Sytze de Roock

Effects of external phosphorus supply on internal phosphorus concentration and the initiation, growth and exudation of cluster roots in Hakea prostrata R.Br.

The response of internal phosphorus concentration, cluster-root initiation, and growth and carboxylate exudation to different external P supplies was investigated in Hakea prostrata R.Br. using a split-root design. After removal of most of the taproot, equal amounts of laterals were allowed to grow in two separate pots fastened together at the top, so that the separate root halves could be exposed to different conditions. Plants were grown for 10 weeks in this system; one root half was supplied with 1 μM P while the other halves were supplied with 0, 1, 25 or 75 μM P. Higher concentrations of P supplied to one root half significantly increased the P concentration of those roots and in the shoots. The P concentrations in root halves supplied with 1 μM P were invariably low, regardless of the P concentration supplied to the other root half. Cluster root initiation was completely suppressed on root halves supplied with 25 or 75 μM P, whereas it continued on the other halves supplied with 1 μM P indicating that cluster-root initiation was regulated by local root P concentration. Cluster-root growth (dry mass increment) on root halves supplied with 1 μM P was significantly reduced when the other half was either deprived of P or supplied with 25 or 75 μM P. Cluster-root growth was favoured by a low shoot P status at a root P supply that was adequate for increased growth of roots and shoots without increased tissue P concentrations. The differences in cluster-root growth on root halves with the same P supply suggest that decreased cluster-root growth was systemically regulated. Carboxylate-exudation rates from cluster roots on root halves supplied with 1 μM P were the same, whether the other root half was supplied with 1, 25 or 75 μM P, but were approximately 30 times faster when the other half was deprived of P. Estimates of root P-uptake rates suggest a rather limited capacity for down-regulating P uptake when phosphate was readily available.

Elevated Th17 response in infants undergoing respiratory viral infection.

IL-17 and T-helper (Th)17 cells contribute to viral airway pathology in human newborns. Because umbilical cord blood T cells fail to differentiate toward the Th17 lineage in the presence of autologous antigen-presenting cells, we asked whether Th17 cells are present in young infants that experience respiratory viral infection. To this end, we analyzed tracheal aspirate samples from infant patients suffering from acute respiratory syncytial virus (RSV) infection and healthy infant controls. Acute RSV infection associates with elevated IL-17 and accumulation of CD161(+) T cells in acute RSV infected lungs. Correspondingly, local Th17 polarizing cytokines were increased. In peripheral blood, we show that Th17 cells are absent in healthy 1-month-old infants, but are present in acute RSV patients. The triggering of pathogen-associated pattern receptors TLR4 and TLR7 promotes the generation of a Th17-polarizing cytokine environment by 1-month-old infant dendritic cell (DC). We thus conclude that although Th17 cells are absent in healthy newborns, Th17 cells are present in peripheral blood and the airways of infants that experience viral infection, thereby contributing to airway immunopathology.

What are the immunological consequences of long-term use of biological therapies for juvenile idiopathic arthritis?

This review summarizes the immunological consequences of biological therapies used in juvenile idiopathic arthritis (JIA). For every frequently used biological agent the characteristics are clearly specified (molecular target, isotype, registered indication for JIA, route of administration, half-life, contraindication, very common side effects, expected time of response and average cost in the first year). The emphasis of this review is on the immunological side effects that have been encountered for every separate agent in JIA populations. For each agent these adverse events have been calculated as incidence per 100 patient-years for the following categories: serious infections, tuberculosis, malignancies, response to vaccination, new-onset autoimmune diseases and development of anti-drug antibodies. There are large differences in side effects between various agents and there is a clear need for an international and standardized collection of post-marketing surveillance data of biologicals in the vulnerable group of JIA patients. Such an international pharmacovigilance database, called Pharmachild, has now been started.

TH17 differentiation capacity develops within the first 3 months of life

6. Kawaguchi M, Takahashi D, Hizawa N, Suzuki S, Matsukura S, Kokubu F, et al. IL17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity. J Allergy Clin Immunol 2006;117:795-801. 7. Pandey RC, Michel S, Tesse R, Binia A, Schedel M, Liang L, et al. Genetic variation in the Toll-like receptor signaling pathway is associated with childhood asthma. J Allergy Clin Immunol 2013;131:602-5. 8. McGovern DP, Rotter JI, Mei L, Haritunians T, Landers C, Derkowski C, et al. Genetic epistasis of IL23/IL17 pathway genes in Crohn’s disease. Inflamm Bowel Dis 2009;15:883-9. 9. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17 T helper cells. Cell 2006;126:1121-33. 10. Lluis A, Ballenberger N, Illi S, Schieck M, Kabesch M, Illig T, et al. Regulation of Th17 markers early in life through maternal farm exposure. J Allergy Clin Immunol 2014;133:864-71.

