Immunogenetic factors determining the evolution of T‐cell large granular lymphocyte leukaemia and associated cytopenias

Abstract

Summary T‐cell large granular lymphocyte leukaemia (T‐LGL) is a chronic clonal proliferation of cytotoxic T lymphocytes (CTL). T‐LGL presents with cytopenias, often accompanied by autoimmune diseases, suggesting clonal transformation arising from an initially polyclonal immune response. Various immunogenetic predisposition factors, previously described for both immune‐mediated bone marrow failure and autoimmune conditions, may promote T‐LGL evolution and/or development of cytopenias. The association of T‐LGL was analysed with a number of immunogenetic factors in 66 patients, including human leucocyte antigen (HLA) and killer‐cell immunoglobulin‐like receptor (KIR) genotype, KIR/KIR‐L mismatch, CTLA‐4 (+49 A/G),CD16−158V/F, CD45 polymorphisms, cytokine single nucleotide polymorphisms including: TNF‐α (−308G/A), TGF‐β1 (codons 10 C/T, 25 G/C), IL‐10 (−1082 G/A), IL‐6 (−174 C/G), and IFN‐γ(+874 T/A). A statistically significant increase in A/A genotype for TNF‐α−308, IL‐10–1082, andCTLA‐4 +49 was observed in T‐LGL patients compared with control, suggesting that the G allele serves a protective role in each case. No association was found between specific KIR/HLA profile and disease. KIR/KIR‐L analysis revealed significant mismatches between KIR3DL2 and KIR2DS1 and their ligands HLA‐A3/11 and HLA‐C group 2 (P = 0·03 and 0·01 respectively); the biological relevance of this finding is questionable. The significance of additional genetic polymorphisms and their clinical correlation to evolution of T‐LGL requires future analysis.

Genetic Polymorphisms in Cytotoxic T-Lymphocyte Antigen 4 and Cancer: The Dialectical Nature of Subtle Human Immune Dysregulation

“…Taking into consideration the role that CTLA-4 plays in suppressing T-cell activation and the effect of CTLs on immunosurveillance of cancer, this opposite direction in association between CTLA-4 49A > G SNP and autoimmune diseases or cancer is biologically plausible. It would be interesting to examine the role of functional CTLA-4 SNPs in susceptibility to cancer developed from the immune system, such as T-cell leukemia and T-cell lymphoma, in which the variant CTLA-4 49A allele might act as a susceptibility factor (30).…”

Outcomes of splenectomy in T-cell large granular lymphocyte leukemia with splenomegaly and cytopenia

“…Clonotypic sequences of expanded Vβ and Jβ families were determined, and expanded CDR3 clonotypes were also detected. [26] Immunophenotyping and Genotyping HLA and killer immunoglobulin-like receptor (KIR) genotyping, KIR and KIR-L assignments, and genotyping of various cytokine polymorphisms were performed as previously described including TGF-β1 (codons 10 C/T, 25 G/C), TNF-α (−308G/A), interleukin-6 (IL-6) (−174 G/C), interleukin-10 (IL-10) (−1082 G/A, −819 C/T, and −592 C/ A), IFN-γ (+874 T/A), CTLA4 (+45 A/G), FcγRIIIa(158V/F) and CD45 (77 C/G) [27].…”

“…We also investigated HLA, KIR/KIR-ligand, and cytokine/cytokine receptor genotypes as previously described [27]. Comparison of patients with and without splenomegaly showed no difference in the KIR/KIR-ligand profile, HLA type, or frequency of cytokine and immunoregulatory receptor studied, including TGF-β1 (codons 10 C/T, 25 G/C), TNF-α (−308G/A), interleukin-6 (IL-6) (−174 G/C), interleukin-10 (IL-10) (−1082 G/A, −819 C/T, and −592 C/A), IFN-γ (+874 T/A), CTLA4 (+45 A/G), FcγRIIIa(158V/F) and CD45 (77 C/ G) [27].…”

MICA polymorphism identified by whole genome array associated with NKG2D-mediated cytotoxicity in T-cell large granular lymphocyte leukemia

“…10 As for various classical autoimmune diseases, several immunogenetic causes have been proposed for the pathogenesis of LGL leukemia, all of which have been postulated to have a role in autoimmunity. Such factors include HLA, 12 KIR/KIR-ligand interaction, 13 minor histocompatibility antigens, natural killer receptors, 14 transforming growth factor-β high secretor genotype, 13 and immunoproteosome abnormalities. Due to its welldefined phenotype, LGL leukemia represents a good target for genomic analysis in order to determine additional immunogenetic factors driving aberrant lymphocytic clonal expansion.…”