The role of CD8+ T cell clones in immune thrombocytopenia

Immune thrombocytopenia (ITP) is traditionally considered an antibody-mediated disease. However, a number of features suggest alternative mechanisms of platelet destruction. In this study, we use a multi-dimensional approach to explore the role of cytotoxic CD8+ T cells in ITP. We characterised patients with ITP and compared them to age-matched controls using immunophenotyping, next-generation sequencing of T cell receptor (TCR) genes, single-cell RNA sequencing, and functional T cell and platelet assays. We found that adults with chronic ITP have increased polyfunctional, terminally differentiated effector memory CD8+ T cells (CD45RA+CD62L-) expressing intracellular interferon-g, tumour necrosis factor-a, and Granzyme B defining them as TEMRA cells. These TEMRA cells expand when the platelet count falls and show no evidence of physiological exhaustion. Deep sequencing of the T cell receptor showed expanded T cell clones in patients with ITP. T cell clones persisted over many years, were more prominent in patients with refractory disease, and expanded when the platelet count was low. Combined single-cell RNA and TCR sequencing of CD8+ T cells confirmed that the expanded clones are TEMRA cells. Using in vitro model systems, we show that CD8+ T cells from patients with ITP form aggregates with autologous platelets, release interferon-g and trigger platelet activation and apoptosis through TCR-mediated release of cytotoxic granules. These findings of clonally expanded CD8+ T cells causing platelet activation and apoptosis provide an antibody-independent mechanism of platelet destruction, indicating that targeting specific T-cell clones could be a novel therapeutic approach for patients with refractory ITP

Psychotic experiences in people who have been sexually assaulted

Objective In recent years, there has been a call for greater awareness of the relationship between trauma and psychosis, and several studies involving patients with psychotic disorders have found a link between traumatic life experience and the development of psychosis. However, little research has examined psychotic experiences in a traumatised population. Method This study investigated psychotic experiences in a sample of 40 survivors of sexual assault (SA) compared to a control group without a history of sexual assault (measured using a self-report questionnaire) and examined the psychological factors that may contribute to the development of psychotic experiences in sexually traumatised individuals. In particular, the role of dissociation and cognitive factors such as post-traumatic cognitions were explored. Results Of the 26 sexually assaulted participants that were interviewed, 46% reported auditory hallucinations and 46% reported visual hallucinations. A significantly higher rate of psychotic phenomena (delusional ideation and predisposition to hallucinations) was found in the sexually assaulted group compared to the control group. Severity of SA trauma was significantly associated with severity of PTSD and psychotic symptomatology. Dissociation was strongly associated with all measures of psychotic phenomena and negative cognitions about the self and the world were associated with predisposition to hallucinations and delusional ideation. Regression analyses revealed that after controlling for the severity of SA trauma, dissociation and negative beliefs about the self significantly predicted delusional distress, and dissociation significantly predicted predisposition to visual hallucinations. Conclusions These exploratory findings support the idea that psychotic phenomena may be caused by traumatic life experiences and highlight the need for further research. The implications of these results for research and clinical practice are discussed

Defining the role of common variation in the genomic and biological architecture of adult human height

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants