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. Author manuscript; available in PMC: 2015 Mar 29.
Published in final edited form as: Hematol Oncol. 2010 Sep;28(3):105–117. doi: 10.1002/hon.917

The root of many evils: indolent large granular lymphocyte leukemia and associated disorders

Ranran Zhang 1, Mithun Vinod Shah 1, Thomas P Loughran Jr 1
PMCID: PMC4377226  NIHMSID: NIHMS671883  PMID: 19645074

Abstract

Large granular lymphocyte (LGL) leukemia can arise from either natural killer (NK) cells or cytotoxic T lymphocytes (CTL). The T-cell form of LGL leukemia has significant overlap with other hematological disorders and autoimmune diseases. Here we provide an overview of LGL biology. We also focus discussion on the indolent LGL leukemia related disorders and their causal relationships. We then discuss the potential relationships and distinctions between indolent LGL leukemia and non-malignant clonal lymphocyte expansion that occur in otherwise healthy individuals, especially elder people.

Keywords: large granular lymphocyte leukemia, autoimmunity, non-malignant clonal lymphocyte expansion

Large granular lymphocyte biology 101

The term “large granular lymphocytes” (LGL) refers to a morphologically distinct subpopulation that normally comprises 10%–15% of peripheral blood mononuclear cells (PBMC). LGL are characterized by high cytoplasmic:nuclear ratio and abundant azurophilic granules. [1, 2] Despite initial characterization of LGL as natural killer (NK) cells, LGL are now shown to contain both cytotoxic T lymphocytes (CTL, CD3+) and NK cells (CD3−), both of which belong to the lymphoid lineage and serve as the main executors of cell-mediated cytotoxicity. [35]

The antigen-specificity of LGL varies with cell types. NK cells, which belong to the innate immune system, possess the least antigen specificity. They are “naturally” armed with cytolytic granules and chronically exhibit the LGL morphology. Their activation does not require interaction with a specific major histocompatibility complex (MHC) – peptide complex. Rather, it depends on the relative signaling strength downstream of the activating and inhibitory NK receptors. The activity of inhibitory NK receptors maintains the resting state of NK cells. Upon encountering non-healthy-self targets such as tumor cells or virus infected cells, activating NK receptors are triggered. NK cells are eventually activated once the balance between activating and inhibitory signaling is broken. [6, 7] Due to their surface expression of the low affinity Fc receptor (CD16), NK cells can also participate in antibody-dependent cell cytotoxicity. [8] Traditionally, NK cells were considered to function primarily at the front line of defense because of their almost immediate target-lysis activity and limited proliferation capability after activation. [4] However, it has been reported that the CD56bright NK population exhibited limited cytotoxicity yet enhanced cytokine secretion and proliferation ability, pointing to their regulatory function. [9] CTL, on the other hand, have relatively stringent antigen-specificity, with αβ lineage more stringent than γδ lineage. αβ T cells and γδ T cells were suggested to share common CD4−CD8− double negative precursors. It is believed that the lineage differences arise after T-cell receptor (TCR) recombination during T-cell development. Cells productively rearrange TCR- γδ differentiate into γδ T-cells and cells successfully rearrange TCR-β mature into αβ T-cells, although the exact mechanisms remain unknown. [10] With increased TCR variety, the activation of αβ-CTL strictly depends on their recognition of specific MHC-peptide complex. They function primarily in the adaptive immune system. On the contrary, γδ-CTL have limited TCR variety yet possess the ability to respond to intact antigen. This feature places them at the intersection between innate and adaptive immune responses. [11] Different from the immediate cytolytic activity of NK cells, both αβ- and γδ-CTL require an activation phase to acquire cytotoxicity and LGL morphology. However, both CTL lineages can undergo extensive expansion after activation, granting them a major role in response to prolonged antigen stimuli or high antigen loads. [4]

Upon activation, there are two major pathways through which LGL execute their targets: granule-mediated pathway and receptor-mediated pathway. [4, 12] Granule-mediated pathway depends on the exocytosis of the cytolytic granules of LGL to induce lysis and apoptosis of the target cells. Upon target recognition, granules are polarized towards the immune synapse where LGL interact with targets. Two major components of cytolytic granules are the pore-forming protein perforin, and a family of serine proteases – granzymes. [13] Perforin, in addition to directly inducing osmotic lysis by forming pores on the target cell membrane, is indispensable for granzyme delivery and activity within target cells. [12, 14] Granzymes, with their protease activity, potentiate the death fate of target cells by cleaving and activating the effector caspases as well as pro-apoptotic Bcl-2 family members. [15] The receptor-mediated pathway relies on the engagement and activation of death receptors, such as Fas (APO-1, CD95), by their ligands. Death receptors are universally expressed on various cell types, while the corresponding ligands are usually elevated on activated LGL. [16] This pathway is not specific for the immune system, and the death receptor-ligand interaction is not MHC-restricted. Instead, LGL-target interaction brings target cells to the proximity of LGL. In addition, it has been reported that LGL can manipulate death receptor expression on the targets which optimizes execution. [17] Upon ligation, death receptors cluster and induce the formation of death inducing signaling complex (DISC), which initiates similar signaling cascade as granzymes. [16, 18] Granule-mediated pathway can be instantly activated upon target recognition, although replenishing the granules takes time. [4, 19] On the other hand, death ligands have extended functional half-life, although a time lag is usually required for their optimum expression on LGL after activation. [4, 20, 21] Together, granule-mediated pathway provides an instant and potent cytolytic force, while the receptor-mediated pathway serves as a gentle yet persistent complement.

Both granule-mediated pathway and receptor-mediated pathway contribute to the LGL elimination after activation, which is termed activation-induced cell death (AICD). Granule-mediated pathway can act on the activated LGL through endocellular or extracellular granule leakage, which triggers similar signaling pathways as in the target cells. [22, 23] Receptor-mediated pathway follows the same strategy. After activation, LGL express elevated death receptors, making themselves sensitive to the death ligands. [16, 24] AICD can occur in a suicide fashion and among LGL from the same or different lineage. [16, 25] To ensure sufficient LGL activity prior to AICD, a delicate resistance system exists. [16, 22, 26] It enables the titration of AICD process and allows the elimination of LGL to occur only after antigen clearance.

Large granular lymphocyte leukemia

LGL leukemia, as implied by the name, refers to the abnormal expansion of LGL in peripheral blood often accompanied by infiltration of marrow, spleen and liver. [27] Based on cell origins, LGL leukemia can be divided into NK-cell LGL leukemia (NK-LGL leukemia) and T-cell LGL leukemia (T-LGL leukemia), with the latter further divided into αβ- (mainly CD4−CD8+) or γδ- (mainly CD4−CD8− or CD4−CD8+) T-LGL leukemia. A more comprehensive review of this disease was provided elsewhere. [27] The molecular signatures of leukemic LGL resemble chronically activated LGL, competent in cytotoxicity. Yet, they are deficient in proliferation and are resistant to receptor-mediated AICD. [2833] Both T and NK forms of LGL leukemia exhibit skewed expression of NK activation receptors [34, 35]. Elevated chemokines, cytokines and death receptor ligand (Fas ligand, FasL) are also observed in patient sera [32, 36]. Other serologic abnormalities, including high titers of rheumatoid factor, anti-nuclear antibody, antineutrophil antibody, antiplatelet antibody and circulating immune complexes are frequently detected in LGL leukemia patients. [37]

Clonal expansion is usually a hallmark for neoplasm. However, in the case of lymphocytes, clonal expansion can be a normal process after encountering antigen. Thus, more caution needs to be taken to distinguish transient immune response and persistent malignancy. The clonality of LGL leukemia is readily confirmed by a specific TCR rearrangement pattern in T-LGL leukemia; or a specific Epstein-Barr virus (EBV) genomic integration site in acute NK-LGL leukemia. [3840] However, other than rare aggressive cases [41, 42], most LGL leukemia patients bear an indolent clinical course, with approximately one third of them asymptomatic at the time of diagnosis. [43] Most patients seek medical care because of LGL leukemia associated conditions (as discussed below), and can be successfully treated by immunosuppressive therapies. [27, 44] Transformation from indolent to aggressive LGL leukemia is very rare [45, 46]. In light of the non-malignant lymphocyte clonal expansion in elder people, the malignant nature of indolent LGL leukemia, particularly αβ-T-LGL leukemia has been questioned. [47, 48] Here, we summarize the clinical features of indolent LGL leukemia by reviewing its associated medical conditions (Table 1) and their causal relationships.

Table 1.

Summary of conditions associated with indolent LGL leukemia

Name of the medical condition Associated subtype
(s) of LGL leukemia
Reference Comment
B-cell conditions Monoclonal gammopathy of unknown significance (MGUS) αβ-T; γδ-T [4952]
B-chronic lymphocytic leukemia (B-CLL) αβ-T; γδ-T [49, 50, 163] [163] is a case of CD56+ variant of T-LGL leukemia
follicular lymphoma αβ-T [49]
hairy cell leukemia (HCL) αβ-T [49, 51, 53]
mantle cell lymphoma (MCL) T [54] Clonality unknown
small B-cell lymphocytic lymphoma αβ-T; γδ-T [51]
lymphoplasmacytic lymphoma αβ-T [49, 51]
plasmablastic myeloma γδ-T [51]
B-cell acute lymphoblastic leukemia (B-ALL) γδ-T [50]
Hodgkin disease T [54] Clonality unknown
polyclonal-hypergammaglobulinemia αβ-T [49]
hypogammaglobulinemia αβ-T [49]
LGL leukemia αβ-T-LGL leukemia γδ-T [50]
αβ-T-LGL leukemia NK [55]
cytopenia and anemia neutropenia αβ-T; γδ-T; NK [27, 5658]
anemia including hemolytic anemia (HA) αβ-T; γδ-T; NK [49, 50, 52, 58, 78]
thrombocytopenia including amegakaryocytic thrombocytopenia and immune thrombocytopenic purpura (ITP) αβ-T; γδ-T; NK [58, 78, 8284]
bone marrow failure syndrome pure red cell aplasia (PRCA) αβ-T; γδ-T; [50, 56, 6470, 110, 113, 114]
aplastic anemia (AA) αβ-T; [79, 80]
paroxysmal nocturnal hemoglobinuria (PNH) αβ-T; [49, 79, 81]
myelodysplastic syndromes (MDS) αβ-T; NK [49, 52, 8487]
periodic hematological disorders cyclic neutropenia (CN) αβ-T [9597]
cyclic thrombocytopenia (CT) T [98, 99]
other hematological disorders hereditary hemochromatosis αβ-T [102, 103] [102] is a case of CD3+CD56+CD57- αβ-T-LGL leukemia
splenic marginal zone lymphoma γδ-T [50]
peripheral T cell lymphoma NK [104]
congenital pancytopenia with interstitial pneumonia NK [105]
Wiskott-Aldrich syndrome (WAS) γδ-T; NK [106108] lymphocyte expansion in [108] affects both T an NK sub-population
autoimmune disorders (arthropathies) rheumatoid arthritis (RA) and Felty’s syndrome αβ-T; γδ-T; NK [37, 49, 50, 52, 58, 110114, 116] NK-LGL leukemia is rarely associate with RA
autoimmune disorders (vessel and skin) pulmonary artery hypertension (PAH) αβ-T; NK [35, 124, 125]
generalized pruritus T [126] 32% lymphocytes are CD56+CD57+
vasculitis αβ-T; NK [58, 104, 127] [127] is a case of CD3+CD4+CD8+CD56+ αβ-T-LGL leukemia
aphthous ulcer NK [58, 104]
livedo reticularis (livedoid vasculopathy) NK [58, 104]
pityriasis lichenoides T [128]
scleroderma (systemic sclerosis) αβ-T [129] CD8+CD56+ αβ-T-LGL leukemia
vascular mammary skin lesion γδ-T [130]
psoriasis γδ-T [50]
allergic skin involvement γδ-T; NK [58, 83, 130]
autoimmune disorders (neuropathies) multiple sclerosis (MS) αβ-T [94, 131] [131] is a case of CD8+CD56+ αβ-T-LGL leukemia
paraneoplastic neuropathy and peripheral neuropathy T; NK [58, 67, 83, 132, 133]
autoimmune disorders (muscular and glandular) myositis and other musculoskeletal symptoms T; NK [58, 136]
Sjögren syndrome αβ-T; γδ-T [52, 126, 129, 137, 138]
autoimmune thyroiditis (Hashimoto’s disease) αβ-T; γδ-T [50, 52, 94, 129, 138]
autoimmune polyglandular syndrome (APS) γδ-T [138]
endocrinopathy, Grave’s disease (hyperparathyroidism) and Cushing’s syndrome αβ-T [52, 94]
autoimmune disorders (other connective tissue disorders) systemic lupus erythematosus (SLE) αβ-T [94, 129, 139]
Behçet disease αβ-T [140]
uveitis and celiac disease αβ-T [141]
other malignancies, transplantations and genetic disorders other malignancies (including thyroid, lung, liver, colon-rectal, prostate, testicular, melanoma, basal cell carcinoma) αβ-T; γδ-T; [50, 52, 94, 150, 151]
bone marrow and solid organ transplantation T [153, 154]
Turner syndrome T [152]

