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Tregs produce chemokines to attract and suppress adaptive immune cells

Regulatory T cells (Tregs) prevent inappropriate responses to self and non-harmful foreign antigens, and modulation of Treg activity is a potential strategy to treat immune-mediated disease. Scott Patterson, Anne Pesenacker, and colleagues demonstrate that Tregs produce the chemokines CCL3 and CCL4 to attract CD4+ and CD8+ T cells via the receptor CCR5, drawing these cell populations close, possibly increasing proximity-dependent regulation of their activity. WT and Ccl3-deficient Tregs were comparable in their activation phenotypes and ability to suppress T cell proliferation in vitro, while Ccl3-deficient Tregs were unable to attract CD4+ and CD8+ T cells. Using murine models of multiple sclerosis and islet allograft rejection, Patterson and colleagues demonstrated that transplantation of Ccl3-deficient Tregs did not lead to the reductions in disease severity or progression that were seen with transplantation of WT Tregs. Finally, they observed that Tregs from patients with established type 1 diabetes had decreased CCL3 and CCL4 production compared to Tregs from healthy individuals.

#ResearchArticle: http://buff.ly/1PXd2v3 #Immunology #MultipleSclerosis #UBC
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Chemokine receptor expression on lymphocytes influences melanoma spread

The abundance, trafficking, and characteristics of tumor infiltrating lymphocytes (TILs) strongly influence the prognosis of human malignancies including metastatic melanoma (MMel). Lymphocyte trafficking into the tumor is largely determined by the expression of chemokine receptors on peripheral T cells (PBMCs). Nicolas Jacquelot and colleagues analyzed PBMCs and TILs from MMel patients to determine if chemokine receptor expression correlated with intratumoral accumulation, metastatic progression, or overall survival. They found that T cell chemokine receptor expression was strongly correlated with MMel dissemination and that the expression of specific chemokine receptors was associated with metastases at different sites, such as the skin, lymph nodes, or lungs. Importantly, expression of CCR9 on naïve CD8+ peripheral T cells correlated with increased overall survival in patients, while inhibition of CCR9 signaling stimulated tumor progression in mice. Taken together, these results suggest that specific chemokine receptor expression patterns could help guide diagnostic and therapeutic approaches.

#ResearchArticle: http://buff.ly/1VRltGl #Oncology #Melanoma
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A new batch of articles is now available online at
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The 2016 Stanley J. Korsmeyer Award

The American Society for Clinical Investigation (ASCI) has named Jean-Laurent Casanova, MD, PhD, as the recipient of the 2016 Stanley J. Korsmeyer Award for his discovery that single-gene inborn errors of immunity can underlie life-threatening infectious diseases in otherwise healthy children and young adults.
Dr. Casanova will receive an unrestricted honorarium of $20,000 from the ASCI and give the Korsmeyer Award Lecture at the upcoming AAP/ASCI/APSA Joint Meeting (http://buff.ly/1UOeUUJ). An interview with Dr. Casanova will be published in the April 2016 issue of the JCI.
Dr. Casanova has been actively publishing in the JCI since 1997. His first paper in the JCI featured a clinically relevant case where a kindred with partial interferon-γ receptor 1 (IFNγR1) deficiency was shown to cause curable tuberculoid bacillus Calmette-Guérin (BCG) infection and clinical tuberculosis, while complete IFNγR1 deficiency was previously known to cause fatal BCG infections (http://buff.ly/1UOeT37).
Visit http://buff.ly/1UOeT3c to see more of Dr. Casanova’s research published in the JCI.
http://buff.ly/1UOeUUR #Awards #Scientist
In 2016, the Association of American Physicians celebrates its 130th meeting! We are proud to acknowledge this important milestone for the AAP as we bring three organizations together -- the Association of American Physicians, the American Society for Clinical Investigation, and the American ...
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From JCI Insight:

