Novel Mechanism Links Inflammation to Heart Failure
Numerous studies have demonstrated that markers of inflammation are linked to a variety of common chronic conditions, including diabetes, obesity, and cardiovascular disease. Despite the wealth of evidence suggesting that inflammation plays a causative role in heart disease, the underlying mechanisms by which an inflammatory state is initiated and maintained in the heart have been elusive. New data from Oka et al. suggest that mitochondrial DNA may be a key upstream player in the inflammatory response that is commonly observed in heart failure. This group’s previous work suggested that autophagy is an adaptive response that protects the heart under conditions of hemodynamic stress. Normally, mitochondria that are damaged by hemodynamic stress are handled by autophagy through the fusing of autophagosomes and lysosomes. The newly published data suggest that when mitochondrial DNAs evade this autophagic response in cardiomyocytes, they induce inflammation that can lead to myocarditis and cardiomyopathy. DNase II plays an important role in this process because it is known to degrade the DNA of apoptotic cells in the lysosome. In a series of experiments in which DNase2−/− and DNase2+/+ mice were exposed to transverse aortic constriction, DNase2−/− mice did not exhibit upregulation in DNase II activity, whereas DNase2+/+ mice responded to the increased pressure by upregulating DNase II. After 28 days, 57% of DNase2−/− mice died, compared to only 14% of DNase2+/+ mice. Finally, the hearts of the DNase2−/− mice showed cell infiltration and fibrosis, as well as upregulation of mRNA of both IL-6 and collagen. Notably, the investigators did not observe a difference in circulating levels of mitochondrial DNA, suggesting that the inflammatory response did not result from mitochondrial DNA in the extracellular space. This report provides new insights into the mechanisms that underpin inflammation in heart failure and raises questions whether intervention on inflammation in heart failure may have implications for other conditions that are characterized by chronic inflammation. — Helaine E. Resnick, PhD, MPH
Oka et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature 2012;485:251–255
Promising Results for Gut Delivery of Autoantigens Using Modified Lactococcus lactis
A key challenge in developing therapies for type 1 diabetes involves reprogramming the immune system in a manner that promotes tolerance of β-cell antigens. Although there is evidence to suggest that type 1 diabetes can be prevented by administering these antigens using intestinal mucosa and other routes, results have not been promising once autoimmunity has set in. In a newly published series of experiments, Takiishi et al. have taken a fresh look at this problem by capitalizing on the idea that, in the gut, humans are routinely exposed to commensal bacteria that do not induce inflammation under normal conditions. The researchers genetically modified one of these bacteria—Lactococcus lactis—to secrete proinsulin autoantigens alone or in combination with IL-10, a tolerance-fostering cytokine. These were delivered orally to newly diagnosed NOD mice with and without low-dose systemic anti-CD3. Mucosal delivery of proinsulin and IL-10 by L. lactis each resulted in a cure rate of 15%, with results being somewhat more favorable for delivery of proinsulin+anti-CD3 and IL-10+anti-CD3. However, mucosal delivery of both proinsulin and IL-10 with anti-CD3 reverted autoimmunity in 59% of treated animals. Notably, the treatment was well tolerated, glycemia levels were stable during the period of observation, and disease did not recur. This vaccination-based approach is potentially appealing for a number of reasons including the safety of this noncolonizing, food-grade, Gram-positive bacterium that can be modified to express a diversity of proteins or peptides in a manner that retains biological function. The results of this intriguing report suggest that gut delivery of diabetes-related autoantigens by L. lactis may be a promising approach for prevention of type 1 diabetes. — H.E.R.
Takiishi et al. Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice. J Clin Invest 2012;122:1717–1725
Continued Progress in the Genetics of Childhood Obesity
Investigation of the genetics of BMI and obesity phenotypes has been the focus of extensive research efforts. In recent years, genome-wide association studies (GWAS) have yielded results connecting specific genetic loci with adult obesity. Many of these associations have been replicated in multiple studies. However, the vast majority of work on the genetics of obesity has been conducted in adults. This should be considered in light of the fact that in the U.S., about 1 in 400 people under the age of 20 has diabetes—a figure representing ∼215,000 children and adolescents, with a majority being overweight or obese. Given that the prevalence of type 2 diabetes in children is expected to grow dramatically as obesity continues to increase in this age-group, understanding the genetic influences on early-onset obesity may be important for identifying novel approaches to prevention. Important new work by Bradfield et al. sheds light on the genetics of obesity in children with a meta-analysis of 14 studies consisting of 5,530 case and 8,318 control subjects. Case subjects were at the $95th percentile of BMI by the age of 18 years, and control subjects were <50th percentile of BMI throughout childhood. Results of this ambitious collaboration showed strong associations with obesity at seven locations that had been previously identified in GWAS in adults, as well as in individual studies of children. In addition to these locations, two new loci were identified—one near OLFM4 and the other in the HOXB5 gene. The latter locations continued to show strong associations with extreme childhood obesity, defined as BMI >99.5th percentile. These newly published findings suggest that childhood and adult obesity share common genetic influences. Despite this progress, an ongoing challenge is identifying ways to translate this information into effective obesity prevention and treatment strategies. — H.E.R.
Bradfield et al. A genome-wide association meta-analysis identifies new childhood obesity loci. Nat Genet 2012;44:526–531
Cyclophilin B Shows Promise for Early Detection of Pancreatic Cancer
Difficulties associated with early detection of pancreatic cancer are a major reason for the high mortality associated with these tumors. Although 5-year survival among pancreatic cancer patients with localized tumors is 23%, only 8% of patients are diagnosed at this stage. By contrast, 53% of pancreatic tumors are diagnosed after the cancer has metastasized, and 5-year survival in this group is only 1.8%. Clearly, a biomarker that is both highly sensitive and specific for pancreatic cancer would be a meaningful addition to the toolkit that is currently available for early detection of this condition. Such a biomarker would also facilitate studies aimed at determining whether diabetes increases the risk for developing this cancer. New work by Ray et al. utilizes aptamers—oligonucleotide ligands that bind with very high specificity—to identify novel biomarkers for pancreatic cancer in the pancreatic secretome. Initial experiments utilized aptamers in an iterative process that identified several sequences showing higher binding to both pancreatic cancer and normal pancreatic secretomes. When tested individually, one aptamer—designated M9-5—showed significantly higher binding to the cancer secretome. Additional experiments in 24 pancreatic cancer patients and 24 control subjects focused on the feasibility of using M9-5 as a pancreatic cancer biomarker and demonstrated significantly higher binding in patients compared with control subjects. Further, M9-5 had sensitivity of 92% and specificity of 4%, with preliminary data suggesting this marker may have favorable properties as a screening instrument. Notably, three of the pancreatic cancer patients in this report had serum available before and after chemotherapy and radiation therapy. In these patients, M9-5 binding showed a modest decrease, indicating that this marker may also hold promise for monitoring treatment response. A series of subsequent experiments strongly suggested that cyclophilin B is the target protein of M9-5. However, the correlation between M9-5 binding and cyclophilin B was not perfect, suggesting that cyclophilin B may be a marker of more generalized pancreatic pathology. This intriguing report provides some optimism that proteins that are differentially secreted by pancreatic cancer cells can be leveraged to develop sensitive and specific tools for early detection of this particularly challenging cancer. By improving pancreatic cancer screening, these tools may also help elucidate whether diabetes plays a meaningful role in development of this cancer. — H.E.R.
Ray et al. Comparing human pancreatic cell secretomes by in vitro aptamer selection identifies cyclophilin B as a candidate pancreatic cancer biomarker. J Clin Invest 2012;122:1734–1741