Disorders related to indolent LGL leukemia

Hematological disorders

Indolent LGL leukemia is frequently associated with other hematological disorders, including disorders arising from both lymphoid and non-lymphoid lineages. Lymphoid disorders are primarily associated with indolent T-LGL leukemia and occur in the form of B-cell dyscrasias. [49] The most common B-cell dyscrasia is monoclonal gammopathy of unknown significance (MGUS), in association with both αβ- and γδ-T-LGL leukemia (3%–19%). [4952] B-chronic lymphocytic leukemia (B-CLL) also occurs together with αβ- and γδ-T-LGL leukemia, but to a less extent (2%–5%). [49, 50] Other associated B-cell dyscrasias reported include follicular lymphoma [49], hairy cell leukemia [49, 51, 53], mantle cell lymphoma [54], small B-cell lymphocytic infiltrate [51], lymphoplasmacytic lymphoma [49, 51], plasmablastic myeloma [51], B-cell acute lymphoblastic leukemia [50] and Hodgkin disease [54]. In addition, hypergammaglobulinemia without other B-cell abnormalities and hypogammaglobulinemia are frequently observed in LGL leukemia patients [49]. In rare cases, it has been reported that more than one form of LGL leukemia occur, such as concomitant αβ- with γδ-T-LGL leukemia [50], and T-LGL leukemia with NK-LGL leukemia [55]. The coexistence of these lymphoid disorders and indolent LGL leukemia are of particular interest because it supports the hypothesis that LGL leukemia results from chronic immune response. Along this lwine, one explanation is that the expansion of immune compartments from several lineages may be caused by normal immune responses against a neoplastic expansion from one lineage. A parallel explanation is that a chronic immune insult such as virus infection causes abnormalities in multiple lineages. [49] Neither explanation suggests a causal relationship between LGL leukemia and other lymphoid disorders. However, identifying the common trigger(s) of the chronic immune response may shed light on the pathogenesis of both.

Another major branch of LGL leukemia associated hematological abnormalities involves various cytopenias and bone marrow failure syndromes. In this category, the most common association in the western world is acquired neutropenia, which affects 70–80% of T-LGL leukemia patients [27, 56, 57], and to a lesser extent NK-LGL patients [58]. In fact, neutropenia related infection is one major reason why LGL leukemia patients seek medical attention. [27] Because of its prevalence, co-occurrence of LGL leukemia and neutropenia is intensively studied.

Acquired neutropenia can be induced by proliferation deficiency (insufficient neutrophil production) or survival deficiency (increased neutrophils destruction). The latter is further divided into splenic sequestration/destruction and peripheral destruction. Despite the frequent presence of splenomegaly [37], splenic sequestration/destruction is unlikely to cause the LGL leukemia associated neutropenia. This is because: 1) the lack of histological evidence for the accumulation or destruction of neutrophils in patient spleen; 2) no correlation shown between the degree of splenomegaly and neutropenia. [59]

Both proliferation deficiency and peripheral destruction are considered plausible reasons for the association of LGL leukemia and neutropenia. Myeloid hypoplasia is frequently observed in LGL leukemia patients, and is potentially cause by the bone marrow infiltration of leukemic LGL. Marrow involvement by leukemic LGL occurs in an interstitial pattern and is best appreciated by immunohistochemical staining. Linear assays of intravascular CD8+, TIA-1+, grazyme B lymphocytes appear specific for LGL leukemia. [60] However, the relationship between the degree of LGL bone marrow infiltration and the severity of neutropenia has not been well studied. [37, 59] Antineutrophil antibodies are usually detected in LGL leukemia patient sera, suggesting antibody-mediated neutrophil destruction. [43] Monoclonal or oligoclonal CTL expansion and increased CTL cytotoxicity was detected in patients with acquired neutropenia even without frank LGL leukemia. [61] This indicates the presence of MHC-restricted neutrophil destruction, and raises the possibility of a similar pathogenesis occurring in the broader group of patients diagnosed with idiopathic neutropenia. Meanwhile, sera from T-LGL patients, which contain high level of soluble FasL, effectively induced apoptosis of normal neutrophils through the receptor-mediated target execution pathway, and blocking this pathway reduced neutrophil apoptosis. [62] This infers MHC-unrestricted neutrophil destruction in LGL leukemia.

As a further evidence of the causal relationship between LGL leukemia and neutropenia, immunosuppression is usually effective in alleviating neutropenia in LGL leukemia patients. The efficacy of this treatment was shown to correlate with the reduction of clonal LGL and serum level of FasL. [27, 62] On the contrary, stimulation of granulocyte production alone using granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) does not result in sustained clinical improvement of neutropenia in all LGL leukemia patients. [59] The clonal expansion, bone marrow infiltration and abnormal immune activity of leukemic LGL is indispensable for the onset of neutropenia in LGL patients. In fact, LGL leukemia is considered one of the major causes of acquired neutropenia. [63]

Interestingly, neutropenia is a relatively less common association with T-LGL leukemia in the eastern world. Instead, pure red cell aplasia (PRCA), which is common but less prevalent than neotropenia in the western world [56, 6466], is prominently associated with T-LGL leukemia. [6770] It is increasingly clear that chronic cytotoxicity of leukemic T-LGL and its bone marrow infiltration are the causes of PRCA, although the surface abnormality of erythroid progenitors may also contribute to this association. Erythroid progenitor colonies from PRCA patients were shown to be more susceptible to leukemic LGL-mediated cytotoxicity due to their low expression of HLA class I molecule, a ligand of killer-cell inhibitory receptors expressed on LGL. This cytotoxicity was shown in vitro as an MHC-unrestricted target lysis [71]. Not surprisingly, controlling the leukemic T-LGL clone through immunosuppression benefits or brings complete remission in PRCA patients. [69, 72, 73] It has been suggested that parvovirus B19 plays a role in pathogenesis in PRCA. [74, 75] Interestingly, serum reactivity against B19 and B19 DNA has been detected in some LGL leukemia patients with PRCA. [76, 77] The different clinical phenotype of LGL leukemia in western and eastern world is quite remarkable. This finding suggests that different genetic backgrounds, immune or environmental insults, or both, may render different populations susceptible to different disease manifestations of LGL leukemia.

In addition to neutropenia and PRCA, both T- and NK-LGL leukemia can be associated with other hematologic problems such as hemolytic anemia (HA) [49, 50, 52, 58, 78], aplastic anemia (AA) [66, 79, 80], paroxysmal nocturnal hemoglobinuria (PNH) [49, 79, 81]; thrombocytopenia including amegakaryocytic thrombocytopenia [58, 78, 8284]; as well as myelodysplastic syndromes (MDS) [49, 52, 8487]. There is clinical overlap in these bone marrow failure syndromes. Interestingly, co-occurrence of these disorders can be observed in the same LGL leukemia patient [78], and in rare cases increase of some lineages and decrease of other lineages [88]. A possible explanation of these observations is that the suppression effect exerted by leukemic LGL is on a hematopoietic stem cell (HSC) or a progenitor. Indeed, it has been proposed that abnormalities of marrow progenitors, as occurring in MDS, trigger the initial infiltration and clonal expansion of LGL, and the following pathological immune attack launched by leukemic LGL results in proliferation deficiency as seen in neutropenia, thrombocytopenia, AA and PRCA. [87] Constant survival pressure on hematopoietic progenitors or HSC can also lead to out-growth of abnormal myeloid clones with increased resistance to LGL-mediated suppression but abnormal hematological functions, as seen in PNH. [87] Same scenario appears to be applicable in the case of NK-LGL leukemia associated with neutropenia and thrombocytopenia in the context of bone marrow granuloma. [89]

In addition to LGL bone marrow infiltration, decreased blood cell survival from splenic sequestration may also play a role in LGL leukemia associated cytopenias, particularly anemia and thrombocytopenia. This is potentially due to the differences of life span and destruction sites among erythrocytes, platelets and neutrophils. Circulating neutrophils have an average half life of 7 hours, and the damaged neutrophils are normally cleared during peripheral circulation and in the lung. [90] In contrast, mature erythrocytes and platelets have an average life span of 120 days [91] and 7 days respectively, while spleen is one of the primary sites of “quality control” and destruction [91, 92]. Increased “screening” time that erythrocytes and platelets spend in the spleen makes anemia and thrombocytopenia potential consequences of splenomegaly. Patients with LGL leukemia often have splenomegaly, which could potentiate anemia and thrombocytopenia, either by promoting splenic sequestration or direct destruction. [59] As in the case of neutropenia, the detection of antiplatelet antibody and circulating immune complexes in LGL leukemia patient sera suggested the involvement of peripheral destruction. [37] Not surprisingly, splenectomy has resulted in sustained clinical benefit for some LGL leukemia patients with autoimmune HA [93] and thrombocytopenia [94].

