Immunologic Aspects of Dyslipidemia: a Critical Regulator of Adaptive Immunity and Immune Disorders

Dyslipidemia is a major cause of cardiovascular diseases which represent a leading cause of death in humans. Diverse immune cells are known to be involved in the pathogenesis of cardiovascular diseases such as atherosclerosis. Conversely, dyslipidemia is known to be tightly associated with immune disorders in humans, as evidenced by a higher incidence of atherosclerosis in patients with autoimmune diseases including psoriasis, rheumatoid arthritis, and systemic lupus erythematosus. Given that the dyslipidemia-related autoimmune diseases are caused by autoreactive T cells and B cells, dyslipidemia seems to directly or indirectly regulate the adaptive immunity. Indeed, accumulating evidence has unveiled that proatherogenic factors can impact the differentiation and function of CD4+ T cells, CD8+ T cells, and B cells. This review discusses an updated overview on the regulation of adaptive immunity by dyslipidemia and proposes a potential therapeutic strategy for immune disorders by targeting lipid metabolism.

Immunologic Aspects of Dyslipidemia: a Critical Regulator of Adaptive Immunity and Immune Disorders

Dyslipidemia is a major cause of cardiovascular diseases which represent a leading cause of death in humans. Diverse immune cells are known to be involved in the pathogenesis of cardiovascular diseases such as atherosclerosis. Conversely, dyslipidemia is known to be tightly associated with immune disorders in humans, as evidenced by a higher incidence of atherosclerosis in patients with autoimmune diseases including psoriasis, rheumatoid arthritis, and systemic lupus erythematosus. Given that the dyslipidemia-related autoimmune diseases are caused by autoreactive T cells and B cells, dyslipidemia seems to directly or indirectly regulate the adaptive immunity. Indeed, accumulating evidence has unveiled that proatherogenic factors can impact the differentiation and function of CD4+ T cells, CD8+ T cells, and B cells. This review discusses an updated overview on the regulation of adaptive immunity by dyslipidemia and proposes a potential therapeutic strategy for immune disorders by targeting lipid metabolism.

Generating Motion- and Distortion-Free Local Field Map Using 3D Ultrashort TE MRI: Comparison with T₂* Mapping

PURPOSE: To generate phase images with free of motion-induced artifact and susceptibility-induced distortion using 3D radial ultrashort TE (UTE) MRI.MATERIALS AND METHODS: The field map was theoretically derived by solving Laplace's equation with appropriate boundary conditions, and used to simulate the image distortion in conventional spin-warp MRI. Manufacturer's 3D radial imaging sequence was modified to acquire maximum number of radial spokes in a given time, by removing the spoiler gradient and sampling during both rampup and rampdown gradient. Spoke direction randomly jumps so that a readout gradient acts as a spoiling gradient for the previous spoke. The custom raw data was reconstructed using a homemade image reconstruction software, which is programmed using Python language. The method was applied to a phantom and in-vivo human brain and abdomen. The performance of UTE was compared with 3D GRE for phase mapping. Local phase mapping was compared with T₂* mapping using UTE.RESULTS: The phase map using UTE mimics true field-map, which was theoretically calculated, while that using 3D GRE revealed both motion-induced artifact and geometric distortion. Motion-free imaging is particularly crucial for application of phase mapping for abdomen MRI, which typically requires multiple breathold acquisitions. The air pockets, which are caught within the digestive pathway, induce spatially varying and large background field. T₂* map, that was calculated using UTE data, suffers from non-uniform T₂* value due to this background field, while does not appear in the local phase map of UTE data.CONCLUSION: Phase map generated using UTE mimicked the true field map even when non-zero susceptibility objects were present. Phase map generated by 3D GRE did not accurately mimic the true field map when non-zero susceptibility objects were present due to the significant field distortion as theoretically calculated. Nonetheless, UTE allows for phase maps to be free of susceptibility-induced distortion without the use of any post-processing protocols.