Critical role for programmed death 1 signaling and protein kinase B in augmented regulatory T-cell induction in cord blood

protein was recently suggested not to be involved in IgE crossreactivity because it was not recognized by sera of patients with latex allergy. However, in contrast to our study, no data on IgE binding to Pt2l4 using sera of subjects with manioc allergy have been provided. Thus this new allergen might in fact be responsible for the observed link between manioc and latex allergy corroborated by the fact that all our patients with manioc allergy reacted to it. In the present study we identified a relevant IgEbinding glutamic acid–rich protein from manioc with 41.8% sequence homology to Hev b 5, an important latex allergen. Although Hev b 5 has not been reported to mediate IgE crossreactivity, our results suggest that it is a strong candidate for involvement in a latex-manioc syndrome. In our study cohort all patients with manioc allergy demonstrated allergic reactions to latex, and clinical histories showed that allergic reactions to latex always preceded symptoms to manioc, leading to the assumption that manioc allergy might be a consequence of primary latex sensitization. In Europe and the United States the incidence of latex allergy has been reduced because of specific guidelines made in the medical field. However, there might be a second wave, especially in countries that are pursuing higher economic and technologic standards. Manioc often represents a staple food in those countries, and therefore new allergies to this plant food source might be an undesirable consequence. Proteomic analysis with patients’ sera enabled the identification of novelmanioc IgE-binding proteins, demonstrating the usefulness of this approach for samples containing unknown allergens. This is the first study presenting a defined cohort of subjects (n 5 9) with clinically relevant allergy to manioc. Here we describe 3 new IgE-binding proteins, fructose bisphosphate aldolase, GAPDH, and a glutamic acid–rich protein similar to latex Hev b 5. Furthermore, we suggest that the glutamic acid–rich protein and, to a lesser extent, GAPDH might be involved in IgE cross-reactivity with latex. Globalization facilitates the entry of exotic foods into Europe and North America, and an increase in the prevalence of food allergy can be anticipated. Manioc has been used worldwide as source of starch and is now being gradually introduced into Europe and North America without detailed information for the consumers. Therefore, it is important for clinicians around the world to be aware of the fact that manioc is a source of allergens involved in the latex-fruit syndrome and can put persons at risk in countries that do not yet directly consume manioc. Keity Souza Santos, PhD Clovis Eduardo Galvao, MD, PhD Gabriele Gadermaier, PhD Virginia Maria Ferreira Resende, BSc Carlo de Oliveira Martins, BSc Denise Shimbo Misumi, BSc Ariana Campos Yang, MD, PhD Fatima Ferreira, PhD Mario Sergio Palma, PhD Jorge Kalil, MD, PhD Fabio Fernandes Morato Castro, MD, PhD

Cord blood CD4+ T cells respond to self heat shock protein 60 (HSP60).

Background To prevent harmful autoimmunity most immune responses to self proteins are controlled by central and peripheral tolerance. T cells specific for a limited set of self-proteins such as human heat shock protein 60 (HSP60) may contribute to peripheral tolerance. It is not known whether HSP60-specific T cells are present at birth and thus may play a role in neonatal tolerance. We studied whether self-HSP60 reactive T cells are present in cord blood, and if so, what phenotype these cells have. Methodology/Principal Findings Cord blood mononuclear cells (CBMC) of healthy, full term neonates (n = 21), were cultured with HSP60 and Tetanus Toxoid (TT) to study antigen specific proliferation, cytokine secretion and up-regulation of surface markers. The functional capacity of HSP60-induced T cells was determined with in vitro suppression assays. Stimulation of CBMC with HSP60 led to CD4+ T cell proliferation and the production of various cytokines, most notably IL-10, Interferon-gamma, and IL-6. HSP60-induced T cells expressed FOXP3 and suppressed effector T cell responses in vitro. Conclusion Self-reactive HSP60 specific T cells are already present at birth. Upon stimulation with self-HSP60 these cells proliferate, produce cytokines and express FOXP3. These cells function as suppressor cells in vitro and thus they may be involved in the regulation of neonatal immune responses.

