Immunology of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) leading to demyelination, axonal damage, and progressive neurologic disability. The development of MS is influenced by environmental factors, particularly the Epstein-Barr virus (EBV), and genetic factors, which include specific HLA types, particularly DRB1*1501-DQA1*0102-DQB1*0602, and a predisposition to autoimmunity in general. MS patients have increased circulating T-cell and antibody reactivity to myelin proteins and gangliosides. It is proposed that the role of EBV is to infect autoreactive B cells that then seed the CNS and promote the survival of autoreactive T cells there. It is also proposed that the clinical attacks of relapsing-remitting MS are orchestrated by myelin-reactive T cells entering the white matter of the CNS from the blood, and that the progressive disability in primary and secondary progressive MS is caused by the action of autoantibodies produced in the CNS by ­meningeal lymphoid follicles with germinal centers

Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort

Background Individuals with rare kidney diseases account for 5–10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure. Methods People aged 0–96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan–Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 m2 (the therapeutic trial window). Findings Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9–16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<0·0001), but better survival rates (standardised mortality ratio 0·42 [95% CI 0·32–0·52]; p<0·0001). Median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window all varied substantially between rare diseases. Interpretation Patients with rare kidney diseases differ from the general population of individuals with chronic kidney disease: they have higher 5-year rates of kidney failure but higher survival than other patients with chronic kidney disease stages 3–5, and so are over-represented in the cohort of patients requiring kidney replacement therapy. Addressing unmet therapeutic need for patients with rare kidney diseases could have a large beneficial effect on long-term kidney replacement therapy demand. Funding RaDaR is funded by the Medical Research Council, Kidney Research UK, Kidney Care UK, and the Polycystic Kidney Disease Charity

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Potentialités de la télédetection rapprochée dans les domaines optique et thermique pour la cartographie d'attaques parasitaires sur culture

National audienc

Agglomeration and transport of drilling generated particles in the oil well

The challenge presented by IRIS was to develop a better understanding of agglomeration and transport of cuttings generated during the drilling of an oil well. There is a myriad of challenges involved in the mathematical modelling of this complex process. For this reason, two complementary approaches are combined in this report. First, we derive a one-dimensional fully-developed model based on the Phillips-type shear induced diffusive migration. We start by assuming a Newtonian nature of the suspending drilling mud, but an extension to account for a non-Newtonian rheology is proposed herein. Second, a direct numerical simulation approach is employed to predict settling rates of drilling cuts when the assumptions made in Part 1 break down and when complex geometries are taken into account. When drilling an oil well, rock cuttings are generated and must be transported to the surface for disposal. For this purpose, drilling fluid (or 'mud') is pumped down inside the drill pipe and exits at the drill bit. There, the drilling fluid combines with the rock cuttings whereupon both are transported through the annulus of the well back to the surface. The cuttings are then separated from the mud as required. This basic process is made complicated by a number of factors. First, the rheology of the drilling fluid is non- Newtonian. Although drilling fluid is normally oil-based or water-based, particles are added to give it a non-Newtonian (shear-thinning) rheology, so as to enhance the transport of the mixture of drilling fluid and cuttings to the surface. Secondly, an oilwell may have significant inclination ('directional wells'), meaning that the cuttings can 'settle' at the bottom of the annulus, forming a 'cuttings bed' potentially leading to clogging of the well. Finally, the drilling is a transient operation characterized by frequent start-ups and shutdowns: typically, the drilling is halted periodically to enable strands of drill pipe to be added as the well grows longer. Frequent shut-downs promote settling and therefore contribute to cuttings-bed formation. The fundamental problem addressed in this Report is to develop a physics-based understanding of the cuttings bed. From a practical aspect this is crucial, as poor control of cuttings may cause critical situations and a loss of the well. In this work, two complementary approaches are taken. In the first approach ("Theoretical Modelling", Part 1), a continuum theory is formulated on the basis that a mixture of drilling fluid and cuttings can be treated in a fluid-mechanical framework. Existing methods concerning dense suspensions can then be applied (and improved as necessary) to predict settling rates as a function of input parameters. For small cutting sizes, such an approach is justified. However, for larger cutting sizes (e.g. rock cuttings comparable to the size of the annular region of the flow domain), such a continuum theory will inevitably break down. To understand the transport processes in this limit, direct numerical simulation is proposed (Part 2). Sample simulations using the freely available OpenFoam fluid solver are presented and future work to improve and refine the computational model is discussed

Confirmation of a second locus for CMT2 and evidence for additional genetic heterogeneity

The Charcot-Marie-Tooth (CMT) neuropathies are a group of disorders exhibiting neurophysical, pathological and genetic heterogeneity. CMT2 is a diagnostic subtype of this group of disorders characterized by variable expression and age-of-onset and normal or slightly diminished nerve conduction velocities. Previously, linkage and heterogeneity had been reported in CMT2 with linked families localizing to chromosome 1p (CMT2A). Recently a second CMT2 locus has been described on chromosome 7 in a single large CMT2 family (CMT2D). We have performed pedigree linkage analysis on 15 CMT2 families (N = 371 individuals, 106 affected family members) and have confirmed linkage to chromosome 7. Furthermore, using both admixture and multipoint linkage analysis we show conclusive evidence for additional heterogeneity within this clinical subtype with evidence of families that exclude linkage to both the CMT2D and CMT2A regions. In addition, unlike the previous report we found no abvious consistend clinical differences between the linked family types