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Guide 7
 

Guide 7

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  • Autoimmunity can be defined as what happens when the immune system becomes activated by self-antigens. Another way of putting it, is that the immune system no longer recognizes itself, and thus mounts a response to its own constituents, destroying itself in the process. Generally, autoimmunity is prevented by the active mechanism of self tolerance. This requires the distinction between self-reactive and non-self reactive lymphocytes. However, the elimination of self-reactive lymphocytes is not absolute because some self-reactive lymphocytes provide immunity against non-self. This means that everyone has some self-reactive antigens, only, they have not activated our antibodies…yet…
  • When the body mounts an immune response against itself, it is impossible for the immune mechanism to eliminate the antigen completely. Consequently, there is a sustained response, which results in chronic inflammation, tissue damage and, in some cases, even death! The type of autoimmune disease resulting from lymphocyte activation by self antigens depends on their target tissue/organ. Fortunately, incidences of autoimmunity are low in the population. The immune system has developed several mechanisms that work together to prevent autoimmune disease. There are several stages in order to compensate for the failure of the other. But sometimes, even they are not enough to protect us.
  • During the development of mature B and T cells, from a lymphoid precursor, antibodies highly attracted to self-antigens are eliminated. However, those antibodies that recognize self-antigens but with low affinity are kept in the periphery. Lymphocytes in the bone marrow will become B-cells and those in the Thymus will become T-cells. As they are maturing, those cells that are self-reactive will undergo apoptosis, in a process that is called central tolerance. Most of the lymphocytes will recognize foreign antigens and, therefore, enter the periphery where they will expand when they meet antigen. A few self-recognizing lymphocytes with low-reactivity with self will also enter the periphery, where they will either remain inactive or be deleted in order to prevent disease. This is called peripheral tolerance.
  • Receptor Editing In receptor editing, the B cell will stop in maturation and rearrange to make a light chain with a different specificity. If, again, they recognizes a self-antigen, they will undergo apoptosis. If they don’t, the B cell will mature and go to the periphery.
  • If the B-cells are recognizing soluble antigens with high affinity, they will go to the periphery and become anergic, i.e. they will become inactive Low affinity B-cells will also go to the periphery but be kept clonally ignorant , meaning that when they encounter self-antigen they will not become activated Finally,if the B-cell does not recognize self-antigen, they will grow and mature, then migrate to the periphery and be functional
  • Once the cells have moved into the periphery, there are still more mechanisms in place to eliminate self-antigens. Some of the mechanisms include: ignorance, antigen sequestration, phenotypic skewing and apoptosis.
  • One of the most important mechanisms. Lymphocytes with low affinity for self-antigen, that have travelled to the periphery, can never encounter self antigen and thus remain ignorant. Some of them can go to the periphery and encounter the self-antigen but can avoid becoming activated by it in normal conditions. They remain ignorant, of self but functional to foreign agents. Unfortunately, ignorance can be overcome by strong stimulus like major infection or tissue damage and can lead to autoimmune reactions.
  • One of the most important mechanisms. Lymphocytes with low affinity for self-antigen, that have travelled to the periphery, can never encounter self antigen and thus remain ignorant. Some of them can go to the periphery and encounter the self-antigen but can avoid becoming activated by it in normal conditions. They remain ignorant, of self but functional to foreign agents. Unfortunately, ignorance can be overcome by strong stimulus like major infection or tissue damage and can lead to autoimmune reactions.
  • Phenotypic Skewing: Some auto-reactive T-cells secrete cytokines that will fail to cause auto-immunity but cause tissue damage instead
  • B-cells increase their affinity for a specific antigen when they encounter an antigen in the periphery. However, some B-cells that become activated by self antigens are removed by apoptosis (programmed cell death).
  • Antigen sequestration: There are immunological privileged sites where self-antigens are sequestered: brain, eye, testis, uterus, etc. Normally, in these privileged sites, there is not T-cell activation. However, if there is a trauma, there is a massive release of self-antigens which can go to the lymph nodes and activate auto-reactive T-cells. Autoimmunity to the traumatized privileged organ will happen and since the T-cells are no longer ignorant to the self-antigen, the traumatized privileged organ will also be affected!
  • Familial studies suggest clear association between genetics and autoimmune disease, particularly for those with an organ-specific pathology. Many were also most commonly found in females, also suggesting a genetic basis to the disorder. However, studies between identical twins show that despite identical genetic background, cellular processes and environment also play a role

