Impairment of organ-specific T cell negative selection by diabetes susceptibility genes: genomic analysis by mRNA profiling

BACKGROUND T cells in the thymus undergo opposing positive and negative selection processes so that the only T cells entering circulation are those bearing a T cell receptor (TCR) with a low affinity for self. The mechanism differentiating negative from positive selection is poorly understood, despite the fact that inherited defects in negative selection underlie organ-specific autoimmune disease in AIRE-deficient people and the non-obese diabetic (NOD) mouse strain RESULTS Here we use homogeneous populations of T cells undergoing either positive or negative selection in vivo together with genome-wide transcription profiling on microarrays to identify the gene expression differences underlying negative selection to an Aire-dependent organ-specific antigen, including the upregulation of a genomic cluster in the cytogenetic band 2F. Analysis of defective negative selection in the autoimmune-prone NOD strain demonstrates a global impairment in the induction of the negative selection response gene set, but little difference in positive selection response genes. Combining expression differences with genetic linkage data, we identify differentially expressed candidate genes, including Bim, Bnip3, Smox, Pdrg1, Id1, Pdcd1, Ly6c, Pdia3, Trim30 and Trim12. CONCLUSION The data provide a molecular map of the negative selection response in vivo and, by analysis of deviations from this pathway in the autoimmune susceptible NOD strain, suggest that susceptibility arises from small expression differences in genes acting at multiple points in the pathway between the TCR and cell death.This work was supported by grants from the NHMRC and the Juvenile Diabetes Research Foundation

Diagnosis, treatment and survival from bladder, upper urinary tract and urethral cancers: Real world findings from NHS England between 2013 and 2019

Objective We report NHS England data for patients with bladder cancer (BC), upper tract urothelial cancer (UTUC: renal pelvic and ureteric), and urethral cancers from 2013 to 2019. Materials and Methods Hospital episode statistics, waiting times, and cancer registrations were extracted from NHS Digital. Results Registrations included 128 823 individuals with BC, 16 018 with UTUC, and 2533 with urethral cancer. In 2019, 150 816 persons were living with a diagnosis of BC, of whom 113 067 (75.0%) were men, 85 117 (56.5%) were aged >75 years, and 95 553 (91.7%) were Caucasian. Incidence rates were stable (32.7–34.3 for BC, 3.9–4.2 for UTUC and 0.6–0.7 for urethral cancer per 100 000 population). Most patients 52 097 (mean [range] 41.3% [40.7–42.0%]) were referred outside the 2-week-wait pathway and 15 340 (mean [range] 12.2% [11.7–12.6%]) presented as emergencies. Surgery, radiotherapy, chemotherapy, or multimodal treatment use varied with disease stage, patient factors and Cancer Alliance. Between 27% and 29% (n = 6616) of muscle-invasive BCs did not receive radical treatment. Survival rates reflected stage, grade, location, and tumour histology. Overall survival rates did not improve over time (relative change: 0.97, 95% confidence interval 0.97–0.97) at 2 years in contrast to other cancers. Conclusion The diagnostic pathway for BC needs improvement. Increases in survival might be delivered through greater use of radical treatment. NHS Digital data offers a population-wide picture of this disease but does not allow individual outcomes to be matched with disease or patient features and key parameters can be missing or incomplete

Achieving benchmarks for national quality indicators reduces recurrence and progression in non-muscle-invasive bladder cancer

