Kevin Tse

T cells in atherosclerosis

Atherosclerosis is a chronic inflammatory disease of the artery wall. Atherosclerotic lesions contain monocytes, macrophages, smooth muscle cells and T lymphocytes. Here, we review the role of T-lymphocyte subsets in atherosclerosis. Among CD4⁺T cells, T(h)1 cells are pro-atherogenic, T(reg) cells are athero-protective and the role of T(h)2 and T(h)17 cells remains unclear. The role of follicular helper T cells in atherosclerosis remains unknown, as is the role of CD8⁺T cells. NKT cells bind glycolipid antigens and exert a pro-atherogenic role. The antigen specificity of T-cell responses in atherosclerosis is poorly understood. In order to enable antigen-specific prevention or therapy, a better understanding of these mechanisms is needed.

Update on toll-like receptor-directed therapies for human disease.

Innate responses to microbes are mediated in large part by toll-like receptors (TLRs), which recognise a diverse range of molecules produced by viruses, bacteria and fungi. Great effort has been directed towards translating this knowledge into the development of new therapies for a wide spectrum of diseases, including infectious, malignant, autoimmune and allergic diseases. This review will provide a brief update on completed, ongoing and planned clinical trials of TLR ligand-based therapies for the treatment of diseases in humans.

Light-sheet Bayesian microscopy enables deep-cell super-resolution imaging of heterochromatin in live human embryonic stem cells

BackgroundHeterochromatin in the nucleus of human embryonic cells plays an important role in the epigenetic regulation of gene expression. The architecture of heterochromatin and its dynamic organization remain elusive because of the lack of fast and high-resolution deep-cell imaging tools. We enable this task by advancing instrumental and algorithmic implementation of the localization-based super-resolution technique.ResultsWe present light-sheet Bayesian super-resolution microscopy (LSBM). We adapt light-sheet illumination for super-resolution imaging by using a novel prism-coupled condenser design to illuminate a thin slice of the nucleus with high signal-to-noise ratio. Coupled with a Bayesian algorithm that resolves overlapping fluorophores from high-density areas, we show, for the first time, nanoscopic features of the heterochromatin structure in both fixed and live human embryonic stem cells. The enhanced temporal resolution allows capturing the dynamic change of heterochromatin with a lateral resolution of 50-60 nm on a time scale of 2.3 s.ConclusionLight-sheet Bayesian microscopy opens up broad new possibilities of probing nanometer-scale nuclear structures and real-time sub-cellular processes and other previously difficult-to-access intracellular regions of living cells at the single-molecule, and single cell level.

Atheroprotective vaccination with MHC-II restricted peptides from ApoB-100

Background: Subsets of CD4+ T-cells have been proposed to serve differential roles in the development of atherosclerosis. Some T-cell types are atherogenic (T-helper type 1), while others are thought to be protective (regulatory T-cells). Lineage commitment toward one type of helper T-cell versus another is strongly influenced by the inflammatory context in which antigens are recognized. Immunization of atherosclerosis-prone mice with low-density lipoprotein (LDL) or its oxidized derivative (ox-LDL) is known to be atheroprotective. However, the antigen specificity of the T-cells induced by vaccination and the mechanism of protection are not known. Methods: Identification of two peptide fragments (ApoB3501–3516 and ApoB978–993) from murine ApoB-100 was facilitated using I-Ab prediction models, and their binding to I-Ab determined. Utilizing a vaccination scheme based on complete and incomplete Freund’s adjuvant (CFA and IFA) [1 × CFA + 4 × IFA], we immunized Apoe−/−mice with ApoB3501–3516 or ApoB978–993 emulsified in CFA once and subsequently boosted in IFA four times over 15 weeks. Spleens, lymph nodes, and aortas were harvested and evaluated by flow cytometry and real time RT-PCR. Total atherosclerotic plaque burden was determined by aortic pinning and by aortic root histology. Results: Mice immunized with ApoB3501–3516 or ApoB978–993 demonstrated 40% reduction in overall plaque burden when compared to adjuvant-only control mice. Aortic root frozen sections from ApoB3501–3516 immunized mice showed a >60% reduction in aortic sinus plaque development. Aortas from both ApoB3501–3516 and ApoB978–993 immunized mice contained significantly more mRNA for IL-10. Both antigen-specific IgG1 and IgG2c titers were elevated in ApoB3501–3516 or ApoB978–993 immunized mice, suggesting helper T-cell immune activity after immunization. Conclusion: Our data show that MHC Class II restricted ApoB-100 peptides can be atheroprotective, potentially through a mechanism involving elevated IL-10.

