Macleod, C. | bioRxiv Science

bioRxiv2018

The global burden of trichiasis in 2016

BackgroundTrichiasis is present when one or more eyelashes touches the eye. Uncorrected, it can cause blindness. Accurate estimates of numbers affected, and their geographical distribution, help guide resource allocation.\n\nMethodsWe obtained district-level trichiasis prevalence estimates for 44 endemic and previously-endemic countries. We used (1) the most recent data for a district, if more than one estimate was available; (2) age- and sex-standardized corrections of historic estimates, where raw data were available; (3) historic estimates adjusted using a mean adjustment factor for districts where raw data were unavailable; and (4) expert assessment of available data for districts for which no prevalence estimates were available.\n\nFindingsInternally age- and sex-standardized data represented 1,355 districts and contributed 662 thousand cases (95% confidence interval [CI] 324 thousand-1.1 million) to the global total. age- and sex-standardized district-level prevalence estimates differed from raw estimates by a mean factor of 0.45 (range 0.03-2.28). Previously non-standardized estimates for 398 districts, adjusted by x0.45, contributed a further 411 thousand cases (95% CI 283-557 thousand). Eight countries retained previous estimates, contributing 848 thousand cases (95% CI 225 thousand-1.7 million). New expert assessments in 14 countries contributed 862 thousand cases (95% CI 228 thousand-1.7 million). The global trichiasis burden in 2016 was 2.8 million cases (95% CI 1.1-5.2 million).\n\nInterpretationThe 2016 estimate is lower than previous estimates, probably due to more and better data; scale-up of trichiasis management services; and reductions in incidence due to lower active trachoma prevalence.\n\nAuthor SummaryAs an individual with trichiasis blinks, the eyelashes abrade the cornea, which can lead to corneal opacity and blindness. Through high quality surgery, which involves correcting the position of the in-turned eyelid, it is possible to reduce the number of people with trichiasis. An accurate estimate of the number of persons with trichiasis and their geographical distribution are needed in order to effectively align resources for surgery and other necessary services. We obtained district-level trichiasis prevalence estimates for 44 endemic and previously-endemic countries. We used the most recently available data and expert assessments to estimate the global burden of trichiasis. We estimated that in 2016 the global burden was 2.8 million cases (95% CI 1.1-5.2 million).\n\nThe 2016 estimate is lower than previous estimates, probably due to more and better data; scale-up of trichiasis management services; and reductions in incidence due to lower active trachoma prevalence.

epidemiology↗

bioRxiv2017

Constraining CD45 exclusion at close-contacts provides a mechanism for discriminatory T-cell receptor signalling

The T-cell receptor (TCR) triggers the elimination of pathogens and tumors by T lymphocytes. In order for this to avoid damage to the host, the receptor has to discriminate between thousands of peptide ligands presented by each host cell. Exactly how the TCR does this is unknown. In resting T-cells, the TCR is largely unphosphorylated due to the dominance of phosphatases over kinases expressed at the cell surface. When agonist peptides are presented to the TCR by major histocompatibility complex (MHC) proteins expressed by antigen-presenting cells (APCs), very fast receptor triggering occurs, leading to TCR phosphorylation. Recent work suggests that this depends on the local exclusion of the phosphatases from regions of contact of the T cells with the APCs. Here, we develop and test a quantitative treatment of receptor triggering reliant only upon TCR dwell-time in phosphatase-depleted cell-cell contacts constrained in area by cell topography. Using the model and experimentally-derived parameters, we find that ligand discrimination is possible but that it depends crucially on individual contacts being 400 nm in diameter or smaller, i.e. the size generated by microvilli. The model not only correctly predicts the relative signaling potencies of known agonists and non-agonists, but achieves this in the absence of conventional, multi-step kinetic proof-reading. Our work provides a simple, quantitative and predictive molecular framework for understanding why TCR triggering is so selective and fast, and reveals that for some receptors, cell topography crucially influences signaling outcomes.\n\nSignificance statementOne approach to testing biological theories is to determine if they are predictive. A simple, theoretical treatment of TCR triggering suggests that ligand discrimination by the receptor relies on just two physical principles: (1) the time TCRs spend in cell-cell contacts depleted of large tyrosine phosphatases; and (2) constraints on contact size imposed by T cells using finger-like protrusions to interrogate their targets. The theory not only allows agonistic and non-agonistic TCR ligands to be distinguished but predicts the relative signalling potencies of agonists with remarkable accuracy. This suggests that the theory captures the essential features of receptor triggering.

immunology↗