A Multi-Scale Model for Correlation in B Cell VDJ Usage of Zebrafish

The zebrafish (\emph{Danio rerio}) is one of the model animals for study of immunology because the dynamics in the adaptive immune system of zebrafish are similar to that in higher animals. In this work, we built a multi-scale model to simulate the dynamics of B cells in the primary and secondary immune responses of zebrafish. We use this model to explain the reported correlation between VDJ usage of B cell repertoires in individual zebrafish. We use a delay ordinary differential equation (ODE) system to model the immune responses in the 6-month lifespan of a zebrafish. This mean field theory gives the number of high affinity B cells as a function of time during an infection. The sequences of those B cells are then taken from a distribution calculated by a "microscopic" random energy model. This generalized $NK$ model shows that mature B cells specific to one antigen largely possess a single VDJ recombination. The model allows first-principles calculation of the probability, $p$, that two zebrafish responding to the same antigen will select the same VDJ recombination. This probability $p$ increases with the B cell population size and the B cell selection intensity. The probability $p$ decreases with the B cell hypermutation rate. The multi-scale model predicts correlations in the immune system of the zebrafish that are highly similar to that from experiment.Comment: 29 pages, 10 figures, 1 tabl

Parallel processing in immune networks

In this work we adopt a statistical mechanics approach to investigate basic, systemic features exhibited by adaptive immune systems. The lymphocyte network made by B-cells and T-cells is modeled by a bipartite spin-glass, where, following biological prescriptions, links connecting B-cells and T-cells are sparse. Interestingly, the dilution performed on links is shown to make the system able to orchestrate parallel strategies to fight several pathogens at the same time; this multitasking capability constitutes a remarkable, key property of immune systems as multiple antigens are always present within the host. We also define the stochastic process ruling the temporal evolution of lymphocyte activity, and show its relaxation toward an equilibrium measure allowing statistical mechanics investigations. Analytical results are compared with Monte Carlo simulations and signal-to-noise outcomes showing overall excellent agreement. Finally, within our model, a rationale for the experimentally well-evidenced correlation between lymphocytosis and autoimmunity is achieved; this sheds further light on the systemic features exhibited by immune networks.Comment: 21 pages, 9 figures; to appear in Phys. Rev.

Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group.

BackgroundNew prognostic markers are needed to identify patients with Ewing sarcoma (EWS) and osteosarcoma unlikely to benefit from standard therapy. We describe the incidence and association with outcome of circulating tumour DNA (ctDNA) using next-generation sequencing (NGS) assays.MethodsA NGS hybrid capture assay and an ultra-low-pass whole-genome sequencing assay were used to detect ctDNA in banked plasma from patients with EWS and osteosarcoma, respectively. Patients were coded as positive or negative for ctDNA and tested for association with clinical features and outcome.ResultsThe analytic cohort included 94 patients with EWS (82% from initial diagnosis) and 72 patients with primary localised osteosarcoma (100% from initial diagnosis). ctDNA was detectable in 53% and 57% of newly diagnosed patients with EWS and osteosarcoma, respectively. Among patients with newly diagnosed localised EWS, detectable ctDNA was associated with inferior 3-year event-free survival (48.6% vs. 82.1%; p = 0.006) and overall survival (79.8% vs. 92.6%; p = 0.01). In both EWS and osteosarcoma, risk of event and death increased with ctDNA levels.ConclusionsNGS assays agnostic of primary tumour sequencing results detect ctDNA in half of the plasma samples from patients with newly diagnosed EWS and osteosarcoma. Detectable ctDNA is associated with inferior outcomes

Temporally consistent species differences in parasite infection but no evidence for rapid parasite-mediated speciation in Lake Victoria cichlid fish

Abstract Parasites may have strong eco-evolutionary interactions with their hosts. Consequently, they may contribute to host diversification. The radiation of cichlid fish in Lake Victoria provides a good model to study the role of parasites in the early stages of speciation. We investigated patterns of macroparasite infection in a community of 17 sympatric cichlids from a recent radiation and 2 older species from 2 non-radiating lineages, to explore the opportunity for parasite-mediated speciation. Host species had different parasite infection profiles, which were only partially explained by ecological factors (diet, water depth). This may indicate that differences in infection are not simply the result of differences in exposure, but that hosts evolved species-specific resistance, consistent with parasite-mediated divergent selection. Infection was similar between sampling years, indicating that the direction of parasite-mediated selection is stable through time. We morphologically identified 6 Cichlidogyrus species, a gill parasite that is considered a good candidate for driving parasite-mediated speciation, because it is host species-specific and has radiated elsewhere in Africa. Species composition of Cichlidogyrus infection was similar among the most closely related host species (members of the Lake Victoria radiation), but two more distantly related species (belonging to non-radiating sister lineages) showed distinct infection profiles. This is inconsistent with a role for Cichlidogyrus in the early stages of divergence. To conclude, we find significant interspecific variation in parasite infection profiles, which is temporally consistent. We found no evidence that Cichlidogyrus-mediated selection contributes to the early stages of speciation. Instead, our findings indicate that species differences in infection accumulate after speciation.Peer reviewe