Defining a role for ambient TLR ligand exposures in the genesis and prevention of allergic diseases

Environmental variables responsible for the increasing allergic disease burden observed in developed countries over the last century have yet to be adequately characterized. Meta-analyses of epidemiological studies presented in the first half of this paper demonstrate a correlation between farm-associated exposures (i.e., livestock, pets, unpasteurized milk, and endotoxin) and a reduction in allergic risk during childhood. Laboratory investigations discussed in the second half of the paper characterize the intrinsic immunostimulatory activities of living environments. Considered together, experimental findings presented herein suggest a novel paradigm by which early life home exposures to microbial products and other allergen-nonspecific immunostimulants modify allergic risk.

Vaccination to modulate atherosclerosis

Abstract Atherosclerosis is a chronic inflammatory disease of the artery wall. Adaptive immunity plays a key role in the pathogenesis of atherosclerosis. Recently, modulation of the immune response against atherosclerotic plaque antigen(s) has attracted attention as a potentially preventive and therapeutic approach. Here, we review a series of studies on immunization with various antigens targeting treatment and prevention of atherosclerosis. Atherosclerosis-related antigens include oxidized low-density lipoprotein (LDL), apolipoprotein B-100 (ApoB-100) and heat shock protein (HSP) 60/65. Accumulating evidence supports the idea that immunization with these antigenic proteins or peptides may reduce atherosclerosis. In this review, we discuss the current status of immunization studies and possible associated mechanisms of atheroprotection.

Heritability of Bone Density: Regional and Gender Differences in Monozygotic Twins

Bone mineral density (BMD) is a measure of a persons skeletal mineral content, and assessing BMD by dual x‐ray absorptiometry (DEXA) can help to diagnose diseases of low bone density. In this study, we determine the heritability of BMD in male and female monozygotic twin subjects using DEXA in 13 specific anatomical regions. In an attempt to quantify the genetic contribution of gender and skeletal region to BMD heritability, we scanned 14 pairs of identical twins using DEXA and calculated the broad‐sense heritability coefficient (H2) in each of the 13 different body regions. The region of the body that was most heritable for both genders was the head (H2 ≥ 95%). When males were compared to females, H2 values for male hip (H2 = 87%) and lower extremities (H2 = 90%) were higher than those in females (H2 = 49% and 56%, respectively). Conversely, H2 value for the female pelvis (H2 = 68%) was higher than that for males (H2 = 26%). These data show that different regions of the skeleton exhibit different degrees of heritability, and that the variation depends on gender.

Recognizing and managing hereditary angioedema.

Hereditary angioedema is a rare but life-threatening disease characterized by recurring attacks of swelling of any part of the body, without hives. Prompt recognition is critical so that treatment can be started to minimize morbidity and the risk of death. Drugs have recently become available to prevent and treat acute attacks. Recognizing this rare but life-threatening disease is crucial, especially now that drugs are available to prevent and treat acute attacks.