Guide 7 Guide 7 Presentation Transcript

  • AUTOIMMUNITY When the Good Turns Bad… - A Guide for Teachers - Prepared by Johanna Mancini for Immunology Montreal August 2008
  • What is autoimmunity?
    • When the immune system is activated by self-antigens
    • When the immune system no longer recognizes itself
    • Generally is prevented by “self-tolerance”, where self-reactive antigens are eliminated
    • But, the body cannot eliminate all self-reactive antigens because some help protect against foreign antigens!
    • This means that everyone has some self-reactive antigens, only, they have not activated our antibodies…yet…
  • What is autoimmunity?
    • When body mounts immune response against self, it is impossible for immune mechanism to eliminate antigen completely
    • Result: a sustained response, chronic inflammation, tissue damage and sometimes death!
  • Tolerance
  • Mechanisms of Self-Tolerance
    • Receptor Editing
    • In receptor editing, the B
    • cell will stop in maturation
    • and rearrange to make a
    • light chain with a different
    • specificity. If, again, they
    • recognizes a self-antigen,
    • they will undergo apoptosis.
    • If they don’t, the B cell will
    • mature and go to the
    • periphery.
  • Mechanisms of Self-Tolerance
    • If the B-cells are recognizing soluble antigens with high affinity, they will go to the periphery and become anergic, i.e. they will become inactive
    • Low affinity B-cells will also go to the periphery but be kept clonally ignorant , meaning that when they encounter self-antigen they will not become activated
    • Finally,if the B-cell does not recognize self-antigen, they will grow and mature, then migrate to the periphery and be functional
  • Peripheral Tolerance
    • Once the cells have moved into the periphery, there are still more mechanisms in place to eliminate self-antigens
      • Ignorance
      • Anergy
      • Phenotypic skewing
      • Apoptosis
      • Antigen sequestration
  • Peripheral Tolerance
    • Ignorance:
    • An important mechanism
    • Lymphocytes with low affinity for self-antigen, can go
    • to the periphery and encounter the self-antigen but
    • can avoid becoming activated by
    • They remain ignorant, of self but functional
    • to foreign agents
    • Unfortunately, ignorance can be overcome by strong
    • stimulus like major infection or tissue damage and
    • can lead to autoimmune reactions
  • Peripheral Tolerance
    • Anergy:
    • B-cells recognize
    • soluble antigen with
    • high affinity and go to
    • periphery, where
    • they become inactive
  • Peripheral Tolerance
    • Phenotypic Skewing:
    • Some auto-reactive T-
    • cells secrete cytokines
    • that will fail to cause
    • auto-immune tissue
    • damage
  • Peripheral Tolerance
    • Apoptosis:
    • B-cells increase their affinity for a
    • specific antigen when they
    • encounter an antigen in the
    • periphery. However, some B-cells
    • that become activated by self
    • antigens are removed by apoptosis
    • (programmed cell death)
  • Peripheral Tolerance
    • Antigen Sequestration:
    • Immunological privileged
    • sites where self-antigens are
    • sequestered, such as the
    • brain, eye, testis, uterus, etc.
    • normally, have no T cell
    • activation. However, if there
    • is a trauma, there is a
    • release of self-antigens
    • which can activate auto-
    • reactive T-cells.
    • Autoimmunity will occur in
    • the traumatized privileged
    • organ since the T-cells are
    • no longer ignorant
  • Types of Autoimmune Disease
    • Autoimmune disease is generally classified into systemic or organ specific diseases
      • Diabetes: involves antibodies against the insulin receptor in the pancreas, causing hyperglycemia
      • Graves Disease: involves antibodies against the thyroid stimulating receptor, causing hyperthyroidism
      • Multiple Sclerosis: involved antibodies that react against the central nervous system
  • Types of Autoimmune Disease
    • However, in some cases, the self-antigen is found everywhere in the body
      • Systemic Lupus: chronic inflammation of the connective tissue, characterized by red scaly skin lesions
      • Rheumatoid Arthritis: chronic inflammation of the joints
      • Myasthenia Gravis: caused by antibodies against acetylcholine receptor
  • Factors Affecting Autoimmunity
    • Familial studies suggest clear association between genetics and autoimmune disease
    • Also found to be more prevalent in women
    • However, studies between identical twins show that despite identical genetic background, cellular processes and environment also play a role
  • Vocabulary
    • anergy: a state of non-responsiveness to antigen
    • antibody: an antigen-binding immunoglobulin, produced by B-ells, that functions as the effector of an immune response
    • antigen: a foreign molecule that does not belong to the host organism and that elicits an immune response
    • B-cell: a type of lymphocyte that develops in the bone marrow and later produces antibodies, which mediate humoral immunity
    • central tolerance: when auto-reactive B-cell in the bone marrow and auto-reactive T-cells in the thymus are eliminated
    • humoral immunity: the type of immunity that fights bacteria and viruses in the body fluids with antibodies that circulate in blood plasma and lymph
    • immune system: is the name used to describe the totality of the host defence mechanism
    • lymphocyte: a class of white blood cells; two main classes: B-cells and T-cells, which mediate humoral and cell-mediated immunity, respectively.
    • peripheral tolerance: is tolerance acquired by mature lymphocytes in the peripheral tissue
    • plasma cell: a derivative of B-cells that secretes antibodies, i.e. antibody factory
    • T-cell: a type of lymphocyte that develops in the thymus
  • References
    • 1) Janeway, Charles A. et al. Immunobiology, 6 th edition. Garland Science, 2005.
    • 2) Wikipedia: Autoimmunity . Accessed August 2007. http://en.wikipedia.org/wiki/Autoimmune
    • 3) Campbell, Neil A., Jane B. Reece, Lawrence G. Mitchell. Biology, 7 th edition . Pearson Education, Inc. 2002.
  • Made possible by: www.immunologymontreal.ca www.cihr-irsc.gc.ca/synapse www.mcgill.ca/hostres/training