The association of LGL leukemia with acquired periodic hematological disorders, including cyclic neutropenia (CN) [9597] and cyclic thrombocytopenia (CT) [98, 99] is extremely rare. However, it provides a niche to dissect the casual relationship between LGL leukemia and most of its associated non-lymphoid hematological disorders. In general, hematopoiesis is regulated by growth factors that reflect the peripheral requirement. Thus, there is a lag between the presence of needs and the initiation of HSC/progenitor proliferation. As other negative control systems with a delay, hematopoiesis has a tendency to oscillate. [100] The transition from hematological homeostasis (a stable state) into periodic hematological disorders (a periodically oscillating state) and the effect of proliferation or survival deficiency on this transition can be mathematically analyzed. Model simulations revealed that as blood cells spend more time in periphery than bone marrow, in the sequence of neutrophils, platelets and erythrocytes, the influence of a survival defect to the corresponding periodic disorders increases, while the importance of a proliferation defect decreases. [100, 101] Interestingly, it was reported that immunosuppression normalized neutrophil count in LGL leukemia associated CN. Yet, similar treatments had limited effect on platelet count and the cycling time in LGL leukemia associated CT. [95, 98, 99] Taken together, these data support the notion that LGL leukemia contributes to its associated hematological disorders primarily through inducing a proliferation defect.

Other hematological conditions associated with LGL leukemia patients have also been reported, including hereditary hemochromatosis [102, 103], splenic marginal zone lymphoma [50], peripheral T lymphoma [104], familial (congenital) pancytopenia with interstitial pneumonia [105] and Wiskott-Aldrich syndrome (WAS) [106108]. Among these, the association between WAS and LGL leukemia represents another possible pathogenic mechanism. WAS is a rare X-linked immunodeficiency disorder caused by WASP gene mutation. WASP is an important regulator of actin polymerization. As seen in WAS patients, WASP mutation induces thrombocytopenia with small platelets, eczema, increased incidence of autoimmune manifestations and malignancies. In rare cases, spontaneous reversion of this mutation or second gain-of-function mutation can occur in WAS patients. [108, 109] If occurring in LGL, this somatic mosaicism can grant clonal LGL growth advantage [106, 108] and may eventually lead to the leukemia state [107].

Autoimmune disorders

LGL leukemia is known to be associated with a wide spectrum of autoimmune disorders, with most of them involving connective tissue. Roughly, these disorders can be divided into arthropathies, vessel and skin disorders, neuropathies, muscular and glandular disorders, and other connective tissue disorders. Arthropathies associated with LGL leukemia primarily contain rheumatoid arthritis (RA), the most common autoimmune disease associated with T-LGL leukemia in the western world. [37, 49, 50, 52, 110114] RA is reported in about one third of T-LGL leukemia patients [27], compared to its presence in 0.5%–1% adult population worldwide [115]. Interestingly, this association is rarely reported in NK-LGL leukemia patients [58, 116], although arthralgia can occur [58]. It is also worth noting that RA has a less frequent association with LGL leukemia in eastern world. [67] This phenomenon cannot be explained by the differences of RA incidences in different populations. [115]

Felty’s syndrome, a specific sub-category of RA featuring the co-occurrence of RA, neutropenia and splenomegaly, is frequently associated with T-LGL leukemia. [59, 117] In fact, LGL leukemia patients with neutropenia and RA closely resemble patients exhibiting Felty’s syndrome and T-cell clonal expansion [59]. Due to the prevalence of the immunogenic marker HLA-DR4 in both diseases, it has been suggested that Felty’s syndrome and LGL leukemia with RA are part of a single disease process. [111] However, the causal relationship between RA and T-LGL leukemia is less clear. Lymphocyte infiltration at the synovial lesions in RA is potentially antigen driven, and subsequent ectopic lymphoid follicle formation is frequently observed. However, the dominant population of lymphocytes is CD4+ T cells. [115, 118] A small group of synovial-specific CD40 ligand (+) perforin (−) CD8+ T cells have been implicated in RA pathogenesis. Although they are essential in maintaining the germinal center of ectopic lymphoid follicle as well as the immune activity of CD4+ T cells and B cells [118], their phenotype and distribution is different from that of leukemic T-LGL [28]. On the other hand, RA is associated with distorted cytokine network, with elevated expression of cytokines promoting the activation and survival of cytotoxic lymphocytes, including interleukin (IL) – 15. [115, 119, 120] Similar cytokine profile is also observed in T-LGL leukemia patients. [36] Recently, network modeling of the survival signaling in T-LGL leukemia revealed that IL-15 is indispensable for the long-term survival of leukemic T-LGL. [121] One hypothesis to explain a link between LGL leukemia and RA would be exposure to a common inciting antigen. Alternatively, this association may be due to the distorted cytokine network in RA which maintains the long-term survival of leukemic LGL.

The usual association of T-LGL leukemia and RA rather than with NK-LGL leukemia might be explained by the initial antigen-specific and MHC-restricted activation of CTL rather than NK cells. In RA, NK cells in synovial fluid have reduced expression of perforin, KIR and functional activity [122, 123].

Vessel and skin disorders can occur in association with T- and NK-LGL leukemia and include pulmonary artery hypertension (PAH) [35, 124, 125], generalized pruritus [126], vasculitis [58, 104, 127], aphthous ulcer [58, 104], livedo reticularis (livedoid vasculopathy) [58, 104], pityriasis lichenoides [128], scleroderma (systemic sclerosis) [129], vascular mammary skin lesion [130], psoriasis [50], and allergic skin involvement [58, 83, 130]. Cutaneous findings occur more frequently in NK-LGL leukemia patients than T-LGL leukemia patients [104]. LGL infiltration is often observed in diseased areas [35, 58, 125]. Moreover, different from NK cells or CD8+ T cells isolated from healthy donors, leukemic LGL isolated from T- or NK-LGL patients with PAH are competent to lyse endothelial cell lines derived from normal pulmonary artery [35, 125]. Immunosuppression benefits some patients in this category [124, 125, 130], suggesting infiltration of leukemic LGL to the diseased areas as a potential mechanism for the onset of vessel and skin disorders in LGL leukemia patients.

Neuropathies can present together with LGL leukemia in forms of multiple sclerosis (MS) [94, 131], paraneoplastic neuropathy, and peripheral neuropathy [58, 67, 83, 132, 133]. In several cases, infiltration of leukemic LGL in affected tissues was observed, and treatments such as steroid, FND (fludarabine, mitoxantrone and dexamethasone), and bone marrow transplantation were shown to be effective. [131133] In terms of the pathogenesis, it has been suggested that neuropathies such as MS may be triggered by an initial infection and distorted immune response. [134] Moreover, certain forms of neuropathies such as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) can be induced by retroviral infection. [135] Thus, it is possible that LGL leukemia and its associated neuropathies share a common initial immune trigger, and prolonged immune response eventually allows for the escape and expansion of autoreactive LGL, which leads to disease onset.

LGL leukemia associated muscular and glandular diseases occur in forms of myositis [136] and other musculoskeletal symptoms [58], Sjögren syndrome [52, 126, 129, 137, 138], autoimmune thyroiditis (Hashimoto’s disease) [50, 52, 94, 129, 138], autoimmune polyglandular syndrome (APS) [138], endocrinopathy, Grave’s disease (hyperparathyroidism) and Cushing’s syndrome. [52, 94] Other connective tissue disorders associated with LGL leukemia involve systemic lupus erythematosus (SLE) [94, 129, 139], Behçet disease [140], uveitis and celiac disease [141]. In these associations, as in RA, T-LGL leukemia is more commonly associated than NK-LGL leukemia.

Viral or non-viral triggers are suggested in most of LGL leukemia associated muscular and glandular diseases. These immune insults potentially induce the characteristic lymphocyte infiltration and adaptive immune system-mediated destruction at the affected tissue in these diseases. [136, 142144] Even in the absence of lymphocytosis, clonal expansion of CD8+ but not CD4+ T cells and reverted CD8:CD4 ratio was observed at the affected tissues or in the periphery of patients with autoimmune thyroiditis and SLE, suggesting chronic CTL response. Interestingly, decreased circulating NK cells were noted in SLE. [145, 146] Alternatively, chronic lymphocyte activation in these diseases might be caused by genetic mutation, as in the case of APS type I. The mutation of an autoimmune suppressor gene AIRE (for autoimmune regulator) hampers the negative selection process during T cell development, breaking self-tolerance and inducing autoimmunity. [143, 147] Together, it is plausible that the clonal expansion of leukemic LGL in patients of this category is a manifestation of an on-going autoimmune response. [137] It is worth noting that there is significant overlap within this group of diseases. They also overlap with many other hematological, neurological or autoimmune disorders associated with LGL leukemia. [137, 142, 148, 149] These data suggest an underlying role of LGL in various autoimmune diseases..

Other associations

The coexistence of LGL leukemia and other malignancies (including thyroid, lung, liver, colon-rectal, prostate, testicular, melanoma, basal cell carcinoma) [50, 52, 94, 150, 151] as well as non-hematological genetic disorders such as Turner syndrome [152] has been reported. LGL leukemia post transplantation has also been discussed. [153, 154] It is conceivable that the association of LGL leukemia and other malignancies results from shared genetic alterations and failure of immune surveillance. A similar scenario may occur in the association of LGL leukemia and transplantation. The massive immunosuppression post transplantation can hamper immune surveillance and promote the outgrowth of an abnormal leukemic LGL clone. On the other hand, chronic antigen stimulation (tumor antigens, graft antigens or abnormal protein products) is present in most of these conditions. Together, these data suggest that specific genetic alteration or chronic exposure to specific antigen(s) may be needed to initiate the expansion of leukemic LGL. Subsequent transformation of these activated LGL might be required for onset of LGL leukemia.

