Research articles

Innate immune responses markedly affect subsequent adaptive responses. Here the authors show that adaptive immunity in the form of memory CD4⁺ T cells can also affect the magnitude of innate inflammatory responses.

Inappropriate wound healing can lead to fibrosis of an organ and interference with its proper function. Joseph Bonventre and his colleagues have found that G2/M cell cycle arrest of tubular epithelial cells in the kidney after acute injury leads to fibrosis and that targeting this arrest, or the signaling that results from this arrest, is ameliorative for disease progression (pages 523–525 and 544–550).

Individuals with obsessive-compulsive disorder (OCD) perform obsessive repetitive actions. Shahin Rafii and his colleagues show that mice lacking the gene Slitrk5 show OCD-like behavioral phenotypes and have deficits in corticostriatal communication in the brain.

Wound repair involves the proper regeneration of the extracellular matrix. When this process goes awry, organ fibrosis results, damaging the organ's function. Now, Michael Zeisberg and his colleagues have uncovered an epigenetic mechanism by which kidney fibrosis occurs, as well as a potential new therapeutic target to prevent it (pages 523–525 and pages 535–543).

Giardia lamblia is a major intestinal pathogen causing acute or chronic diarrhea. It is thought to evade the immune system by switching its expression of the variant-specific surface protein (VSP), resulting in antigenic variation. Rivero et al. now report that by interfering with the machinery that restricts VSP expression, they can subvert antigenic variation and generate trophozoites that simultaneously express many VSPs and induce broadly reactive immunity against infection with various G. lamblia isolates (pages 522–523).

Chromosomal translocations involving the gene encoding MOZ, a transcriptional regulator, can result in the production of fusion proteins that promote acute myeloid leukemia. In a mouse model of acute myeloid leukemia induced by a MOZ-containing fusion protein, Yukiko Aikawa et al. now identify a potential new therapeutic target, the cytokine receptor CSF1R, which is present on leukemia stem cells and is needed for leukemia induction and progression.

A three-gene expression signature can predict long-term prognosis in two autoimmune diseases, antineutrophil cytoplasmic antibody-associated vasculitis and systemic lupus erythematosus.

T cell receptor (TCR) gene therapy is a promising immunotherapy for cancer and infectious disease. But introducing exogenous TCR α and β chains into T cells may have unintended consequences. In this issue, Bendle et al. show that the transfer of TCR-transduced T cells into mice triggered a lethal pathology that resembles graft-versus-host disease and is caused by the pairing of endogenous and exogenous TCR chains resulting in autoreactive T cells (pages 520–521).

The omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid alleviate inflammatory pain in patients. Ru-Rong Ji and his colleagues find that the resolvins RvE1 and RvD1, which are derived from omega-3 fatty acids, potently reduce pain in a number of animal models of inflammatory pain. These effects are mediated by both peripheral and central mechanisms and suggest that resolvins may represent a new class of analgesics for inflammatory pain (pages 518–520).

Most cases of esophageal cancer can be prevented if detected early at the precancerous high-grade dysplasia stage in patients presenting with Barrett's esophagus, a condition that almost always precedes this form of cancer. Here, Qiu and colleagues have developed a multispectral imaging system that uses endoscopic polarized scanning spectroscopy to perform rapid optical scanning and imaging of the entire esophageal surface, providing a diagnosis in near real time.

Individuals with the disease hereditary hemorrhagic telangiectasia have vascular defects that lead to frequent hemorrhages. Franck Lebrin et al. now show that thalidomide, tested as a therapy in a small set of individuals with this disease, lowers the frequency of hemorrhaging and the need for blood transfusions. The authors tie the antihemorrhagic effects of thalidomide to its ability to promote blood vessel maturation through effects on PDGF-B expression by endothelial cells and on pericyte cell proliferation (pages 370–372).

Proper body weight is determined by orexigenic and anorexigenic neurons in the hypothalamus. Lori Zeltser and her colleagues have found that a subset of neurons in the developing hypothalamus expressing a potent orexigenic hormone is derived from precursors expressing an anorexigenic hormone. These results suggest that developing feeding circuits are more plastic than previously thought and give rise to new concerns about the effects of a mother's diet during pregnancy on her offspring.

Although infectious agents contribute to epilepsy, seizures can also be elicited through inflammatory pathways in sterile conditions. Vezzani and her colleagues demonstrate in both acute and chronic models of epilepsy that HMGB1, a protein normally found in the nucleus, is released by damaged or highly stressed cells and, by binding TLR4, lowers seizure threshold and increases time spent in seizures. Selective inhibition of this pathway retards seizure generation, suggesting new targets for anticonvulsant therapy (pages 369–370).

Insulin can signal through phosphotidylinositol 3-kinase (PI3K) to increase cellular growth, which often results in increased protein translation and stress of the endoplasmic reticulum (ER). Umut Ozcan and his colleagues now find that insulin signaling leads to the disassociation of p85α and p85β, the heterodimeric regulatory subunits of PI3K, allowing them to interact with and increase the nuclear localization of a key transcription factor that resolves ER stress. Thus, in states of insulin resistance, such as in prediabetes, resolution of ER stress is hampered, further exacerbating the disease (pages 374–376 and 438–445).

Interferon-β (IFN-β) is a mainstay therapy for multiple sclerosis. However, only two thirds of patients respond to therapy, and clinical symptoms worsen in some patients. Chandar Raman and his colleagues show that IFN-β alleviates disease induced by T helper type 1 cells and exacerbates disease induced by T helper type 17 cells in mice. They also show that these effects of IFN-β rely on IFN-γ signaling (pages 376–377).

Insulin signals through phosphoinositide 3-kinase (PI3K) to induce cell growth, which often increases protein translation and stress of the endoplasmic reticulum (ER). In two new studies, Umut Ozcan and Ron Kahn and their colleagues now find that in response to insulin signaling, p85α and p85β, the heterodimeric regulatory subunits of PI3K, can increase the nuclear localization of a key transcription factor that resolves ER stress (pages 374–376 and pages 429–437).

A new transpeptidase that modifies the structure of the cell wall of Mycobacterium tuberculosis is important for bacterial virulence and could become the target of new antituberculosis agents.

A technique for expanding hematopoietic stem cell numbers could have many clinical applications, including improving bone marrow transplantation and recovery from myelotoxic chemotherapy. In this report, Heather Himburg et al. suggest a new strategy to accomplish this by identifying pleiotrophin, a growth factor not previously known to affect hematopoiesis, as an inducer of both mouse and human hematopoietic stem cell expansion ex vivo and of hematopoietic stem cell regeneration in vivo.

Although the precipitating mechanisms of atrial fibrillation are not fully understood, atrial fibrosis is thought to set the stage for arrhythmia. Volker Rudolph et al. now show that the enzyme myeloperoxidase, released by inflammatory cells, is a key inducer of atrial fibrosis and arrhythmia in a mouse model of atrial fibrillation, and that myeloperoxidase levels are associated with atrial fibrillation in humans.

McMillin et al. describe a drug screening platform that takes into account the tumor microenvironment, in particular tumor-stromal interactions, enabling the screening of the antitumor activity of candidate anticancer agents in the context of such interactions. The in vitro tumor cell–specific bioluminescence imaging assay is both high throughput and scalable.