Volume 18 Issue 5, May 2012

In April, China's Minister of Health Chen Zhu and his mentor, Wang Zhen-yi of the Shanghai Jiao Tong University School of Medicine, received the Albert Szent-Györgi Prize from the Washington, DC–based National Foundation for Cancer Research, in recognition for their work on acute promyelocytic leukemia. On that occasion, Victoria Aranda and Roxanne Khamsi asked Chen about his plans for cancer research and for improving stem cell regulation in China.

Everyone from rock stars to nonagenarians experiences hearing loss, but no drugs have ever been approved specifically to prevent or treat this problem. Recently, a handful of drug companies have started to make some noise, with a number of experimental compounds now in human trials. Elie Dolgin sounds off on what could be a multibillion dollar market.

The World Health Organization (WHO) is facing an unprecedented crisis that threatens its position as the premier international health agency. To ensure its leading role, it must rethink its internal governance and revamp its financing mechanisms.

A new study using a mouse model of lung diseases is the first demonstration in vivo that bone marrow–derived stromal cells can repair tissue injury through the transfer of mitochondria (pages 751–758). This suggests that rescue of injured cells through mitochondrial transfer may be an important process in many diseases.

The normally harmless behavior of bacteria in the intestinal tract is maintained by community structure and the integrity of host defenses. When either or both of these are compromised, a few disgruntled outcasts can cause a riot, taking down the whole neighborhood (pages 799–806).

Clinicians note that bariatric operations can dramatically resolve type 2 diabetes, often before and out of proportion to postoperative weight loss. Now two randomized controlled trials formally show superior results from surgical compared with medical diabetes care, including among only mildly obese patients. The concept of 'metabolic surgery' to treat diabetes has taken a big step forward.

Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly. AMD progression is associated with alterations in inflammatory pathways and the immune system. A new study identifies a protective role for inflammasomes in AMD, suggesting that inflammasome activation might be manipulated as a potential therapeutic strategy for this condition (pages 791–798).

Alternative splicing ensures the expression of functionally diverse proteins from individual genes; however, aberrant mRNA splicing is associated with various conditions, including heart disease. A recent study provides new mechanistic insights into heart failure by showing that a human cardiomyopathy-linked mutation in a cardiac splice factor affects post-transcriptional regulation, causing the expression of anomalous isoforms of a whole network of cardiac proteins (pages 766–773).

Mechanisms triggering methicillin-resistant Staphylococcus aureus (MRSA) epidemics are poorly understood. A recent study provides new evidence that horizontal gene transfer may be the culprit for the emergence of new resistant and virulent MRSA clones.

Losing weight can pose a challenge, but how to avoid putting those pounds back on can be a real struggle. A major health problem for obese people is that diseases linked to obesity, such as type 2 diabetes and cardiovascular disease, put their lives at risk, even in young individuals. Although bariatric surgery—a surgical method to reduce or modify the gastrointestinal tract—was originally envisioned for the most severe cases of obesity, evidence suggests that the benefit of this procedure may not be limited to the staggering weight loss it causes. Endogenous factors released from the gut, and modified after surgery, may explain why bariatric surgery can be beneficial for obesity-related diseases and why operated individuals successfully maintain the weight loss. In 'Bedside to Bench,' Rachel Larder and Stephen O'Rahilly peruse a human study with dieters who regained weight despite a successful diet. Appetite-regulating hormones in the gut may be responsible for this relapse in the long term. In 'Bench to Bedside,' Keval Chandarana and Rachel Batterham examine how two different methods of bariatric surgery highlight the relevance of gut-derived hormones not only in inducing sustained weight loss but also in improving glucose homeostasis. These insights may open new avenues to bypass the surgery and obtain the same results with targeted drugs.

Allergen sensitization is triggered by activating receptors of the innate arm of the immune system. This leads to the recruitment and activation of dendritic cells, which have a sentinel role in orchestrating the attendant adaptive response. Stephen Holgate highlights recent findings on how innate receptors are triggered, cellular sources of cytokines driving immune cell activation and the identification of new helper T cell subsets driving chronic allergic airway inflammation.

The airway epithelium has a sentinel role in initiating allergic responses and asthma. Bart Lambrecht and Hamida Hammad review recent findings on how allergens activate epithelial cells and induce the production of cytokines and chemokines that recruit and activate dendritic cells and other cells of the innate immune system. Activation of these cell types promotes adaptive immune responses, which are, the authors argue, further maintained and perpetuated by their interaction with airway epithelial cells.

Both mast cells and IgE play crucial parts during the initiation and amplification of the allergic response during asthma, as well as during the tissue remodeling that occurs at the chronic stage. This review discusses how these two players can affect the development of asthma through independent and interdependent functions and the therapeutic implications for treating the clinical symptoms derived from allergic disease.

Efficient trafficking of lymphocytes between the blood, lymphoid organs and peripheral tissues is essential for an effective immune response. Sabina Islam and Andrew Luster summarize recent findings on the regulation of leukocyte homing to the lungs, gut and skin in allergic inflammation and how leukocyte trafficking can be targeted clinically.

The growing appreciation of asthma as a heterogeneous disease has led to the concept that asthma consists of multiple, different phenotypes, but now the challenge is to link underlying biology to phenotypes to allow a more robust classification and understanding of asthma. This review discusses the progress in defining asthma phenotypes and provides insights into how to apply this knowledge to provide more personalized approaches to treating asthma.