Kidney fibrosis in older transplants links to failure

Clinically, kidney fibrosis can be used to assess stage, progression, and prognosis for both kidney transplants and kidney disease. There is debate as to whether kidney fibrosis is a maladaptive, injury-triggered process that inherently progresses to kidney failure or an adaptive wound-healing process that stabilizes the injury site. A new study in the inaugural issue of JCI Insight supports the hypothesis that fibrosis in kidney transplants is driven by continuous injury and not the result of an unstoppable cascade of events. Philip Halloran and colleagues at the University of Alberta in Edmonton, Canada performed transcriptome analysis on kidney biopsies from 681 transplant recipients. There was no evidence of fibrosis in kidneys at the time of transplant. However, biopsies taken a few months after transplant exhibited mild fibrosis that correlated with the expression of genes associated with acute kidney injury, and this early fibrosis did not associate with progression to failure. Conversely, fibrosis in biopsies taken more than a year after transplant exhibited a different gene signature, infiltration of immune cells, and elevated levels of fibrillar collagen, likely reflecting ongoing injury. Moreover, the presence of fibrosis in older transplants was associated with an increased risk of kidney failure. This study reveals that detection of fibrosis in transplanted kidneys is indicative of injury and that progression to failure is the result of continuous injury. The accompanying image depicts a nephron-centric model of renal transplant fibrosis based on the results of this study.

#ResearchArticle: http://buff.ly/23raY2m #Nephrology #Transplant #UAlberta
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February 2016 issue published:
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Lysine-specific demethylase 2B regulates hematopoietic lineage commitment

Transcriptional and epigenetic networks regulate hematopoietic lineage specification and these networks are frequently dysregulated in hematopoietic malignancies. Jaclyn Andricovich and colleagues investigated the role of lysine-specific demethylase 2B (KDM2B) in lineage commitment by analyzing hematopoietic stem and progenitor cells (HSPCs) from mice that were engineered to conditionally ablate or overexpress KDM2B in the hematopoietic system. They found that KDM2B was required for embryonic development and definitive hematopoiesis. RNA sequencing revealed that KDM2B regulates developmental pathways by binding repressed and activated chromatin through interactions with polycomb and trithorax group complexes, respectively. Additionally, they demonstrated that KDM2B functions as either a tumor suppressor or an oncogene, depending on the cellular context. The accompanying image shows accelerated Kras-driven myeloid transformation in KDM2B-deficient peripheral blood.

#ResearchArticle: http://buff.ly/1nccjcf
#Hematology
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From JCI Insight:

Identification of a driver of fibrosis in chronic kidney disease

Chronic kidney disease can develop in response to a variety of insults and is characterized by progressive renal fibrosis and atrophy of kidney tubule. Therapeutic options are limited and the disease is often not detected until later stages. A new study in the inaugural issue of JCI Insight identifies the Wnt pathway modulator Dickkopf-3 (DKK3) as a driver of kidney fibrosis. A team led by Bernd Arnold and Hermann-Josef Gröne at the German Cancer Research Center in Heidelberg, Germany determined that DKK3 expression is elevated in tubular epithelia upon stress and associates with profibrotic T cell responses. In mouse models of CKD, genetic loss of Dkk3 or antibody blockade of DKK3 mitigated interstitial fibrosis and improved kidney function. DKK3 was secreted in the urine of mice following renal injury and associated with the extent of damage. Importantly, in patients with CKD of various etiologies, DKK3 levels in urine were elevated and correlated with the extent of fibrosis and tubular atrophy. The results of this study identify DKK3 as a driver of renal fibrosis and as a potential biomarker of disease severity. The accompanying image shows Mason’s trichome-stained kidney sections from WT (top row) and DKK3-deficeint (bottom row) mice at prior to (left column) and 21 days (right column) after unilateral ureteral obstruction.

