Immune mechanisms are involved in the pathophysiology of aplastic anemia (AA) and myelodysplastic syndrome (MDS) .

In myelodysplastic syndromes (MDS) increased chromosomal breaks point toward defects in DNA repair machinery including base excision repair (BER) pathway involved in handling of oxidative DNA damage. We investigated whether defects in this pathway can be found in MDS. Elevated levels of 8-oxoguanine (8-OG) were found in a significant proportion of MDS patients, indicating increased oxidative DNA damage or defective handling of oxidative load. In a distinct subgroup of patients, increased 8-OG content was associated with increased hOGG1 mRNA expression and activity. In some patients, increased numbers of abasic sites (AP sites) correlated with low levels of POLb. To further investigate the nature of this defect, we examined genetic lesions potentially explaining accumulation of 8-OG and AP sites. We genotyped a large cohort of MDS patients and found a correlation between increased oxidative damage and the presence of the hOGG1-Cys326 allele suggesting inadequate compensatory feedback. Overall, this hOGG1 variant was more frequent in MDS, particularly in advanced forms, as compared to controls. In summary, we demonstrated that BER dysfunction in some MDS patients may be responsible for the increased 8-OG incorporation and explains one aspect of the propensity to chromosomal breaks in MDS but other mechanisms may also be involved.

T cell large granular lymphocyte leukemia (T-LGL) is a chronic clonal lymphoproliferation of CTL. In many ways, T-LGL clones resemble terminal effector CTL, including down-modulation of CD28 and overexpression of perforin, granzymes, and CD57. We studied the transcriptome of T-LGL clones and compared it with healthy CD8+CD57+ effector cells as well as CD8+CD57− populations. T-LGL clones were sorted based on their TCR variable β-chain restriction, and controls were obtained by pooling cell populations from 14 donors. Here, we focus our analysis on immunological networks, as immune mechanisms play a prominent role in the etiology of bone marrow failure in T-LGL. Informative genes identified by expression arrays were studied further in an independent cohort of patients using Taqman PCR, ELISA assays, and FACS analysis. Despite a strikingly similar gene expression profile between T-LGL clones and their healthy counterparts, important phenotypic differences were identified, including up-modulation of TNFRS9, myeloid cell leukemia sequence 1, IFN-γ, and IFN-γ-related genes, and several integrins/adhesion molecules. In addition, T-LGL clones were characterized by an overexpression of chemokines and chemokine receptors that are typically associated with viral infections (CXCL2, Hepatitis A virus cellular receptor 1, IL-18, CCR2). Our studies suggest that immunodominant LGL clones, although phenotypically similar to effector CTL, show significantly altered expression of a number of genes, including those associated with an ongoing viral infection or chronic, antigen-driven immune response.

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.