Novel self-epitopes derived from aggrecan, fibrillin, and matrix metalloproteinase-3 drive distinct autoreactive T-cell responses in juvenile idiopathic arthritis and in health

Juvenile idiopathic arthritis (JIA) is a heterogeneous autoimmune disease characterized by chronic joint inflammation. Knowing which antigens drive the autoreactive T-cell response in JIA is crucial for the understanding of disease pathogenesis and additionally may provide targets for antigen-specific immune therapy. In this study, we tested 9 self-peptides derived from joint-related autoantigens for T-cell recognition (T-cell proliferative responses and cytokine production) in 36 JIA patients and 15 healthy controls. Positive T-cell proliferative responses (stimulation index ≥2) to one or more peptides were detected in peripheral blood mononuclear cells (PBMC) of 69% of JIA patients irrespective of major histocompatibility complex (MHC) genotype. The peptides derived from aggrecan, fibrillin, and matrix metalloproteinase (MMP)-3 yielded the highest frequency of T-cell proliferative responses in JIA patients. In both the oligoarticular and polyarticular subtypes of JIA, the aggrecan peptide induced T-cell proliferative responses that were inversely related with disease duration. The fibrillin peptide, to our knowledge, is the first identified autoantigen that is primarily recognized in polyarticular JIA patients. Finally, the epitope derived from MMP-3 elicited immune responses in both subtypes of JIA and in healthy controls. Cytokine production in short-term peptide-specific T-cell lines revealed production of interferon-γ (aggrecan/MMP-3) and interleukin (IL)-17 (aggrecan) and inhibition of IL-10 production (aggrecan). Here, we have identified a triplet of self-epitopes, each with distinct patterns of T-cell recognition in JIA patients. Additional experiments need to be performed to explore their qualities and role in disease pathogenesis in further detail.     

Carrying BioMath Education in a Leaky Bucket

In this paper, we describe a project-based mathematical lab implemented in our Applied Mathematics in Biology course. The Leaky Bucket Lab allows students to parameterize and test Torricelli's law and develop and compare their own alternative models to describe the dynamics of water draining from perforated containers. In the context of this lab students build facility in a variety of applied biomathematical tools and gain confidence in applying these tools in data-driven environments. We survey analytic approaches developed by students to illustrate the creativity this encourages as well as prepare other instructors to scaffold the student learning experience. Pedagogical results based on classroom videography support the notion that the Biology-Applied Math Instructional Model, the teaching framework encompassing the lab, is effective in encouraging and maintaining high-level cognition among students. Research-based pedagogical approaches that support the lab are discussed.     

Barley as a green factory for the production of functional Flt3 ligand

Biologically active recombinant human Flt3 ligand was expressed and isolated from transgenic barley seeds. Its expression is controlled by a tissue specific promoter that confines accumulation of the recombinant protein to the endosperm tissue of the seed. The recombinant Flt3 ligand variant expressed in the seeds contains an HQ-tag for affinity purification on immobilized metal ion affinity chromatography (IMAC) resin. The tagged protein was purified from seed extracts to near homogeneity using sequential chromatography on IMAC affinity resin and cation exchange resin. We also show that the recombinant Flt3 ligand protein undergoes posttranslational modifications: it is a glycoprotein containing α-1,3-fucose and α-1,2-xylose. The HQ-tagged Flt3 ligand variant exhibits comparable biological activity to commercial Flt3 ligand. This is the first report showing expression and accumulation of recombinant human growth factor in barley seeds with a yield of active protein similar to a bacterial expression system. The present results demonstrate that plant molecular farming is a viable approach for the bioproduction of human-derived growth factors.     