The Effectiveness of Ferritin as a Contrast Agent for Cell Tracking MRI in Mouse Cancer Models

PURPOSE: We aimed to investigate the effectiveness of ferritin as a contrast agent and a potential reporter gene for tracking tumor cells or macrophages in mouse cancer models. MATERIALS AND METHODS: Adenoviral human ferritin heavy chain (Ad-hFTH) was administrated to orthotopic glioma models and subcutaneous colon cancer mouse models using U87MG and HCT116 cells, respectively. Brain MR images were acquired before and daily for up to 6 days after the intracranial injection of Ad-hFTH. In the HCT116 tumor model, MR examinations were performed before and at 6, 24, and 48 h after intratumoral injection of Ad-hFTH, as well as before and every two days after intravenous injection of ferritin-labeled macrophages. The contrast effect of ferritin in vitro was measured by MR imaging of cell pellets. MRI examinations using a 7T MR scanner comprised a T1-weighted (T1w) spin-echo sequence, T2-weighted (T2w) relaxation enhancement sequence, and T2*-weighted (T2*w) fast low angle shot sequence. RESULTS: Cell pellet imaging of Ad-hFTH in vitro showed a strong negatively enhanced contrast in T2w and T2*w images, presenting with darker signal intensity in high concentrations of Fe. T2w images of glioma and subcutaneous HCT116 tumor models showed a dark signal intensity around or within the Ad-hFTH tumor, which was distinct with time and apparent in T2*w images. After injection of ferritin-labeled macrophages, negative contrast enhancement was identified within the tumor. CONCLUSION: Ferritin could be a good candidate as an endogenous MR contrast agent and a potential reporter gene that is capable of maintaining cell labeling stability and cellular safety.

Development of (1)H-(31)P Animal RF Coil for pH Measurement Using a Clinical MR Scanner

PURPOSE: To establish a pH measurement system for a mouse tumor study using a clinical scanner, to develop the (1)H and (31)P radio frequency (RF) coil system and to test pH accuracy with phantoms. MATERIALS AND METHODS: The (1)H and the (31)P surface coils were designed to acquire signals from mouse tumors. Two coils were positioned orthogonally for geometric decoupling. The pH values of various pH phantoms were calculated using the (1)H decoupled (31)P MR spectrum with the Henderson-Hasselbalch equation. The calculated pH value was compared to that of a pH meter. RESULTS: The mutual coil coupling was shown in a standard S12. Coil coupling (S12) were -73.0 and -62.3 dB respectively. The signal-to-noise ratio (SNR) obtained from the homogeneous phantom (1)H image was greater than 300. The high resolution in vivo mice images were acquired using a (31)P-decoupled (1)H coil. The pH values calculated from the (1)H-decoupled (31)P spectrum correlated well with the values measured by pH meter (R(2)=0.97). CONCLUSION: Accurate pH values can be acquired using a (1)H-decoupled (31)P RF coil with a clinical scanner. This two-surface coil system could be applied to other nuclear MRS or MRI.

Perfusion Parameters of Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Patients with Rectal Cancer: Correlation with Microvascular Density and Vascular Endothelial Growth Factor Expression

