Cross-Presentation: How to Get there – or How to Get the ER

Antigen cross-presentation enables dendritic cells (DCs) to present extracellular antigens on major histocompatibility complex (MHC) I molecules, a process that plays an important role in the induction of immune responses against viruses and tumors and in the induction of peripheral tolerance. In order to allow intracellular processing for cross-presentation, internalized antigens are targeted by distinct endocytic receptors toward specific endosomal compartments, where they are protected from rapid lysosomal degradation. From these compartments, antigens are processed for loading onto MHC I molecules. Such processing generally includes antigen transport into the cytoplasm, a process that is regulated by members of the ER-associated degradation (ERAD) machinery. After proteasomal degradation in the cytoplasm, antigen-derived peptides have been shown to be re-imported into the same endosomal compartment by endosomal transporter associated with antigen processing, another ER protein, which is recruited toward the endosomes after DC maturation. In our review, we highlight the recent advances on the molecular mechanisms of cross-presentation. We focus on the necessity of such antigen storage compartments and point out important parallels to MHC I-restricted presentation of endogenous antigens. We discuss the composition of such endosomes and the targeting of extracellular antigens into this compartment by specific endocytic receptors. Finally, we highlight recent advances on the recruitment of the cross-presentation machinery, like the members of the MHC I loading complex and the ERAD machinery, from the ER toward these storage compartments, a process that can be induced by antigen encounter or by activation of the dendritic cell after contact with endotoxins

Traumatic Encephalopathy Syndrome and Tauopathy in a 19-Year-Old With Child Abuse

The majority of traumatic encephalopathy syndrome (TES) cases have been reported in former contact sport athletes. This is the first case with TES in a 19-year-old male patient with progressive cognitive decline after daily domestic physical violence through repeated hits to the head for 15 years. The patient presented with a moderate depressive episode and progressive cognitive decline. Tau positron emission tomography (PET) with 220 MBq of [18F]PI-2620 revealed increased focal signal at the frontal and parietal white/gray matter border. Brain magnetic resonance imaging (MRI) showed a cavum septum pellucidum, reduced left-sided hippocampal volume, and a left midbrain lesion. Cerebrospinal fluid results showed elevated total and p-tau. Neurocognitive testing at admission showed memory deficits clearly below average, and hampered dysfunctions according to the slow processing speed with a low mistake rate, indicating the acquired, thus secondary, attentional deficits. We diagnosed the patient with a TES suggestive of chronic traumatic encephalopathy and classified him as having subtle/mild functional limitation with a most likely transition to mild dementia within the TES criteria. This report underlines child abuse as a relevant criterion in diagnosing TES in cases with repetitive hits to the head. In addition to clinical markers, we show the relevance of fluid tau biomarkers and tau-PET to support the diagnosis of TES according to the recently published diagnosis criteria for TES

Mutations and Deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascades Which Alter Therapy Response

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Certain components of these pathways, RAS, NF1, BRAF, MEK1, DUSP5, PP2A, PIK3CA, PIK3R1, PIK3R4, PIK3R5, IRS4, AKT, NFKB1, MTOR, PTEN, TSC1, and TSC2 may also be activated/inactivated by mutations or epigenetic silencing. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of these cascades can contribute to: resistance to other pathway inhibitors, chemotherapeutic drug resistance, premature aging as well as other diseases. This review will first describe these pathways and discuss how genetic mutations and epigenetic alterations can result in resistance to various inhibitors

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

Purpose By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). Methods We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. Results We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. Conclusion The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS