News From The Journal Of Clinical Investigation: April 24, 2013

Date: Apr-25-2013An ACE in the hole for hypertension

There are multiple environmental triggers that contribute to high blood pressure (hypertension), including aging, obesity, stress, alcohol intake, and excess dietary salt; however, the physiological mechanisms that are regulated by these triggers are not fully understood. Blood pressure is controlled in part by the renin angiotensin system (RAS), which manages the release of the hormone angiotensin to control blood vessel constriction. ACE is an enzyme that converts angiotensin to its active form, Ang II, and ACE inhibitors are commonly prescribed to treat hypertension. ACE acts in the kidneys, but also in the systemic circulation, the brain, and many other tissues. In this issue of the Journal of Clinical Investigation, Romer Gonzalez-Villalobos and colleagues at Cedars-Sinai Medical Center in Los Angeles, demonstrated that RAS in the kidneys plays a fundamental role in hypertension. Using transgenic mice, they demonstrated that mice that do not express ACE in the kidney are resistant to hypertension. These findings indicate that ACE plays a fundamental role in the responses of the kidney to conditions that lead to hypertension and suggest that targeting angiotensin production and activation in the kidneys may be an effective approach to treat hypertension. In an accompanying commentary, Timothy Reudelhuber of the University of Montreal discusses how these findings impact our understanding of hypertension.

TITLE: The absence of intrarenal ACE protects against hypertension

View this article at: http://www.jci.org/articles/view/65460?key=afacf01376ff3cd0acc2

ACCOMPANYING COMMENTARY
TITLE: Where hypertension happens

View this article at: http://www.jci.org/articles/view/69296?key=ca4e5c58a7ac9abed6fe

Linking a genetic variant to autoimmune disease susceptibility

Autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, Graves' disease, and systemic lupus erythematosus, are associated with a variant in the gene encoding the protein LYP. In this issue of the Journal of Clinical Investigation, David Rawlings and colleauges at the Seattle Children's Research Institute, generated mice that express an autoimmune disease-associated LYP variant to determine how the protein contributes to autoimmune disorders. They found that expression of the variant alters the function of immune cells. Further, as mice expressing the LYP variant aged, they developed antibodies targeted against their own tissues and exhibited systemic autoimmunity. These findings demonstrate that a naturally-occurring LYP variant impacts the function of the immune system and explains why this gene variant increases susceptibility to autoimmune disorders. In a companion commentary, John Cambier of National Jewish Health and the University of Colorado at Denver discusses how these findings fit with our current understanding of autoimmune diseases.







TITLE: A disease-associated PTPN22 variant promotes systemic autoimmunity in murine models

View this article at: http://www.jci.org/articles/view/66963?key=4c855168aaf9c6e8648d

ACCOMPANYING COMMENTARY
TITLE: Genetics of autoimmunity: from mice to men and back again

View this article at: http://www.jci.org/articles/view/69289?key=bea30596ee494ba2f8c6

Hide and seek: immune system recognition of acute myeloid leukemia

Even though cancer cells express proteins that can be detected by immune cells (antigens), they frequently avoid detection and destruction by the immune system (immune evasion). Several new therapeutic strategies are focused on making the immune system better at detecting and killing cancer cells; however, these therapeutics are largely targeted to solid tumors. In this issue of the Journal of Clinical Investigation, Justin Kline and colleagues at the University of Chicago identified a regulatory mechanism that allows acute myeloid leukemia (AML) cells to hide from the immune system. By injecting mice with AML cells, Kline and colleagues found that the cancer cells rapidly hide from the immune system by inducing immune tolerance and subverting the activation of a specific subset of immune cells known as T cells. Treating the mice with an antibody targeting the protein CD40 protected the T cells and allowed them to become active, leading to the elimination of the cancerous cells and prolonging the survival of AML cell-bearing mice. These findings indicate that AML cells induce T cell-mediated tolerance to evade the immune system. Further, these results provide a rationale for evaluating CD40 antibodies for the treatment of AML.

TITLE: CD40 ligation reverses T cell tolerance in acute myeloid leukemia

View this article at: http://www.jci.org/articles/view/63980?key=99fe4f964c61b7104d5a

Fishing for a "complement" in tissue inflammation

The complement system is an immune response that helps antibodies and immune cells clear pathogens from the body. It consists of a number of small proteins in the blood that circulate as inactive precursor proteins. During complement activation, a protein known as C3 is cleaved into smaller fragments that bind to tissue surfaces, initiating a cascade that targets specific cells for destruction. C3 accumulation on tissues is a marker for tissue inflammation. In this issue of the Journal of Clinical Investigation, Joshua Thurman and colleagues at the University of Colorado at Denver report the development of antibodies that specifically recognize tissue-bound C3 fragments. The authors hope that this new technology can be used to develop diagnostic and therapeutic tools for diseases associated with tissue inflammation.

TITLE: Detection of complement activation using monoclonal antibodies to C3d

View this article at: http://www.jci.org/articles/view/65861?key=f5fd75674e3ed56878bb
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