APOPTOSIS
Sujata Sawhney*
Consultant Pediatric and Adolescent Rheumatologist Center for Child Health Sir Ganga Ram Hospital, New Delhi.*
Apoptosis is the term that is applied to programmed cell death that results in ordered fragmentation of the cell, the process is slow and in contrast to necrotic cells the cells that undergo apoptosis are shrunken, have condensed nuclei and undergo dissolution by blebbing. The resulting apoptotic bodies are phagocytosed by surrounding cells and are rapidly degraded in lysozymes. Normally:
  • Cell death by this process is slow (6-48 hours)
  • Removal of apoptotic fragments is rapid
  • There is no activation of the immune system and therefore no inflammatory response ensues

Biochemistry of Apoptosis
The biochemical pathways that are responsible for apoptosis have been discovered only in the last decade or so. Cell death has a number of stages that are listed below:
  • Inductive stimuli which can be death or stress pathways
  • Signal transduction
  • Activation of caspases (are specific proteases that cause cell lysis)
  • Activation of nucleases
  • Redistribution of cellular contents into apoptotic bodies
  • Removal of the dying cells
Apoptosis and its relevance to the Immune system:

10⁹ lymphocytes are produced in the bone marrow and in addition a number are clonally expanded in the periphery following contact with antigens. Therefore in order to maintain the lymphocyte pool, an equivalent rate of cell death should occur.

In addition to maintaining the homeostasis, the number of cells in the immune system apoptosis is very important for the induction/preservation of immunologic tolerance.
The basic principles that determine the fate of the lymphocytes is that the:
  • Self reactive cells die
  • Useless lymphocytes die
  • Cells recruited into an immune response by foreign antigens initiate a survival pathway
Central Lymphoid System (Thymus and Bone marrow)
Lymphocytes are poised to die at all stages of maturation.
  • Immature cells die when their antigen receptors fail to undergo productive rearrangement
  • When their antigen receptors bind with high affinity ( negative selection)

T lymphocytes need low affinity binding to self MHC through their antigen receptors to survive and are then seeded to the periphery.

The Peripheral Immune System
Following activation by foreign micro-organisms, the lymphocytes are fully armed/secrete pro-inflammatory cytokines. Once the organism is destroyed, the activated lymphocyte should be removed to avoid unnecessary tissue damage. Apoptosis of the activated cell occurs by
  • Cytokine withdrawal leading to death by the intrinsic pathway
  • Death receptor induction: TNF alpha and Fas

In addition, the down modulation of the immune responses occurs by the T cell surface molecule CTLA 4. Absence of CTLA 4 causes massive inflammation and lymphocyte infiltration of organs in mice deficient for this molecule.

Disposal of apoptotic cells and tolerance
The innate immune system plays an important role in the disposal of macrophages which have engulfed apoptotic material. Avoidance of an immune response to self is ensured by the production of anti inflammatory molecules such as TGF -β₁ and PGE-2.

Apoptosis and its relevance to SLE
  • Apoptosis plays a pivotal role in tolerance induction and maintenance.
  • Handles a large burden of self antigens that are disposed of by this process
  • Abnormalities result in systemic autoimmunity.

Defects in induction/regulation of apoptosis
  • Fas receptor/ligand important to cause apoptosis via death receptor pathways. Mutations have arisen in three mouse strains all have developed massive lymphadenopathy and lupus like disease. They all cause impaired Fas mediated apoptosis.
  • Bcl 2 is an anti apoptotic protein. Manipulations of this gene cause lupus like disease in mice.
  • PTEN deficiency leads to increased activation of Akt; this in turn causes increased cell survival. PTEN +/- heterozygote mice develop lupus and die from glomerulonephritis.
  • Deficiencies of IL-2 cause a lupus like illness, partly because Il2 is needed to decrease the expression of FLIP.

Thus, mutations in the apoptosis inducing molecules or over expression of molecules that promotes lymphocyte survival results in a lupus like syndrome. Why does this occur?
  • Auto reactive cells fail to be deleted
  • When lymphocytes are stimulated by foreign antigens but fail to die they have an increased opportunity to cross react with foreign antigens in the periphery.
  • When this occurs with B cells they have the opportunity to mutate their antigen receptors towards higher affinity binding for self antigens.

Apoptosis and effect clearance of dying cells is a complex phenomenon. There are proteins and receptors that control apoptosis and some that promote cell survival. The clearance of apoptotic cells needs effective macrophage and complement function. Abnormalities in these pathways that impair apoptosis, promote cell survival or prevent effective clearance of the dying cells all promote autoimmunity and SLE. Only a few human with specific abnormalities and a few knock out mice models have been developed to date. Further studies in this field are ongoing.
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