Understanding inflammation in juvenile idiopathic arthritis : How immune biomarkers guide clinical strategies in the systemic onset subtype

The translation of basic insight in immunological mechanisms underlying inflammation into clinical practice of inflammatory diseases is still challenging. Here we describe how—through continuous dialogue between bench and bedside—immunological knowledge translates into tangible clinical use in a complex inflammatory disease, juvenile idiopathic arthritis (JIA). Systemic JIA (sJIA) is an autoinflammatory disease, leading to the very successful use of IL‐1 antagonists. Further immunological studies identified new immune markers for diagnosis, prediction of complications, response to and successful withdrawal of therapy. Myeloid related protein (MRP)8, MRP14, S100A12, and Interleukin‐18 are already used daily in clinic as markers for active sJIA. For non‐sJIA subtypes, HLA‐B27, antinuclear‐antibodies, rheumatoid factor, erythrocyte sedimentation rate, and C‐reactive protein are still used for classification, prognosis or active disease. MRP8, MRP14, and S100A12 are now under study for clinical practice. We believe that with biomarkers, algorithms can soon be designed for the individual risk of disease, complications, damage, prediction of response to, and successful withdrawal of therapy. In that way, less time will be lost and less pain will be suffered by the patients. In this review, we describe the current status of immunological biomarkers used in diagnosis and treatment of JIA.

Developing clinically relevant biomarkers in inflammatory arthritis: A multiplatform approach for serum candidate protein discovery

To identify candidate biomarkers that have the potential to distinguish between patients with psoriatic arthritis (PsA) or rheumatoid arthritis (RA) and explore the value of combining different protein discovery platforms for the development of a multiplexed protein biomarker panel.

Clinical Juvenile Arthritis Disease Activity Score proves to be a useful tool in treat-to-target therapy in juvenile idiopathic arthritis

Objectives To assess if the Juvenile Arthritis Disease Activity Score (JADAS71) could be used to correctly identify patients with juvenile idiopathic arthritis (JIA) in need of antitumour necrosis factor therapy (anti-TNF) therapy 3 and 6 months after start of methotrexate (MTX). Methods Monocentric retrospective cohort study from 2011 to 2015 analysing all patients with oligoarticular JIA (OJIA) (n=39) and polyarticular course JIA (PJIA) (n=74) first starting MTX. Three and 6 months after MTX start, clinical and laboratory features and the 2011 American College of Rheumatology (ACR) JIA treatment recommendations (ACR clinical practice guideline (ACR-CPG)) were compared between groups starting and not starting anti-TNF therapy. The sensitivity and specificity of the ACR-CPG, JADAS71 and the clinical JADAS to identify non-responders after 12 months were calculated. Results Physicians escalated patients with significantly higher physician global assessment, clinical JADAS (cJADAS) and patient Visual Analogue Scale (VAS). The decision not to escalate was correct in 70%–75% as shown by MTX response. The implementation of the ACR-CPG would increase the current anti-TNF use from 12% to 65%. The use of (c)JADAS in identifying patients in need of anti-TNF therapy outperformed the ACR-CPG with a much higher sensitivity, specificity and accuracy. The cJADAS threshold for treatment escalation at month 3 and 6 was >5 and >3 for OJIA and >7 and >4 for PJIA, respectively. The performance of the cJADAS decreased when the patient VAS contribution to the total score was restricted and overall did not improve by adding the erythrocyte sedimentation rate. Conclusions The cJADAS identifies patients in need of anti-TNF and is a user-friendly tool ready to be used for treat to target in JIA. The patient VAS is a critical item in the cJADAS for the decision to escalate to anti-TNF.

The human microbiome and juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. The pathogenesis of JIA is thought to be the result of a combination of host genetic and environmental triggers. However, the precise factors that determine one’s susceptibility to JIA remain to be unravelled. The microbiome has received increasing attention as a potential contributing factor to the development of a wide array of immune-mediated diseases, including inflammatory bowel disease, type 1 diabetes and rheumatoid arthritis. Also in JIA, there is accumulating evidence that the composition of the microbiome is different from healthy individuals. A growing body of evidence indeed suggests that, among others, the microbiome may influence the development of the immune system, the integrity of the intestinal mucosal barrier, and the differentiation of T cell subsets. In turn, this might lead to dysregulation of the immune system, thereby possibly playing a role in the development of JIA. The potential to manipulate the microbiome, for example by faecal microbial transplantation, might then offer perspectives for future therapeutic interventions. Before we can think of such interventions, we need to first obtain a deeper understanding of the cause and effect relationship between JIA and the microbiome. In this review, we discuss the existing evidence for the involvement of the microbiome in JIA pathogenesis and explore the potential mechanisms through which the microbiome may influence the development of autoimmunity in general and JIA specifically.