Novel self-epitopes derived from aggrecan, fibrillin, and matrix metalloproteinase-3 drive distinct autoreactive T-cell responses in juvenile idiopathic arthritis and in health

Juvenile idiopathic arthritis (JIA) is a heterogeneous autoimmune disease characterized by chronic joint inflammation. Knowing which antigens drive the autoreactive T-cell response in JIA is crucial for the understanding of disease pathogenesis and additionally may provide targets for antigen-specific immune therapy. In this study, we tested 9 self-peptides derived from joint-related autoantigens for T-cell recognition (T-cell proliferative responses and cytokine production) in 36 JIA patients and 15 healthy controls. Positive T-cell proliferative responses (stimulation index > or =2) to one or more peptides were detected in peripheral blood mononuclear cells (PBMC) of 69% of JIA patients irrespective of major histocompatibility complex (MHC) genotype. The peptides derived from aggrecan, fibrillin, and matrix metalloproteinase (MMP)-3 yielded the highest frequency of T-cell proliferative responses in JIA patients. In both the oligoarticular and polyarticular subtypes of JIA, the aggrecan peptide induced T-cell proliferative responses that were inversely related with disease duration. The fibrillin peptide, to our knowledge, is the first identified autoantigen that is primarily recognized in polyarticular JIA patients. Finally, the epitope derived from MMP-3 elicited immune responses in both subtypes of JIA and in healthy controls. Cytokine production in short-term peptide-specific T-cell lines revealed production of interferon-gamma (aggrecan/MMP-3) and interleukin (IL)-17 (aggrecan) and inhibition of IL-10 production (aggrecan). Here, we have identified a triplet of self-epitopes, each with distinct patterns of T-cell recognition in JIA patients. Additional experiments need to be performed to explore their qualities and role in disease pathogenesis in further detail.     

Leading Students to Investigate Diffusion as a Model of Brine Shrimp Movement

Integrating experimental biology laboratory exercises with mathematical modeling can be an effective tool to enhance mathematical relevance for biologists and to emphasize biological realism for mathematicians. This paper describes a lab project designed for and tested in an undergraduate biomathematics course. In the lab, students follow and track the paths of individual brine shrimp confined in shallow salt water in a Petri dish. Students investigate the question, “Is the movement well characterized as a 2-dimensional random walk?” Through open, but directed discussions, students derive the corresponding partial differential equation, gain an understanding of the solution behavior, and model brine shrimp dispersal under the experimental conditions developed in class. Students use data they collect to estimate a diffusion coefficient, and perform additional experiments of their own design tracking shrimp migration for model validation. We present our teaching philosophy, lecture notes, instructional and lab procedures, and the results of our class-tested experiments so that others can implement this exercise in their classes. Our own experience has led us to appreciate the pedagogical value of allowing students and faculty to grapple with open-ended questions, imperfect data, and the various issues of modeling biological phenomena.     

Profibrinolytic Effect of the Epigenetic Modifier Valproic Acid in Man

Aims

The aim of the study was to test if pharmacological intervention by valproic acid (VPA) treatment can modulate the fibrinolytic system in man, by means of increased acute release capacity of tissue plasminogen activator (t-PA) as well as an altered t-PA/Plasminogen activator inhibitor -1 (PAI-1) balance. Recent data from in vitro research demonstrate that the fibrinolytic system is epigenetically regulated mainly by histone deacetylase (HDAC) inhibitors. HDAC inhibitors, including VPA markedly upregulate t-PA gene expression in vitro.

Methods and Results

The trial had a cross-over design where healthy men (n = 10), were treated with VPA (Ergenyl Retard) 500 mg depot tablets twice daily for 2 weeks. Capacity for stimulated t-PA release was assessed in the perfused-forearm model using intra-brachial Substance P infusion and venous occlusion plethysmography. Each subject was investigated twice, untreated and after VPA treatment, with 5 weeks wash-out in-between. VPA treatment resulted in considerably decreased levels of circulating PAI-1 antigen from 22.2 (4.6) to 10.8 (2.1) ng/ml (p<0.05). It slightly decreased the levels of circulating venous t-PA antigen (p<0.05), and the t-PA:PAI-1 antigen ratio increased (p<0.01). Substance P infusion resulted in an increase in forearm blood flow (FBF) on both occasions (p<0.0001 for both). The acute t-PA release in response to Substance P was not affected by VPA (p = ns).

