title: Immunogenetic factors determining the evolution of T-cell large granular lymphocyte leukaemia and associated cytopenias.
abstract: 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-alpha (-308G/A), TGF-beta1 (codons 10 C/T, 25 G/C), IL-10 (-1082 G/A), IL-6 (-174 C/G), and IFN-gamma(+874 T/A). A statistically significant increase in A/A genotype for TNF-alpha-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.
authors.affiliation: Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clnic, Cleveland, OH, USA.
authors.forename: Zachary P
authors.initials: ZP
authors.lastname: Nearman
authors.forename: Marcin
authors.initials: M
authors.lastname: Wlodarski
authors.forename: Anna M
authors.initials: AM
authors.lastname: Jankowska
authors.forename: Evan
authors.initials: E
authors.lastname: Howe
authors.forename: Yadira
authors.initials: Y
authors.lastname: Narvaez
authors.forename: Edward
authors.initials: E
authors.lastname: Ball
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000235:genetics; D000943:Antigens, Differentiation / Q000235:genetics; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D016207:Cytokines / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D005787:Gene Frequency; D005838:Genotype; D015395:Histocompatibility Antigens Class I; D006801:Humans; D007125:Immunogenetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D016130:Immunophenotyping; D015458:Leukemia, T-Cell / Q000235:genetics / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000235:genetics; D008024:Ligands; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018121:Receptors, Cytokine / Q000235:genetics; D017452:Receptors, IgG / Q000235:genetics; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054347:Receptors, KIR3DL2; D018709:Statistics, Nonparametric; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; C496124:FCGR3A protein, human; D015395:Histocompatibility Antigens Class I; D007135:Immunoglobulin Variable Region; C515084:KIR3DL2 protein, human; D008024:Ligands; D018121:Receptors, Cytokine; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054347:Receptors, KIR3DL2; D014409:Tumor Necrosis Factor-alpha; D017493:Leukocyte Common Antigens