FOCIS Centers of Excellence ReviewT cell large granular lymphocyte leukemia associated with rheumatoid arthritis and neutropenia
Section snippets
Case presentation
A 62 year old Hispanic male presented to the rheumatology clinic at Duke University Medical Center for evaluation of a chronic inflammatory syndrome. Eight months earlier, the patient had developed right ankle pain and a sore throat. He then developed fevers up to 104°F with shaking chills that recurred on a weekly basis. These febrile episodes were accompanied by profound fatigue as well as polyarthritis affecting his shoulders, elbows, wrists, hands, ankles, and feet. Extensive medical
Brief literature review
T-LGL is a lymphoproliferative syndrome marked by a clonal expansion of large granular lymphocytes (LGLs) usually of T cell origin; however, the abnormal LGL clone rarely may arise from the natural killer (NK) cell lineage. Many patients with T-LGL have a co-existent autoimmune disorder. In one study, one-third of patients with T-LGL had been diagnosed with RA [1], while in another study, 13 of 48 patients with T-LGL had primary Sjögren's syndrome [2]. We aim in this article to review the
LGL immunophenotyping
For classification of LGLs, flow cytometry is used to identify the phenotype of the expanded cell population. Typically, in T-LGL, the expanded clonal population is CD3+, CD4−, CD8+, CD16+, CD28−, and CD57+[3], [4], [5], [6]. The rare aggressive form of T-LGL will in addition often express CD26 [3]. Up to 80% of T-LGL leukemias will exhibit altered (typically absent or dim) expression of CD5 and/or CD7 [11]. Approximately 40% of patients with FS have a polyclonal expansion of peripheral LGL
T cell clonality
Theoretically, clonal expansion of T-LGLs may arise by chronic antigen stimulation, with disruption of homeostatic mechanisms regulating the persistence of antigen-primed CTLs (e.g. initiation of apoptosis). PCR (and Southern blotting originally) is used to characterize T cell clonality through the detection of specific TCR rearrangements for comparison with predictable patterns of variable (V) gene expression from a healthy immune system. TCR consists of either αβ or δγ chains. Typically, the
Mechanisms of neutropenia
The neutropenia in T-LGL and FS is likely to be multifactorial and depend on both cellular and humoral mechanisms (Fig. 4). Cellular mechanisms likely predominate in suppressing the proliferation of neutrophil progenitors through cell–cell interactions and secretion of cytokines and chemokines. Humoral mechanisms are believed to be mostly responsible for survival defects. In T-LGL and FS, these mechanisms may include direct destruction of myeloid precursors by the infiltrating leukemic cells,
Treatment
The treatment (from a hematologic perspective) of T-LGL is directed at reducing any symptoms of a proinflammatory state and preventing recurrent infections due to severe neutropenia. In monitoring response to therapy, there is often no observable correlation between symptoms and number of T-LGL cells in the marrow or periphery as the treatment is primarily immunomodulatory and not cytotoxic [7]. Treatment with low weekly doses of MTX has been associated with remission in 50% of cases, with
Conclusions
T-LGL should be suspected is patients with RA and neutropenia. In the case herein, T-LGL and neutropenia developed concurrently with the onset of RA and was characterized clinically by an indolent course. The diagnosis was established by the finding of a sustained expansion of T-LGLs with a characteristic phenotype and the demonstration of T cell clonality by PCR of the V gamma gene. The T-LGLs may have caused neutropenia by suppressing granulopoesis through the secretion of cytokines and
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