The Molecular Basis for

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The Molecular Basis for Autoimmune Diseases Dr.
Adel Almogren Dept of Pathology, Immunology
unit Email almogren_at_ksu.edu.sa Office 467-1843
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Autoimmunity
Immune system has evolved to discriminate between
self and nonself or safe and dangerous signals
Ability developed during fetal life
Tolerance, a form of censorship of the immune
system, is acquired by

• Deletion (clonal deletion)
• OR
• B) Functional inactivation (clonal anergy)
• of developing lymphocytes that possess antigenic
  receptors with high affinity for self-antigens.

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Central and Peripheral Tolerance
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Peripheral Tolerance of T Lymphocytes
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Peripheral B cell Tolerance Mechanisms
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Autoimmune Diseases
Self-reactive lymphocytes (the forbidden clones)
should be eliminated from the immunological
repertoire.
Diseases involving an immunological response to
normal tissue termed autoimmunity or
autoimmune diseases.
Original concept the receptors of lymphocytes
with specificity for foreign antigens underwent
mutation results in a new class of receptors
with specificity for self-antigens.  
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Autoimmune Diseases in Humans
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Pathology of Autoimmune Diseases
Most of the autoimmune diseases attributed to
autoantibodies. Other autoimmune diseases have
an autoreactive T cell component. Disease
processes and tissue damage are due to Type II
Type III and Type IV hypersensitivity reactions.
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Type II Hypersensitivity Autoimmunity
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Autoimmune Diseases due to Type II
Hypersensitivity
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Type III Hypersensitivity Autoimmunity
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Autoimmune Diseases due to Type III
Hypersensitivity
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Type IV Hypersensitivity
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Autoimmune Diseases due to Type IV
Hypersensitivity
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• Organ specific AI diseases
• (mediated by direct cellular damage)
• Hashimoto thyroiditis Autoabs T DTH
• Autoimmune Anaemia Pernicious A, A hemolytic A,
  Druginduced A.
• Goodpastures syndrome
• Insulin dep. DM (IDDM)
• the second category is
• (mediated by stimulating or blocking
  autoantibodies)
• Graves disease
• Myasthenia gravis

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Graves Disease

• Production of thyroid hormones is regulated by
  thyroid-stimulating hormones (TSH)
• The binding of TSH to a receptor on thyroid cells
  activates adenylate cyclase and stimulates the
  synthesis of two thyroid hormones thyroxine and
  triiodothyronine
• A person with Graves Disease makes
  auto-antibodies to the receptor for TSH. The
  binding of these auto-antibodies to the receptor
  mimics the normal action of TSH, without the
  regulation, leading to overstimulation of the
  thyroid
• The auto-antibodies are called long-acting
  thyroid stimulating hormones

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Myasthenia gravis
Motor end-plates of muscles
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• American College of Rheumatology
• 4 out of 11
• Malar rash
• DSL
• PS
• OU
• NA
• S
• RD
• ND
• HD
• ImD
• ANA

• Systemic AI diseases
• SLE
• SLE patient

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1. Multiple sclerosis affects CNS. autoreactive T
   cells myelin sheath of nerve fibers

Individuals with the DR2DR3 variant of MHC
genes are most susceptible to the disease.
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1. RA

Rheumatoid arthritis (RA) affects peripheral
joints and may cause destruction of both
cartilage and bone. The disease affects mainly
individuals carrying the DR4 variant of MHC
genes. This fact can lead to better prognoses
and in aiding efforts to change immune reactions
that involve the DR4 variant while leaving other
reactions intact.
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Proposed Mechanisms of Autoimmunity
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Release of Sequestered Antigens
Induction of tolerance in self-reactive T cells
occurs through the exposure of immature T cells
to self-antigens in the thymus. The
elimination/silencing of all self-reactive T
cells requires that all self-antigens be
presented within the thymic environment. Some
self-antigens are sequestered in specialized
tissues and may not be expressed in the
thymus. These are not seen by the developing
immune system will not induce
self-tolerance. Exposure of T cells to these
normally sequestered/tissue-specific
self-antigens in the periphery results in their
activation.
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Examples of Sequestered Antigens
Myelin basic protein (MBP), associated with
MS. Sperm-associated antigens in some individuals
following vasectomy. Lens and corneal proteins of
the eye following infection or trauma. Heart
muscle antigens following myocardial infarction.
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Cross-reacting Antigens (Molecular Mimicry)
Viruses and bacteria possess antigenic
determinants that are very similar, or even
identical, to normal host cell components. This
phenomenon, known as molecular mimicry, occurs in
a wide variety of organisms. Molecular mimicry
may be the initiating step in a variety of
autoimmune diseases.
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Examples of Molecular Mimicry
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Inappropriate Expression of Class II MHC
Molecules
The elimination of self-reactive T cells involves
contact with APC presenting self-peptides within
the thymic environment. Results in deletion or
functional inactivation.
Highly tissue specific proteins not expressed
within the thymus, do not induce clonal deletion
or tolerance. T cells will not respond in the
periphery if the tissue expressing these specific
proteins does not express class II MHC
molecules. Class II MHC ordinarily expressed on
antigen presenting cells, such as macrophages,
dendritic cells and B cells. The aberrant
expression of MHC determinants allows the
recognition of these autoantigens by
self-reactive T cells. Results from the local
production of IFN-?, which is known to increase
class II MHC expression on a variety of
cells. The inducer of IFN-? under these
circumstances could be a viral infection.
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Type I Diabetes Pancreatic ß cells express
abnormally high levels of MHC I and MHC II
(?) MHC II APC only! This may hypersensitize
TH cells to ß cell peptides.
Normal Pancreas Pancreas with
Insulitis
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Polyclonal B Cell Activation
Viruses and bacteria can induce nonspecific
polyclonal B cell activation, including   Certain
gram negative bacteria Herpes simplex
virus. Cytomegalovirus Epstein Barr Virus Human
immunodeficiency virus (HIV)   Induce the
proliferation of numerous clones of B cells to
secrete IgM in the absence of a requirement for
CD4 T cell help. Polyclonal activation leads to
the activation of self-reactive B cells and
autoantibody production. Patients with
mononucleosis (caused by EBV) and AIDS (HIV) have
a variety of autoantibodies.
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• Autoimmunity can be caused by immunological,
  genetic, viral, drug-induced, and hormonal
  factors.
• There are 4 immunological mechanisms of
  autoimmunity.
• All mechanisms cause abnormal B or T cell
  activation.
• Most instances of autoimmune diseases occur with
  multiple mechanisms, which makes treatment
  difficult.

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• Read Understand page 470-471
• Why are women more susceptible than men to
  autoimmunity?