The mononuclear phagocyte system has been defined as a family of cells comprising bone marrow progenitors, blood monocytes and tissue macrophages. Monocytes develop from a pluripotent stem cell in the bone marrow, termed colony-forming unit - granulocyte, erythrocyte, monocyte, megakaryocyte (CFU-GEMM) and the more committed CFU-GM. This stem cell can commit to both the neutrophil and monocytic pathways. Cytokines and growth factors, such as monocyte colony-stimulating factor (M-CSF), GM-CSF and IL-3, allow the commitment along monocytic pathways. M-CSF, also known as colony-stimulating factor-1 (CSF-1), is the most important factor in the development of monocytes and macrophages, and is necessary but not sufficient for their activation.
Following their release into the circulation, monocytes rapidly partition between the marginating and circulating pools. The circulating monocytes have a highly convoluted surface and a lobulated nucleus. They can be further characterized by non-specific esterase and contain a single type of nucleus with staining characteristics of lysosomes. After migration into tissues, they become larger and acquire the characteristics of tissue macrophages. Monocytes contain lysosomal hydrolases and the intracellular enzymes elastase and cathepsin. After transformation into tissue macrophages they produce predominantly met-alloproteases and metalloprotease inhibitors, lose expression of hydrolases, and express macrophage-specific genes and products such as inducible nitrous oxide synthase (NOS) and IFN-y. Tissue macrophages are long-lived and self-sustaining cells.
Macrophage activation is the acquisition of competence to perform specific and complex functions as a result of exposure to a constellation of cytokines and other factors in their environment, rather than achievement of a universal activated state. Physiological factors from the host such as cytokines and growth factors as well as environmental factors from micro-organisms constitute this constellation and their combined effect is synergistic. Macrophage activating factor (MAF), identified as IFN-y, as well as IL-2, IL-4, M-CSF and GM-CSF are either directly or indirectly, through IFN-y, responsible for macrophage activation. They stimulate monocyte/macrophage proliferation, increase adhesive receptor expression and stimulate the production of proteolytic agents responsible for pathogen clearance.
Whereas production of IFN-y by the T helper 1 cells (Th1) results in a cytocidal macrophage state, IL-4 and IL-13 produced by the Th2 population of T lymphocytes stimulate the antigen-presenting cell (APC) state. These cytokines then enhance macrophage stimulation of T cells by inducing class II MHC antigen and co-stimulatory molecule expression. Activated macrophages, in turn, produce cytokines that stimulate both types of helper T cells.
Several cytokines including IL-4, IL-10, IL-13 and TGF-P can inhibit different aspects of macrophage function. Furthermore, prostaglandin E2, elaborated by macrophages as well as cor-ticosteroids can suppress various actions of macrophages. These provide a feedback loop mechanism for the control of the immune response.
Disorders of monocyte/macrophages
Monocytosis and monocytopenia
Chronic inflammatory conditions, both infectious and immune in nature, are associated with monocytosis (Table 17.11). These
Table 17.11 Causes of monocytosis.
Infections Tuberculosis Bacterial endocarditis Fever of unknown origin Syphilis
Systemic lupus erythematosus
Cyclic neutropenia Chronic idiopathic neutropenia Kostmann's syndrome Post splenectomy include tuberculosis, bacterial endocarditis, syphilis, collagen vascular disease, sarcoidosis and ulcerative colitis. Monocytosis is also commonly seen in a number of haematological malignancies such as AML, Hodgkin's disease, non-Hodgkin's lymphomas, and histiocytosis. Decreased number of circulating monocytes has been reported with endotoxaemia, cortico-steroid administration and hairy cell leukaemia.
