Lymphocyte-variant hypereosinophilia

Lymphocyte-variant hypereosinophila is a rare disorder in which eosinophilia or hypereosinophilia (i.e. a large or extremely large increase in the number of eosinophils in the blood circulation) is caused by an aberrant population of lymphocytes. These aberrant lymphocytes function abnormally by stimulating the proliferation and maturation of bone marrow eosinophil-precursor cells termed colony forming unit-Eosinophils or CFU-Eos.

The overly stimulated CFU-Eos cells mature to apparently normal appearing but possibly overactive eosinophils which enter the circulation and may accumulate in and damage various tissues. The disorder is usually indolent or slowly progressive but may proceed to a leukemic phase sometimes classified as acute eosinophilic leukemia. Lymphocyte-variant hypereosinophilia can therefore be regarded as a precancerous disorder.

The disorder merits therapeutic intervention to avoid or reduce eosinophil-induced tissue injury and treat its leukemic phase. The latter phase is aggressive and typically responds relatively poorly to anti-leukemia chemotherapeutic drug regimens.

Presentation

The typical patient with lymphocyte-variant hypereosinophilia presents with an extended history of hypereosinophilia and cutaneous allergy-like symptoms. Skin symptoms, which occur in >75% of patients, include erythroderma, pruritus, eczema, Poikiloderma, urticarial, and episodic angioedema. The symptom of episodic angioedema (i.e. soft tissue swelling of the face, tongue, larynx, abdomen, arms, or legs) in lymphocyte-variant hypereosinophilia resembles that occurring in Gleich's syndrome, a rare disease that is accompanied by secondary hypereosinophilia plus a sub-population of CD3(-), CD4(+) T cells; this involvement of the latter cell types supports the notion that Gleich's syndrome is a subtype of lymphocyte-variant hypereosiophilia. Biopsies of skin lesions commonly find prominent accumulations of eosinophils. Other presentations include:

* a) lymphadenopathy occurring in ~60% of patients;
* b) eosinophil infiltrations in lung similar to, and often diagnosed as, eosinophilic pneumonia, occurring in ~20% of patients;
* c) episodic angioedema-related gastrointestinal symptoms that are sometimes similar to symptoms of the irritable bowel syndrome occurring in ~20% of patients;
* d) rheumatologic manifestations of inflammatory arthralgias in ~20% of patients; and
* e) splenomegaly occurring in ~10% of patients.

Cardiovascular complications such as various types of heart damage due to eosinophilic myocarditis and vascular disorders due to eosinophil infiltration of the vascular wall that lead to vascular thrombosis are often critical components of persistent hypereosinophilia syndromes; These complications are not a prominent component of lymphocyte-variant hypereosionophilia, occurring in <10% of patients.

Other lymphoid disorders associated with eosinophilia

Lymphoid neoplasms can be associated with eosinophilia presumably because of the secretion of eosinophil/eosinophil precursor cell-stimulating cytokines by the malignant lymphoid cells. Most commonly, this is seen in cutaneous T cell lymphoma, Adult T-cell leukemia/lymphoma, and angioimmunoblastic T cell lymphoma. Less often, it is seen in B cell neoplasms such as Hodgkin's lymphoma, and B cell acute lymphoblastic leukemia, particularly forms of the latter disease associated with the t(5;9)(q31;p24) translocation creating gene fusion between the ''IL3'' (at chromosome 5q31) and the ''JAK2'' (at chromosome 9p24). The ''JAK2-IL3'' fusion gene associated disease is accompanied by the overproduction of IL3, a simulator of eosinophil and eosinophil precursor cell growth.

Pathogenesis

Following the historical findings cited above, studies identified the cytokine, interleukin 5 (IL5), as the eosinophil growth-stimulating CFU made by T cells from patients suffering the idiopathic hypereosinophilic syndrome. Subsequent studies likewise identified IL5 as a cytokine being overproduced by certain lymphocytes taken from patients with lymphocyte-variant eosinophilia. These and other studies support the view that lymphocyte-variant hypereosinophilia is a unique disease characterized by hypereosinophilia secondary to the pathological production of eosinophil growth factors, particularly IL5 but possibly also IL4; IL13, and GM-CSF by one or more aberrant clones of T cells. The aberrant T cell clone, as defined by immunophenotyping their expression of certain cell surface molecules, the cluster of differentiation (i.e. CD) proteins, varies from patient to patient; furthermore, some of these clones also exhibit clonal rearrangements in their T-cell receptor gene. The most common immunophenotypes in lymphocyte-variant eosinophilia are: a) CD3(−), CD4(+) T cells, b) CD3(+), CD4+, CD8(−) T cells, c) CD3(+), CD4(+), CD7(−) T cells also bearing αβ+ T cell receptors, d) CD3(+), CD4(+), CD7(-) T cells, and e) CD3(+), CD4(+), CD2(-) T cells. Chromosome abnormalities such as breakage of the long ("q") arm of chromosome 16, partial deletions in the q arm of chromosome 6 or short ("p") arm of chromosome 10, and trisomy of chromosome 7 are occasionally detected in these T cells. Regardless of immunophenotype, these T cells typically express CD45RO plus HLA-DR and/or IL2RA (also termed CD25} cell surface antigens. Expression of these antigens is characteristic of activated memory T cells.

The underlying cause(s) for the origination and expansion of the phenotypically and clonally aberrant T cells in lymphocyte-variant hypereosinophilia remains unclear. In all events, these aberrant T cells are not, at least initially, malignant although they do exhibit pathological behavior. They produce, in addition to interleukin 5, another eosinophil-stimulating cytokine, Granulocyte macrophage colony-stimulating factor. The aberrant T cells also produce: IL4, a T cell-stimulating cytokine; interleukin 13, a cytokine mediator of allergic reactions, particularly those occurring in the lung; IL2, a t cell-stimulating cytokine, tumor necrosis factor alpha, a proinflammatory cytokine that regulates immune responses, and, at least in the aberrant T cells of certain patients, Interferon gamma (i.e. IFGγ), s cytokine that regulates innate

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