Richard A. Flavell

Bio: Richard A. Flavell is an academic researcher from Yale University. The author has contributed to research in topics: Immune system & T cell. The author has an hindex of 231, co-authored 1328 publications receiving 205119 citations. Previous affiliations of Richard A. Flavell include National Institute for Medical Research & University of Michigan.

Molecular basis of T-cell differentiation.

Abstract: In summary, a multitude of regulatory systems are employed to cause the selective activation of target cytokine genes in Th1 and Th2 effector cells. These mechanisms involve both positive and negative regulation and employ at least three kinds of mechanisms. In the first, selective expression of transcription factors such as GATA3 in Th2 cells and the homeobox gene HLX in Th1 cells occurs, and appears in both cases to play a causal role. Another example of this would be c-maf, discovered by the Glimcher laboratory. A second mechanism is by the selective accumulation of protein through posttranscriptional mechanisms. Thus, junB accumulates in Th2 cells despite the fact that the junB mRNA levels are not different between Th1 and Th2 cells. Finally, the selective use of signaling pathways, in the case studied here MAP kinase pathways, leads to the selective activation of target genes. We believe that transcriptional up-regulation of rac2 leads to the coupling of both the p38 and JNK MAP kinase pathways to the T-cell receptor and/or costimulatory receptors, thereby providing a lineage-specific signal.

Plasticity of Th17 Cells in Autoimmune Kidney Diseases.

Abstract: The ability of CD4(+) T cells to differentiate into pathogenic Th1 and Th17 or protective T regulatory cells plays a pivotal role in the pathogenesis of autoimmune diseases. Recent data suggest that CD4(+) T cell subsets display a considerable plasticity. This plasticity seems to be a critical factor for their pathogenicity, but also for the potential transition of pathogenic effector T cells toward a more tolerogenic phenotype. The aim of the current study was to analyze the plasticity of Th17 cells in a mouse model of acute crescentic glomerulonephritis and in a mouse chronic model of lupus nephritis. By transferring in vitro generated, highly purified Th17 cells and by using IL-17A fate reporter mice, we demonstrate that Th17 cells fail to acquire substantial expression of the Th1 and Th2 signature cytokines IFN-γ and IL-13, respectively, or the T regulatory transcription factor Foxp3 throughout the course of renal inflammation. In an attempt to therapeutically break the stability of the Th17 phenotype in acute glomerulonephritis, we subjected nephritic mice to CD3-specific Ab treatment. Indeed, this treatment induced an immunoregulatory phenotype in Th17 cells, which was marked by high expression of IL-10 and attenuated renal tissue damage in acute glomerulonephritis. In summary, we show that Th17 cells display a minimum of plasticity in acute and chronic experimental glomerulonephritis and introduce anti-CD3 treatment as a tool to induce a regulatory phenotype in Th17 cells in the kidney that may be therapeutically exploited.

Treatment of granuloma annulare and suppression of proinflammatory cytokine activity with tofacitinib.

Abstract: Background Granuloma annulare (GA) is a common cutaneous inflammatory disorder characterized by macrophage accumulation and activation in skin. Its pathogenesis is poorly understood, and there are no effective treatments. The potential health implications of severe GA are unknown. Objective We sought to better understand GA pathogenesis and evaluate a molecularly targeted treatment approach for this disease. Methods We used single-cell RNA sequencing to study the immunopathogenesis of GA and also evaluated the efficacy of tofacitinib (a Janus kinase 1/3 inhibitor) in 5 patients with severe, long-standing GA in an open-label clinical trial. Results Using single-cell RNA sequencing, we found that in GA lesions IFN-γ production by CD4+ T cells is upregulated and is associated with inflammatory polarization of macrophages and fibroblasts. In particular, macrophages upregulate oncostatin M, an IL-6 family cytokine, which appears to act on fibroblasts to alter extracellular matrix production, a hallmark of GA. IL-15 and IL-21 production appears to feed back on CD4+ T cells to sustain inflammation. Treatment of 5 patients with recalcitrant GA with tofacitinib inhibited IFN-γ and oncostatin M, as well as IL-15 and IL-21, activity and resulted in clinical and histologic disease remission in 3 patients and marked improvement in the other 2. Inhibition of these effects at the molecular level paralleled the clinical improvement. Evidence of systemic inflammation is also present in some patients with severe GA and is mitigated by tofacitinib. Conclusions The Janus kinase-signal transducer and activator of transcription pathway is activated in GA, likely in part through the activity of IFN-γ and oncostatin M, and Janus kinase inhibitors appear to be an effective treatment.

Death by numbers.

Abstract: One of the most significant breakthroughs of the past decade in biology is the realization that physiological cell death, also called apoptosis, is an essential part of life. The search for its biochemical mechanism has led to identification of an elaborate pathway that triggers cell death by activating a group of intracellular proteases known as caspases, through a highly ordered and precisely controlled process1. On page 768 of this tissue, Varner and colleagues2 present the first mathematical description of caspase activation through incorporating various key elements involved in apoptosis. Their effort is not just another “proof-of-concept” exercise, but may well represent an important first step toward rational identification of best strategies to regulate apoptosis for clinical applications. Such potential therapeutic opportunities exist because apoptosis is a key mechanism for ensuring cellular homeostasis, through active elimination of excessive and potentially dangerous cell populations3. Consequently, impaired regulation of apoptosis may contribute to the pathogenesis of many human diseases. For example, defective apoptosis may underlie neoplasia and autoimmune syndromes, whereas excessive apoptosis has been implicated in stroke and neurodegeneration. These findings suggest that the apoptotic pathway is a promising target for novel drug discovery, and both the pharmaceutical industry and a number of biotechnology companies are actively exploiting our rapidly growing understanding of the cellular death machinery. Although many of the details remain to be solved, diverse apoptotic stimuli, both intracellular and extracellular, induce cell death by activating members of the caspase family in a stepwise process known as the caspase cascade (Fig. 1). Activation of initiator caspases is under stringent control and requires stimulispecific formation of specialized caspase-activating complexes, such as the apoptosome and the death-inducing signaling complex (DISC). For example, apoptosome formation is induced by the mitochondrially mediated intrinsic pathway and results in activation of initiator caspase-9, whereas DISC formation Death by numbers

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei

Abstract: We have developed a procedure for preparing extracts from nuclei of human tissue culture cells that directs accurate transcription initiation in vitro from class II promoters. Conditions of extraction and assay have been optimized for maximum activity using the major late promoter of adenovirus 2. The extract also directs accurate transcription initiation from other adenovirus promoters and cellular promoters. The extract also directs accurate transcription initiation from class III promoters (tRNA and Ad 2 VA).

Apoptosis: A Review of Programmed Cell Death

Abstract: The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.