiocytosis requires identification of specific cell markers. A histiocytosis may be inflammatory (polyclonal) or neoplastic (clonal). Because tissue macrophages can take on highly specialized phenotypes and localize in different tissues, histiocytosis is further defined by whether they carry markers of these cell types (e.g., Langerhans cells, interdigitating dendritic cells; Chap. 71).

THROMBOATHEROGENESIS

The complex interrelationships among monocytes, atherogenesis, and coagulation are discussed in several other chapters in the text (Chaps. 115 and 134). Monocytes may play a central role in the pathologic aspects of both processes, as a repository for tissue factor, inflammatory cytokines, and a key element in the inflammatory precursor lesions of atheroma formation (Table 69–1, sections VIII and IX).

Dendritic cells and macrophages belong to a family of antigen-presenting cells and in the laboratory can be generated from a common precursor. So-called monocyte-derived dendritic cells are easily produced in the culture vessel by the appropriate cytokines. Indeed, the use of GM-CSF as an adjuvant in cancer vaccines may relate in part to the cytokine’s ability to activate monocytes and foster conversion to dendritic (antigen-presenting) cells in vivo (Chaps. 26 and 27). Dendritic cells can be defined by phenotype into two principal types—myeloid and lymphoid (plasmacytoid) dendritic cells—of which there are likely subtypes. Monocyte-derived dendritic cells are a subset of the myeloid type (Chap. 20).

Flow cytometry using cluster of differentiation (CD) markers and antidendritic cell surface antibodies have permitted the enumeration of myeloid (human leukocyte antigen-D related [HLA-DR]+, CD11c+, CD123–) and lymphocytic-plasmacytoid (HLA-DR+, CD11c–, CD123+, CD303+) dendritic cells in human blood in normal subjects and subjects with disease. Their centrality in the immune response as premier antigen-presenting cells may result in nonspecific alterations in their blood concentration or function in many generalized or localized inflammatory, infectious, and neoplastic diseases. Plasmacytoid dendritic cells may be decreased in numbers with aging, further impairing the immune response of older individuals (Chap. 9). Dendritic cells are also profoundly decreased in patients with hairy cell leukemia and are dysfunctional in patients with chronic lymphocytic leukemia.