T cells from RA patients are hypoglycolytic due to insufficient induction of the glycolytic activator PFKFB3, resulting in impaired autophagy and reduced ROS production.

To promote their pathology, CD4 T-cells from patients with rheumatoid arthritis (RA) have to clonally expand and differentiate into cytokine-producing effector cells. In contrast to healthy T-cells, naïve RA T-cells have a defect in glycolytic flux due to upregulation of glucose-6-phosphate dehydrogenase (G6PD). Excess G6PD shunts glucose into the pentose phosphate pathway (PPP), resulting in NADPH accumulation and ROS consumption. With surplus reductive equivalents, RA T-cells insufficiently activate the redox-sensitive kinase ATM; bypass the G2/M cell cycle checkpoint and hyperproliferate. Insufficient ATM activation biases T-cell differentiation towards the Th1 and Th17 lineages, imposing a hyper-inflammatory phenotype. We have identified several interventions that replenishing intracellular ROS, correct the abnormal proliferative behavior of RA T-cells and successfully suppress synovial inflammation. Rebalancing glucose utilization and restoring oxidant signaling may provide a novel therapeutic strategy to prevent autoimmunity in RA.

Renal fibrosis is the common pathological hallmark of progressive chronic kidney disease (CKD) with diverse aetiologies. Recent researches have highlighted the critical role of hypoxia during the development of renal fibrosis as a final common pathway in end‐stage kidney disease (ESKD), which joints the scientist's attention recently to exploit the molecular mechanism underlying hypoxia‐induced renal fibrogenesis. The scaring formation is a multilayered cellular response and involves the regulation of multiple hypoxia‐inducible signalling pathways and complex interactive networks. Therefore, this review will focus on the signalling pathways involved in hypoxia‐induced pathogenesis of interstitial fibrosis, including pathways mediated by HIF, TGF‐β, Notch, PKC/ERK, PI3K/Akt, NF‐κB, Ang II/ROS and microRNAs. Roles of molecules such as IL‐6, IL‐18, KIM‐1 and ADO are also reviewed. A comprehensive understanding of the roles that these hypoxia‐responsive signalling pathways and molecules play in the context of renal fibrosis will provide a foundation towards revealing the underlying mechanisms of progression of CKD and identifying novel therapeutic targets. In the future, promising new effective therapy against hypoxic effects may be successfully translated into the clinic to alleviate renal fibrosis and inhibit the progression of CKD.

No abstract

Immune aging is best known for its immune defects that increase susceptibility to infections and reduce adaptive immune responses to vaccination. In parallel, the aged immune system is prone to autoimmune responses and many autoimmune diseases increase in incidence with age or are even preferentially encountered in the elderly. Why an immune system that suboptimally responds to exogenous antigen fails to maintain tolerance to self-antigens appears to be perplexing. In this review, we will discuss age-associated deviations in the immune repertoire and the regulation of signaling pathways that may shed light on this conundrum.