As described above, bone marrow monocytes enter the circulation and transform into tissue-specific macrophages under the influence of the local environment thus becoming cells of the mononuclear phagocytic system (MPS). Dendritic cells also have their origin in the bone marrow and share common progenitors with macrophages. Progenitors of dendritic cells are released from the bone marrow and enter tissues in which they differentiate into functional, antigen-presenting dendritic cells. The ordinary tissue macrophages have IgG Fc receptors, whereas the tissue-based dendritic cells comprising the dendritic cell system (DCS), lack phagocytic capacity or Fc receptors, and are predominantly antigen-presenting cells. The dendritic Langerhans cells are found in virtually all tissues except the brain and are the major immunological cellular components of the skin and mucosa. Their racquet-shaped ultrastructural inclusions (Birbeck bodies) distinguish them from other tissue cells. They interact with and process antigen, then migrate to lymphoid organs, where, through interaction with T-cells, they generate cellular and humoral immune responses. This ability of dendritic cells to interact with T cells and other inflammatory cells contributes to the often varied clinical manifestations of the histiocytic disorders.
The histiocytic disorders comprise varied haematological disorders with cells of the MPS or the DCS involved in their pathogenesis. In general, disease associated with proliferation of histiocytes can be grouped into two different categories: inflammatory disorders and neoplastic (clonal) disorders (Table 17.12). In the more recent classifications by the World Health Organization Committee on Histiocytic/Reticulum Cell Proliferations, other disorders in which histiocytes are implicated such as storage diseases (Gaucher's and Niemann-Pick) have been excluded. Abnormal immune response mediated by cytokines has been proposed to be the inciting factor for the two more common disorders: Langerhans cell histiocytosis (LCH) and haemophagocytic lymphohistiocytosis (HLH). It is, however, unclear whether the histiocytes themselves or other immune cells are the defective cell population.
It has been recognized that the offending cells in the disorders previously referred to as 'histiocytosis X' (including eosinophilic granuloma, Letterer-Siwe disease and Hand-Sculler-Christian disease) have the characteristics of the epidermal Langerhans cells. These disorders, now collectively referred to as LCH, have
Table 17.12 Histiocytic disorders.
Disorders of varied biological behaviour
Related to dendritic cells
Langerhans cell histiocytosis
Juvenile xanthogranuloma and related disorders
Solitary dendritic cell histiocytoma
Related to macrophages
Primary - familial haemophagocytic histiocytosis Secondary - infectious, tumour associated, drug associated (e.g. phenytoin)
Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy)
Solitary macrophage histiocytoma
Related to monocytes
Leukaemia - FAB M4 and M5, acute myelomonocytic leukaemia, chronic myelomonocytic leukaemia, extramedullar^ monocytic tumours
Related to dendritic cells
Histiocytic sarcoma (malignant histocytosis) - localized or disseminated
Histiocytic sarcoma (malignant histiocytosis) - localized or disseminated variable clinical features depending on the organs infiltrated by the responsible Langerhans and accompanying cells. The true prevalence of these disorders is seven cases per million. The majority of cases occur in children under 15 years of age, but they can occur at any age.
The aetiology of these disorders is far from clear, but a number of clues from their biology and epidemiology are emerging. Associations with malignancies and an inherited predisposition based on studies in identical twins have been suggested. No seasonal variations or geographic or racial clustering has been reported, disputing the possibility of an infectious aetiology. Flow cytometry and chromosomal analysis of cells from LCH infiltrates as well as methods to assess clonality based on X chromosome inactivation have suggested the possibility of a clonal nature, although no consistent chromosomal alterations have been reported so far.
However, it is now clear that LCH is characterized by a clonal proliferation of CD1a+ cells. The Langerhans cells from the lesions of patients demonstrate several phenotypic changes that distinguish them from their normal counterparts. Differences in staining by the lectin, peanut agglutinin (PNA), expression of placental alkaline phosphatase (PLAP), expression of the interferon-y receptor, and expression of co-stimulatory receptors such as CD86 and CD80 have been reported between LCH lesional cells and their normal counterparts. There is extensive expression of GM-CSF, IL-1, IL-3, IL-4, IL-8, TNF and LIF in the LCH lesions, suggestive of activation of T lymphocytes as well as recruitment of macrophages, eosinophils and granulocytes. The accumulation of IL-1 and prostaglandin E2 may explain the association of these lesions with bone loss. It is of note that such increases in immunostimulatory and tissue-damaging cytokines are at local sites, usually without high systemic levels.
