Polyclonal expansion of CD3+/CD4+/CD56+ large granular lymphocytes and autoimmunity associated with dysregulation of Fas/FasL apoptotic pathway

Camagna, A; Cedrone, Letizia; Caré, Alessandra; Samoggia, Paola; Marco, María C. de; Duca, P.; Martinis, C. De; Testa, Ugo

doi:10.1046/j.1365-2141.2001.02483.x

Cited by 12 publications

(10 citation statements)

References 17 publications

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“…8 Others have described polyclonal expansion of CD4 1 CD56 1 LGL in autoimmunity as mediated through the Fas/Fas ligand pathways. 9 All of these observations, as well as those in the current study, point toward aberrant LGL expansion in autoimmunity as an important mechanism. Measurement of such a population may be clinically useful both as a diagnostic markers and as a measure of therapeutic response.…”

mentioning

confidence: 70%

STAT3 mutations and persistence of autoimmunity

Schultz

2013

Blood

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mentioning

confidence: 70%

STAT3 mutations and persistence of autoimmunity

Schultz

2013

Blood

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“…Several reports have suggested that the abnormal clonal size of TLGL is owed to a defect in apoptosis, 3,15,42 the pathway of programmed cell death confining the clonal size of CD8 ϩ T cells. However, TLGL cells are only refractory to apoptosis when tested directly ex vivo but become sensitive after a short culture in vitro, 15,43 which again is not so different from normal CD8 ϩ effector cells.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that more than 50% of the CD8 ϩ CD27 Ϫ CD28 Ϫ effector T cells may be monoclonal, 40 which matches the finding that in healthy controls single CD8 ϩ T-cell clones often represent more than 10% of the total T-cell population. 41 Hence, stable monoclonal expansions of 0.1 ϫ 10 9 /L to 0.5 ϫ 10 9 /L are probably not exceptional and, although the difference with the clonal size of a TLGL clone may appear critical to the hematologist, it might be less so for a T cell that needs only a couple of divisions to reach this size.Several reports have suggested that the abnormal clonal size of TLGL is owed to a defect in apoptosis, 3,15,42 the pathway of programmed cell death confining the clonal size of CD8 ϩ T cells. However, TLGL cells are only refractory to apoptosis when tested directly ex vivo but become sensitive after a short culture in vitro, 15,43 which again is not so different from normal CD8 ϩ effector cells.…”

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confidence: 99%

Monoclonal T-cell expansions in asymptomatic individuals and in patients with large granular leukemia consist of cytotoxic effector T cells expressing the activating CD94:NKG2C/E and NKD2D killer cell receptors

