Type II cytokines direct choices of early thymic progenitor lineage and influence negative selection of myelin-reactive T cells

Autoimmune diseases have been known for having a strong genetic component; however, there is growing indication that shows the environment also plays an important role. One way in which the environment plays a role is though influencing central tolerance via fine tuning of the thymic microenvironment. It has been shown that early thymic progenitors (ETPs) that express the heteroreceptor (HR), which are comprised of both IL-13R[alpha]1 and IL- 4R[alpha] chain, are directed toward the myeloid lineage and serve as antigen presenting cells (APCs). Due to the role of APCs in T cell negative selection, this research looks to investigate whether type II cytokines can determine ETP lineage choice and subsequently alter negative T cell selection. --Introduction.Funding: NIH grant, RO1 NS057194.Hannah Gavin (Undergraduate Student, University of Missouri School of Medicine at Columbia), Alexis Cattin-Roy (Molecular Microbiology and Immunology Department, University of Missouri Hospital, MO, 65201), Habib Zaghouani (Molecular Microbiology and Immunology Department, University of Missouri Hospital)

Construction of a knockout targeting vector to generate an Interleukin-13 Receptor α1 deficient Balb/c mouse

Abstract only availableA recent publication from our lab has provided evidence for the involvement of the α1 chain of the Interleukin-13 cytokine receptor (IL-13Rα1) in the development of the neonatal immune system. Specifically, we have shown that cell death of T helper type 1 (Th1) effector cells can be prevented by antibody-mediated blockade of IL-13Rα1. Currently, a knockout mouse deficient in expression of IL-13Rα1 is not available and the development of an IL-13Rα1 knockout mouse will provide new insights on the relationship between IL-13Rα1 signaling and neonatal immunity. In this effort we have begun construction of a targeting vector that will bear sufficient homology to the IL-13Rα1 wild-type locus to allow for deletion of exons 7, 8, and 9 via homologous recombination, thereby rendering that allele non-functional. After construction of the targeting vector, a collaborative effort between the Transgenic Animal Core facility here at the University of Missouri will continue throughout the remainder of the cell culture, embryonic manipulation, and screening processes.Life Sciences Fellowships/Meyerhoff Scholars Progra

Understanding T regulatory cell development in the thymus using both in vivo and in vitro models

Abstract only availableMultiple sclerosis (MS) is an autoimmune disease caused by autoreactive T cells attacking myelin sheath proteins in nerve fibers of the central nervous system resulting in paralysis and death. Conventional T cells (cytolytic and helper) initiate disease in MS, and T regulatory cells (Tregs) are conventional T cell suppressors. By studying the development of Tregs, a T cell suppressor, we can stop T cells from attacking myelin sheath proteins and prevent disease progression. All T cells develop in the thymus in three stages: double negative, double positive, and single positive. In the stage of my research's interest, the double positive stage, the T cell undergoes two educational phases, positive and negative selection. In positive selection, an antigen presenting cell (APC) presents a peptide to the T cell's T cell receptor (TCR). If the interaction between the peptide on the APC and TCR has a low affinity, then the T cell survives. However, if the affinity between the peptide and the TCR is high, the T cell dies via apoptosis. We hypothesize that Tregs require a strong affinity between the peptide and TCR to continue to the next educational phase. Interestingly, exposure high affinity peptides resulted in a decrease in Treg apoptosis both in vitro and in vivo. This observation is opposite to conventional T cell selection. We want to determine the ability of medium affinity peptide, PLP-Y, to prevent Treg apoptosis in vitro because ex vivo analysis shows PLP-Y does prevent Treg apoptosis in the thymus. Our results from in vitro experiments, however, did not show prevention of Treg death. Thus, it is likely more peptide is needed to provide the signal strength necessary for prevention of Treg death. Since many autoimmune diseases arise from poor Treg development, a better knowledge of the selection process may lead to potential therapies.Life Sciences Undergraduate Research Opportunity Progra

Reversal of severe autoimmune diabetes at the stem cell level by bone marrow-derived endothelial progenitors

This poster presents the process for treating severe autoimmune diabetes in mice through the use of bone marrow-derived endothelial cells

Therapy of experimental allergic encephalomyelitis under circumstances relevant to human multiple sclerosis

Abstract only availableExperimental allergic encephalomyelitis (EAE) is an inflammatory disease of the central nervous system (CNS) that resembles human multiple sclerosis (MS). EAE and MS develop when proteins of the myelin sheath that covers axons are released and encounter cells of the immune system such as T lymphocytes. Activation of these lymphocytes will trigger inflammation that destroys the myelin leading to clinical signs that manifest mostly in the form of motion impairment and muscle paralysis. Inactivation of myelin specific lymphocytes is currently viewed as a means to halt immune attack against the brain and reverse the course of disease. In this study we devised an antigen specific approach against EAE and tested its efficacy in an advanced genetic setting, which would better represent the human genetic polymorphism. Therefore, we have created an F1(SJL/J x Bl/6) mouse for analysis of the reversal of compatible as well as “in trans” EAE where the disease is induced by a peptide restricted to one parent and the treatment uses a fusion protein carrying a peptide restricted to the other parent. The results indicate that the effectiveness of the treatment depends on the method of disease induction and the genetic makeup of the mouse.Life Sciences Undergraduate Research Opportunity Progra