Chasing the genes that control resistance to gastrointestinal nematodes

The host-protective immune response to infection with gastrointestinal (GI) nematodes involves a range of interacting processes that begin with recognition of the parasite’s antigens and culminate in an inflammatory reaction in the intestinal mucosa. Precisely which immune effectors are responsible for the loss of specific worms is still not known although many candidate effectors have beenproposed. However, it is now clear that many different genes regulate the response and that differences between hosts (fast or strong versus slow or weak responses) can be explained by allelic variation in crucial genes associated with the gene cascade that accompanies the immune response and/or genes encoding constitutively expressed receptor/signalling molecules. Major histocompatibility complex (MHC) genes have been recognized for some time as decisive in controlling immunity, and evidence that non-MHC genes are equally, if not more important in this respect has also been available for two decades. Nevertheless, whilst the former have been mapped in mice, only two candidate loci have been proposed for non-MHC genes and relatively little is known about their roles. Now, with the availability of microsatellite markers, it is possible to exploit linkage mapping techniques to identify quantitative trait loci (QTL) responsible for resistance to GI nematodes. Four QTL for resistance to Heligmosomoides polygyrus, and additional QTL affecting faecal egg production by the worms and the accompanying immune responses, have been identified. Fine mapping and eventually the identification of the genes (and their alleles) underlying QTL for resistance/susceptibility will permit informed searches for homologues in domestic animals, and human beings, through comparative genomic maps. This information in turn will facilitate targeted breeding to improve resistance in domestic animals and, in human beings, focused application of treatment and control strategies for GI nematodes

Immunological changes in nestlings growing under predation risk

Predation is one of the most relevant selective forces in nature. However, the physiological mechanisms behind anti-predator strategies have been overlooked, despite their importance to understand predator-prey interactions. In this context, the immune system could be especially revealing due to its relationship with other critical functions and its ability to enhance prey's probabilities of survival to a predator's attack. Developing organisms (e.g. nestlings) are excellent models to study this topic because they suffer a high predation pressure while undergoing the majority of their development, which maximizes potential trade-offs between immunity and other biological functions. Using common blackbirds Turdus merula as model species, we experimentally investigated whether an elevated nest predation risk during the nestling period affects nestlings' immunity and its possible interactions with developmental conditions (i.e. body condition and growth). Experimental nestlings modified some components of their immunity, but only when considering body condition and growth rate, indicating a multifaceted immunological response to predation risk and an important mediator role of nestlings' developmental conditions. Predation risk induced a suppression of IgY but an increase in lymphocytes in nestlings with poor body condition. In addition, experimental but not control nestlings showed a negative correlation between growth and heterophils, demonstrating that nest predation risk can affect the interaction between growth and immunity. This study highlights the importance of immunity in anti-predator response in nestlings and shows the relevance of including physiological components to the study of predation risk.</p

Mincle is a long sought receptor for mycobacterial cord factor

Mycobacterium tuberculosis is a leading killer worldwide, yet the adjuvancy of its cell wall has proven to be a valuable therapeutic tool for vaccination and immunotherapy. Much research effort has focused on the mycobacterial glycolipid trehalose-6,6’-dimycolate (TDM), a potent immunostimulant that is also known as cord factor. Now, the identification of the monocyte-inducible C-type lectin (Mincle) as an essential receptor for TDM provides new insight into the formation of the characteristic granulomas in tuberculosis and an avenue for rational adjuvant design

Phage Display in the Quest for New Selective Recognition Elements for Biosensors

Phages are bacterial viruses that have gained a significant role in biotechnology owing to their widely studied biology and many advantageous characteristics. Perhaps the best-known application of phages is phage display that refers to the expression of foreign peptides or proteins outside the phage virion as a fusion with one of the phage coat proteins. In 2018, one half of the Nobel prize in chemistry was awarded jointly to George P. Smith and Sir Gregory P. Winter "for the phage display of peptides and antibodies." The outstanding technology has evolved and developed considerably since its first description in 1985, and today phage display is commonly used in a wide variety of disciplines, including drug discovery, enzyme optimization, biomolecular interaction studies, as well as biosensor development. A cornerstone of all biosensors, regardless of the sensor platform or transduction scheme used, is a sensitive and selective bioreceptor, or a recognition element, that can provide specific binding to the target analyte. Many environmentally or pharmacologically interesting target analytes might not have naturally appropriate binding partners for biosensor development, but phage display can facilitate the production of novel receptors beyond known biomolecular interactions, or against toxic or nonimmunogenic targets, making the technology a valuable tool in the quest of new recognition elements for biosensor development.This study was supported by the Ministry of Economy and Competitiveness (Ministerio de Ciencia, Innovación y Universidades RTI2018-096410-B-C21). R.P. acknowledges UCM for a predoctoral grant and R.B. the PI17CIII/00045 grant from the AES-ISCIII program.S