Bigouret

Hoffmann

Arlettaz

et al. 2003

Blood

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We have analyzed the phenotype, cytokine profile, and mitotic history (telomere length) of monoclonal T-cell expansions in 5 CD3 ؉ T-cell large granular lymphocyte (TLGL) leukemia patients by fluorescence activated cell sorting (FACS) and single-cell polymerase chain reaction (PCR). We confirm that the common phenotype of TLGL leukemia is CD3 ؉ CD8 ؉ CD45RA ؉ CD27 ؊ CD94 ؉ (CD57 ؉ ). Interestingly, the C-type lectin-like type killer cell receptor CD94 was invariably associated with the activating form of its signaltransducing molecule NKG2. Furthermore, when judged by criteria such as interferon gamma (IFN-␥)/tumor necrosis factor (TNF) production, expression of granzyme, FasL, and NKG2D, the TLGL cells had all the features of a cytotoxic effector T cell. Telomere shortening in TLGL cells was in the normal range for CD8 ؉ T cells, indicating that they had not divided significantly more than chronically stimulated CD8 ؉ T cells in healthy individuals. In 25 of 27 controls, cells with a TLGL phenotype occurred at low (1%-3%) frequencies. However, in the other 2 individuals (ages 28-36 years), large stable (> 3 years) monoclonal expansions of CD3 ؉ CD8 ؉ CD45RA ؉ CD27 ؊ CD57 ؉ CD94 ؉ NKG2C ؉ were found which rendered these controls phenotypically indistinguishable from TLGL leukemia patients. We believe that the TLGL clonopathy, rather than being IntroductionLymphoproliferative disorders of large granular lymphocytes (LGLs) are classified as lymphoid neoplasms. 1,2 They are divided into 2 distinct entities: approximately 10% to 20% are of the natural killer (NK) lineage (CD3 Ϫ CD16 ϩ ), whereas the others consist of mature CD3 ϩ T cells expressing either an ␣␤ or a ␥␦ T-cell receptor (TCR). NK-LGL leukemia is by far the more aggressive form. Most patients have more than 10 ϫ 10 9 /L LGLs in their blood and a significant percentage dies within 2 months after diagnosis. 3 By contrast, CD3 ϩ T-cell LGL (TLGL) leukemia that affects mainly elderly patients progresses in a much milder way. Lymphocytosis is usually modest 4 and many patients may even remain asymptomatic. 3,[5][6][7] Moreover, clinical complications consist primarily of neutropenia or autoimmune features. 8 Therefore, it remains under debate whether this T-cell clonopathy of variable significance 9 should be considered as a malignancy or rather as a secondary reactive phenomenon. 6 Apart from the low malignancy of TLGL leukemia, there are more indications that the clonal expansion is the result of a perhaps rather common dysregulation of CD8 ϩ T cells. In fact, large oligoclonal expansions of CD8 ϩ T cells are quite frequent in elderly people. 10 Such clones that may be maintained by cytokines rather than by antigen 11 are of a phenotype similar to that of normal CD8 ϩ effector T cells of which the clonal size is still controlled through apoptosis. The latter is also true for the TLGL clone. In the majority of patients, these cells are CD8 ϩ CD45RA ϩ CD27 Ϫ , 6,7,12,13 express Fas and FasL,14,15 and may or may not express CD57. 6,7 Therefore, they share m...

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“…31 Particularly, a dysregulation of Fas/Fas-L apoptotic pathway was shown to be involved in the pathogenesis of LGL expansion. [31][32][33] Fas-L concentration can be useful as an indicator of LGL activity. Soluble Fas-L levels were not determined in the sera of the patients from the current study.…”

Section: Discussionmentioning

confidence: 99%

Features of large granular lymphocytes (LGL) expansion following allogeneic stem cell transplantation: a long-term analysis

et al. 2002

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Large granular lymphocyte (LGL) proliferation typically follows a chronic course during which major features are cytopenia and immune abnormalities. Elevated numbers of LGL were reported in a few cases following allogeneic stem cell transplantation (allo-SCT). In this report, we present a retrospective analysis of LGL cases that occurred following allo-SCT in a cohort of 201 consecutive patients transplanted over a period of 7 years. Six cases were identified and LGL expansion occurred more frequently following a reduced fludarabine and anti-T lymphocyte globulin-based preparative regimen (4 cases/49), than after a conventional myeloablative regimen (2 cases/152). Expansion of LGL was seen between 3 and 15 months following allo-SCT. Hematopoiesis, with mild to severe cytopenia, was a favored target for LGL. Autoimmune manifestations including polyarthritis and hypergammaglobulinemia were also observed. LGL proliferation was observed in the context of chronic antigenic stimulation associated with recurrent viral infections especially CMV. Moreover, five out of these six high risk patients achieved a long-term complete remission concomitant or following LGL expansion. These data suggest that LGL might be a subset of effector lymphocytes which may participate to the graft-versus-tumor effect.

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Polyclonal expansion of CD3⁺/CD4⁺/CD56⁺ large granular lymphocytes and autoimmunity associated with dysregulation of Fas/FasL apoptotic pathway

Cited by 12 publications

References 17 publications

STAT3 mutations and persistence of autoimmunity

STAT3 mutations and persistence of autoimmunity

Monoclonal T-cell expansions in asymptomatic individuals and in patients with large granular leukemia consist of cytotoxic effector T cells expressing the activating CD94:NKG2C/E and NKD2D killer cell receptors

Features of large granular lymphocytes (LGL) expansion following allogeneic stem cell transplantation: a long-term analysis

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