OBJECTIVE: To determine whether quantitative perfusion parameters of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) correlate with immunohistochemical markers of angiogenesis in rectal cancer. MATERIALS AND METHODS: Preoperative DCE-MRI was performed in 63 patients with rectal adenocarcinoma. Transendothelial volume transfer (Ktrans) and fractional volume of the extravascular-extracellular space (Ve) were measured by Interactive Data Language software in rectal cancer. After surgery, microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression scores were determined using immunohistochemical staining of rectal cancer specimens. Perfusion parameters (Ktrans, Ve) of DCE-MRI in rectal cancer were found to be correlated with MVD and VEGF expression scores by Spearman's rank coefficient analysis. T stage and N stage (negative or positive) were correlated with perfusion parameters and MVD. RESULTS: Significant correlation was not found between any DCE-MRI perfusion parameters and MVD (rs = -0.056 and p = 0.662 for Ktrans; rs = -0.103 and p = 0.416 for Ve), or between any DCE-MRI perfusion parameters and the VEGF expression score (rs = -0.042, p = 0.741 for Ktrans ; r = 0.086, p = 0.497 for Ve) in rectal cancer. TN stage showed no significant correlation with perfusion parameters or MVD (p > 0.05 for all). CONCLUSION: DCE-MRI perfusion parameters, Ktrans and Ve, correlated poorly with MVD and VEGF expression scores in rectal cancer, suggesting that these parameters do not simply denote static histological vascular properties.

Contralaterally transplanted human embryonic stem cell-derived neural precursor cells (ENStem-A) migrate and improve brain functions in stroke-damaged rats

The transplantation of neural precursor cells (NPCs) is known to be a promising approach to ameliorating behavioral deficits after stroke in a rodent model of middle cerebral artery occlusion (MCAo). Previous studies have shown that transplanted NPCs migrate toward the infarct region, survive and differentiate into mature neurons to some extent. However, the spatiotemporal dynamics of NPC migration following transplantation into stroke animals have yet to be elucidated. In this study, we investigated the fates of human embryonic stem cell (hESC)-derived NPCs (ENStem-A) for 8 weeks following transplantation into the side contralateral to the infarct region using 7.0T animal magnetic resonance imaging (MRI). T2- and T2*-weighted MRI analyses indicated that the migrating cells were clearly detectable at the infarct boundary zone by 1 week, and the intensity of the MRI signals robustly increased within 4 weeks after transplantation. Afterwards, the signals were slightly increased or unchanged. At 8 weeks, we performed Prussian blue staining and immunohistochemical staining using human-specific markers, and found that high percentages of transplanted cells migrated to the infarct boundary. Most of these cells were CXCR4-positive. We also observed that the migrating cells expressed markers for various stages of neural differentiation, including Nestin, Tuj1, NeuN, TH, DARPP-32 and SV38, indicating that the transplanted cells may partially contribute to the reconstruction of the damaged neural tissues after stroke. Interestingly, we found that the extent of gliosis (glial fibrillary acidic protein-positive cells) and apoptosis (TUNEL-positive cells) were significantly decreased in the cell-transplanted group, suggesting that hESC-NPCs have a positive role in reducing glia scar formation and cell death after stroke. No tumors formed in our study. We also performed various behavioral tests, including rotarod, stepping and modified neurological severity score tests, and found that the transplanted animals exhibited significant improvements in sensorimotor functions during the 8 weeks after transplantation. Taken together, these results strongly suggest that hESC-NPCs have the capacity to migrate to the infarct region, form neural tissues efficiently and contribute to behavioral recovery in a rodent model of ischemic stroke.

Determining the Location of Metallic Needle from MR Images Distorted by Susceptibility Difference

PURPOSE: To calculate the appearance of the image distortion from metallic artifacts and to determine the location of a metallic needle from a distorted MR image. MATERIALS AND METHODS: To examine metal artifacts, an infinite metal cylinder in a strong magnetic field are assumed. The cylinder's axis leaned toward the magnetic field along some arbitrary angle. The Laplace equation for this situation was solved to investigate the magnetic field distortion, and the simulation was performed to evaluation the image artifact caused by both readout and slice-selection gradient field. Using the result of the calculation, the exact locations of the metal cylinder were calculated from acquired images. RESULTS: The distances between the center and the folded point are measured from images and calculated. Percentage errors between the measured and calculated distance were less than 5%, except for one case. CONCLUSION: The simulation was successfully performed when the metal cylinder was skewed at an arbitrary tilted angle relative to the main magnetic field. This method will make it possible to monitor and guide both biopsy and surgery with real time MRI.