Persistent Large Granular Lymphocyte Clonal Expansions: “The Root of Many Evils”—And of Some Goodness

Bravo-Pérez, Carlos; Carrillo-Tornel, Salvador; García-Torralba, Esmeralda; Jerez, Andrés

doi:10.3390/cancers14051340

Cited by 8 publications

(6 citation statements)

References 186 publications

(260 reference statements)

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“…Furthermore, we found that similar phenotypical changes (most notably CD57 with co-expression of KLRG1 and a downregulation of CD5) extended to the CD4 + T cells and γδ T cells. Similarly, cases of CD4 + and γδ T cell T-LGL leukemia have been described previously, although their reported prevalence was lower than for CD8 + T-LGL leukemia ( 16 , 19 , 30 ). To our knowledge, our study represents the first instance of simultaneously investigating these phenotypical changes across the CD8 + , CD4 + and γδ T cell landscape in IBM.…”

Section: Discussionsupporting

confidence: 61%

“…Moreover, the association between autoimmunity and T-LGLL is well-documented with approximately 15-40% of cases having concomitant rheumatic disorders including rheumatoid arthritis (RA) with Felty’s syndrome, systemic lupus erythematosus (SLE), Sjogren’s syndrome, and systemic sclerosis ( 14 , 16 , 18 ). Despite these associations, the pathological mechanisms connecting these disorders remain undetermined, although the general consensus is that chronic autoantigen stimulation drives T-LGL differentiation, transformation and persistence into a leukemic state ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

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Uncovering the significance of expanded CD8+ large granular lymphocytes in inclusion body myositis: Insights into T cell phenotype and functional alterations, and disease severity

et al. 2023

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IntroductionInclusion body myositis (IBM) is a progressive inflammatory myopathy characterised by skeletal muscle infiltration and myofibre invasion by CD8+ T lymphocytes. In some cases, IBM has been reported to be associated with a systemic lymphoproliferative disorder of CD8+ T cells exhibiting a highly differentiated effector phenotype known as T cell Large Granular Lymphocytic Leukemia (T-LGLL). MethodsWe investigated the incidence of a CD8+ T-LGL lymphoproliferative disorder in 85 IBM patients and an aged-matched group of 56 Healthy Controls (HC). Further, we analysed the phenotypical characteristics of the expanded T-LGLs and investigated whether their occurrence was associated with any particular HLA alleles or clinical characteristics. ResultsBlood cell analysis by flow cytometry revealed expansion of T-LGLs in 34 of the 85 (40%) IBM patients. The T cell immunophenotype of T-LGLHIGH patients was characterised by increased expression of surface molecules including CD57 and KLRG1, and to a lesser extent of CD94 and CD56 predominantly in CD8+ T cells, although we also observed modest changes in CD4+ T cells and γδ T cells. Analysis of Ki67 in CD57+ KLRG1+ T cells revealed that only a small proportion of these cells was proliferating. Comparative analysis of CD8+ and CD4+ T cells isolated from matched blood and muscle samples donated by three patients indicated a consistent pattern of more pronounced alterations in muscles, although not significant due to small sample size. In the T-LGLHIGH patient group, we found increased frequencies of perforin-producing CD8+ and CD4+ T cells that were moderately correlated to combined CD57 and KLRG1 expression. Investigation of the HLA haplotypes of 75 IBM patients identified that carriage of the HLA-C*14:02:01 allele was significantly higher in T-LGLHIGH compared to T-LGLLOW individuals. Expansion of T-LGL was not significantly associated with seropositivity patient status for anti-cytosolic 5'-nucleotidase 1A autoantibodies. Clinically, the age at disease onset and disease duration were similar in the T-LGLHIGH and T-LGLLOW patient groups. However, metadata analysis of functional alterations indicated that patients with expanded T-LGL more frequently relied on mobility aids than T-LGLLOW patients indicating greater disease severity. ConclusionAltogether, these results suggest that T-LGL expansion occurring in IBM patients is correlated with exacerbated immune dysregulation and increased disease burden.

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Section: Discussionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Uncovering the significance of expanded CD8+ large granular lymphocytes in inclusion body myositis: Insights into T cell phenotype and functional alterations, and disease severity

et al. 2023

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“…Clonal proliferation of T-LGLs has been detected in various clinical conditions, including autoimmune disorders, myeloid or lymphoid clonal hematologic malignancies, pure red cell aplasia, aplastic anemia, and paroxysmal nocturnal hemoglobinuria ( 29 – 33 ). In addition, small clonal proliferations of T-LGLs have been observed after allogeneic stem cell transplantation ( 34 , 35 ) and solid organ transplantation ( 36 – 38 ) as well as in patients with HIV ( 39 ) or cytomegalovirus infection ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

