T-cell metabolism in rheumatoid arthritis: focus on mitochondrial and lysosomal dysfunction.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by immune cell dysregulation, synovial hyperplasia, and progressive cartilage destruction. The loss of immunological self-tolerance against autoantigens is the crucial insult responsible for the pathogenesis of RA. These immune abnormalities are experienced many years before the onset of clinical arthritis. OBJECTIVE: This review aims to discuss the metabolic status of T-cells in RA and focuses mainly on mitochondrial and lysosomal dysfunctions involved in altering the T-cell metabolism. DISCUSSION: T-cells are identified as the primary initiators of immunological abnormalities in RA. These RA T-cells show a distinct metabolic pattern compared to the healthy individuals. Dampened glycolytic flux, poor ATP production, and shifting of glucose to the pentose phosphate pathway resulting in increased NADPH and decreased ROS levels are the common metabolic patterns observed in RA T-cells. Defective mtDNA due to lack of MRE11A gene, a key molecular actor for resection, and inefficient lysosomal function due to misplacement of AMPK on the lysosomal surface were found to be responsible for mitochondrial and lysosome dysfunction in RA. Targeting this mechanism in RA can alleviate aggressive T-cell phenotype and may control the severity of RA.

Targeting Epigenetic Mechanisms: A Boon for Cancer Immunotherapy.

Immunotherapy is rapidly emerging as a promising approach against cancer. In the last decade, various immunological mechanisms have been targeted to induce an increase in the immune response against cancer cells. However, despite promising results, many patients show partial response, resistance, or serious toxicities. A promising way to overcome this is the use of immunotherapeutic approaches, in combination with other potential therapeutic approaches. Aberrant epigenetic modifications play an important role in carcinogenesis and its progression, as well as in the functioning of immune cells. Thus, therapeutic approaches targeting aberrant epigenetic mechanisms and the immune response might provide an effective antitumor effect. Further, the recent development of potent epigenetic drugs and immunomodulators gives hope to this combinatorial approach. In this review, we summarize the synergy mechanism between epigenetic therapies and immunotherapy for the treatment of cancer, and discuss recent advancements in the translation of this approach.