Non-malignant clonal lymphocyte expansion versus LGL leukemia

Characteristics of non-malignant LGL expansion

Non-malignant clonal lymphocyte expansion primarily refers to the clonal CD8+ αβ-T cell expansion. By definition, it occurs in the absence of absolute lymphocytosis and associated disease. It is a surprisingly common phenomenon in elder people. In some studies, it has been reported that the expansion of CD8+ T cells with restricted clonality was observed in one third of total population over the age of 65 years. [155] Increased clonal restriction of CD8+ T cells also correlates to reduced portion of the naïve CD8+ T cells and the reversed CD4+:CD8+ ratio observed in elder people. [156] In the case of γδ-T cells, it was reported that an increased cell portion has undergone previous activation [157], which potentially restricts the diversity of antigen recognition. The total number of γδ-T cells is significantly lower in elder people compared to young people, which was due to the decrease of Vδ2 cells. [158] The number of Vδ1 cells is not changed with aging [158], rendering its relative expansion within the γδ-T cell population. On the other hand, with increase in age, there is an increased number of CD56dim NK cells (high NK activity) [159] and a decreased number of CD56bright NK cells [160]. However, the total NK cell number is relatively stable at different ages. [160]

The onset of non-malignant CD8+ T cell clonal expansion in healthy elderly people is potentially due to the combination of immune senescence and molecular alterations in CD8+ T cells. In order to mount successful immune response, clonal expansion is an indispensable process after T cell activation. Despite the existence of AICD process that maintain T cell homeostasis after activation, prolonged immune insult may lead to immune senescence, which hampers T cell proliferation after activation as well as AICD and alters the CD4+:CD8+ ratio. Moreover, it has been shown that the clonally expanded T cells in elderly people have shortened telomere, impaired proliferation ability and resistant to receptor-mediated AICD process. [156, 161] Thus, the persistence of non-malignant T cell clonal expansion is suspected to be the remnant of chronic infection throughout a life time. Cytomegalovirus (CMV) and EBV appear to be enticing candidates for this hypothesis due to their prevalence. T cell clonal expansion was also reported in human immunodeficiency virus (HIV) infected patients. [156] However, there is no known common antigen specificity observed across individuals exhibiting non-malignant T cell clonal expansion. [47]

CD8+ T cell molecular alteration was also proposed to explain the non-malignant T cell clonal expansion in elderly people. As human beings age, certain molecular alterations might occur in CD8+ cells due to intrinsic (genetic alteration) or extrinsic (virus infection) factors, which grants the affected clone growth and survival advantages over its normal counterparts. The altered clone may also undergo further differentiation and form the expanded clonal terminally differentiated T cells (TEMRA) as observed in the peripheral blood of elderly people. The persistence of clonally expanded CD8+ T cells can be antigen dependent or independent. [47] However, a difficulty for this hypothesis is how to explain the preferential CD8+ T cell clonal expansion over other immune compartments. Taken together, it is more likely that both immune senescence and molecular alterations of CD8+ T cells are needed for the persistence of non-malignant CD8+ T cell clonal expansion, while the degree of their contributions might vary in different cases.

Similarities and differences between non-malignant T cell clonal expansion and indolent LGL leukemia

There are significant overlaps between non-malignant T cell clonal expansion and indolent LGL leukemia, particularly CD8+ αβ-T-LGL leukemia. In both cases, the expanded CD8+ T cells are clonal and competent in cytotoxicity. Phenotypically, the dominant CD8+ clones resemble TEMRA and experience telomere shortening. They showed impaired proliferation as well as AICD after in vitro stimulation [28, 30, 156, 162]. Both expansions are suggested to be triggered by an initial immune response. The expanded clones present chronically rather than transiently, and occur primarily in elderly people.

With this said, there are distinct features of CD8+ αβ-T-LGL leukemia as well as LGL leukemia in general compared to non-malignant T cell clonal expansion. First, bone marrow and tissue infiltration of leukemic LGL, which can be interpreted as a form of invasion, is absent in non-malignant T cell clonal expansion by definition, although the destruction cause by this “invasion” in LGL leukemia is not through “replacement” but through immune response [59]. Second, lymphocytosis, which is common in LGL leukemia patients, is by definition absent from non-malignant T cell clonal expansion. This suggests the loss of homeostasis in LGL leukemia but not non-malignant T cell clonal expansion. Third, the wide-spread hematological disorders and autoimmune diseases associated with LGL leukemia suggest the acquisition of autoreactivity of leukemic LGL, while non-malignant T cell clonal expansion by definition does not lead to autoimmunity. Finally, unlike clonal expansion of CD8+ αβ-T cells observed in aging population, a similar expansion of γδ-T cells or NK cells is not seen. Thus, it is more likely that LGL leukemia exists as a unique clinical entity which is different from the non-malignant T cell clonal expansion observed in elderly people, although they might share common initiation mechanisms.

Conclusion

LGL leukemia is characterized by abnormal clonal expansion of mature LGL that remain long-term competent. In this review, we provide an overview of conditions associated with this rare leukemia, particularly the indolent form. We also discuss underlying mechanisms for these associations. This review outlines clinical presentations where the presence of LGL leukemia can be suspected.

Going back to the initial discussion of the malignancy of indolent LGL leukemia, despite an absence of consistent genetic disorders [27], a survival advantage of the clonal leukemic LGL over their normal counterparts is clearly seen in patients. Moreover, tissue invasion is a common feature of leukemic LGL, which leads to the wide spectrum of LGL leukemia associated hematological and autoimmune disorders. Together, as suggested previously [28], although the exact survival mechanisms of leukemic LGL are unknown, the evidence presented in this review points indolent LGL leukemia to the intersection of malignancy and autoimmunity, suggesting the possibility of a common pathogenesis in LGL leukemia and many hematological disorders as well as autoimmune diseases.

