The early colocalization of T cells and the potent immunostimulatory cytokine IFN-␥ to atherosclerotic lesions suggest that the immune system contributes to atherogenesis. Since mice with a targeted disruption of the apoE gene (apoE 0 mice) develop profound atherosclerosis, we examined the role of IFN-␥ in this process. First, the presence of CD4 ϩ and CD8 ϩ cells, which secrete lesional IFN-␥ , was documented in apoE 0 atheromata. Then, the apoE 0 mice were crossed with IFN-␥ receptor (IFN ␥ R) 0 mice to generate apoE 0/IFN ␥ R 0 mice. Compared to the apoE 0 mice, the compound knock-out mice exhibited a substantial reduction in atherosclerotic lesion size, a 60% reduction in lesion lipid accumulation, a decrease in lesion cellularity, but a marked increase in lesion collagen content. Evaluation of the plasma lipoproteins showed that the compound knockout mice had a marked increase in potentially atheroprotective phospholipid/apoA-IV rich particles as well. This correlated with an induction of hepatic apoA-IV transcripts. These observations suggest that IFN-␥ promotes and modifies atherosclerosis through both local effects in the arterial wall as well as a systemic effect on plasma lipoproteins. Therefore, therapeutic inhibition of IFN-␥ signaling may lead to the formation of more lipid-poor and stable atheromata. ( J. Clin. Invest. 1997. 99:2752-2761.)

No abstract

The TH17 lineage is a novel CD4+ T cell effector subset that plays a key role in inflammatory and autoimmune responses, via its ability to produce IL-17 and IL-21. Given the potentially deleterious effects of TH17 cells, their generation needs to be strictly controlled. The regulatory pathways that prevent the inappropriate development of TH17 cells have not been fully elucidated. IRF-4 is a transcription factor that has recently emerged as a key regulator of TH17 differentiation. Our laboratory has isolated a protein, which interacts with IRF-4, that we have termed IBP (IRF-4 Binding Protein). Our studies previously demonstrated that IBP can act as an activator of Rho GTPases and that mice deficient in IBP develop a lupus-like syndrome upon aging. Here we show that TCR transgenic IBP deficient mice rapidly develop rheumatoid arthritis-like joint disease and large-vessel vasculitis. The pathology observed in the absence of IBP is associated with an enhanced responsiveness of T cells to low-levels of stimulation and with the inappropriate synthesis of IL-17 and IL-21. Furthermore, we demonstrate that the effect of IBP on cytokine production is due to its ability to sequester IRF-4 and prevent it from targeting the transcriptional regulatory regions of the IL-17 and IL-21 genes. Consistent with this finding, the enhanced ability of IBP deficient T cells to produce IL-17 and IL-21 is abolished by the concurrent lack of IRF-4. Taken together these studies suggest that IBP plays a key regulatory role in the prevention of T cell-mediated autoimmunity by ensuring that the production of IL-17 and IL-21 does not occur in response to self-antigens.

TRAF6 expression is enhanced during muscle atrophy and induces activation of signal transduction cascades that promote muscle wasting.

Object. Standard techniques for pedicle screw fixation of the lumbar spine involve open exposures and extensive muscle dissection. The purpose of this study was to report the initial clinical experience with a novel device for percutaneous posterior fixation of the lumbar spine. Methods. An existing multiaxial lumbar pedicle screw system was modified to allow screws to be placed percutaneously by using an extension sleeve that permits remote manipulation of the polyaxial screw heads and remote engagement of the screw-locking mechanism. A unique rod-insertion device was developed that linked to the screw extension sleeves, allowing for a precut and -contoured rod to be placed through a small stab wound. Because the insertion device relies on the geometrical constraint of the rod pathway through the screw heads, minimal manipulation is required to place the rods in a standard submuscular position, there is essentially no muscle dissection, and the need for direct visual feedback is avoided. Twelve patients (six men and six women) who ranged in age from 23 to 68 years underwent pedicle screw fixation in which the rod-insertion device was used. Spondylolisthesis was present in 10 patients and osseous nonunion of a prior interbody fusion was present in two. All patients underwent successful percutaneous fixation. Ten patients underwent single-level fusions (six at L5—S1, three at L4–5, and one at L2–3), and two underwent two-level fusions (one from L3–5 and the other from L4—S1). The follow-up period ranged from 10 to 19 months (mean 13.8 months). Conclusions. Although percutaneous lumbar pedicle screw placement has been described previously, longitudinal connector (rod or plate) insertion has been more problematic. The device used in this study allows for straightforward placement of lumbar pedicle screws and rods through percutaneous stab wounds. Paraspinous tissue trauma is minimized without compromising the quality of spinal fixation. Preliminary experience involving the use of this device has been promising.