Disorders of neutrophil function

Neutropenias may also arise as a side effect or deliberate consequence of therapy. For example, some drugs used in the treatment of inflammatory disorders are immunosuppressive, and if these decrease the number of circulating neutrophils to below the critical threshold level, then susceptibility to infection may result. During chemotherapy for the treatment of solid tumours, an inevitable consequence of cytotoxic therapy is that the bone marrow will be destroyed by the drugs thus, patients will have a considerable risk of infection during this induction period. Similarly, during the treatment of haematological disorders (e.g. leukemias and myelodysplastic syndromes), the aim of therapy is to attack the bone marrow so as to destroy 

Other neutrophil disorders are related to specific defects in key neutrophil enzymes or processes these are described in detail in the following sections. Many of these diseases are rare and have only recently been discovered. The survival of such patients is possible today only because these specific defects are now more readily identified, and because infections can be carefully managed using a wide range of potent antibiotics. In some patients (e.g. those with CGD), cytokine therapy may again prove useful. 

On the other hand, there are a number of human diseases associated with an overactivity of neutrophil function. Many facets of the neutrophil antimicrobial arsenal, such as reactive oxygen metabolites and proteases, can attack host tissues as effectively as they can attack microbial targets. For this reason, activation of neutrophils under physiological conditions is carefully regulated and damage restricted for the following reasons  

However, it is now recognised that neutrophils can contribute to host-tissue damage if they are activated to secrete reactive oxidants and granule enzymes, and if the local concentrations of anti-oxidants and protease inhibitors within the tissue are low or defective. Thus, inappropriate neutrophil activation leading to host-tissue damage has been implicated in reperfusion injury, Crohn s disease, adult respiratory distress syndrome (ARDS) and rheumatoid arthritis. In these conditions, it is envisaged that neutrophils accumulate in tissues and become inappropriately activated to secrete their cytotoxic products, which then initiate or contribute to host-tissue damage. 

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Infection is the most common cause of morbidity and mortality in MDS patients, accounting for 40-60% of deaths in various studies. The common infections are those normally associated with neutropenias, such as Gramnegative septicaemia and bacterial bronchopneumonias. Indeed, most MDS patients are neutropenic at some stage in their disease. Even those who do not have a neutropenia may have a defect in their neutrophil function. Many patients have clearly-defined defects in T- and B-lymphocyte functions, and variable defects in monocyte numbers or function have been described. Disorders of neutrophil function are common. Many reports indicate that phagocytosis, chemotaxis, respiratory-burst activity and degranulation are defective in some MDS patients, and hypogranulation is often observed. 

Ward, P. A., Disorders of leukocyte function. Annu. J. Pathol. 88, 7(X)-752 (1977). Whittaker, J. A., Khurshid, M., and Hughes, H. R., Neutrophil function in chronic granulocytic leukemia before and after Busulphan treatment. Br. J. Haematol. 28, 541-549 (1974). 

G-CSF increases the number of progenitor cells in the bloodstream tenfold. It has been used in the treatment of patients with myelodysplastic syndromes (MDS 8.8) where it can increase neutrophil counts and sometimes improve neutrophil function in these patients. Because some leukaemic cells are able to proliferate rather than differentiate in response to G-CSF, this CSF may potentially induce a leukaemic transformation in these patients however, its combined use with cytotoxic agents such as cytosine arabinoside appears to decrease this possibility. No doubt clinical trials already underway will establish the optimal treatment regimen for G-CSF, so that the beneficial effects of this cytokine for the treatment and management of haematological disorders can be realised. 

Neutrophil-Specific Granule Deficiency. In this rare disorder, secondary or specific granules in neutrophils are absent. The defect may arise from a mutation that leads to the loss of function of the transcription factor CCAAT/enhancer binding protein e (C/EBPe), which is needed for neutrophil response to inflammation (91). Specific granule deficiency affecfs fhe migration of neutrophils. 

In adults, a severe form of lung injury can develop in association with sepsis, pneumonia, and injury to the lungs due to trauma or surgery. This catastrophic disorder is known as acute respiratory distress syndrome (ARDS) and has a mortality rate of more than 40%. In ARDS, one of the major problems is a massive influx of activated neurophils which damage both vascular endothelium and alveolar epithelium and result in massive pulmonary edema and impairment of surfactant function. Neutrophil proteinases (e.g., elastase) break down surfactant proteins. A potential therapeutic strategy in ARDS involves administration of both surfactant and antiproteinases (e.g., recombinant a I -antitrypsin). 

There has been a great deal of interest in the use of colony-stimulating factors to treat MDS. GM-CSF and G-CSF, which have been used in clinical trials, offer a potential dual benefit. Firstly, they can affect neutrophil development in the bone marrow, and so can improve the neutropenia that is associated with these disorders. Secondly, they have the potential to increase or repair the function of circulating neutrophils. Indeed, there are some reports to indicate that these CSFs can result in enhanced function of peripheral blood neutrophils in these patients. Most patients show improvements in neutrophil counts after GM-CSF or G-CSF administration. In some cases, this has been associated with a decrease in the number of infective episodes. 

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