Footnotes

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Reference

  • 1.Loughran TP., Jr Clonal diseases of large granular lymphocytes. Blood. 1993;82(1):1–14. [PubMed] [Google Scholar]
  • 2.Timonen T, Ortaldo JR, Herberman RB. Characteristics of human large granular lymphocytes and relationship to natural killer and K cells. J. Exp. Med. 1981;153(3):569–582. doi: 10.1084/jem.153.3.569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Young LHY, Liu CC, Joag S, Rafii S, Young JDE. How Lymphocytes Kill. Annual Review of Medicine. 1990;41(1):45–54. doi: 10.1146/annurev.me.41.020190.000401. [DOI] [PubMed] [Google Scholar]
  • 4.Russell JH, Ley TJ. Lymphocyte-mediated cytotoxicity. Annual Review of Immunology. 2002;20(1):323–370. doi: 10.1146/annurev.immunol.20.100201.131730. [DOI] [PubMed] [Google Scholar]
  • 5.Di Santo JP. Natural killer cell developmental pathways: a question of balance. Annual Review of Immunology. 2006;24(1):257–286. doi: 10.1146/annurev.immunol.24.021605.090700. [DOI] [PubMed] [Google Scholar]
  • 6.Caligiuri MA. Human natural killer cells. Blood. 2008;112(3):461–469. doi: 10.1182/blood-2007-09-077438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Lanier LL. Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol. 2008;9(5):495–502. doi: 10.1038/ni1581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008;9(5):503–510. doi: 10.1038/ni1582. [DOI] [PubMed] [Google Scholar]
  • 9.Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends in Immunology. 2001;22(11):633–640. doi: 10.1016/s1471-4906(01)02060-9. [DOI] [PubMed] [Google Scholar]
  • 10.Lauritsen JPH, Haks MC, Lefebvre JM, Kappes DJ, Wiest DL. Recent insights into the signals that control alphabeta/gammadelta-lineage fate. Immunological Reviews. 2006;209(1):176–190. doi: 10.1111/j.0105-2896.2006.00349.x. [DOI] [PubMed] [Google Scholar]
  • 11.Thedrez A, Sabourin C, Gertner J, Devilder M-C, Allain-Maillet S, Fournie J-J, et al. Self/non-self discrimination by human gammadelta T cells: simple solutions for a complex issue? Immunological Reviews. 2007;215(1):123–135. doi: 10.1111/j.1600-065X.2006.00468.x. [DOI] [PubMed] [Google Scholar]
  • 12.Liu C-C, Young LHY, Young JD-E. Lymphocyte-Mediated Cytolysis and Disease. N Engl J Med. 1996;335(22):1651–1659. doi: 10.1056/NEJM199611283352206. [DOI] [PubMed] [Google Scholar]
  • 13.Voskoboinik I, Smyth MJ, Trapani JA. Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol. 2006;6(12):940–952. doi: 10.1038/nri1983. [DOI] [PubMed] [Google Scholar]
  • 14.Bolitho P, Voskoboinik I, Trapani JA, Smyth MJ. Apoptosis induced by the lymphocyte effector molecule perforin. Current Opinion in Immunology. 2007;19(3):339–347. doi: 10.1016/j.coi.2007.04.007. [DOI] [PubMed] [Google Scholar]
  • 15.Lord SJ, Rajotte RV, Korbutt GS, Bleackley RC. Granzyme B: a natural born killer. Immunological Reviews. 2003;193(1):31–38. doi: 10.1034/j.1600-065x.2003.00044.x. [DOI] [PubMed] [Google Scholar]
  • 16.Krueger A, Fas SC, Baumann S, Krammer PH. The role of CD95 in the regulation of peripheral T-cell apoptosis. Immunological Reviews. 2003;193(1):58–69. doi: 10.1034/j.1600-065x.2003.00047.x. [DOI] [PubMed] [Google Scholar]
  • 17.Oshimi Y, Oda S, Honda Y, Nagata S, Miyazaki S. Involvement of Fas ligand and Fas-mediated pathway in the cytotoxicity of human natural killer cells. J Immunol. 1996;157(7):2909–2915. [PubMed] [Google Scholar]
  • 18.Wajant H. The Fas Signaling Pathway: More Than a Paradigm. Science. 2002;296(5573):1635–1636. doi: 10.1126/science.1071553. [DOI] [PubMed] [Google Scholar]
  • 19.Clark R, Griffiths GM. Lytic granules, secretory lysosomes and disease. Current Opinion in Immunology. 2003;15(5):516–521. doi: 10.1016/s0952-7915(03)00113-4. [DOI] [PubMed] [Google Scholar]
  • 20.Vignaux F, Vivier E, Malissen B, Depraetere V, Nagata S, Golstein P. TCR/CD3 coupling to Fas-based cytotoxicity. J. Exp. Med. 1995;181(2):781–786. doi: 10.1084/jem.181.2.781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Montel AH, Bochan MR, Hobbs JA, Lynch DH, Brahmi Z. Fas Involvement in Cytotoxicity Mediated by Human NK Cells. Cellular Immunology. 1995;166(2):236–246. doi: 10.1006/cimm.1995.9974. [DOI] [PubMed] [Google Scholar]
  • 22.Ida H, Utz PJ, Anderson P, Eguchi K. Granzyme B and natural killer (NK) cell death. Modern Rheumatology. 2005;15(5):315–322. doi: 10.1007/s10165-005-0426-6. [DOI] [PubMed] [Google Scholar]
  • 23.Laforge M, Bidere N, Carmona S, Devocelle A, Charpentier B, Senik A. Apoptotic Death Concurrent with CD3 Stimulation in Primary Human CD8+ T Lymphocytes: A Role for Endogenous Granzyme B. J Immunol. 2006;176(7):3966–3977. doi: 10.4049/jimmunol.176.7.3966. [DOI] [PubMed] [Google Scholar]
  • 24.Spaggiari GM, Contini P, Dondero A, Carosio R, Puppo F, Indiveri F, et al. Soluble HLA class I induces NK cell apoptosis upon the engagement of killer-activating HLA class I receptors through FasL-Fas interaction. Blood. 2002;100(12):4098–4107. doi: 10.1182/blood-2002-04-1284. [DOI] [PubMed] [Google Scholar]
  • 25.Spaggiari GM, Contini P, Carosio R, Arvigo M, Ghio M, Oddone D, et al. Soluble HLA class I molecules induce natural killer cell apoptosis through the engagement of CD8: evidence for a negative regulation exerted by members of the inhibitory receptor superfamily. Blood. 2002;99(5):1706–1714. doi: 10.1182/blood.v99.5.1706. [DOI] [PubMed] [Google Scholar]
  • 26.Trapani JA, Sutton VR. Granzyme B: pro-apoptotic, antiviral and antitumor functions. Current Opinion in Immunology. 2003;15(5):533–543. doi: 10.1016/s0952-7915(03)00107-9. [DOI] [PubMed] [Google Scholar]
  • 27.Sokol L, Loughran TP., Jr Large granular lymphocyte leukemia. Oncologist. 2006;11(3):263–273. doi: 10.1634/theoncologist.11-3-263. [DOI] [PubMed] [Google Scholar]
  • 28.Shah MV, Zhang R, Irby R, Kothapalli R, Liu X, Arrington T, et al. Molecular profiling of LGL leukemia reveals role of sphingolipid signaling in survival of cytotoxic lymphocytes. Blood. 2008;112(3):770–781. doi: 10.1182/blood-2007-11-121871. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Choi YL, Makishima H, Ohashi J, Yamashita Y, Ohki R, Koinuma K, et al. DNA microarray analysis of natural killer cell-type lymphoproliferative disease of granular lymphocytes with purified CD3-CD56+ fractions. Leukemia. 2004;18(3):556–565. doi: 10.1038/sj.leu.2403261. [DOI] [PubMed] [Google Scholar]
  • 30.Yang J, Epling-Burnette PK, Painter JS, Zou J, Bai F, Wei S, et al. Antigen activation and impaired Fas-induced death-inducing signaling complex formation in T-large-granular lymphocyte leukemia. Blood. 2008;111(3):1610–1616. doi: 10.1182/blood-2007-06-093823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Kothapalli R, Bailey R, Kusmartseva I, Mane S, Epling-Burnette P, Loughran TP., Jr Constitutive expression of cytotoxic proteases and down-regulation of protease inhibitors in LGL leukemia. Int J Oncol. 2003;22(1):33–39. [PubMed] [Google Scholar]
  • 32.Lamy T, Liu JH, Landowski TH, Dalton WS, Loughran TP., Jr Dysregulation of CD95/CD95 Ligand-Apoptotic Pathway in CD3+ Large Granular Lymphocyte Leukemia. Blood. 1998;92(12):4771–4777. [PubMed] [Google Scholar]
  • 33.Liu JH, Wei S, Lamy T, Li Y, Epling-Burnette PK, Djeu JY, et al. Blockade of Fas-dependent apoptosis by soluble Fas in LGL leukemia. Blood. 2002;100(4):1449–1453. [PubMed] [Google Scholar]
  • 34.Epling-Burnette PK, Painter JS, Chaurasia P, Bai F, Wei S, Djeu JY, et al. Dysregulated NK receptor expression in patients with lymphoproliferative disease of granular lymphocytes. Blood. 2004;103(9):3431–3439. doi: 10.1182/blood-2003-02-0400. [DOI] [PubMed] [Google Scholar]
  • 35.Chen X, Bai F, Sokol L, Zhou J, Ren A, Painter JS, et al. A critical role for DAP10 and DAP12 in CD8+ T cell-mediated tissue damage in large granular lymphocyte leukemia. Blood. 2008 doi: 10.1182/blood-2008-07-168245. blood-2008-07-168245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Kothapalli R, Nyland S, Kusmartseva I, Bailey R, McKeown T, Loughran TP., Jr Constitutive production of proinflammatory cytokines RANTES, MIP-1beta and IL-18 characterizes LGL leukemia. Int J Oncol. 2005;26(2):529–535. [PubMed] [Google Scholar]
  • 37.Loughran TP, Jr, Starkebaum G. Large granular lymphocyte leukemia. Report of 38 cases and review of the literature. Medicine (Baltimore) 1987;66(5):397–405. [PubMed] [Google Scholar]
  • 38.Aisenberg AC. Utility of Gene Rearrangements in Lymphoid Malignancies. Annual Review of Medicine. 1993;44(1):75–84. doi: 10.1146/annurev.me.44.020193.000451. [DOI] [PubMed] [Google Scholar]
  • 39.Kawa-Ha K, Ishihara S, Ninomiya T, Yumura-Yagi K, Hara J, Murayama F, et al. CD3-negative lymphoproliferative disease of granular lymphocytes containing Epstein-Barr viral DNA. J Clin Invest. 1989;84(1):51–55. doi: 10.1172/JCI114168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Hart DN, Baker BW, Inglis MJ, Nimmo JC, Starling GC, Deacon E, et al. Epstein-Barr viral DNA in acute large granular lymphocyte (natural killer) leukemic cells. Blood. 1992;79(8):2116–2123. [see comments]. [PubMed] [Google Scholar]
  • 41.Gentile TC, Uner AH, Hutchison RE, Wright J, Ben-Ezra J, Russell EC, et al. CD3+, CD56+ aggressive variant of large granular lymphocyte leukemia. Blood. 1994;84(7):2315–2321. [see comments]. [PubMed] [Google Scholar]
  • 42.Greer JP, Kinney MC, Loughran TP., Jr T Cell and NK Cell Lymphoproliferative Disorders. Hematology. 2001;2001(1):259–281. doi: 10.1182/asheducation-2001.1.259. [DOI] [PubMed] [Google Scholar]
  • 43.Lamy T, Loughran TP. Large Granular Lymphocyte Leukemia. Cancer Control. 1998;5(1):25–33. doi: 10.1177/107327489800500103. [DOI] [PubMed] [Google Scholar]
  • 44.Alekshun T, Sokol L. Diseases of large granular lymphocytes. Cancer Control. 2007;14(2):141–150. doi: 10.1177/107327480701400207. [DOI] [PubMed] [Google Scholar]
  • 45.Roullet MR, Cornfield DB. Large natural killer cell lymphoma arising from an indolent natural killer cell large granular lymphocyte proliferation. Arch Pathol Lab Med. 2006;130(11):1712–1714. doi: 10.5858/2006-130-1712-LNKCLA. [DOI] [PubMed] [Google Scholar]
  • 46.Huang Q, Chang KL, Gaal KK, Weiss LM. An aggressive extranodal NK-cell lymphoma arising from indolent NK-cell lymphoproliferative disorder. Am J Surg Pathol. 2005;29(11):1540–1543. doi: 10.1097/01.pas.0000168510.54867.9a. [DOI] [PubMed] [Google Scholar]
