7/31/2019 Discuss How and Why Abnormalities of White Cells May Arise Other Than as a Result of Primary Haematological Malignancies

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3. Discuss how and why abnormalities of white cells may arise other than as a result of primary

haematological malignancies.

Overall, non-malignant disorders of leukocytes are far more frequently encountered than malignant diseases

such as the leukaemias. The most common abnormalities are acquired quantitative disorders. Inherited non-

malignant leukocyte disorders are mainly rare conditions. Non-malignant disorders can affect all types of

leukocytes; neutrophils, eosinophils, basophils, monocytes and lymphocytes.

Quantitative neutrophil disorders are extremely common and frequently indicate an underlying disease

process. They manifest as neutrophilia, an increased number of circulating neutrophils, and neutropenia, a

decreased number of circulating neutrophils. Neutrophilia is the body's normal response to bacterial

infection. It is often accompanied by a 'left shift' of the cells, e.g. band forms, meaning that the circulating

cells have fewer lobes to their nuclei, and have been prematurely released. In severe responses, 'toxic

granulation' can be seen, which is thought to be due to impaired cytoplasmic maturation, in the effort to

rapidly generate large numbers of granulocytes Other causes of neutrophilia include inflammatory

conditions such as Crohn's Disease, ulcerative colitis, as well as trauma and surgery, haemorrhage, and

metabolic abnormalities such as uraemia and gout. In Crohns Disease, neutrophils are recruited by pro-inflammatory cytokines such as TNF- and IL-8.

As previously mentioned, neutropenia is a reduction in the number of neutrophils in the peripheral blood

circulation. Neutropenia may be classified into mild (1.0-1.5 x 109/L), moderate (0.5-1.0 x 10

9/L) and severe

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causing a defect in the P-selectin ligand on the neutrophil surface, which impairs neutrophil tethering and

rolling. LAD-3 is caused by mutations in the gene that encodes kindlin 3, an intracellular protein that acts as a

regulator of integrin activation. A defect in NADPH oxidase activity can cause the rare inherited disorder

chronic granulomatous disease; hydrogen peroxide is not produced, and as a consequence superoxide and

hydrogen peroxide generation does not occur in the neutrophil and intracellular killing is defective

Eosinophilia is defined as an increase in the absolute eosinophil count above 0.5 x 109

. The non-malignantcauses of eosinophilia include reactive eosinophilia and eosinophilic syndromes. Reactive eosinophilia can be

transient, caused by infections, allergic reactions, drug reactions, chronic helminth infections and

autoimmune diseases, or chronic, caused by chronic GVHD, atopic diseases and endocrinopathies. The most

commonly associated chronic reactive eosinophilia is persistent helminth infections, including tape worms,

roundworms and flukes. Eosinophilia results from stem cell activation by eosinopoietic growth factors such

as IL-4, IL-5 and IL-13, which are secreted by activated T cells and mast cells. Eosinophils have granules

which contain cationic enzymes, which mediate parasite defence reactions and allergic responses. In the

developed world, helminth infections are less common, and eosinophilia is associated with acute

exacerbations of allergic and autoimmune disorders. In allergic asthma, IL- promotes eosinophil maturation

as well as blood eosinophilia in the presence of an allergen.

Eosinophilic syndromes can be organ-restricted (e.g. eosinophil gastritis) or non-organ-restricted (e.g.

Kimura disease, Shulman's disease and Churg-Strauss syndrome). In Churg-Strauss syndrome, three distinct

clinical phasesasthma, tissue eosinophilia, and vasculitis usually occur. Allergic inflammation can arise

after inhalation of a foreign antigen resulting in rhinosinusitis and asthma. Blood and tissue eosinophilia then

arise and cause infiltrative eosinophilic pneumonia in some patients. Vascular inflammation may result from

endothelial-cell adhesion and eosinophil degranulation, with subsequent necrotising vasculitis in several

organ systems, especially the lung, heart, peripheral nervous system, skin, and gastrointestinal tract.

Non-malignant causes of basophilia are uncommon, but have been reported in hypothyroidism,hypersensitivity reactions and allergy and inflammation. The most common clinical setting in which

basophilopaenia has been detected is after an acute MI or lobar pneumonia. These findings may reflect the

effects of increased release of corticosteroids in these conditions, as administration of ACTH and

corticosteroids reduces basophil and eosinophil counts.

Monocytopenia is rare, and usually only occurs as part of a generalised leukopenia, in autoimmune diseases

for example, but monocytosis is much more common and frequently occurs in inflammatory conditions (SLE

and RA), and chronic infections (TB, brucellosis), especially when the neutrophil response is compromised or

ineffective, for example, infection with encapsulated microorganisms.

Lymphocytosis and lymphopenia can occur in a variety of conditions. Lymphocytosis is usually a sign of an

active immune response, such as in response to a viral infection, against EBV, CMV and rubella. Protozoal

infections, particularly toxoplasmosis, but also malaria can cause lymphocytosis. One of the most marked

examples of lymphocytosis can be seen in whooping cough, where the lymphocyte count is increased to

defend against Bordetella pertussis. A variety of non-infectious causes including serum sickness, drug

reactions (e.g. phenytoin) and hyperthyroidism cause lymphocytosis as well. Lymphopenia can occur in

infections (HIV, miliary TB, malaria and influenza) and also a variety of other conditions including connective

tissue disease, BM failure, and as a consequence of immunosuppressive, cytotoxic or radiotherapy.

In conclusion, there are a wide range of non-malignant leukocyte disorders, which can arise from infection,but also non-infectious and inflammatory causes. The majority of these disorders are acquired rather than

inherited.