Articles in 2009

TLR4 has a key role in driving inflammation in mouse models of arthritis and may also have a role in the human disease. The extracellular matrix protein tenascin-C is upregulated in the joints of individuals with rheumatoid arthritis. Here Kim Midwood and her colleagues show that tenascin-C is an endogenous activator of TLR4 and that it contributes to the maintenance of arthritis in mice.

Highly active antiretroviral therapy is unable to eliminate HIV infection, because the virus persists in latently infected CD4⁺ T cells—a so-called virus reservoir. Rafick-Pierre Sekaly and his colleagues have shown that central memory CD4⁺ T cells and transitional memory CD4⁺ T cells are the main cellular reservoirs for HIV, and they suggest a mechanism that ensures the stability of this reservoir of virus.

Natural hosts of simian immunodeficiency virus (SIV)—such as African green monkeys—have evolved to tolerate SIV infection without developing immune deficiency. Jason Brenchley and his colleagues provide a mechanism. They show that CD4⁺ T cells from these animals downregulate the CD4 receptor upon entering the memory pool. Immune functions normally attributed to CD4⁺ T cells are preserved, but the cells become resistant to SIV infection.

Christopher Kirk and his colleagues have developed the first specific inhibitor of the immunoproteasome. They find that the immunoproteasome has a major role in regulating cytokine production, as well as antigen presentation, and their inhibitor has good efficacy in animal models of arthritis.

T-cell recognition of autoantigens is important in the development of autoimmune disease. Now, Hartmut Wekerle and his colleagues demonstrate that organ-specific autoimmune responses may be driven by T cells that simultaneously respond to two different autoantigens found within the same target tissue.

In this report, Witold Kilarski et al. show that the rapid formation of new vessels in healing wound tissue does not depend on endothelial cell proliferation and sprouting, which typically have been presumed to be needed for the growth of new blood vessels. Instead, preexisting vessels enlarge and translocate, a process driven by the tension generated by contracting fibroblasts and/or myofibroblasts (pages 608–610).

Prostaglandins play a key role in inflammation in a variety of settings. Now, Shuh Narumiya and colleagues show that prostaglandin E2 drives the production of inflammatory T helper cells, and that this can be blocked by inhibiting its EP4 receptor subtype. EP4 inhibitors were also effective at inhibiting disease pathogenesis in animal models of two inflammatory diseases.

Warwick Nesbitt, Erik Westein and coworkers describe a new mechanistic model for thrombus growth within a blood vessel, providing evidence that blood flow shear gradients—which can arise from vessel injury, stenosis or obstruction—are important in driving thrombus formation. Rapid changes in blood shear rates lead to dynamic restructuring of membranous structures, called 'tethers', on the platelet surface, facilitating stable platelet deposition onto a growing thrombus (pages 607–608).

Staphylococcal superantigens are potent activators of T cells, causing toxic shock syndrome and death. But surprisingly few staphylococcal infections of humans are associated with TSS, even though the bacteria produce the superantigen toxins. Joaquin Madrenas and his colleagues report that other components of the bacteria can downregulate the superantigen-induced T cell activation, protecting the host from death by TSS.

Proper calcium levels are needed to maintain healthy bones. Michael Amling and his colleagues now show that gastric acidification is a key part of in this process. These findings have possible important clinical implications for patients with osteoporosis and/or those on proton-pump inhibitors, as well as those with a rare genetic disease that causes excess bone mass.

Antibodies capable of neutralizing a wide array of HIV isolates are rarely elicited by the adaptive immune response during HIV infection, and it is not known how to elicit such protective antibodies by vaccination. Philip Johnson and his colleagues have circumvented this hurdle through gene transfer technology. They show that it is possible to protect monkeys from SIV infection by administering intramuscular injections of adeno-associated virus vectors that express broadly neutralizing antibodies that can access the circulation (841–842 pages 951–954).

It has been well shown that NF-κB has a crucial role in promoting the maturation of bone-resorbing osteoclasts. Now, Cun-Yu Wang and his colleagues show that it also has a role in inhibiting the function of mature bone-forming osteoblasts. They go on to show that deficiency of NF-κB specifically in osteoblasts increases bone formation and protects against bone loss in experimentally-induced osteoporosis in mice.

The pathogenesis of aortic aneurysms involves inflammatory cell recruitment and increased levels of reactive oxygen species and matrix metalloproteases. Kimio Satoh et al. now mechanistically link the protein cyclophilin A—expressed in vascular smooth muscle cells—to these known mediators of aortic aneurysm formation and provide evidence in both mice and humans for the importance of cyclophilin A in aortic aneurysm formation.

Several tuberculosis drugs are prodrugs that have to be enzymatically activated during metabolism. Ethionamide is such a drug and is activated by the monooxygenase EthA. EthA is itself regulated by the transcriptional repressor EthR. Here Alain Baulard and his colleagues have designed inhibitors of EthR that boost the antimycobacterial efficacy of ethionamide both in vitro and in vivo. Current therapy with ethionamide requires the use of high doses, often eliciting side effects. Its combination with the EthR repressor should allow lower doses to be used.

Salt intake is associated with hypertension, but the mechanisms by which salt affects blood pressure remain unclear. Agnes Machnik et al. now show that mononuclear cells such as macrophages respond to dietary salt intake by producing the growth factor VEGF-C, leading to expansion of the lymphatic capillary network. Interference with this response in rats fed a high-salt diet exacerbates the increase in blood pressure caused by a high-salt dietpages 487–488..

Polymorphisms in a primate-specific isoform of K⁺ channel KCNH2 are associated with schizophrenia. This isoform induces a rapidly deactivating K⁺ current and high-frequency neuronal firing pattern. The disease-associated alleles predict lower intelligence quotient scores, lower speed of cognitive processing and altered memory. This channel isoform represents a potential new drug target for psychotherapypages 488–490.

Interleukin-7 (IL-7) promotes immune responses and has been touted as a potential tool for improving immune targeting of tumors. Here Pellegrini et al. investigate the mechanisms by which IL-7 increases antitumor responses and the treatment strategies necessary to optimize its effects.

T cells must enter the brain to induce the autoimmune disease multiple sclerosis. Lydia Sorokin and her colleagues identify a mechanism by which T cells migrate across the endothelial basement membrane, a key step to their passage from the blood into the brain.

Kurt Redlich and his colleagues show that estrogen deficiency results in increased numbers of preosteoclast progenitor cells in the bones of mice. But they also find that lack of CCR2 in these future bone-resorbing cells prevents their maturation and thus protects the mice from osteoporosis, suggesting a future target for therapy in humans.

House dust mite allergen (HDM) is a potent trigger of airway inflammation. Dendritic cells (DCs) and lung epithelial cells both express the pathogen receptor TLR4, which senses lipopolysaccharide contaminating the allergen. Bart Lambrecht and his colleagues show that TLR4 on the epithelial cells, not the DCs, is the primary sensor of HDM. TLR4 on these lung structural cells is required for recruitment of DCs and the induction of allergic inflammation in response to HDM (pages 366–367).