Viral infections can worsen episodes of allergic sensitization to allergens, putting the affected individuals, often children, at risk for developing persistent asthma during adult life. Understanding how the mechanisms mediating the antiviral response and driving allergic inflammation caused by allergens interact is crucial. This will provide insights into when and what player or molecule to target for treatment and prevention of asthma in children at the early stages of the disease.

This review outlines recent advances in the development of therapeutics that induce immune tolerance to treat asthma and allergic disease. It focuses on the distinct approaches of allergen-specific immunotherapy and biological immune modifiers and also highlights the possibility of combining these two strategies to harness the advantages of both types of therapy and address current unmet clinical needs associated with these conditions.

Interleukin-25 (IL-25) is released from lung epithelial cells in response to allergen challenge and promotes type 2 immune responses and allergic airway inflammation. Nicholas Lukacs and his colleagues now report that IL-25 acts on a myeloid population in the lung. These cells represent a major source of IL-4 and IL-13, promote allergic lung inflammation and are steroid resistant. The frequency of IL-4– and IL-13–producing myeloid cells is increased in individuals with asthma, suggesting these cells may have a crucial role in the development of asthma.

Bone-marrow–derived stromal cells are known to protect against acute lung injury. Jahar Bhattacharya and colleagues now show that one way these cells offer such protection is to transfer their mitochondria to the injured lung epithelia to improve the bioenergetics of the recipient cells, thus probably allowing them to recover from injury more efficiently.

Alternative splicing affects the function of many cardiac proteins, including that of the sarcomeric protein titin. Wei Guo et al. now show that the gene RBM20, previously identified as mutated in some individuals with dilated cardiomyopathy, is a splicing factor that regulates the alternative splicing of the gene encoding titin and many other key cardiac genes.

Tobias Eckle et al. describe a new regulatory circuit in the heart by which adenosine receptor signaling controls expression of the circadian protein Per2, which stabilizes the transcription factor Hif-1α, promotes glycolytic metabolism and has cardioprotective effects. Exposing mice to intense light was able to stabilize Per2 in the heart and reduce cardiac injury after myocardial ischemia.

Ataxia-telangiectasia is a multifaceted disease that includes motor dysfunction caused by neuron death in the cerebellum. Now, Karl Herrup and colleagues report that ATM, the gene that is lost in the disease, keeps HDAC4 out of the nucleus and in the cytoplasm to maintain cerebellar neuron health.

Age-related macular degeneration is a blinding disease associated with accumulation of aggregates called drusen in the retina. Now, Matthew Campbell and colleagues show that drusen can activate the inflammasome and that this activation protects against disease progression.

The maintenance of a normal intestinal microbiota is associated with gut integrity and healthy immune responses. In this issue, Janelle Ayres and her colleagues report that disruption of the gut microbiome with antibiotics, coupled with gut injury, leads to the outgrowth of a pathogenic commensal bacterium and a sepsis-like disease. Their results show that the Naip5-Nlrc4 inflammasome is crucial for sensing the pathobiont and is a key factor in triggering the disease phenotype.

Engineered T cells expressing a tumor antigen specific T cell receptor (TCR) have shown promise for cancer immunotherapy. However, the introduced TCR chains can pair with the endogenous TCR chains in T cells, and in mice, these mismatched TCRs can cause a lethal autoimmune reaction. Provasi et al. now show that they can eliminate expression of the endogenous TCR chains using zinc finger nucleases and express only the desired exogenous TCR by lentiviral transduction. The resultant TCR-edited lymphocytes showed tumor specificity without the risk of off-target toxicity.

A mobile genetic element—sasX—has a key role in the pathogenesis of methicillin-resistant Staphylococcus aureus (MRSA) infection. This rapidly spreading determinant of MRSA pathogenic success markedly enhances nasal colonization, lung disease and immune evasion.

The adipocyte-derived hormone leptin acts on the brain to signal the long-term status of energy balance in the body. Martin Myers and his colleagues narrow down the population of neurons in the brain that actuate leptin's effects on food intake, and thus systemic energy balance, to a relatively small percentage of Nos1⁺ cells in the hypothalamus.

Finding new methods to define the target antigens recognized by MHC class I–restricted T cells is an unmet need. Katherina Siewert and her colleagues have developed a sensitive technique based on recombinatorial plasmid screening of T cell receptors (TCRs) isolated from individual T cells that overcomes many of the current limitations and enables the characterization of T cell antigens from most T cells, including those isolated from frozen biopsy samples by laser microdissection. The approach was validated using a well-characterized influenza virus–specific TCR, MHC and peptide combination.

The ability to effectively assess tumor margins for brain tumor resection is a crucial factor in determining outcome in patients with brain tumors. Moritz Kircher and colleagues have developed a gold-silica nanoparticle that provides a triple-mode imaging capability of magnetic resonance, photoacoustic and Raman imaging, capitalizing on the complementary strengths of each modality for noninvasively delineating brain tumor margins both preoperatively and intraoperatively. The approach was tested in several mouse models, including one that recapitulates the infiltrating growth pattern of human gliomas.

Asthma affects an estimated 300 million people worldwide. Despite the availability of therapies for symptomatic control of the disease, a significant fraction of patients remain refractory to treatment and progress to severe asthma. This series of reviews highlights recent advances in our understanding of asthma pathogenesis, clinical presentation of disease, and novel therapies aimed at targeting pathologic mechanisms initiating and sustaining allergic inflammation.