Conclusion

Valproic acid treatment lowers plasma PAI-1 antigen levels and changes the fibrinolytic balance measured as t-PA/PAI-1 ratio in a profibrinolytic direction. This may in part explain the reduction in incidence of myocardial infarctions by VPA treatment observed in recent pharmacoepidemiological studies.

Trial Registration

The EU Clinical Trials Register 2009-011723-31     

Winter survival of Ceramica pisi (Lepidoptera: Noctuidae) in Iceland

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Mathematically modeling dynamics of T cell responses: predictions concerning the generation of memory cells

Mathematical models of T cell population dynamics after infection typically assume that T cells differentiate according to a linear process in which they first become effector cells, and then after some time, differentiate further into memory cells. In this paper, we offer a different mathematical model which can equally well capture T cell dynamics, using data from lymphocytic choriomeningitis (LCMV) infection. Our model assumes that memory cells are intermediates that further differentiate into effector cells only from additional or stronger antigenic stimulation. Our assumption naturally leads to a testable prediction about the generation of T cell memory-that the memory phenotype of T cells should be present in detectable numbers during the expansion phase of the response. We use our model to estimate a rate of differentiation from memory type cells to effectors. We argue that this differentiation assumption, where memory cells are intermediates, captures recent experimental work on T cell differentiation, and hence this new mathematical model could be helpful in doing further studies of T cell population dynamics. We also propose a method of distinguishing the models by examining the ratio of memory T cells detectable long after an infection to the peak numbers of T cells at the end of the expansion phase.     

The effect of insect herbivory on seed production of Lupinus nootkatensis,an introduced species in Iceland

1. Lupinus nootkatensis is an exotic plant species that has been used for large‐scale sowing all around Iceland for land reclamation of eroded surfaces protected from livestock grazing.
2. Until the early 1990s, L. nootkatensis was free from any significant arthropod herbivory in Iceland, whereas, after 1991, many outbreaks of native insect species, primarily Ceramica pisi and Eupithecia satyrata, have been recorded. These outbreaks have caused repeated total defoliation of extensive areas of L. nootkatensis, although the effects on its development are mostly unknown.
3. We studied the effect of: (i) reduced herbivory; (ii) increased herbivory; and (iii) simulated increased herbivory, compared with (iv) unmanipulated herbivory, on defoliation and seed production of L. nootkatensis in a 3‐year field study within two sites at contrasting ages and successional stages.
4. The results obtained showed that: (i) seed production across all treatments was negatively related to defoliation; (ii) reduced herbivory had a positive effect on the number of flowering stems and seed yield; and (iii) these effects depended on age and/or the successional stage because they were only significant in the older L. nootkatensis site.
5. These findings indicate that arthropod herbivory may affect the invasiveness of L. nootkatensis in Iceland by reducing the seed production and the spatial distribution rate of late successional lupin communities.

     

The effect of the pine woolly aphid (Pineus pini) on survival,growth and natural selection in Scots pine (Pinus sylvestris) in Iceland

1. Scots pine Pinus sylvestris was originally introduced to Iceland in the beginning of the 20th Century. Extensive plantings started in the late 1940s and, in total, 2–3 million Scots pine seedlings were planted, mainly originating from two counties in northern Norway. Part of this plant material was imported as seedlings.
2. Pine woolly aphid Pineus pini was introduced to Iceland before 1940, most likely on imported seedlings in 1937.
3. High mortality of Scots pine, concurrent with high infestation of the pine woolly aphid, was observed in Iceland during the late 1950s and 1960s and planting was discontinued.
4. Provenance trials with Scots pine were established in Iceland in 2004–2006. They consisted of 15 provenances from Norway, four from Finland, four from Scotland, one from Russia, one from the Austrian Alps and three first generation Scots pine provenances from Iceland, collected from survivors of the epidemic in the 1950s and 1960s. In total, there were 28 provenances.
5. The Icelandic provenances had significantly lower P. pini infestation than all the provenances of non‐Icelandic origin, which indicates that natural selection in Scots pine in Iceland has occurred in favour of individuals less susceptible to P. pini.