#ResearchArticle: http://buff.ly/23rbDkb #Nephrology #Renal #Immunology
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Antiretroviral therapy reduces HIV in the female reproductive tract

A recent HIV prevention clinical trial demonstrated 93% protection against secondary heterosexual transmission when infected partners received early antiretroviral therapy (ART). Rikke Olesen and colleagues tested the hypothesis that ART reduces genital cell-free or genital cell-associated HIV to levels that are too low to support HIV transmission. Using the humanized BM/liver/thymus (BLT) mouse model, they demonstrated that humanized CD4+ T cells were present throughout the female reproductive tract (FRT) and that these cells were shed into cervicovaginal secretions (CVS). HIV infection increased the number of CD4+ and CD8+ T cells in the CVS and virus was present throughout the FRT (see the accompanying image) and in CVS. ART strongly suppressed CVS viral load; however, HIV-RNA+ cells were present in both the FRT and the CVS, though these cells did not transmit HIV in an in vitro co-culture assay.

#ResearchArticle: http://buff.ly/1PX6Jrf #HIV #AIDS #UNC
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Bringing glycoscience back into the mainstream

This month’s issue of the JCI features a Perspective from a working group that was convened by the NHLBI to discuss the value of training the next generation of biomedical researchers in the glycosciences. The group discusses the current lack of support for glycoscience research and provides recommendations for incorporating glycoscience into the curricula of medical, graduate, and postgraduate training to help incorporate this discipline into biomedical research.

Read the article: http://buff.ly/1Sc2GIe #glycoscience #glycobiology #NHLBI
1Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA. 2Department of Chemistry, Stanford University, Stanford, California, USA. 3Lawrence Berkeley National Laboratory, Division of Biological ...
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New Review Series: HIV

The development of combination antiretroviral therapy in the mid-1990s initially raised hopes that HIV was a curable disease; however, further studies revealed that the virus persists, even in patients with undetectable levels of HIV in their plasma. Resting CD4+ T cells harbor stably integrated viral genomes that can produce infectious virus following T cell activation. Importantly, treatment interruption leads to a rapid recrudescence of infection from this latent reservoir, usually within two to three weeks. Several distinct areas of HIV research are now focused on the development of strategies to prevent the latent reservoir from replicating or to eliminate it entirely. Reviews in this series detail progress in our understanding of the molecular and cellular mechanisms of viral latency, efforts to accurately assess the size and composition of the latent viral reservoir, the characterization and development of HIV-targeted broadly neutralizing antibodies and cytolytic T lymphocytes, and animal models for the study of HIV latency and therapeutic strategies.

Read the Review series: http://buff.ly/1QE5OL5 #HIV #AIDS
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TLR9 is activated by hepatocyte mitochondrial DNA in non-alcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is the most common liver disease in the US and can lead to cirrhosis, cancer, and death; however, the drivers of NASH development are poorly understood. In this episode, Wajahat Mehal and colleagues reveal that levels of mitochondrial DNA, which activates TLR9, are elevated in plasma of mice and patients with NASH. Importantly, pharmacological or genetic inhibition of TLR9 blocked NASH development in mice fed a high-fat diet. The results of this study identify TLR9 activation via mitochondrial DNA as a driver of NASH and suggest targeting this pathway should be further explored for treatment of NASH.

Watch the Author’s Take Video: http://buff.ly/1QteJx4
Read the article: http://buff.ly/1QteJNm #Hepatology #Yale
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Premiere venue for discoveries in basic and clinical biomedical science.
Introduction
The Journal of Clinical Investigation (JCI) is a top-tier venue for discoveries in basic and clinical biomedical research that will advance the practice of medicine. Founded in 1924, the journal is published by the American Society for Clinical Investigation (ASCI) and has a 2014 Impact Factor of 13.261. Since 2012, the JCI has been headed by Dr. Howard A. Rockman, Editor, with an Editorial Board of peer scientists at Duke University Medical Center, the University of North Carolina, Duke-NUS, and the Sanford-Burnham Medical Research Institute. The JCI provides free access to all of its research articles.