Autophagy in autoimmune disease

Abstract

Autophagy is a protective and life-sustaining process in which cytoplasmic components are packaged into double-membrane vesicles and targeted to lysosomes for degradation. This process of cellular self-digestion is an essential stress response and is cytoprotective by removing damaged organelles and proteins that threaten the cell’s survival. Key outcomes include energy generation and recycling of metabolic precursors. In the immune system, autophagy regulates processes such as antigen uptake and presentation, removal of pathogens, survival of short- and long-lived immune cells and cytokine-dependent inflammation. In all cases, a window of optimal autophagic activity appears critical to balance catabolic, reparative and inflammation-inducing processes. Dysregulation of autophagosome formation and autophagic flux can have deleterious consequences, ranging from a failure to “clean house” to the induction of autophagy-induced cell death. Abnormalities in the autophagic pathway have been implicated in numerous autoimmune diseases. Genome-wide association studies have linked polymorphisms in autophagy-related genes with predisposition for tissue-destructive inflammatory disease, specifically in inflammatory bowel disease and systemic lupus erythematosus. Although the precise mechanisms by which dysfunctional autophagy renders the host susceptible to continuous inflammation remain unclear, autophagy’s role in regulating the long-term survival of adaptive immune cells has recently surfaced as a defect in multiple sclerosis and rheumatoid arthritis. Efforts are underway to identify autophagy-inducing and autophagy-suppressing pharmacologic interventions that can be added to immunosuppressive therapy to improve outcomes of patients with autoimmune disease.

Aging of the Immune System. Mechanisms and Therapeutic Targets

“…Multiple critical functions of proliferating and differentiating T cells are dependent on oxidant signaling, leaving individuals with prematurely aged T cells with a functionally reprogrammed immune system (Figure 2). Notably, PFKFB3 is also involved in inducing autophagy, and PFK-deficient RA T cells fail to rely on autophagy as a means of energy generation (43,44). The energy stress of aging T cells is aggravated by the disproportionate expression of the ATPase CD39 (45).…”

The Role of Cell Autophagy in Toxicity Caused by Dental Nanomaterials

“…Mammalian cells use three basic autophagic pathways for "self eating": macroautophagy, microautophagy and Chaperone Mediated Autophagy (CMA) [21].…”

“…Autophagy is a self degradation process to recycle cellular components under stressed conditions, such as a lack of nutrients. Autophagy has been regarded as a nonselective process in the past however, accumulating evidence shows that it can be selective to remove specific proteins and damaged organelles, such as mitochondria under certain conditions [21]. Autophagy consists of 4 sequential steps: initiation of autophagosome formation, elongation and closure of autophagic membrane, fusion between autophagosome and lysome and degradation.…”

“…In recent years the range of autophagy substrates has also been extended to lipids termed lipophagy. Autophagy is recognized as playing a central role in cell survival and longevity.Mammalian cells use three basic autophagic pathways for "self eating": macroautophagy, microautophagy and Chaperone Mediated Autophagy (CMA) [21].All of them use lysosomes as a tool for degradation of substrates. They differ from each other in mechanism by which cargo is delivered to the lysosomes and each of them is also activated under different conditions.…”

Pathogenic Role of Autophagy in Rheumatic Diseases

“…In microautophagy, cytoplasmic proteins and organelles are processed by inward invagination of the lysosomal membrane. In chaperone-mediated autophagy, target contents are selectively recognized by a cytosolic chaperone that delivers them to the lysosomal-associated membrane protein type 2A and internalization followed by degradation [4,5].…”