Background Noncompliance with evidence-based interventions and guidelines contributes to significant and variable recurrence and progression in patients with non–muscle-invasive bladder cancer (NMIBC). The implementation of a quality performance indicator (QPI) programme in Scotland’s National Health Service (NHS) aimed to improve cancer outcomes and reduce nationwide variance. Objective To evaluate the effect of hospitals achieving benchmarks for two specific QPIs on time to recurrence and progression in NMIBC. Design, setting, and participants QPIs for bladder cancer (BC) were enforced nationally in April 2014. NHS health boards collected prospective data on all new BC patients. Prospectively recorded surveillance data were pooled from 12 collaborating centres. Intervention QPIs of interest were (1) hospitals achieving detrusor muscle (DM) sampling target at initial transurethral resection of bladder tumour (TURBT) and (2) use of single instillation of mitomycin C after TURBT (SI-MMC). Outcome measurements and statistical analysis The primary and secondary endpoints were time to recurrence and progression, respectively. Kaplan-Meier and Cox multivariable regression analyses were performed. Key findings and limitations Between April 1, 2014 and March 31, 2017, we diagnosed 3899 patients with new BC, of which 2688 were NMIBC . With a median follow up of 60.3 mo, hospitals achieving the DM sampling target had a 5.4% lower recurrence rate at 5 yr than hospitals not achieving this target (442/1136 [38.9%] vs 677/1528 [44.3%], 95% confidence interval [CI] = 1.6–9.2, p = 0.005). SI-MMC was associated with a 20.4% lower recurrence rate (634/1791 [35.4%] vs 469/840 [55.8%], 95% CI = 16.4–24.5, p < 0.001). On Cox multivariable regression, meeting the DM target and SI-MMC were associated with significant improvement in recurrence (hazard ratio [HR] 0.81, 95% CI = 0.73–0.91, p = 0.0002 and HR 0.66, 95% CI = 0.59–0.74, p < 0.004, respectively) as well as progression-free survival (HR 0.62, 95% CI = 0.45–0.84, p = 0.002 and HR 0.65, 95% CI = 0.49–0.87, p = 0.004, respectively). We did not have a national multicentre pre-QPI control. Conclusions Within a national QPI programme, meeting targets for sampling DM and SI-MMC in the real world were independently associated with delays to recurrence and progression in NMIBC patients. Patient summary Following the first 3 yr of implementing a novel quality performance indicator programme in Scotland, we evaluated compliance and outcomes in non–muscle-invasive bladder cancer. In 2688 patients followed up for 5 yr, we found that achieving targets for sampling detrusor muscle and the single instillation of mitomycin C during and after transurethral resection of bladder tumour, respectively, were associated with delays in cancer recurrence and progression

The why and how of thymocyte negative selection

The generation of T cell receptor (TCR) sequence diversity is the strength of adaptive immunity, yet is also the Achilles' heel. To purge highly self-reactive T cells from the immune system, generation of diversity has coevolved with a mechanism of negative selection. Recent studies have revealed new insights addressing the why and how of negative selection by examining situations in which negative selection has failed in human and animals models of autoimmunity. Both thymocyte extrinsic and intrinsic mechanisms are required to restrict the TCR repertoire to a non-autoreactive set. Negative selection also ensures that T cells emerge with receptors that are focussed on the peptide moiety of MHC-peptide complexes

Genetic control of T cell immune tolerance mechanisms and susceptibility to autoimmune disease

The majority of human autoimmune diseases have a complex aetiology with strong genetic and environmental components. The genetic component of disease susceptibility is generally highly polygenic, with multiple loci acting synergistically, and genetically heterogenous, with diverse sets of polymorphic loci capable of driving the same autoimmune reaction. The genetics of autoimmunity is further complicated by the division of genetic susceptibility into general autoimmune propensity polymorphisms and disease-specific polymorphisms. Despite the complexity of autoimmune genetics at the locus level, it appears that a limited number of conserved mechanistic pathways are affected by genetic polymorphisms. The conserved tolerance pathways subverted by autoimmune polymorphisms are being unravelled by the analysis of mouse models of autoimmunity. These models have identified three key fragile links in the T cell tolerance pathway-antigen presentation and the apoptotic response in the thymus, cis-and transacting peripheral suppression of autoreactive T cells, and the target organ response to autoimmunity. © 2008 Nova Science Publishers, Inc. All rights reserved.status: publishe