  • 47.Clambey ET, van Dyk LF, Kappler JW, Marrack P. Non-malignant clonal expansions of CD8+ memory T cells in aged individuals. Immunological Reviews. 2005;205(1):170–189. doi: 10.1111/j.0105-2896.2005.00265.x. [DOI] [PubMed] [Google Scholar]
  • 48.Bigouret V, Hoffmann T, Arlettaz L, Villard J, Colonna M, Ticheli A, et al. 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. Blood. 2003;101(8):3198–3204. doi: 10.1182/blood-2002-08-2408. [DOI] [PubMed] [Google Scholar]
  • 49.Viny AD, Lichtin A, Pohlman B, Loughran T, Maciejewski J. Chronic B-cell dyscrasias are an important clinical feature of T-LGL leukemia. Leukemia and Lymphoma. 2008;49(5):932–938. doi: 10.1080/10428190801932635. [DOI] [PubMed] [Google Scholar]
  • 50.Sandberg Y, Almeida J, Gonzalez M, Lima M, Barcena P, Szczepanski T, et al. TCRgamma][delta]+ large granular lymphocyte leukemias reflect the spectrum of normal antigen-selected TCRgamma][delta]+ T-cells. Leukemia. 2006;20(3):505–513. doi: 10.1038/sj.leu.2404112. [DOI] [PubMed] [Google Scholar]
  • 51.Papadaki T, Stamatopoulos K, Kosmas C, Paterakis G, Kapsimali V, Kokkini G, et al. Clonal T-large granular lymphocyte proliferations associated with clonal B cell lymphoproliferative disorders: report of eight cases. Leukemia. 2002;16(10):2167–2169. doi: 10.1038/sj.leu.2402643. [DOI] [PubMed] [Google Scholar]
  • 52.Dhodapkar MV, Li CY, Lust JA, Tefferi A, Phyliky RL. Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance? Blood. 1994;84(5):1620–1627. [PubMed] [Google Scholar]
  • 53.Marolleau JP, Henni T, Gaulard P, Le Couedic JP, Gourdin MF, Divine M, et al. Hairy cell leukemia associated with large granular lymphocyte leukemia: immunologic and genomic study, effect of interferon treatment. Blood. 1988;72(2):655–660. [PubMed] [Google Scholar]
  • 54.Papadaki T, Stamatopoulos K, Stavroyianni N, Paterakis G, Phisphis M, Stefanoudaki-Sofianatou K. Evidence for T-large granular lymphocyte-mediated neutropenia in Rituximab-treated lymphoma patients: report of two cases. Leukemia Research. 2002;26(6):597–600. doi: 10.1016/s0145-2126(01)00183-7. [DOI] [PubMed] [Google Scholar]
  • 55.Sandberg Y, Dezentje VO, Szuhai K, van Houte AJ, Tielemans D, Wolvers-Tettero ILM, et al. Clonal T- and natural killer-cell large granular lymphocyte proliferations in a single patient established by array-based comparative genomic hybridization analysis. Leukemia. 2006;20(12):2212–2214. doi: 10.1038/sj.leu.2404451. [DOI] [PubMed] [Google Scholar]
  • 56.Rose MG, Berliner N. T-cell large granular lymphocyte leukemia and related disorders. Oncologist. 2004;9(3):247–258. doi: 10.1634/theoncologist.9-3-247. [DOI] [PubMed] [Google Scholar]
  • 57.Zambello R, Semenzato G. Large granular lymphocytosis. Haematologica. 1998;83(10):936–942. [PubMed] [Google Scholar]
  • 58.Rabbani GR, Phyliky RL, Tefferi A. A long-term study of patients with chronic natural killer cell lymphocytosis. British Journal of Haematology. 1999;106(4):960–966. doi: 10.1046/j.1365-2141.1999.01624.x. [DOI] [PubMed] [Google Scholar]
  • 59.Burks EJ, Loughran JTP. Pathogenesis of neutropenia in large granular lymphocyte leukemia and Felty syndrome. Blood Reviews. 2006;20(5):245–266. doi: 10.1016/j.blre.2006.01.003. [DOI] [PubMed] [Google Scholar]
  • 60.Morice WG, Kurtin PJ, Tefferi A, Hanson CA. Distinct bone marrow findings in T-cell granular lymphocytic leukemia revealed by paraffin section immunoperoxidase stains for CD8, TIA-1, and granzyme B. Blood. 2002;99(1):268–274. doi: 10.1182/blood.v99.1.268. [DOI] [PubMed] [Google Scholar]
  • 61.Wlodarski MW, Nearman Z, Jiang Y, Lichtin A, Maciejewski JP. Clonal predominance of CD8+ T cells in patients with unexplained neutropenia. Experimental Hematology. 2008;36(3):293–300. doi: 10.1016/j.exphem.2007.11.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Liu JH, Wei S, Lamy T, Epling-Burnette PK, Starkebaum G, Djeu JY, et al. Chronic neutropenia mediated by Fas ligand. Blood. 2000;95(10):3219–3222. [PubMed] [Google Scholar]
  • 63.Berliner N, Horwitz M, Loughran TP., Jr Congenital and Acquired Neutropenia. Hematology. 2004;2004(1):63–79. doi: 10.1182/asheducation-2004.1.63. [DOI] [PubMed] [Google Scholar]
  • 64.Go RS, Li C-Y, Tefferi A, Phyliky RL. Acquired pure red cell aplasia associated with lymphoproliferative disease of granular T lymphocytes. Blood. 2001;98(2):483–485. doi: 10.1182/blood.v98.2.483. [DOI] [PubMed] [Google Scholar]
  • 65.Lacy MQ, Kurtin PJ, Tefferi A. Pure red cell aplasia: association with large granular lymphocyte leukemia and the prognostic value of cytogenetic abnormalities. Blood. 1996;87(7):3000–3006. [see comments]. [PubMed] [Google Scholar]
  • 66.Go RS, Lust JA, Phyliky RL. Aplastic anemia and pure red cell aplasia associated with large granular lymphocyte leukemia. Seminars in Hematology. 2003;40(3):196–200. doi: 10.1016/s0037-1963(03)00140-9. [DOI] [PubMed] [Google Scholar]
  • 67.Kwong YL, Wong KF. Association of pure red cell aplasia with T large granular lymphocyte leukaemia. J Clin Pathol. 1998;51(9):672–675. doi: 10.1136/jcp.51.9.672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Masuda M, Teramura M, Matsuda A, Bessho M, Shimamoto T, Ohyashiki K, et al. Clonal T cells of pure red-cell aplasia. American Journal of Hematology. 2005;79(4):332–333. doi: 10.1002/ajh.20374. [DOI] [PubMed] [Google Scholar]
  • 69.Tse E, Chan JCW, Pang A, Au WY, Leung AYH, Lam CCK, et al. Fludarabine, mitoxantrone and dexamethasone as first-line treatment for T-cell large granular lymphocyte leukemia. Leukemia. 2007;21(10):2225–2226. doi: 10.1038/sj.leu.2404767. [DOI] [PubMed] [Google Scholar]
  • 70.Kwong YL, Wong KF, Chan LC, Liang RH, Chan JK, Lin CK, et al. Large granular lymphocyte leukemia. A study of nine cases in a Chinese population. Am J Clin Pathol. 1995;103(1):76–81. doi: 10.1093/ajcp/103.1.76. [DOI] [PubMed] [Google Scholar]
  • 71.Handgretinger R, Geiselhart A, Moris A, Grau R, Teuffel O, Bethge W, et al. Pure Red-Cell Aplasia Associated with Clonal Expansion of Granular Lymphocytes Expressing Killer-Cell Inhibitory Receptors. N Engl J Med. 1999;340(4):278–284. doi: 10.1056/NEJM199901283400405. [DOI] [PubMed] [Google Scholar]
  • 72.Yamada O, Yun-Hua W, Motoji T, Mizoguchi H. Clonal T-cell proliferation causing pure red cell aplasia in chronic B-cell lymphocytic leukaemia: successful treatment with cyclosporine following in vitro abrogation of erythroid colony-suppressing activity. British Journal of Haematology. 1998;101(2):335–337. doi: 10.1046/j.1365-2141.1998.00711.x. [DOI] [PubMed] [Google Scholar]
  • 73.Au W-Y, Lam CCK, Chim C-S, Pang AWK, Kwong Y-L. Alemtuzumab induced complete remission of therapy-resistant pure red cell aplasia. Leukemia Research. 2005;29(10):1213–1215. doi: 10.1016/j.leukres.2005.02.018. [DOI] [PubMed] [Google Scholar]
  • 74.Servey JT, Reamy BV, Hodge J. Clinical presentations of parvovirus B19 infection. Am Fam Physician. 2007;75(3):373–376. [PubMed] [Google Scholar]
  • 75.Chisaka H, Morita E, Yaegashi N, Sugamura K. Parvovirus B19 and the pathogenesis of anaemia. Reviews in Medical Virology. 2003;13(6):347–359. doi: 10.1002/rmv.395. [DOI] [PubMed] [Google Scholar]
  • 76.Kondo H, Mori A, Watanabe J, Takada J, Takahashi Y, Iwasaki H. Pure red cell aplasia associated with parvovirus B19 infection in T-large granular lymphocyte leukemia. Leuk Lymphoma. 2001;42(6):1439–1443. doi: 10.3109/10428190109097777. [DOI] [PubMed] [Google Scholar]
  • 77.Ergas D, Resnitzky P, Berrebi A. Pure red blood cell aplasia associated with parvovirus B19 infection in large granular lymphocyte leukemia [letter] Blood. 1996;87(8):3523–3524. [PubMed] [Google Scholar]
  • 78.Akashi K, Shibuya T, Taniguchi S, Hayashi S, Iwasaki H, Teshima T, et al. Multiple autoimmune haemopoietic disorders and insidious clonal proliferation of large granular lymphocytes. British Journal of Haematology. 1999;107(3):670–673. doi: 10.1046/j.1365-2141.1999.01734.x. [DOI] [PubMed] [Google Scholar]
  • 79.Karadimitris A, Li K, Notaro R, Araten DJ, Nafa K, Thertulien R, et al. Association of clonal T-cell large granular lymphocyte disease and paroxysmal nocturnal haemoglobinuria (PNH): further evidence for a pathogenetic link between T cells, aplastic anaemia and PNH. British Journal of Haematology. 2001;115(4):1010–1014. doi: 10.1046/j.1365-2141.2001.03172.x. [DOI] [PubMed] [Google Scholar]
  • 80.Go RS, Tefferi A, Li C-Y, Lust JA, Phyliky RL. Lymphoproliferative disease of granular T lymphocytes presenting as aplastic anemia. Blood. 2000;96(10):3644–3646. [PubMed] [Google Scholar]
  • 81.Risitano AM, Maciejewski JP, Muranski P, Wlodarski M, O'Keefe C, Sloand EM, et al. Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal hemoglobinuria (PNH) patients. Leukemia. 2005;19(2):217–222. doi: 10.1038/sj.leu.2403617. [DOI] [PubMed] [Google Scholar]
  • 82.Lai DW, Loughran TP, Jr, Maciejewski JP, Sasu S, Song SX, Epling-Burnette PK, et al. Acquired amegakaryocytic thrombocytopenia and pure red cell aplasia associated with an occult large granular lymphocyte leukemia. Leukemia Research. 2008;32(5):823–827. doi: 10.1016/j.leukres.2007.08.012. [DOI] [PubMed] [Google Scholar]
  • 83.Wex H, Aumann V, Häusler M, Vorwerk P, Mittler U. Chronic natural killer cell lymphocytosis is associated with elevated cytotoxic activity of natural killer cells. J Pediatr Hematol Oncol. 2005;27(2):85–89. doi: 10.1097/01.mph.0000152571.06437.3f. [DOI] [PubMed] [Google Scholar]
  • 84.Okuno SH, Tefferi A, Hanson CA, Katzmann JA, Li CY, Witzig TE. Spectrum of diseases associated with increased proportions or absolute numbers of peripheral blood natural killer cells. British Journal of Dermatology. 1996;93(4):810–812. [PubMed] [Google Scholar]
  • 85.Epperson DE, Nakamura R, Saunthararajah Y, Melenhorst J, Barrett AJ. Oligoclonal T cell expansion in myelodysplastic syndrome: evidence for an autoimmune process. Leukemia Research. 2001;25(12):1075–1083. doi: 10.1016/s0145-2126(01)00083-2. [DOI] [PubMed] [Google Scholar]