The diagnosis of LCH is based on a biopsy of the involved organs with the key diagnostic feature being the presence of pathological Langerhans cells, which can be identified by demonstration of either CD1a surface antigen, or the presence of Birbeck granules on electron microscopy (Figure 17.5). Mitoses are usually not present and when found have no prognostic significance. Early lesions are generally cellular and locally destructive with abundance of essentially normal Langerhans cells. As the lesions mature, there are fewer Langerhans cells with occasional necrosis.
The lesions of LCH occur in skin, bone, lymph nodes, liver, spleen, bone marrow, lungs, the central nervous system and the gastrointestinal tract. Clinical features are varied and depend on the organs involved. It may involve single organs or be multisystem, and assessment of organ function is important as it can have prognostic significance. Initial investigations should include a full blood count, assessment of renal and hepatic function, a skeletal survey and a technetium bone scan; these latter studies are complementary with the latter being more sensitive for early lesions. Other investigations include a chest radiograph, and possibly magnetic resonance imaging (MRI) of the brain to rule out central nervous system (CNS) involvement. Additional testing for diabetes insipidus and other organ involvement should be carried out as indicated.
Solitary or multifocal eosinophilic granuloma (SEG or MEG) is found mainly in older children and young adults and accounts for the majority of cases of LCH. Hand-Sculler-Christian disease occurs in younger children (2-5 years) and often presents with exophthalmos due to a tumour mass in the orbital cavity. Letterer-Siwe disease is the rarest and often most severe form of LCH, typically presenting with a scaly, seborrhoeic, eczematoid and, occasionally, purpuric or ulcerative rash in infants younger than 2 years. Bone involvement in LCH can lead to a tender swelling (as a result of infiltration of adjacent tissues) and inability to bear weight. On radiography, lesions appear as 'punched out' holes sometimes with sclerotic edges. Other clinical manifestations include rashes, which may be maculopapular, nodular or vesicular, ear discharge, lymphadenopathy, diabetes insipidus due to the involvement of hypothalamus and the pituitary, respiratory symptoms with radiographic changes such as micro-nodular infiltrates due to lung involvement, hepatomegaly with laboratory evidence of liver dysfunction, splenomegaly, CNS
disease with ataxia, dysarthria, cranial nerve palsies and, rarely, gut involvement with diarrhoea, malabsorption and protein-losing enteropathy.
The prognosis of patients with LCH depends on age of onset, number of involved organs and degree of their dysfunction. In general, infants with multiorgan disease have the worst prognosis. There is also growing realization that multiple recurrences of the disease can occur indefinitely, and those patients with multisystem involvement can have long-term sequelae of their disease and/or its treatment. These include neurocognitive and psychosocial problems, neurological complications with a neurodegenerative pattern of CNS involvement, orthopaedic problems, hearing loss, and hypothalamic/pituitary axis deficiencies, leading to stunted growth and other endocrine problems.
Spontaneous resolution in a significant proportion of patients with LCH can occur and patients with a limited disease usually do not require systemic therapy. In contrast, patients with multifocal disease generally benefit from systemic therapy. Treatment options have included low-dose radiation for symptomatic single lesions, local injection of steroids, topical steroids, PUVA, non-steroidal anti-inflammatory drugs, high-dose systemic steroids, and systemic multi-agent chemotherapy regimens with agents such as prednisolone, vinblastine, vincristine, etoposide and 6-mercaptopurine. Other agents, that have been tested in patients with disease progression while on therapy include cyclosporin, antithymocyte globulin, 2-chlorodeoxyadenosine (2CDA), thalidomide, TNF inhibitors, anti-CD1a antibodies and haemopoietic stem cell transplantation.
