Neutrophils

The blood neutrophil (Fig 3.1a) is the end-product of an orchestrated sequence of differentiation in the myeloid cells of the bone marrow. The mature cell has a multi-lobed nucleus and four different types of granules in the cytoplasm. Neutrophils have a limited lifespan of around 5–6 days in the blood. Approximately half the cells are included in a normal blood count (the circulating pool), the remainder being in the ‘marginal pool’. The essential function of all these cells is to enter the tissues and combat infection. This requires both migration to the site of infection or tissue injury (chemotaxis) and the destruction of foreign material (phagocytosis). Normal chemotaxis is dependent on the release of chemotactic factors generated by bacteria and leucocytes already present at the infection site. Neutrophils may migrate intravascularly as they navigate healthy tissues to reach the site of tissue injury.

Neutrophil mobility is imbued both by the presence of adhesion molecules on the cell surface and by an actin–myosin assembly in the cell membrane, the latter mediating the movement necessary for locomotion and phagocytosis. Once the cell is at the target site the foreign antigen or particle is recognised via cell surface receptors and engulfed within a phagocytic vacuole. There are various methods of killing; key mechanisms are the generation of nitric oxide and antimicrobial proteins, and oxidative metabolism in which antimicrobial oxidants are formed (the ‘respiratory burst’). Cytokines such as G-CSF and GM-CSF (see p. 3) not only increase neutrophil production but also promote chemotaxis and phagocytosis.

In clinical practice an increase in neutrophils in the blood (‘neutrophil leucocytosis’ or ‘neutrophilia’) is a common accompaniment to infection and tissue injury (Table 3.1). The strain on the neutrophil compartment often leads to younger ‘band forms’ being discharged from the marrow into the bloodstream and the appearance of toxic changes, including coarsened granulation and vacuolation. Occasionally, phagocytosed bacteria are visible (Fig 3.1b).

Reduced neutrophils in the blood (neutropenia) is seen in a wide range of inherited and acquired disorders. Serious infection is not seen regularly until the count falls below 0.5 × 10⁹/L. Neutropenia may be an isolated abnormality or associated with a pancytopenia. Some causes of an isolated neutropenia are listed in Table 3.2. In general, neutropenia may be caused by underproduction from the marrow (e.g. leukaemia), reduced neutrophil lifespan (e.g. immune neutropenia), or pooling of neutrophils in a large spleen. It is important to remember that drugs may be responsible. The term chronic benign neutropenia is generally used in patients who have an isolated moderate neutropenia with no clear aetiology and a benign course. There may be an associated monocytosis. There is some ethnic variation in neutrophil counts with black people having a lower normal reference range than white people. In the rare genetic disorder cyclical neutropenia, the neutrophil count falls every 15–35 days and recurrent infections occur.

In addition to quantitative abnormalities, neutrophils can be functionally abnormal. There are several rare inherited diseases characterised by impaired neutrophil adherence, chemotaxis or bactericidal activity. In chronic granulomatous disease, neutrophils are able to phagocytose but not kill catalase-positive microorganisms. Inheritance is autosomal or X-linked and patients suffer recurrent purulent infections and associated granuloma formation. Diagnosis is made in the nitroblue tetrazolium test where the patient’s neutrophils fail to reduce the dye.

Eosinophils

Eosinophils (Fig 3.1c) are characterised by their two-lobed nucleus and red-orange staining granules. They have significant proinflammatory and cytotoxic activity and play a role in the pathogenesis of various allergic, parasitic and neoplastic disorders. Interleukin 5 is a key mediator of eosinophil differentiation and activation.

The most common causes of eosinophilia in the Western world are allergic disorders such as asthma, eczema and hay fever. In developing countries, parasitic infections are frequently implicated. Other relatively common aetiologies are drug hypersensitivity, malignancy, various skin diseases and connective tissue disorders. Hypereosinophilic syndrome is characterised by a marked sustained eosinophilia and associated tissue damage. The disorder is very variable with several subtypes. The myeloproliferative variant is associated with a FIP1L1-PDGFRA fusion gene and often responds to imatinib (see p. 45).

Basophils

Basophils are the least numerous of the blood leucocytes. They are easily recognised by their abundant dark purple cytoplasmic granules (Fig 3.1d). The granules contain mediators of acute inflammation, including heparin and histamine. Basophils and their tissue equivalent, mast cells, have receptors for the Fc portion of IgE. They play a central role in immediate hypersensitivity reactions. Basophilia is usually associated with myeloproliferative disorders (e.g. chronic myeloid leukaemia). However, it may be reactive to a range of systemic diseases including inflammatory bowel disease and hypothyroidism. It sometimes occurs during the recovery phase from acute infection.

Monocytes

Monocytes circulate in the blood before entering the tissues where they undergo transformation into macrophages. Monocyte colony-stimulating factor (M-CSF) is vital for monocyte and macrophage development and activation. The ‘mononuclear phagocyte’ system consisting of monocytes and macrophages is a potentially confusing concept as macrophages subserve different functions and adopt discrete nomenclature in different tissues (e.g. osteoclasts in bone, Kuppfer cells in liver). Macrophages are phagocytic cells but unlike neutrophils are able to survive the phagocytic event. They also act as accessory cells in the immune response by presenting antigens to T-lymphocytes (see p. 8) and secreting a wide range of cytokines involved in inflammation, immunity and haematopoiesis.

Blood monocytes typically have a kidney-shaped nucleus (Fig 3.1e). A monocytosis in the blood occurs in chronic bacterial infections such as tuberculosis and may accompany a wide range of infective, inflammatory and malignant disorders. Monocytopenia is less frequently noted but can be severe in patients receiving corticosteroid treatment.