APOPTOSIS AND IMMUNOLOGICAL TOLERANCE

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APOPTOSIS AND IMMUNOLOGICAL TOLERANCE

• April 3, 2001

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apoptosis

• From classical Greek, it means falling off, as
  in the falling off of petals from a flower or
  leaves from a tree.

WHY?
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Apoptosis (a-po-TOE-sis)

• Apoptosis (also known as Programmed Cell Death
  (PCD) or Cell Suicide) is a genetically
  prescribed series of events leading to the death
  of a cell and its rapid phagocytosis (uptake) by
  surrounding scavenger cells.

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The Death Of A Cell

• NECROSIS
• Caused by cellular trauma or injury
• Results in swelling/ lysis of cell and release of
  cell contents into surrounding environment
• Causes inflammation and (potentially) autoimmune
  response

• APOPTOSIS
• Triggered as a controlled response
• Results in compaction of cell and
  compartmentalization of cellular contents into
  blebs
• Avoids inflammation associated with necrosis

Bad Death
Good Death
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Apoptosis - History

• Most of the characteristics had been described
  by the early 50s, but the scientific community
  didnt really begin to appreciate its
  significance until 1972.

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Apoptosis in Scientific Literature
Number of MedLine Citations
Year
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Fields Impacted By The Study Of Apoptosis

• Immunology
• Developmental Biology
• Cell Biology
• Neuroscience
• Cancer Biology
• Plant Biology

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Morphological Characteristics

• Nuclear compaction
• Cytoplasmic condensation
• Breakdown of nucleus into discrete fragments
• Cell breakdown into membrane-bound apoptotic
  bodies (blebs) containing intact organelles

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Biochemical Characteristics

• Upregulation of endonuclease
• Cleavage of DNA into 200 bp fragments

• Mitochondrial release of Cytochrome C
• Activation of caspase (cysteine-aspartic acid
  protease) enzymes

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Apoptosis Is Under Genetic Control
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Stimuli Which Trigger Apoptosis

• Withdrawal of growth factors
• Irradiation (gamma, U.V.)
• Heat-shock/cold-shock
• Steroid treatment
• Treatment with chemotherapeutic agents
• Engagement of death receptors

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Diseases Associated With Apoptosis

• Excess/Inappropriate Apoptosis
• AIDS
• Neurodegenerative Disorders
• Alzheimers Disease
• Parkinsons Disease
• ALS (Lou Gehrigs Disease)
• Ischemic Injury
• Myocardial Infarction
• Stroke
• Toxin-induced liver disease
• Alcohol

• Defective Apoptosis
• Cancer
• Follicular Lymphomas
• Hormone-dependent tumors
• Breast Cancer
• Prostate Cancer
• Ovarian Cancer
• Autoimmune Disorders
• Systemic Lupus Erythematosus
• Glomerulonephritis

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Apoptosis And The Immune System

• CTL-mediated (CD8 T cell-mediated) cytotoxicity

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Apoptosis And The Immune System

• CTL-mediated (CD8 T cell-mediated) cytotoxicity
• Lymphocyte development and homeostasis
• Deletion of non-productively rearranged
  immunoglobulin and T cell receptor (TCR)
  molecules
• Deletion of autoreactive B and T lymphocytes
• Deletion of activated peripheral lymphocytes to
  limit an ongoing immune response
• Establishment of immune privilege

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Immune Privilege
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ApoptosisAndImmunologicTolerance
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Immunologic Tolerance

• Negative selection during T cell/B cell
  development in thymus/bone marrow
• Peripheral tolerance induction in B cells
• Receptor blockade
• B cell anergy
• Memory B cells
• Peripheral tolerance induction in T cells
• Activation-induced cell death (AICD)
• Clonal anergy
• Recptor downmodulation
• Natural Killer (NK) cell tolerance

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Oral Tolerance

• Ingestion of antigen can induce tolerance
  (immunologic unresponsiveness).
• Different forms of antigen can skew towards a
  humoral, cellular, or combined immune response.
• Feeding of MBP (myelin basic protein) may
  tolerize autoreactive cells and ameliorate MS
  (multiple sclerosis)

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apoptosis (a-po-TOE-sis)

• From classical Greek, it means falling off, as
  in the falling off of petals from a flower or
  leaves from a tree.

WHY?