These disorders include primary (familial) and secondary (related to infections or malignancy) with the familial form affecting neonates and infants and occurring in 1-2 children per million white people per year. Males and females are equally affected and over two-thirds of cases occur in siblings. The familial form is an autosomal recessive disease without a well-defined genetic defect. Recently, several defects in genes important for immune functions have been reported in patients with familial HLH and include mutations in the genes for perforin, the y-chain of IL-2 receptor and purine nucleoside phosphorylase.
It is hypothesized that the disease is caused by impaired lymphocyte-mediated cytotoxicity and defective triggering of apoptosis. Perforin, normally secreted by cytotoxic T cells and natural killer (NK) cells, can form cell death-inducing pores through which toxic granzymes may enter the target cell and trigger apoptosis. Mutations of the perforin gene have been reported in several patients with familial HLH and result in defective lymphocyte cytotoxic activity. The manifestations of the disease are thought to be mediated by such inflammatory cytokines as IFN-y TNF-a, soluble IL-2 receptor, FAS ligand and GM-CSF. Such excess of proinflammatory cytokines results in tissue infiltration by lymphocytes and macrophages, leading to haemophagocytosis.
The secondary form of HLH is commonly precipitated by viral (particularly Epstein-Barr virus and other herpesviruses), bacterial, fungal and protozoan infections, often in an immunocompromised host. Other factors that have been associated with secondary HLH include malignancies (particularly lympho-proliferative disorders), autoimmune disorders, drugs (such as phenytoin) and Chediak-Higashi disease. It is important to distinguish patients with the secondary form of the disease from individuals with familial HLH and a precipitant viral infection.
Clinical presentations of HLH commonly include fever, anorexia, malaise, irritability and vomiting. Hepatic and splenic enlargement, lymphadenopathy, pancytopenia, abnormal liver function, coagulopathy, and CNS signs and symptoms are also common. Other features include hypertriglyceridaemia, hypo-fibrinogenaemia, cerebrospinal fluid pleocytosis, and rashes. Marrow examination is often hyperplastic with increased numbers of haemophagocytic histiocytes. Histopathological features of lymph node or other involved tissue are often diagnostic, showing infiltration by lymphocytes and histiocytes and the characteristic prominent erythrophagocytosis and haemophago-cytosis, which is essential for diagnosis. There are no specific diagnostic tests, but during the acute phase of the illness, the plasma concentrations of inflammatory cytokines IFN-y, TNF-a, soluble IL-2 receptor and IL-6 are often markedly elevated.
Treatment of familial HLH has traditionally involved the use of corticosteroids, cyclosporin and etoposide. Although high initial responses are observed, disease recurrence within months is usual. Adequate control of CNS disease is important but the value of routine prophylaxis with intrathecal methotrexate is controversial. Patients are at high risk of opportunistic infections because of their underlying immune dysfunction and the effects of therapy. Age is an important prognostic factor with the higher likelihood of survival in children older than 2 years of age. Haemopoietic stem cell transplant from a matched sibling is the definitive treatment modality in patients with familial HLH.
Sinus histiocytosis with massive lymphadenopathy or Rosai-Dorfman syndrome is characterized as a benign, frequently chronic, painless lymphadenopathy involving the cervical nodes and less commonly other nodal areas. Other features may include fever, weight loss, extranodal disease in skin, soft tissues, orbits, upper respiratory mucosa, bone and other organs. Although the disease commonly occurs in the first two decades of life, all ages can be affected. Diagnostic evaluation of involved lymph nodes reveals infiltration by histiocytes and multinu-cleated giant cells associated with erythrophagocytosis. The proliferating histiocytes are morphologically distinguished from Langerhans cells of LCH by the absence of Birbeck granules on electron microscopy as well as their surface phenotype. Treatment is usually unnecessary and ineffective with the disease manifestations usually subsiding over several months to years.
Although monocytic leukaemias are included in the classification of histiocytic disorders, their discussion is beyond the scope of this chapter and will be dealt with elsewhere.
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