  • 86.Saunthararajah Y, Molldrem JJ, Rivera M, Williams A, Stetler-Stevenson M, Sorbara L, et al. Coincident myelodysplastic syndrome and T-cell large granular lymphocytic disease: clinical and pathophysiological features. British Journal of Haematology. 2001;112(1):195–200. doi: 10.1046/j.1365-2141.2001.02561.x. [DOI] [PubMed] [Google Scholar]
  • 87.Maciejewski JP, O'Keefe C, Gondek L, Tiu R. Immune-mediated bone marrow failure syndromes of progenitor and stem cells: molecular analysis of cytotoxic T cell clones. Folia Histochem Cytobiol. 2007;45(1):5–14. [PubMed] [Google Scholar]
  • 88.Saitoh T, Karasawa M, Sakuraya M, Norio N, Junko T, Shirakawa K, et al. Improvement of extrathymic T cell type of large granular lymphocyte (LGL) leukemia by cyclosporin A: the serum level of Fas ligand is a marker of LGL leukemia activity. European Journal of Haematology. 2000;65(4):272–275. doi: 10.1034/j.1600-0609.2000.065004272.x. [DOI] [PubMed] [Google Scholar]
  • 89.Tefferi A, Li C-Y. Bone marrow granulomas associated with chronic natural killer cell lymphocytosis. American Journal of Hematology. 1997;54(3):258–262. doi: 10.1002/(sici)1096-8652(199703)54:3<258::aid-ajh14>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
  • 90.Cartwright GE, Athens JW, Wintrobe MM. Analytical Review: The Kinetics of Granulopoiesis in Normal Man. Blood. 1964;24(6):780–803. [PubMed] [Google Scholar]
  • 91.Bratosin D, Mazurier J, Tissier JP, Estaquier J, Huart JJ, Ameisen JC, et al. Cellular and molecular mechanisms of senescent erythrocyte phagocytosis by macrophages. A review. Biochimie. 1998;80(2):173–195. doi: 10.1016/s0300-9084(98)80024-2. [DOI] [PubMed] [Google Scholar]
  • 92.Klonizakis I, Peters AM, Fitzpatrick ML, Kensett MJ, Lewis SM, Lavender JP. Spleen function and platelet kinetics. J Clin Pathol. 1981;34(4):377–380. doi: 10.1136/jcp.34.4.377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.Gentile TC, Loughran TP., Jr Resolution of autoimmune hemolytic anemia following splenectomy in CD3+ large granular lymphocyte leukemia. Leuk Lymphoma. 1996;23(3–4):405–408. doi: 10.3109/10428199609054846. [DOI] [PubMed] [Google Scholar]
  • 94.Subbiah V, Viny AD, Rosenblatt S, Pohlman B, Lichtin A, Maciejewski JP. Outcomes of splenectomy in T-cell large granular lymphocyte leukemia with splenomegaly and cytopenia. Experimental Hematology. 2008;36(9):1078–1083. doi: 10.1016/j.exphem.2008.04.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95.Loughran TP, Jr, Clark EA, Price TH, Hammond WP. Adult-onset cyclic neutropenia is associated with increased large granular lymphocytes. Blood. 1986;68(5):1082–1087. [PubMed] [Google Scholar]
  • 96.Loughran TP, Jr, Hammond WP., IV Adult-onset cyclic neutropenia is a benign neoplasm associated with clonal proliferation of large granular lymphocytes. J Exp Med. 1986;164(6):2089–2094. doi: 10.1084/jem.164.6.2089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Dale DC, Hammond WP. Cyclic neutropenia: A clinical review. Blood Reviews. 1988;2(3):178–185. doi: 10.1016/0268-960x(88)90023-9. [DOI] [PubMed] [Google Scholar]
  • 98.Füreder W, Mitterbauer G, Thalhammer R, Geissler K, Panzer S, Krebs M, et al. Clonal T cell-mediated cyclic thrombocytopenia. British Journal of Haematology. 2002;119(4):1059–1061. doi: 10.1046/j.1365-2141.2002.03951.x. [DOI] [PubMed] [Google Scholar]
  • 99.Fogarty PF, Stetler-Stevenson M, Pereira A, Dunbar CE. Large granular lymphocytic proliferation-associated cyclic thrombocytopenia. American Journal of Hematology. 2005;79(4):334–336. doi: 10.1002/ajh.20375. [DOI] [PubMed] [Google Scholar]
  • 100.Foley C, Mackey M. Dynamic hematological disease: a review. Journal of Mathematical Biology. 2009;58(1):285–322. doi: 10.1007/s00285-008-0165-3. [DOI] [PubMed] [Google Scholar]
  • 101.Apostu R, Mackey MC. Understanding cyclical thrombocytopenia: A mathematical modeling approach. Journal of Theoretical Biology. 2008;251(2):297–316. doi: 10.1016/j.jtbi.2007.11.029. [DOI] [PubMed] [Google Scholar]
  • 102.Gaur S, Mansoor S, Aish L. T-cell large granular lymphocytic leukemia and hereditary hemochromatosis: A fortuitous association? American Journal of Hematology. 2005;78(4):299–301. doi: 10.1002/ajh.20279. [DOI] [PubMed] [Google Scholar]
  • 103.Cardoso C, Porto G, Lacerda R, Resende D, Rodrigues P, Bravo F, et al. T-Cell receptor repertoire in hereditary hemochromatosis: a study of 32 hemochromatosis patients and 274 healthy subjects. Human Immunology. 2001;62(5):488–499. doi: 10.1016/s0198-8859(01)00233-6. [DOI] [PubMed] [Google Scholar]
  • 104.Vanness ER, Davis MDP, Tefferi A. Cutaneous findings associated with chronic natural killer cell lymphocytosis. International Journal of Dermatology. 2002;41(12):852–857. doi: 10.1046/j.1365-4362.2002.01671.x. [DOI] [PubMed] [Google Scholar]
  • 105.Ishida T, Sadaoka K, Takeyabu K, Yamaguchi E, Isobe H, Kawakami Y, et al. Lymphoproliferative disorder of granular lymphocytes (natural killer cell type) with interstitial pneumonia in a patient with familial pancytopenia. Intern Med. 1996;35(4):331–336. doi: 10.2169/internalmedicine.35.331. [DOI] [PubMed] [Google Scholar]
  • 106.Lutskiy MI, Beardsley DS, Rosen FS, Remold-O'Donnell E. Mosaicism of NK cells in a patient with Wiskott-Aldrich syndrome. Blood. 2005;106(8):2815–2817. doi: 10.1182/blood-2004-12-4724. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107.Boztug K, Baumann U, Ballmaier M, Webster D, Sandrock I, Jacobs R, et al. Large granular lymphocyte proliferation and revertant mosaicism: two rare events in a Wiskott-Aldrich syndrome patient. Haematologica. 2007;92(3):e43–e45. doi: 10.3324/haematol.11222. [DOI] [PubMed] [Google Scholar]
  • 108.Du W, Kumaki S, Uchiyama T, Yachie A, Yeng LC, Kawai S, et al. A second-site mutation in the initiation codon of WAS (WASP) results in expansion of subsets of lymphocytes in an Wiskott-Aldrich syndrome patient. Human Mutation. 2006;27(4):370–375. doi: 10.1002/humu.20308. [DOI] [PubMed] [Google Scholar]
  • 109.Ochs HD, Thrasher AJ. The Wiskott-Aldrich syndrome. Journal of Allergy and Clinical Immunology. 2006;117(4):725–738. doi: 10.1016/j.jaci.2006.02.005. [DOI] [PubMed] [Google Scholar]
  • 110.Bourgault-Rouxel AS, Loughran TP, Jr, Zambello R, Epling-Burnette PK, Semenzato G, Donadieu J, et al. Clinical spectrum of [gamma][delta]+ T cell LGL leukemia: Analysis of 20 cases. Leukemia Research. 2008;32(1):45–48. doi: 10.1016/j.leukres.2007.04.011. [DOI] [PubMed] [Google Scholar]
  • 111.Starkebaum G. Leukemia of large granular lymphocytes and rheumatoid arthritis. The American Journal of Medicine. 2000;108(9):744–745. doi: 10.1016/s0002-9343(00)00386-7. [DOI] [PubMed] [Google Scholar]
  • 112.Samanta A, Grant I, Nichol FE, Pringle JH, Wood JK, Campbell AC. Large granular lymphocytosis associated with rheumatoid arthritis. Ann Rheum Dis. 1988;47(10):873–875. doi: 10.1136/ard.47.10.873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 113.Horiuchi T, Hirokawa M, Satoh K, Kitabayashi A, Muira AB. Clonal expansion of γδ-T lymphocytes in an HTLV-I carrier, associated with chronic neutropenia and rheumatoid arthritis. Annals of Hematology. 1999;78(2):101–104. doi: 10.1007/s002770050483. [DOI] [PubMed] [Google Scholar]
  • 114.Prochorec-Sobieszek M, Chelstowska M, Rymkiewicz G, Majewski M, Warzocha K, Maryniak R. Biclonal T-cell receptor gammadelta+ large granular lymphocyte leukemia associated with rheumatoid arthritis. Leukemia and Lymphoma. 2008;49(4):828–831. doi: 10.1080/10428190801895337. [DOI] [PubMed] [Google Scholar]
  • 115.Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423(6937):356–361. doi: 10.1038/nature01661. [DOI] [PubMed] [Google Scholar]
  • 116.Machatschek JN, Westerman D, Prince HM, Seymour JF. A Case of Clinical Indolent Natural Killer Cell Lineage Large Granular Lymphocytic Leukemia in a Patient with Rheumatoid Arthritis. Leukemia and Lymphoma. 2003;44:1223–1227. doi: 10.1080/1042819031000079203. [DOI] [PubMed] [Google Scholar]
  • 117.Abdou NI, NaPombejara C, Balentine L, Abdou NL. Suppressor cell-mediated neutropenia in Felty's syndrome. J Clin Invest. 1978;61(3):738–743. doi: 10.1172/JCI108987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 118.Kang YM, Zhang X, Wagner UG, Yang H, Beckenbaugh RD, Kurtin PJ, et al. CD8 T Cells Are Required for the Formation of Ectopic Germinal Centers in Rheumatoid Synovitis. J. Exp. Med. 2002;195(10):1325–1336. doi: 10.1084/jem.20011565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 119.Fehniger TA, Suzuki K, Ponnappan A, VanDeusen JB, Cooper MA, Florea SM, et al. Fatal Leukemia in Interleukin 15 Transgenic Mice Follows Early Expansions in Natural Killer and Memory Phenotype CD8+ T Cells. J. Exp. Med. 2001;193(2):219–232. doi: 10.1084/jem.193.2.219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 120.Hsu C, Jones SA, Cohen CJ, Zheng Z, Kerstann K, Zhou J, et al. Cytokine-independent growth and clonal expansion of a primary human CD8+ T-cell clone following retroviral transduction with the IL-15 gene. Blood. 2007;109(12):5168–5177. doi: 10.1182/blood-2006-06-029173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 121.Zhang R, Shah MV, Yang J, Nyland SB, Liu X, Yun JK, et al. Network model of survival signaling in large granular lymphocyte leukemia. Proceedings of the National Academy of Sciences. 2008;105(42):16308–16313. doi: 10.1073/pnas.0806447105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 122.Kim GS, Youn JK, Kim JD, Hyun Kim N. Natural Killer Cell Activity in Rheumatoid Arthritis Measured by a Single Cell Cytotoxicity Assay. Yonsei Med J. 1988;29(2):160–165. doi: 10.3349/ymj.1988.29.2.160. [DOI] [PubMed] [Google Scholar]
  • 123.Pridgeon C, Lennon GP, Pazmany L, Thompson RN, Christmas SE, Moots RJ. Natural killer cells in the synovial fluid of rheumatoid arthritis patients exhibit a CD56bright, CD94bright, CD158negative phenotype. Rheumatology. 2003;42(7):870–878. doi: 10.1093/rheumatology/keg240. [DOI] [PubMed] [Google Scholar]
  • 124.Rossoff LJ, Genovese J, Coleman M, Dantzker DR. Primary Pulmonary Hypertension in a Patient With CD8/T-cell Large Granulocyte Leukemia: Amelioration by Cladribine Therapy. Chest. 1997;112(2):551–553. doi: 10.1378/chest.112.2.551. [DOI] [PubMed] [Google Scholar]
