Summary Immunological responses are increasingly recognised as being important in the initiation and progression of myelodysplastic syndrome (MDS). Indeed, autoimmune diseases commonly occur in association with MDS, particularly in subtypes with a low risk of leukaemic transformation. This study showed for the first time that the numbers of CD3+ CD4+ IL‐17 producing T cells (Th17) were markedly increased in low risk MDS compared with high risk MDS (P < 0·01). An inverse relationship between the numbers of Th17 cells and naturally occurring CD4+CD25high FoxP3+ regulatory T cells (Tregs) were also described. The Th17:Tregs ratio was significantly higher in low risk disease (P < 0·005) compared with high risk MDS and was correlated with increased bone marrow (BM) apoptosis (P < 0·01). Tregs from MDS patients suppressed interferon‐γ (IFN‐γ) secretion by effector CD4+ T cells but had no effect on interleukin (IL)‐17 production. In addition, the serum levels of IL‐7, IL‐12, RANTES and IFN‐γ are significantly elevated in low risk MDS, while inhibitory factors, such as IL‐10 and soluble IL‐2 receptor, are significantly higher in high risk disease. The ‘unfavourable’ Th17:Tregs ratio in low risk MDS may explain the higher risk of autoimmunity and the improved response to immune suppression in patients with low risk MDS compared to those with high risk disease.

The molecular mechanisms underlying the development and evolution of myelodysplastic syndrome (MDS) are largely unknown. The increasing number of blast cells in the bone marrow correlate with poor prognosis and risk of developing acute leukemia. Such progression is frequently associated with increasing chromosomal abnormalities and genetic mutations. A cohort of 75 MDS patients were investigated for RAS, FMS and p53 mutations, and these molecular findings were related to cytogenetics, clinical status, transformation to acute leukemia, prognostic scores and survival. A mutation incidence of 57% (43/75) was found, with 48% (36/75) RAS mutations, 12% (9/75) FMS mutations and 8% (4/50) p53 mutations. The mutation status for RAS and FMS was related to MDS subgroup, increasing with poor-risk disease. The highest incidence was in the chronic myelomonocytic leukemia (CMML) subgroup. The most frequent RAS mutations were of codon 12 and a predominance of FMS codon 969 mutations was observed. A statistically significant increased frequency of transformation to AML was observed in MDS patients harboring RAS or FMS mutations (P Ͻ 0.02). Patients with oncogene mutations had a significantly poorer survival compared with those without mutations at 2 years and at the end of the period of follow-up (P Ͻ 0.02). Multivariate analysis including mutation, age, gender, diagnosis (FAB), cytogenetics and International score shows that the International score and mutation and age is the best predictive model of a poor outcome, (P Ͻ0.0001). When the analysis was undertaken without the International score, mutation and gender was the best predictor of poor survival (P = 0.005). This study shows that oncogene mutation, indicative of genetic instability, is associated with disease progression and poor survival in MDS.

The activation of T cells plays a central role in antitumor immunity. In order to activate naïve T cells, two key signals are required. Signal one is provided through the T-cell receptor (TCR) while signal two is that of costimulation. The CD28:B7 molecules are one of the best-studied costimulatory pathways, thought to be the main mechanism through which primary T-cell stimulation occurs. However, a number of molecules have been identified which serve to amplify and diversify the T-cell response, following initial Tcell activation. These include the more recently described 4-1BB:4-1BB ligand (4-1BBL) molecules. 4-1BB:4-1BBL are a member of the TNFR:TNF ligand family, which are expressed on T cells and antigen-presenting cells (APCs), respectively. Therapies utilizing the 4-1BB:4-1BBL signaling pathway have been shown to have antitumor effects in a number of model systems. In this paper, we focus on the 4-1BB:4-1BBL costimulatory molecules. In particular, we will describe the structure and function of the 4-1BB molecule, its receptor and how 4-1BB:4-1BBL costimulation has and may be used for the immunotherapy of cancer.

ObjectiveLate diagnosis of Alzheimer’s disease (AD) may be due to diagnostic uncertainties. We aimed to determine the sequence and timing of the appearance of established early signs and symptoms in people who are subsequently diagnosed with AD.MethodsWe used systematic review methodology to investigate the existing literature. Articles were reviewed in May 2016, using the following databases: MEDLINE, PsycINFO, CINAHL, British Nursing Index, PubMed central and the Cochrane library, with no language restriction. Data from the included articles were extracted independently by two authors and quality assessment was undertaken with the quality assessment and diagnostic accuracy tool-2 (QUADAS tool-2 quality assessment tool).ResultsWe found that depression and cognitive impairment were the first symptoms to appear in 98.5% and 99.1% of individuals in a study with late-onset AD (LOAD) and 9% and 80%, respectively, in early-onset AD (EOAD). Memory loss presented early and was experienced 12 years before the clinically defined AD dementia in the LOAD. However, the rapidly progressive late-onset AD presented predominantly with 35 non-established focal symptoms and signs including myoclonus (75%), disturbed gait (66%) and rigidity. These were misdiagnosed as symptoms of Creutzfeldt-Jacob disease (CJD) in all the cases. The participant with the lowest mini-mental state examination score of 25 remained stable for 2 years, which is consistent with the score of the healthy family members.ConclusionsThe findings of this review suggest that neurological and depressive behaviours are an early occurrence in EOAD with depressive and cognitive symptoms in the measure of semantic memory and conceptual formation in LOAD. Misdiagnosis of rapidly progressive AD as CJD and the familial memory score can be confounding factors while establishing a diagnosis. However, the study was limited by the fact that each one of the findings was based on a single study.