A divergent autoantigen-responsive CD4⁺T cell population is present in infancy, before autoimmunity in type 1 diabetes.

Longitudinal monitoring of BCR-ABL transcript levels in peripheral blood of CML patients treated with tyrosine kinase inhibitors (TKI) revealed a typical biphasic response. Although second generation TKIs like dasatinib proved more efficient in achieving molecular remission compared to first generation TKI imatinib, it is unclear how individual responses differ between the drugs and whether mechanisms of drug action can be deduced from the dynamic data. We use time courses from the DASISION trial to address statistical differences in the dynamic response between first line imatinib vs. dasatinib treatment cohorts and we analyze differences between the cohorts by fitting an established mathematical model of functional CML treatment to individual time courses. On average, dasatinib-treated patients show a steeper initial response, while the long-term response only marginally differed between the treatments. Supplementing each patient time course with a corresponding confidence region, we illustrate the consequences of the uncertainty estimate for the underlying mechanisms of CML remission. Our model suggests that the observed BCR-ABL dynamics may result from different, underlying stem cell dynamics. These results illustrate that the perception and description of CML treatment response as a dynamic process on the level of individual patients is a prerequisite for reliable patient-specific response predictions and treatment optimizations.

Plasmacytoid dendritic cells (pDCs) regulate innate and adaptive immunity. Neurotrophins and their receptors control the function of neuronal tissue. In addition, they have been demonstrated to be part of the immune response but little is known about the effector immune cells involved. We report, for the first time, the expression and immune-regulatory function of the low affinity neurotrophin receptor p75NTR by the antigen-presenting plasmacytoid dendritic cells (pDCs), mediated by Toll-like receptor (TLR) 9 activation and differential phosphorylation of interferon regulatory factor (IRF) 3 and 7. The modulation of p75NTR on pDCs significantly influences disease progression of asthma in an ovalbumin-induced mouse model mediated by the TLR9 signaling pathway. p75NTR activation of pDCs from patients with asthma increased allergen-specific T cell proliferation and cytokine secretion in NGF concentration dependent manner. Further, p75NTR activation of pDCs delayed the onset of autoimmune diabetes in RIP-CD80GP mice and aggravated Graft-versus-Host disease in a xenotransplantation model. Thus, p75NTR signaling on pDCs constitutes a new and critical mechanism connecting neurotrophin signaling and immune response regulation with great therapeutic potential for a variety of immune disorders.

The pathogenesis of ocular adnexal marginal zone lymphomas of mucosa-associated lymphatic tissue-type (OAML) is not fully understood. We performed whole genome sequencing (WGS) and/or whole exome sequencing (WES) for 13 cases of OAML and sequenced 38 genes selected from this analysis in a large cohort of 82 OAML. Besides confirmation of frequent mutations in the genes transducin beta like 1 X-linked receptor 1 (TBL1XR1) and cAMP response element binding protein (CREBBP), we newly identifed JAK3 as a frequently mutated gene in OAML (11% of cases). In our retrospective cohort, JAK3 mutant cases had a shorter progression-free survival compared with unmutated cases. Other newly identified genes recurrently mutated in 5–10% of cases included members of the collagen family (collagen type XII alpha 1/2 (COL12A1, COL1A2)) and DOCK8. Evaluation of the WGS data of six OAML did not reveal translocations or a current infection of the lymphoma cells by viruses. Evaluation of the WGS data for copy number aberrations confirmed frequent loss of TNFAIP3, and revealed recurrent gains of the NOTCH target HES4, and of members of the CEBP transcription factor family. Overall, we identified several novel genes recurrently affected by point mutations or copy number alterations, but our study also indicated that the landscape of frequently (>10% of cases) mutated protein-coding genes in OAML is now largely known.

BACKGROUND AND PURPOSE: Detection and evaluation of ruptured aneurysms is critical for choosing an appropriate endovascular or neurosurgical intervention. Our aim was to assess whether bone-subtraction CTA is capable of guiding treatment for cerebral aneurysms in patients with acute SAH and could replace DSA. MATERIALS AND METHODS: We prospectively studied 116 consecutive patients with SAH with 16–detector row bone-subtraction CTA and DSA before intracranial aneurysm treatment. Two independent neuroradiologists reviewed the bone-subtraction CTA blinded to DSA (reference standard). We determined the accuracy of bone-subtraction CTA for aneurysm detection and the measurement of aneurysm dimensions and compared the radiation doses of the 2 imaging modalities. RESULTS: Seventy-one patients (61%) had 74 aneurysms on DSA. Bone-subtraction CTA detected 73 of these aneurysms, but it detected 1 additional aneurysm. On a per-aneurysm basis, sensitivity, specificity, and positive and negative predictive values for bone-subtraction CTA were 99%, 98%, and 99% and 98%, respectively. For aneurysms of ≤3 mm, sensitivity was 94% (95% CI, 73%–99%). Bone-subtraction CTA slightly overestimated neck and dome diameters by <0.2 mm and overestimated the dome-to-neck ratios by 2% on average. Dose-length product was 565 ± 201 mGy × cm for bone-subtraction CTA and 1609 ± 1300 mGy × cm for DSA. CONCLUSIONS: Bone-subtraction CTA is as accurate as DSA in detecting cerebral aneurysms after SAH, provides similar information about aneurysm configuration and measures, and reduces the average effective radiation dose for vascular diagnostics by 65%. Diagnostic equivalence in association with dose reduction suggests replacing DSA with bone-subtraction CTA in the diagnostic work-up of spontaneous SAH.