No Overt Clinical Immunodeficiency Despite Immune Biological Abnormalities in Patients With Constitutional Mismatch Repair Deficiency

Transplantation and immunomodulatio

New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Remote monitoring of short-term body mass variation in savanna ungulates

Large herbivores in seasonal environments often experience mass variation due to temporal changes in the availability of critical resources like water and forage, as well as due to breeding events. Yet the documentation of mass variation in mammals of highly seasonal savanna habitats, which host the highest densities of grazing ungulates globally, has rarely been explored. Here, we showcase a method to evaluate seasonal mass variation in bovids. Our method used mineral-baited scales and camera traps to enable us to track the body mass of three species through a period of wet and dry seasons in a South African savanna ecosystem. To illustrate one potential application of the method, we related body mass data to time, weather and resource availability. This showed that individuals altered their body masses markedly between seasons with, for example, female Kudu (Tragelaphus strepsiceros) gaining, on average, >21 kg over the 15-week wet-season period in one year. These changes were positively related to factors such as vegetation productivity (assessed using NDVI) and the frequency of rains. This method enables easy, non-lethal and non-invasive acquisition of mass data. The equipment is easy to deploy concurrently over large areas. Monitoring by this method has a variety of possible applications, potentially providing a useful early-warning indicator of body condition to inform management, or providing information about ecological states, such as parturition or the reproductive effort of males. Given the longer and harsher dry seasons experienced in many arid systems in recent decades, and projected in future, this method may provide a straightforward means of monitoring long-term body condition in animals as a result of environmental change

Xenotropic and polytropic retrovirus receptor 1 regulates procoagulant platelet polyphosphate.

Polyphosphate is a procoagulant inorganic polymer of linear-linked orthophosphate residues. Multiple investigations have established the importance of platelet polyphosphate in blood coagulation; however, the mechanistic details of polyphosphate homeostasis in mammalian species remain largely undefined. In this study, xenotropic and polytropic retrovirus receptor 1 (XPR1) regulated polyphosphate in platelets and was implicated in thrombosis in vivo. We used bioinformatic analyses of omics data to identify XPR1 as a major phosphate transporter in platelets. XPR1 messenger RNA and protein expression inversely correlated with intracellular polyphosphate content and release. Pharmacological interference with XPR1 activity increased polyphosphate stores, led to enhanced platelet-driven coagulation, and amplified thrombus formation under flow via the polyphosphate/factor XII pathway. Conditional gene deletion of Xpr1 in platelets resulted in polyphosphate accumulation, accelerated arterial thrombosis, and augmented activated platelet-driven pulmonary embolism without increasing bleeding in mice. These data identify platelet XPR1 as an integral regulator of platelet polyphosphate metabolism and reveal a fundamental role for phosphate homeostasis in thrombosis

Potential BSE risk posed by the use of ruminant collagen and gelatine in feed for non-ruminant farmed animals

EFSA was requested to estimate the cattle bovine spongiform encephalopathy (BSE) risk (C-, L- and H-BSE) posed by ruminant collagen and gelatine produced from raw material fit for human consumption, or from material classified as Category 3 animal by-products (ABP), to be used in feed intended for non-ruminant animals, including aquaculture animals. Three risk pathways (RP) were identified by which cattle could be exposed to ruminant feed cross-contaminated with ruminant collagen or gelatine: 1) recycled former foodstuffs produced in accordance with Regulation (EC) No 853/2004 (RP1), 2) technological or nutritional additives or 3) compound feed, produced either in accordance with Regulation (EC) No 853/2004 (RP2a) or Regulation (EU) No 142/2011 (RP2b). A probabilistic model was developed to estimate the BSE infectivity load measured in cattle oral ID50 (CoID50)/kg, in the gelatine produced from the bones and hide of one infected animal older than 30 months with clinical BSE (worst-case scenario). The amount of BSE infectivity (50th percentile estimate) in a member state (MS) with negligible risk status was 7.6  7 10\u20132 CoID50/kg, and 3.1  7 10\u20134 CoID50/kg in a MS with controlled risk status. The assessment considered the potential contamination pathways and the model results (including uncertainties) regarding the current epidemiological situation in the EU and current statutory controls. Given the estimated amount of BSE infectivity to which cattle would be exposed in a single year, and even if all the estimated undetected BSE cases in the EU were used for the production of collagen or gelatine (either using raw materials fit for human consumption or Category 3 ABP raw materials), it was concluded that the probability that no new case of BSE in the cattle population would be generated through any of the three RP is 99\u2013100% (almost certain)