  • 125.Epling-Burnette PK, Sokol L, Chen X, Bai F, Zhou J, Blaskovich MA, et al. Clinical improvement by farnesyltransferase inhibition in NK large granular lymphocyte leukemia associated with imbalanced NK receptor signaling. Blood. 2008;112(12):4694–4698. doi: 10.1182/blood-2008-02-136382. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 126.Mallo S, Coto P, Caminal L, Rayon C, Balbim M, Sanchez-Del Rio J, et al. Generalized pruritus as presentation of T-cell large granular lymphocyte leukaemia. Clinical and Experimental Dermatology. 2008;33(3):348–349. doi: 10.1111/j.1365-2230.2007.02651.x. [DOI] [PubMed] [Google Scholar]
  • 127.Meyer N, Dufour J, Lamy T, Chevrant-Breton J. Cutaneous vasculitis and T-large granular lymphocyte leukaemia with parallel evolution. British Journal of Dermatology. 2007;157(3):631–633. doi: 10.1111/j.1365-2133.2007.08035.x. [DOI] [PubMed] [Google Scholar]
  • 128.Magro C, Crowson AN, Kovatich A, Burns F. Pityriasis lichenoides: A clonal T-cell lymphoproliferative disorder. Human Pathology. 2002;33(8):788–795. doi: 10.1053/hupa.2002.125381. [DOI] [PubMed] [Google Scholar]
  • 129.Shvidel L, Duksin C, Tzimanis A, Shtalrid M, Klepfish A, Sigler E, et al. Cytokine release by activated T-cells in large granular lymphocytic leukemia associated with autoimmune disorders. Hematol J. 2002;3(1):32–27. doi: 10.1038/sj.thj.6200149. [DOI] [PubMed] [Google Scholar]
  • 130.Granjo E, Lima M, Correia T, Lisboa C, Magalhaes C, Cunha N, et al. Cd8(+)vbeta5.1(+) large granular lymphocyte leukemia associated with autoimmune cytopenias, rheumatoid arthritis and vascular mammary skin lesions: successful response to 2-deoxycoformycin. Hematological Oncology. 2002;20(2):87–93. doi: 10.1002/hon.695. [DOI] [PubMed] [Google Scholar]
  • 131.Nasa G, Littera R, Cocco E, Battistini L, Marrosu M, Contu L. Allogeneic hematopoietic stem cell transplantation in a patient affected by large granular lymphocyte leukemia and multiple sclerosis. Annals of Hematology. 2004;83(6):403–405. doi: 10.1007/s00277-003-0801-3. [DOI] [PubMed] [Google Scholar]
  • 132.Au WY, Mak W, Ho SL, Leung SY, Kwong YL. Reversible paraneoplastic neuropathy associated with T-cell large granular lymphocyte leukemia. Neurology. 2004;63(3):588–589. doi: 10.1212/01.wnl.0000133410.41914.ad. [DOI] [PubMed] [Google Scholar]
  • 133.Noguchi M, Yoshita M, Sakai K, Matsumoto Y, Arahata M, Ontachi Y, et al. Peripheral neuropathy associated with chronic natural killer cell lymphocytosis. Journal of the Neurological Sciences. 2005;232(1–2):119–122. doi: 10.1016/j.jns.2005.01.013. [DOI] [PubMed] [Google Scholar]
  • 134.Frohman EM, Racke MK, Raine CS. Multiple Sclerosis -- The Plaque and Its Pathogenesis. N Engl J Med. 2006;354(9):942–955. doi: 10.1056/NEJMra052130. [DOI] [PubMed] [Google Scholar]
  • 135.Barmak K, Harhaj E, Grant C, Alefantis T, Wigdahl B. Human T cell leukemia virus type I-induced disease: pathways to cancer and neurodegeneration. Virology. 2003;308(1):1–12. doi: 10.1016/s0042-6822(02)00091-0. [DOI] [PubMed] [Google Scholar]
  • 136.Rosche B, Jacobsen M, Cepok S, Barth P, Sommer N, Hemmer B. Myositis in a patient with large granular leukocyte leukemia. Muscle & Nerve. 2004;29(6):873–877. doi: 10.1002/mus.10570. [DOI] [PubMed] [Google Scholar]
  • 137.Friedman J, Schattner A, Shvidel L, Berrebi A. Characterization of T-Cell Large Granular Lymphocyte Leukemia Associated with Sjogren's Syndrome--An Important but Underrecognized Association. Seminars in Arthritis and Rheumatism. 2006;35(5):306–311. doi: 10.1016/j.semarthrit.2005.07.001. [DOI] [PubMed] [Google Scholar]
  • 138.Ergas D, Tsimanis A, Shtalrid M, Duskin C, Berrebi A. T-gamma large granular lymphocyte leukemia associated with amegakaryocytic thrombocytopenic purpura, Sjoren's syndrome, and polyglandular autoimmune syndrome type II, with subsequent development of pure red cell aplasia. American Journal of Hematology. 2002;69(2):132–134. doi: 10.1002/ajh.10024. [DOI] [PubMed] [Google Scholar]
  • 139.Marlton P, Taylor K, Elliott S, McCormack J. Monoclonal large granular lymphocyte proliferation in SLE with HTLV-I seroreactivity. Internal Medicine Journal. 1992;22(1):54–55. doi: 10.1111/j.1445-5994.1992.tb01711.x. [DOI] [PubMed] [Google Scholar]
  • 140.Saitoh T, Matsushima T, Kaneko Y, Yokohama A, Handa H, Tsukamoto N, et al. T cell large granular lymphocyte (LGL) leukemia associated with Behcet's disease: high expression of sFasL and IL-18 of CD8 LGL. Annals of Hematology. 2008;87(7):585–586. doi: 10.1007/s00277-008-0438-3. [DOI] [PubMed] [Google Scholar]
  • 141.Molitor J, Saint-Louis J, Louvet C, Vachon A, Vincent L, Beaulieu R. Large granular T-cell lymphocytic leukemia disclosed by bilateral uveitis: association with celiac disease. Rev Med Interne. 1997;18(3):238–239. doi: 10.1016/s0248-8663(97)89302-2. [DOI] [PubMed] [Google Scholar]
  • 142.Fox RI. Sjoren's syndrome. The Lancet. 2005;366(9482):321–331. doi: 10.1016/S0140-6736(05)66990-5. [DOI] [PubMed] [Google Scholar]
  • 143.Eisenbarth GS, Gottlieb PA. Autoimmune Polyendocrine Syndromes. N Engl J Med. 2004;350(20):2068–2079. doi: 10.1056/NEJMra030158. [DOI] [PubMed] [Google Scholar]
  • 144.Caturegli P, Kimura H, Rocchi R, Rose NR. Autoimmune thyroid diseases. Curr Opin Rheumatol. 2005;19(1):44–48. doi: 10.1097/BOR.0b013e3280113d1a. [DOI] [PubMed] [Google Scholar]
  • 145.McIntosh RS, Watson PF, Weetman AP. Analysis of the T Cell Receptor V{alpha} Repertoire in Hashimoto's Thyroiditis: Evidence for the Restricted Accumulation of CD8+ T Cells in the Absence of CD4+ T Cell Restriction. J Clin Endocrinol Metab. 1997;82(4):1140–1146. doi: 10.1210/jcem.82.4.3868. [DOI] [PubMed] [Google Scholar]
  • 146.Wouters CHP, Diegenant C, Ceuppens JL, Degreef H, Stevens EAM. The circulating lymphocyte profiles in patients with discoid lupus erythematosus and systemic lupus erythematosus suggest a pathogenetic relationship. British Journal of Dermatology. 2004;150(4):693–700. doi: 10.1111/j.0007-0963.2004.05883.x. [DOI] [PubMed] [Google Scholar]
  • 147.Peterson P, Peltonen L. Autoimmune polyendocrinopathy syndrome type 1 (APS1) and AIRE gene: New views on molecular basis of autoimmunity. Journal of Autoimmunity. 2005;25(Supplement 1):49–55. doi: 10.1016/j.jaut.2005.09.022. [DOI] [PubMed] [Google Scholar]
  • 148.Cikes N, Bosnic D, Sentic M. Non-MS autoimmune demyelination. Clinical Neurology and Neurosurgery. 2008;110(9):905–912. doi: 10.1016/j.clineuro.2008.06.011. [DOI] [PubMed] [Google Scholar]
  • 149.Schiess N, Pardo CA. Hashimoto's Encephalopathy. Annals of the New York Academy of Sciences. 2008;1142:254–265. doi: 10.1196/annals.1444.018. (The Year in Neurology 2008) [DOI] [PubMed] [Google Scholar]
  • 150.Borgonovo G, Secondo V, Varaldo E, Pistoia V, Gobbi M, Mattioli FP. Large granular lymphocyte leukemia associated with hepatocellular carcinoma: a case report. Haematologica. 1996;81(2):172–174. [PubMed] [Google Scholar]
  • 151.Rossi D, Franceschetti S, Capello D, Conconi A, Casadio C, Valente G, et al. Simultaneous diagnosis of CD3+ T-cell large granular lymphocyte leukaemia and true thymic hyperplasia. Leukemia Research. 2007;31(7):1019–1021. doi: 10.1016/j.leukres.2006.10.019. [DOI] [PubMed] [Google Scholar]
  • 152.Manola KN, Sambani C, Karakasis D, Kalliakosta G, Harhalakis N, Papaioannou M. Leukemias associated with Turner syndrome: Report of three cases and review of the literature. Leukemia Research. 2008;32(3):481–486. doi: 10.1016/j.leukres.2007.06.004. [DOI] [PubMed] [Google Scholar]
  • 153.Au WY, Lam CCK, Lie Albert KW, Pang A, Kwong YL. T-Cell Large Granular Lymphocyte Leukemia of Donor Origin After Allogeneic Bone Marrow Transplantation. Am J Clin Pathol. 2003;120(4):626–630. doi: 10.1309/VA75-5A03-PVRV-9XDT. [DOI] [PubMed] [Google Scholar]
  • 154.Sabnani I, Zucker MJ, Tsang P, Palekar S. Clonal T-Large Granular Lymphocyte Proliferation in Solid Organ Transplant Recipients. Transplantation Proceedings. 2006;38(10):3437–3440. doi: 10.1016/j.transproceed.2006.10.045. [DOI] [PubMed] [Google Scholar]
  • 155.Ricalton NS, Roberton C, Norris JM, Rewers M, Hamman RF, Kotzin BL. Prevalence of CD8+ T-cell expansions in relation to age in healthy individuals. J Gerontol A Biol Sci Med Sci. 1998;53(3):B196–B203. doi: 10.1093/gerona/53a.3.b196. [DOI] [PubMed] [Google Scholar]
  • 156.Effros RB, Dagarag M, Spaulding C, Man J. The role of CD8+ T-cell replicative senescence in human aging. Immunological Reviews. 2005;205(1):147–157. doi: 10.1111/j.0105-2896.2005.00259.x. [DOI] [PubMed] [Google Scholar]
  • 157.Re F, Poccia F, Donnini A, Bartozzi B, Bernardini G, Provinciali M. Skewed representation of functionally distinct populations of V[gamma]9V[delta]2 T lymphocytes in aging. Experimental Gerontology. 2005;40(1–2):59–66. doi: 10.1016/j.exger.2004.09.008. [DOI] [PubMed] [Google Scholar]
  • 158.Argentati K, Re F, Donnini A, Tucci MG, Franceschi C, Bartozzi B, et al. Numerical and functional alterations of circulating {gamma}{delta} T lymphocytes in aged people and centenarians. J Leukoc Biol. 2002;72(1):65–71. [PubMed] [Google Scholar]
  • 159.Sansoni P, Vescovini R, Fagnoni F, Biasini C, Zanni F, Zanlari L, et al. The immune system in extreme longevity. Experimental Gerontology. 2008;43(2):61–65. doi: 10.1016/j.exger.2007.06.008. [DOI] [PubMed] [Google Scholar]
  • 160.Chidrawar S, Khan N, Chan YLT, Nayak L, Moss P. Ageing is associated with a decline in peripheral blood CD56bright NK cells. Immunity & Ageing. 2006;3(1):10. doi: 10.1186/1742-4933-3-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 161.Hsu H-C, Scott DK, Mountz JD. Impaired apoptosis and immune senescence: cause or effect? Immunological Reviews. 2005;205(1):130–146. doi: 10.1111/j.0105-2896.2005.00270.x. [DOI] [PubMed] [Google Scholar]
  • 162.Melenhorst JJ, Brummendorf TH, Kirby M, Lansdorp PM, Barrett AJ. CD8+ T cells in large granular lymphocyte leukemia are not defective in activation- and replication-related apoptosis. Leukemia Research. 2001;25(8):699–708. doi: 10.1016/s0145-2126(01)00010-8. [DOI] [PubMed] [Google Scholar]
  • 163.Lesesve JF, Feugier P, Lamy T, Bene MC, Gregoire MJ, Lenormand B, et al. Association of B-chronic lymphocytic leukaemia and T-large granular lymphocyte leukaemia. Clinical and Laboratory Haematology. 2000;22(2):121–122. doi: 10.1046/j.1365-2257.2000.00294.x. [DOI] [PubMed] [Google Scholar]

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