Tolerance

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• Tolerance
• And
• Autoimmune Diseases

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Tolerence

• It is a specific immunologic unresponsiveness
• i.e. the absence of specific immunoresponses
  to a particular antigen in a fully
  immunocomptent person
• Unresponsiveness to self antigens is known as
  auto tolerance
• Both B-cells and T-cells participate in
  tolerence
• But T-cells play the primary role

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Central Tolerance

• Clonaldeletion
• The process by which T-cells acquire the
  ability to distinguish self from non self, in
  fetal thymus
• This involves the killing of T-cells that react
  against antigens present in the fetus at that time

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Peripheral Tolerance

• T-cell tolerance (clonal anergy)
• Some self-reactive T cells are not killed in
  thymus
• Functional inactivation of surviving
  self-reactive T cells

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Tolerance

• B-cells become tolerant to self by two
  mechanisms
• 1) Clonal deletion
• Probably while B-cell precursors are in bon
  marrow
• 2) Clonal anergy
• B cells in the periphery
• Tolerance in B-cells is less complete than in
  T-cells
• The most autoimmune diseases are mediated by
  antibodies

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Factors Influencing The Induction Tolerance

• 1) Immunologic maturity of the host
• Neonates are immunologically immature and
  well
• accept allograft that would be rejected by
  mature host
• 2) Structure and dose of antigen
• a- Simple molecules induce tolerance more
  readily than
• complex ones
• b- Very high and very low doses of antigen may
  result
• in tolerance

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Factors Influencing The Induction Tolerance

• 3) T-cells become tolerant more readily and
  remain
• tolerant longer than B-cells
• 4) The continuous presence of antigen helps to
• maintain tolerance
• 5) Administration of immunosuppressive drugs
  enhances tolerance as in transplantation

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Clinical Importance of Tolerance

• 1) Organ transplantation
• Introduction of tolerance may help in
  prevention of rejection
• 2) Tumor development
• Tolerance to tumor antigen results in growth
  of the
• tumor without being detected by the immune
  mechanisms
• 3) Autoimmune disorders
• Disturbance of self-tolerance results in
  autoimmune disease

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• Autoimmune Diseases

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Autoimmune Diseases

• Autoimmune diseases occur due to breakdown of
  the mechanisms that maintain auto tolerance
• Auto-antibodies and self reactive T-cells are
  produced, resulting in tissue damage by several
  mechanisms

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Etiology Of Autoimmune Diseases

• 1) Genetic predisposition
• - Familial incidence of autoimmune diseases
• - Most of them appear to be associated with
  certain
• MHC genes, specially MHC II genes
• e.g. Rheumatoid arthritis is associated with
  DR4
• Thyroditis with DR5
• Multiple sclerosis with DR2
• SLE with DR2/DR3
• Type I diabetes with DR3/DR4
• Ankylosing spondylitis with B27

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Rheumatoid Arthritis
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Etiology Of Autoimmune Diseases

• 2) Exposure to infectious antigens that cross
  react
• with self antigens
• - An immune response to these antigen will
  result
• in immune attack against self antigens
• e.g. Antibodies against M protein of
  Streptococcus pyogens may react with heart valves
  and cause Rheumatic fever
• 3) Alteration of self antigens or the appearance
  of new antigens under the effect of drugs,
  chemicals, or viral infections
• 4) Hormonal influences play a role e.g. SLE
  affects women 10 times more than men

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Mechanisms Of Disease Production

• The disease may be organ specific
• e.g Hashimoto thyroditis
• The disease may be systemic
• e.g. SLE or rheumatoid arthritis
• 1) Binding of an autoantibody to host cells
  result in complement fixation and tissue
  destruction
• e.g. Haemolytic anemia (Type II
  hypersensitivity)

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Mechanisms Of Disease Production

• 2) Formation of immune complexes and their
• deposition in tissues, joints, kidney and
  skin
• The immune complexes fix complement resulting
  in
• tissue damage
• e.g. SLE and rheumatoid arthritis (Type III
  hyper.)
• 3) DTH reactions (Type IV)) due to auto reactive
  T-cells
• e.g. Ulcerative colitis, multiple sclerosis
  and
• type I diabetes

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Laboratory Diagnosis

• 1- There is elevated serum immunoglobulins
• 2- Complement levels may be decreased
• 3- Immune complexe detected in serum or organ
  biopsy
• 4- Auto antibodies can be detected in serum
• e.g. anti-nuclear, anti-smooth muscles, Rh
  factor
• and anti-mitochondrial Ab
• 5- Testing for antibodies specific to particular
  Ag,
• involved in organ specific diseases
  (anti-thyroid Ab)

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• Thanks