Aberrant hexanucleotide repeat expansions in C9orf72 are the most common genetic change underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). RNA transcripts containing these undergo repeat-associated non-ATG translation (RAN-T) to form five dipeptide proteins (DPRs). DPRs found as aggregates throughout CNS of C9orf72-ALS/FTD patients, some cause degeneration when expressed vitro neuronal cultures vivo animal models. The spread characteristic disease-related...

AAV gene transfer is a promising treatment for many patients with life-threatening genetic diseases. However, host immune response to the vector poses significant challenge durability and safety of AAV-mediated therapy. Here, we characterize innate in human whole blood. We identified neutrophils, monocyte-related dendritic cells, monocytes as most prevalent cell subsets able internalize particles, while conventional cells were activated terms CD86 co-stimulatory molecule upregulation....

12/15-lipoxygenase (12/15-LO), one of a family fatty acid oxidoreductase enzymes, reacts with polyenoic acids to produce proinflammatory lipids. 12/15-LO is expressed in macrophages and pancreatic beta-cells. It enhances interleukin 12 production by macrophages, several its products induce apoptosis beta-cells at nanomolar concentrations vitro. We had previously demonstrated role for beta-cell damage the streptozotocin model diabetes. Since gene encoding (gene designation Alox15) lies within...

We examined the formation, participation, and functional specialization of virus-reactive Foxp3(+) regulatory T cells (Tregs) in a mouse model influenza virus infection. "Natural" Tregs generated intrathymically, based on interactions with self-peptide, proliferated response to homologous viral Ag lungs and, lesser extent, lung-draining mediastinal lymph nodes (medLNs) virus-infected mice. In contrast, conventional CD4(+) identical TCR specificity underwent little or no conversion become...

CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells are generated during thymocyte development and play a crucial role in preventing the immune system from attacking body's tissues. However, how formation of these is directed by T-cell receptor (TCR) recognition self-peptide:major histocompatibility complex (MHC) ligands remains poorly understood. We show that an agonist self-peptide with which TCR strongly reactive can induce combination deletion Treg cell vivo. A weakly cross-reactive partial...

Background Recent literature has indicated the feasibility of microarray analysis in characterization chronic sinusitis. We hypothesized that previously unexplored inflammatory mechanisms would be involved pathophysiology noneosinophilic rhinosinusitis with nasal polyps (NE-CRSwNP) and this technology could used to identify gene expression these novel known mediators. Methods Patients CRSwNP failing medical therapy were prospectively enrolled NP tissue was removed at time surgery. NE-CRSwNP...

Autoreactive CD4(+) CD8(-) (CD4SP) thymocytes can be subjected to deletion when they encounter self-peptide during their development, but also undergo selection become CD4SPFoxp3(+) Treg cells. We have analyzed the relationship between these distinct developmental fates using mice in which signals transmitted by TCR been attenuated mutation of a critical tyrosine residue adapter protein SLP-76. In containing polyclonal repertoires, caused increased frequencies thymocytes. CD4SP expressing...

CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are required to restrain the immune system from mounting an autoaggressive systemic inflammatory response, but why their activity can prevent (or allow) organ-specific autoimmunity remains poorly understood. We have examined how TCR specificity contributes Treg using a mouse model of spontaneous autoimmune arthritis, in which CD4(+) expressing clonotypic induce disease by IL-17-dependent mechanism. Administration polyclonal Tregs suppressed...

We have examined mechanisms underlying the formation of pathologic Th17 cells using a transgenic mouse model in which autoreactive CD4(+) T recognize influenza virus hemagglutinin (HA) as ubiquitously expressed self-Ag and induce inflammatory arthritis. The lymph nodes arthritic mice contain elevated numbers monocytes (iMO) with an enhanced capacity to promote cell differentiation, regional response develops paw-draining by IL-17-dependent mechanism. activation these Th17-trophic iMO...

Abstract How the formation and activity of CD4+Foxp3+ regulatory T cells (Tregs) are shaped by TCR recognition diverse array peptide:MHC complexes that can be generated from self-antigens and/or foreign Ags in vivo remains poorly understood. We show a self-peptide with low (but not high) stimulatory potency promotes thymic Treg induce conventional CD4+ periphery to become Tregs express different levels transcription factor Helios according anatomical location. When response this subsequently...

Although therapies targeting distinct cellular pathways (e.g., anticytokine versus anti-B cell therapy) have been found to be an effective strategy for at least some patients with inflammatory arthritis, the mechanisms that determine which promote arthritis development are poorly understood. We used a transgenic mouse model examine how variations in CD4(+) T response surrogate self-peptide can affect required development. cells highly reactive induce affects male and female mice equally....

When studying patient specific induced pluripotent stem cells (iPS cells) as a disease model, the ideal control is an isogenic line that has corrected point mutation, instead of iPS from siblings or other healthy subjects. However, repairing mutation in even with newly developed CRISPR-Cas9 technique remains difficult and time-consuming. Here we report strategy makes Cas9 "knock-in" methodology both hassle-free error-free. Instead selecting recognition site close to chose located nearest...

Abstract We have examined the formation, participation and functional specialization of virus-reactive Foxp3+ regulatory T cells (Tregs) in a mouse model influenza virus infection. “Natural” Tregs generated intra-thymically based on interactions with self-peptide proliferated response to homologous viral antigen lungs, lesser extent lung-draining mediastinal LN (medLN), virus-infected mice. By contrast, conventional CD4+ identical TCR specificity underwent little or no conversion become...

Abstract Th17 cells have been implicated in a number of autoimmune and inflammatory disorders, yet signals that can lead to response vivo are poorly understood. We analyzed this question using transgenic mouse model which autoreactive CD4+ T recognizing ubiquitously expressed surrogate self-antigen (influenza HA) induce arthritis by an IL-17-dependent mechanism. Arthritis development is accompanied accumulation the joint draining lymph nodes monocytes (iMOs) enhanced capacity support...

Abstract It is generally accepted that developing thymocytes can become Foxp3+ regulatory T cells (Tregs) through recognition of self-antigens during thymic selection. Tregs also develop from conventional CD4+ responding to exogenously administered peptides (including food antigens) in vivo, and via TGF-β signaling activation vitro, but the processes by which Treg induction may occur response self-peptides periphery remain unclear. We are examining this question transferring CD4+CD25-Foxp3-...

Abstract CD4+ T cells make a crucial contribution to the development of inflammatory arthritis both in humans and mouse models. However, how affinity with which recognize target antigens might shape disease influence treatment modalities is poorly understood. We have examined these phenomena models autoimmune arthritis: TS1xHACII TS1(SW)xHACII mice express influenza hemagglutinin (HA) as neo-self peptide co-express transgenic TCRs that either high (TS1xHACII) or low (TS1(SW)xHACII) for...