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Molecular and Cellular Pathogenesis of Systemic Lupus Erythematosus
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
George C. Tsokos, Yuang-Taung Juang, Christos G. Tsokos, Madhusoodana P. Nambiar
Dissociation of the lipid-rafts by cholesterol depletion using methyl-ß-cyclodextrin, showed increased percentage of the residual membrane bound T cell receptor ζ chain in the lipid-rafts in resting SLE T cell membranes.27 Fluorescence microscopy indicated that the residual T cell receptor ζ chain is more clustered on the cell membranes of SLE T cells compared to normal. Faster kinetics of T cell receptor/CD3 mediated intracellular calcium response in SLE T cells also support the clustering or cross-talk between signaling pathways in SLE. Upon T cell receptor/CD3 activation, ζ chain clusters became more prominent in SLE T cells and they superimpose with linker for activation of T cells suggesting that they are colocalized to lipid rafts. Increased lipid-raft association and surface clustering of the residual T cell receptor ζ chain may explain the increased T cell receptor/ CD3-mediated intracellular response in SLE T cells. Based on these data, we have proposed a model that suggests that in SLE T cells, although there is a deficiency, the residual T cell receptor ζ chain is more associated with membrane lipid rafts resulting in more preformed T cell receptor clustering. Increased membrane T cell receptor clustering, as well as replacement of the deficient T cell receptor ζ chain by FceRTv chain, could lead to increased intracellular calcium response under T cell receptor ζ chain deficiency and decreased tolerance in SLE T cells. In support of this view, recently, it has been reported that mice with N-acetylglucosaminyltransferase deficiency show decreased glycosylation of T cell membrane proteins that prevent galectin binding and thereby disrupting the galectin-glycoprotein lattice, leading to increased clustering of T cell receptor.43 Increased T cell receptor clustering in these autoimmune mice had a very similar phenotype to human SLE, with lowered T cell activation thresholds and increased T cell receptor signaling.44 Similarly, it has also been suggested that genetic remodeling of protein glycosylation by mutation of α mannosidase II induce autoimmune disease.45 As the association between the residual ζ chain with the lipid rafts, T cell receptor clustering and T cell effector functions is further explored, it is likely that important new insights will emerge that will explain ζ chain abnormalities and autoreactivity of T cells.
Cardiorespiratory fitness and targeted proteomics involved in brain and cardiovascular health in children with overweight/obesity
Published in European Journal of Sport Science, 2023
Abel Plaza-Florido, Maria Rodriguez-Ayllon, Signe Altmäe, Francisco B. Ortega, Irene Esteban-Cornejo
LAT and CXCL1 proteins (from Neurology and Cardiovascular panels) showed the highest mean differences (-1.00 and -1.04 NPX values respectively; A 1 NPX value difference means a doubling of protein concentration) between fit and unfit groups (downregulated in plasma of fit compared to unfit children with OW/OB). LAT (Linker for activation of T-cells family member 1) is part of the T-cell receptor complex (TCR). It works as an integrator node of several signalling pathways regulating T cell activation (Bartelt & Houtman, 2013). In this context, obesity is characterized by chronic “over-activation” of the immune system, which is reflected by altered T cell activity and infiltration in adipose tissue contributing to systemic low-grade chronic inflammation (Wang et al., 2021). Thus, we could hypothesize that lower levels of LAT in plasma of fit compared to unfit children with OW/OB could be indicative of a lower chronic “over-activation” of the immune system. In the brain health context, an experiment in the zebrafish model showed that LAT could impact early neurogenesis (Loviglio et al., 2017). LAT suppression was associated with increasing brain cells number and size. Conversely, LAT overexpression was associated with decreased cell proliferation in the brain and microcephaly in zebrafish (Loviglio et al., 2017). CXCL1 (C-X-C Motif Chemokine Ligand 1) is involved in the immune- inflammatory response (i.e. contribute to attracting immune cells into injury sites) (Wang et al., 2018), and higher CXCL1 levels in plasma were associated with more adiposity in young adults (Klevebro et al., 2021). Childhood obesity is characterized by a systemic low-grade inflammation that is related to a higher risk of CVD (Barton, 2012; Ortega et al., 2016). In this context, CXCL1 has been considered a pro-inflammatory chemokine and its neutralization has been proposed as a therapeutic target for CVD treatment (Wang et al., 2018). Interestingly, regular physical activity, which can increase CRF levels, decreased CXCL1 levels in serum of rodents (Jablonski et al., 2020). Our findings suggest that CRF could contribute to reduced CXCL1 levels in plasma of children with OW/OB.