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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.
Neutrophils release neutrophil extracellular traps (NETs), chromatin fibers that can ensnare bacteria. In small-vessel vasculitis (SVV), a chronic inflammatory condition linked to antineutrophil autoantibodies, these NETs express SVV-associated autoantigens, accumulate in inflamed kidneys and promote the autoimmune response against neutrophils in people with SVV.
In a new report, Satoru Noguchi and his colleagues have shown that oral administration of various sialic acid compounds helps improve the behavior of skeletal muscles in a mouse model of a severely debilitating human muscle disease—one with no current treatment option. Given the simplicity of their approach, it is possible these findings could have immediate clinical impact.
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 (841–842pages 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.