Atheroprotective vaccination with MHC-II-restricted ApoB peptides induces peritoneal IL-10-producing CD4 T cells

Although immunization with major histocompatibility complex (MHC) class II-restricted apolipoprotein B (ApoB) peptides has been shown to be atheroprotective, the mechanism is unclear. Here, we investigated CD4+ T cell populations in immunized atherosclerotic mice. Peptides (16-mers) from mouse ApoB, the core protein of low-density lipoprotein (LDL), were screened for binding to I-Ab by computer prediction and confirmed by radiolabeled peptide competition. Three new peptides, P101 (FGKQGFFPDSVNKALY, 5.5 nM IC50), P102 (TLYALSHAVNSYFDVD, 6.8 nM), and P103 (LYYKEDKTSLSASAAS, 95 nM), were tested in an atherosclerosis model (Apoe-/- mice on Western diet). Immunization with each of the three peptides (1 time in complete Freunds adjuvant subcuntaneously and 4 time in incomplete Freunds adjuvant intraperitoneally) but not with adjuvant alone showed significantly reduced atherosclerotic plaques in the aortic root by serial sections and in the whole aorta by en face staining. There were no differences in body weight, LDL cholesterol, or triglycerides. Peritoneal leukocytes from ApoB peptide-immunized mice, but not control mice, secreted significant amounts of IL-10 (150 pg/ml). Flow cytometry showed that peptide immunization induced IL-10 in 10% of peritoneal CD4+ T cells, some of which also expressed chemokine (C-C motif) receptor 5 (CCR5). Vaccination with ApoB peptides expanded peritoneal FoxP3+ regulatory CD4+ T cells and more than tripled the number of CCR5+FoxP3+ cells. Similar trends were also seen in the draining mediastinal lymph nodes but not in the nondraining inguinal lymph nodes. We conclude that vaccination with MHC class II-restricted autologous ApoB peptides induces regulatory T cells (Tregs) and IL-10, suggesting a plausible mechanism for atheroprotection.NEW & NOTEWORTHY Vaccination against apolipoprotein B (ApoB), the protein of LDL, attracts attention as a novel approach to prevent atherosclerosis. We discovered major histocompatibility complex class II-restricted ApoB peptides, which reduce atherosclerosis and induce IL-10-producing CD4+ T cells and chemokine (C-C motif) receptor 5 expression on regulatory T cells, suggesting that immunization with ApoB peptides inhibits atherosclerosis by inducing anti-inflammatory cytokines.

Effect of catastrophic wildfires on asthmatic outcomes in obese children: breathing fire.

BACKGROUND Air pollutants from wildfires and obesity independently exacerbate asthma, yet no study has determined the combined effects of these 2 variables on asthma outcomes. OBJECTIVE To determine the effect of 2 catastrophic wildfires affecting the Southern California region (in 2003 and 2007) on several asthma outcomes in a cohort of children. METHODS To investigate the association between wildfire exposure and asthma outcomes, we stratified our study population by body mass index categories (underweight, normal, overweight, and obese) and zip codes (to distinguish individuals who were closer to the fires vs farther away). The primary outcome was the prevalence of physician-dispensed short-acting β-agonist (SABAs). Secondary outcomes included the rate of emergency department visits and/or hospitalizations for asthma, the frequency of oral corticosteroid use for asthma, and number of new diagnoses of asthma. RESULTS A total of 2,195 and 3,965 asthmatic children were analyzed as part of our retrospective cohort during the 2003 and 2007 wildfires, respectively. SABA dispensing increased the most in the obese group after the 2003 wildfires (P < .05). Increased prevalence of SABA dispensing was also noted in the obese group in 2007, but this was not statistically higher than the increases seen in other body mass index groups. There was no observed increase in emergency department and/or hospitalization rates, oral corticosteroid dispensing frequency, or new asthma diagnoses after either wildfire. CONCLUSION Catastrophic wildfires lead to worsening asthma outcomes, particularly in obese individuals. This study gives further evidence of a link between obesity and asthma severity and suggests that air pollutants released during wildfires can have substantial detrimental effects on asthma control.