Pneumomédiastin au cours d’une dermatomyosite, une entité rare: à propos d’un cas

la dermatomyosite est une connective caractérisée par une inflammation du muscle squelettique associée à des manifestations cutanées caractéristiques. Leurs étiologies, encore méconnues, associent facteurs environnementaux et génétiques. Parmi les complications pulmonaires décrites, les pneumopathies interstitielles qui sont des complications fréquentes. D'autres complications sont plus rarement rapportées comme le pneumomédiastin. Nous rapportons une observation de pneumomédiastin avec dissection aérique sous cutanée massive survenus chez une patiente atteinte de dermatomyosite. Nous discutons, à la vue des données de la littérature de la fréquence, des causes et des mécanismes physiopathologiques de cette pathologie.Pan African Medical Journal 2016; 2

On the Role of Dendritic Cells in Peripheral T Cell Tolerance and Modulation of Autoimmunity

Recently, it has become clear that dendritic cells (DCs) are essential for the priming of T cell responses. However, their role in the maintenance of peripheral T cell tolerance remains largely undefined. Herein, an antigen-presenting cell (APC) transfer system was devised and applied to experimental allergic encephalomyelitis (EAE), to evaluate the contribution that DCs play in peripheral T cell tolerance. The CD8α−CD4+ subset, a minor population among splenic DCs, was found to mediate both tolerance and bystander suppression against diverse T cell specificities. Aggregated (agg) Ig-myelin oligodendrocyte glycoprotein (MOG), an Ig chimera carrying the MOG 35–55 peptide, binds and cross-links FcγR on APC leading to efficient peptide presentation and interleukin (IL)-10 production. Furthermore, administration of agg Ig-MOG into diseased mice induces relief from clinical EAE involving multiple epitopes. Such recovery could not occur in FcγR-deficient mice where both uptake of Ig-MOG and IL-10 production are compromised. However, reconstitution of these mice with DC populations incorporating the CD8α−CD4+ subset restored Ig-MOG–mediated reversal of EAE. Transfer of CD8α+ or even CD8α−CD4− DCs had no effect on the disease. These findings strongly implicate DCs in peripheral tolerance and emphasize their functional potency, as a small population of DCs was able to support effective suppression of autoimmunity

Delayed maturation of an IL-12–producing dendritic cell subset explains the early Th2 bias in neonatal immunity

Primary neonatal T cell responses comprise both T helper (Th) cell subsets, but Th1 cells express high levels of interleukin 13 receptor α1 (IL-13Rα1), which heterodimerizes with IL-4Rα. During secondary antigen challenge, Th2-produced IL-4 triggers the apoptosis of Th1 cells via IL-4Rα/IL-13Rα1, thus explaining the Th2 bias in neonates. We show that neonates acquire the ability to overcome the Th2 bias and generate Th1 responses starting 6 d after birth. This transition was caused by the developmental maturation of CD8α+CD4− dendritic cells (DCs), which were minimal in number during the first few days of birth and produced low levels of IL-12. This lack of IL-12 sustained the expression of IL-13Rα1 on Th1 cells. By day 6 after birth, however, a significant number of CD8α+CD4− DCs accumulated in the spleen and produced IL-12, which triggered the down-regulation of IL-13Rα1 expression on Th1 cells, thus protecting them against IL-4–driven apoptosis

Innocuous IFNγ induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production

The role of Th17 cells in type I diabetes (TID) remains largely unknown. Glutamic acid decarboxylase (GAD) sequence 206–220 (designated GAD2) represents a late-stage epitope, but GAD2-specific T cell receptor transgenic T cells producing interferon γ (IFNγ) protect against passive TID. Because IFNγ is known to inhibit Th17 cells, effective presentation of GAD2 peptide under noninflammatory conditions may protect against TID at advanced disease stages. To test this premise, GAD2 was genetically incorporated into an immunoglobulin (Ig) molecule to magnify tolerance, and the resulting Ig-GAD2 was tested against TID at different stages of the disease. The findings indicated that Ig-GAD2 could not prevent TID at the preinsulitis phase, but delayed TID at the insulitis stage. More importantly, Ig-GAD2 sustained both clearance of pancreatic cell infiltration and β-cell division and restored normoglycemia when given to hyperglycemic mice at the prediabetic stage. This was dependent on the induction of splenic IFNγ that inhibited interleukin (IL)-17 production. In fact, neutralization of IFNγ led to a significant increase in the frequency of Th17 cells, and the treatment became nonprotective. Thus, IFNγ induced by an adjuvant free antigen, contrary to its usual inflammatory function, restores normoglycemia, most likely by localized bystander suppression of pathogenic IL-17–producing cells