STAT3 mutations in “gray-zone” cases of T-cell large granular lymphocytic leukemia associated with autoimmune rheumatic diseases

et al. 2022

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A persistently increased T-cell large granular lymphocyte (T-LGL) count in the blood of more than 2 × 109/L for at least 6 months is necessary for a reliable diagnosis of T-LGL leukemia. In cases with LGL counts of approximately 0.5–2 × 109/L, a diagnosis of T-LGL leukemia can be made if clonal rearrangement of T-cell receptor (TCR) genes is present and if the patient shows typical manifestations of T-LGL leukemia, such as cytopenia, splenomegaly, or concomitant autoimmune disease. However, in cases with LGL counts of less than 0.5 × 109/L, the diagnosis of T-LGL leukemia is questionable (termed as “gray-zone” cases). Although mutations in signal transducer and activator of transcription 3 (STAT3) gene are the molecular hallmark of T-LGL leukemia, their diagnostic value in the “gray-zone” cases of T-LGL leukemia has not been evaluated – our study has been aimed to examine the prevalence of STAT3 mutations in these cases. Herein, we describe 25 patients with autoimmune rheumatic diseases, neutropenia, clonal rearrangement of TCR genes, and circulating LGL count of less than 0.5 × 109/L. Splenomegaly was observed in 19 (76%) patients. Mutations in the STAT3 were detected in 56% of patients using next-generation sequencing. Importantly, in 3 patients, no involvement of the blood and bone marrow by malignant LGLs was noted, but examination of splenic tissue revealed infiltration by clonal cytotoxic T-lymphocytes within the red pulp, with greater prominence in the cords. We suggest using the term “splenic variant of T-LGL leukemia” for such cases.

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“…T‐cell clonality testing by TCR gene rearrangement is an important tool in the diagnosis of T‐cell lymphoproliferative disorders; however, interpretation of test results can prove challenging in practice given the high prevalence of clonal T‐cell proliferations in patients without underlying disease 5,7,8,11 . The presence of monoclonal T‐cell populations in non‐malignant conditions is well‐described, 12 most commonly associated with rheumatoid arthritis but also found in other conditions autoimmune conditions, including autoimmune hemolytic anemia where the clinical significance of clonal T‐cell populations remains to be elucidated 13 …”

Section: Discussionmentioning

confidence: 99%

“…The latter group underlying disease. 5,7,8,11 The presence of monoclonal T-cell populations in non-malignant conditions is well-described, 12 most commonly associated with rheumatoid arthritis but also found in other conditions autoimmune conditions, including autoimmune hemolytic anemia where the clinical significance of clonal T-cell populations remains to be elucidated. 13 Our study helps to characterize the real-world of 0.97 versus 2.78 Â 10 9 /L in patients who were treated versus untreated (Table 4).…”

Section: Methodsmentioning

confidence: 99%

T‐cell clonality testing for the diagnosis of T‐cell large granular lymphocytic leukemia: Are we identifying pathology or incidental clones?

Chin‐Yee

Suthakaran

Hedley

et al. 2022

Int J Lab Hematology

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Introduction: T-cell clonality testing by T-cell receptor (TCR) gene rearrangement is key to the diagnosis of T-cell lymphoproliferative disorders such as T-cell large granular lymphocytic (T-LGL) leukemia. Benign clonal T-cell expansions, however, are commonly found in patients without identifiable disease, a condition referred to as T-cell clones of uncertain significance (T-CUS). In practice, T-cell clonality testing is performed for a range of reasons and results are often challenging to interpret given the overlap between benign and malignant clonal T-cell proliferations and uncertainties in the management of T-CUS. Methods: We conducted a 5-year retrospective cohort study of 211 consecutive patients who underwent PCR-based T-cell clonality testing for suspected T-LGL leukemia at our institution to characterize the use of T-cell clonality testing and its impact on patient management. Results: Overall, 46.4% (n = 98) of individuals tested had a clonal T-cell population identified. Patients with a monoclonal T-cell population were more likely to be older, have rheumatoid arthritis and have higher lymphocyte counts compared to patients with polyclonal populations. The majority of patients eventually diagnosed and treated for T-LGL leukemia had rheumatoid arthritis and lower neutrophil counts compared to untreated patients with monoclonal T-cell populations. A diagnosis of T-LGL leukemia was made in only a minority of patients (n = 48, 22.7%), and only a small proportion were treated (n = 17, 8.1%). Conclusion: Our study suggests that T-cell clonality testing most commonly identifies incidental T-cell clones with only a minority of patients receiving a diagnosis of T-LGL leukemia and fewer requiring active treatment. These finding indicate an opportunity to improve utilization of T-cell clonality testing in clinical practice to better target patients where the results of testing would impact clinical management.

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Persistent Large Granular Lymphocyte Clonal Expansions: “The Root of Many Evils”—And of Some Goodness

Cited by 8 publications

References 186 publications

Uncovering the significance of expanded CD8+ large granular lymphocytes in inclusion body myositis: Insights into T cell phenotype and functional alterations, and disease severity

Uncovering the significance of expanded CD8+ large granular lymphocytes in inclusion body myositis: Insights into T cell phenotype and functional alterations, and disease severity

STAT3 mutations in “gray-zone” cases of T-cell large granular lymphocytic leukemia associated with autoimmune rheumatic diseases

T‐cell clonality testing for the diagnosis of T‐cell large granular lymphocytic leukemia: Are we identifying pathology or incidental clones?

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