Role of Interleukin-17 in the Adaptive Immune Response in Lyme Arthritis

Lyme arthritis is a devastating symptom of Lyme borreliosis that causes severe inflammation of the synovial joints. Interleukin-17 (IL-17) plays a role in the pathogenesis of various arthritides, including, possibly, Lyme arthritis, by causing the expression of genes involved in the production of inflammatory cytokines by synoviocytes. However, the cellular sources of IL-17 in the context of Borrelia burgdorferi infection are unknown, as are the effects of these cells on the development of arthritis and stimulation of humoral immunity through the production of borreliacidal antibodies. Using multiple models of Lyme arthritis, the hypothesis that IL-17 produced by CD4+ cells contributes to the inflammation associated with B. burgdorferi infection and is associated with an increase in borreliacidal antibody production was tested. Serum IL-17 levels were increased during Borrelia infection, especially at the time of peak swelling. Neutralization of interferon-gamma increased these IL-17 levels, and the addition of anti-CD4 antibodies to cultures of stimulated cells isolated during peak swelling reduced IL-17 levels. In addition, a role for IL-10 in the production of IL-17 was demonstrated. Furthermore, increased IL-17 was associated with an increase of borreliacidal antibodies. These findings suggest CD4+ cells (possibly T cells) contribute to the production of IL-17 following infection with B. burgdorferi and that levels of this cytokine may affect borreliacidal antibody production

Regulatory Mechanisms in Borrelia Burgdorferi-Induced Arthritis

Lyme arthritis is a common symptom of Lyme borreliosis that involves inflammation of the synovial joints. Elucidating the immune events involved in Lyme arthritis is complicated by the fact that not all individuals infected with B. burgdorferi develop arthritis. Additionally, Lyme arthritis manifests in different severities between affected individuals. It is known that an inflammatory response is initiated by B. burgdorferi infection and that inflammatory T cells contribute to the development of arthritis. However, the anti-inflammatory mechanisms that regulate the pathogenic T cells’ response are not entirely understood. Here, the hypothesis that a dysregulated immune response results in an excessive inflammatory response and the development of arthritis following B. burgdorferi infection was tested. Interleukin-10 (IL-10) is involved in regulating the immune response during infection with B. burgdorferi. We demonstrate that IL-10 regulates the development of Lyme arthritis through inhibition of interleukin-17 (IL-17) production. We also demonstrate that IL-10 regulates the production of IL-17 by Borrelia-primed CD4+ cells early after interaction with Lyme spirochetes in vitro, and that infection of Borrelia-primed mice with B. burgdorferi leads to significant production of IL-17 that contributes to the development of severe arthritis. Further, we demonstrate that regulatory T (Treg) cell depletion prior to infection results in hind paw swelling and the development of arthritis along with an increased B. burgdorferi-specific antibody response in an arthritis-resistant mouse model. We further demonstrate that Treg cells inhibit paw swelling and inflammatory cytokine production during the course of B. burgdorferi infection, but may not modulate severity of arthritis in established disease. Based on our findings, this suggests that Treg cells present prior to B. burgdorferi infection results in regulation of IL-17 by IL-10, thereby inhibiting pathology. Our findings identify novel regulatory mechanisms that may be responsible for resistance to Lyme arthritis, and suggest that modulation of Treg cells may prove useful in the development of new strategies for treatment and/or prevention of Lyme arthritis

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Injectable and Degradable Poly(Oligoethylene glycol methacrylate) Hydrogels with Tunable Charge Densities as Adhesive Peptide-Free Cell Scaffolds

Injectable, dual-responsive, and degradable poly­(oligo ethylene glycol methacrylate) (POEGMA) hydrogels are demonstrated to offer potential for cell delivery. Charged groups were incorporated into hydrazide and aldehyde-functionalized thermoresponsive POEGMA gel precursor polymers via the copolymerization of N,<i>N</i>′-dimethylaminoethyl methacrylate (DMAEMA) or acrylic acid (AA) to create dual-temperature/pH-responsive in situ gelling hydrogels that can be injected via narrow gauge needles. The incorporation of charge significantly broadens the swelling, degradation, and rheological profiles achievable with injectable POEGMA hydrogels without significantly increasing nonspecific protein adsorption or chronic inflammatory responses following in vivo subcutaneous injection. However, significantly different cell responses are observed upon charge incorporation, with charged gels significantly improving 3T3 mouse fibroblast cell adhesion in 2D and successfully delivering viable and proliferating ARPE-19 human retinal epithelial cells via an “all-synthetic” matrix that does not require the incorporation of cell-adhesive peptides