Apoptosis, autophagy, and necrosis

Two and a half millennia ago Hippocrates used the word “apoptosis” to describe the gangrene resulting from treatment of fractures with bandages. Interestingly, he was describing a pathological form of tissue (cell) death. In 1972 Kerr reused the word “apoptosis” with a different connotation, to describe a physiological form of cell demise with profound biological and pathological implications. Indeed today, 4 decades later, this form of cell death is considered an essential mechanism in all fields of biology and has proven to be a fundamental mechanism in SLE pathogenesis.

In the last 2 decades it has become clear that cell death can occur with multiple modalities and most forms are tightly regulated and molecularly programmed. They all play a role in systemic lupus erythematous (SLE) and they are commonly defined as apoptosis and necrosis; the first is generally considered noninflammatory while the latter pro-inflammatory.

Definition

The definition of a dead cell is more complex than one would anticipate and it has undergone several modifications over the last century. The 2018 updated recommendations by the Nomenclature Committee on Cell Death (NCCD) reevaluated the definitions based primarily on the molecular processes rather than a dying cell morphology, albeit the latter is still widely used. Nevertheless, the committee still considers dead only cells that either exhibit irreversible plasma membrane permeabilization or have undergone complete fragmentation. Generally, cell death should be divided into two main categories, that is, accidental and regulated cell death (ACD and RCD, respectively). ACD is induced by extreme physical or chemical insults, for example, high pressures or temperatures and pH variations and cannot be reversed or delayed; RCD on the other hand is extraordinarily structured and its molecular pathways are evolutionary preserved. RCD is genetically predetermined and it can be modified both genetically and pharmacologically; when its functions are primarily during the embryonic life or to maintain tissue homeostasis or generally in strictly physiological scenarios than it is described as programmed cell death (PCD). Finally, RCD is generally divided into caspase-dependent and caspase-independent, and the major two forms are apoptosis and necrosis, respectively.

Apoptosis

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