Disorders of basophils and mast cells

High basophil numbers are commonly seen in patients with myeloproliferative disorders, in particular chronic myeloid leukaemia (CML). Basophil number can be strikingly elevated in patients with CML, accounting for over 20% of circulating leucocytes in the more advanced stages of the disease. They are a part of the neoplastic clone expressing the Philadelphia chromosome or the BCR-ABL fusion gene. In other myeloproliferative disorders such as myelofibrosis and polycythaemia vera, elevation of basophil numbers is usually more modest. Cases of AML with high levels of immature basophils have also been reported. Rarely, basophils may constitute over 80% of circulating leucocytes, a condition sometimes referred to as basophilic leukaemia. These patients may exhibit clinical features related to the release of histamine and other basophil granular contents, and their treatment can be difficult owing to the possibility of massive release of these mediators secondary to cellular lysis. Other causes of basophilia include ulcerative colitis, myxoe-dema, recovery from acute illness and drug allergies, although these conditions are usually associated only with modest elevations of circulatory basophils.

As discussed earlier, SCF or c-kit ligand is an important factor in mast cell development. Therefore, it is plausible that conditions leading to its excessive production and mutation of c-kit, leading to its constitutive activation, can cause mastocytosis. An increased number of tissue mast cells can be seen in a number of disorders, including atopy, parasitic diseases, Hodgkin's and other lymphoproliferative disorders, some neoplasms and rheumatoid arthritis.

Several conditions, ranging from isolated cutaneous masto-cytomas to mast cell leukaemia, are associated with mast cell proliferation. Solitary mastocytomas generally regress spontaneously. The more common cutaneous mastocytosis or urticaria pigmentosa typically presents with multiple small round reddish-brown maculopapular lesions, which, when subjected to minimal trauma, lead to intense pruritus. In some patients, this disease progresses to the systemic variety, with involvement of bone marrow, spleen, liver and the gastrointestinal tract. Systemic mastocytosis can also occur without prior or concurrent cutaneous disease, and in association with haematolo-gical disorders, including leukaemias and lymphomas. Organ dysfunction may be secondary to the release of biochemical mediators by mast cells, such as peptic ulcer disease secondary to histamine release. Mast cell leukaemia, a rare condition, presents with circulating mast cells of abnormal morphology (accounting for up to 95% of circulating nucleated cells), peptic ulcer disease, constitutional symptoms, anaemia and

Table 17.10 Basophil and mast cell granules, and their contents.

Component

Function

Main physiological role

Other properties

Cell specificity

Protein Histamine

Proteoglycan Heparin

Chondroitin sulphates

Enzymes Chymase

Tryptase

Cathepsin G-like protease

Carboxypeptidase

Binds to Hp H2, H3 Hypersensitivity reactions receptors and inflammation

Package of basic proteins into granules

Package of basic proteins into granules

Inactivates bradykinin, Affects microcirculation, activates angiotensin 1, activates precursor IL-1ß

Cleaves C3 to C3a and C3b

Activates metalloproteinase 3, inactivates fibrinogen Degrades calcitonin gene-related peptide modulates microcirculation, modulates skin, inflammation

Proinflammatory, stimulates neutrophil chemotaxis and adherence

Regulates collagenase, attenuates fibrin deposition

Binds and stabilizes proteases

Binds and stabilizes proteases

Tetrameric when bound to heparin, monomer inactive, restricted substrate specificity, raised levels in mast cell disorders

Basophils, mast cells

Connective tissue mast cells

Basophils

Connective tissue mast cells

Mast cells

Connective tissue mast cell

Connective tissue mast cell

Other

Charcot-Leyden crystal protein

Major basic protein

Sulphatase

Exoglycosidase

Lysophospholipase

Phospholipid metabolism Disrupts membranes

Neutralizes pulmonary Basophil surfactant

Basophil hepatosplenomegaly. It should be distinguished from AML, which can develop in association with systemic mastocytosis.

Management of patients within all categories of mastocytosis includes careful counselling of patients and care providers, avoidance of factors triggering acute mediator release, treatment of acute and chronic mast cell mediator release, an attempt to treat organ infiltration by mast cells, and treatment of any associated haematological disorder. The agents and modalities commonly used in treating patients with mastocytosis include antihistamines, H2-receptor blockers, adrenaline, steroids, cromolyn sodium, proton pump inhibitors, ultraviolet light with psoralen (PUVA), chemotherapy, radiation, IFN-a, cyclosporin, 2-chlorodeoxyadenosine and splenectomy. With increased availability of small-molecular-weight inhibitors of signal transduction, targeting of the constitutively active mutated c-kit has attracted more attention. Two classes of constitutive activating c-kit mutations have been reported. The more frequent occurs in the catalytic pocket coding region, with substitutions at codon 816, and the other in the intracellular juxtamembrane coding region. Therefore, kinase inhibitors that block mutated c-kit activity might be used as therapeutic agents in systemic mastocytosis. Imatinib mesylate inhibits both wild-type and juxtamembrane mutant c-Kit kinase activity, but has no effect on the activity of the D816V mutant, commonly seen in patients with mastocytosis. Therefore, imatinib mesylate does not appear to be an effective therapy for this disease. However, activity of imatinib has been reported in a subset of patients with associated eosinophilia, who express the FIP1L1-PDGFRafusion gene.

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