AUTOIMMUNITY

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AUTOIMMUNITY

• Prof. Emad A Koshak
• Professor and Consultant
• Internal Medicine, Allergy Immunology
• King Abdulaziz University- Faculty of Medicine

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The immune system normally acquires self
tolerance by clonal deletion of autoreactive T
cells in the thymus before birth and by
functional suppression of autoreactive T and B
cells at later stages of development.
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Background on inflammation
The word inflammation literally means "burning."
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Inflammation occurs in response to a range of
traumas from sunburn and wounds, to infection and
auto-immune conditions. Whatever the cause, this
process is basically the same....
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SHARP
Swelling
Heat
Redness
Pain
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Heat and redness result from dilation of the
small blood vessels in the injured area and
increased local blood flow.
Because blood vessels become more
permeable during inflammation, protein rich
exudate escapes from blood plasma to the damaged
tissue and causes swelling.
Pain is believed to result from such chemical
substances as serotonin, specific cytokines or
from tension of tissue over the inflamed area.
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Autoimmune disorders are a diverse group of
conditions, which occur due to abnormal
stimulation and signaling within the immune
system. "Self" versus "non-self" recognition is
altered.
An autoimmune response occurs because, for
some reason, helper T cells recognize a cell of
the body (or self cell) as foreign, and mark it
for destruction.
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Examples of Autoimmune Diseases
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Nervous System
Multiple sclerosis Myasthenia gravis
(acetylcholine receptor
autoantibodies) Autoimmune neuropathies
such as Guillain-Barré Autoimmune
uveitis


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Gastrointestinal System
Crohn's Disease
Ulcerative colitis
Primary biliary cirrhosis
Autoimmune hepatitis
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Blood
Autoimmune hemolytic anemia
Pernicious anemia
Autoimmune thrombocytopenia
Antiphospholipid antibody
Meisha, a lab/terrier/spaniel mix, was 3 years
old when she was diagnosed with autoimmunue
hemolytic anemia in January of 1992.
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Skin
Psoriasis
Dermatitis herpetiformis
Pemphigus vulgaris
Vitiligo
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Endocrine
DM
Hashimoto thyroiditis
DM is an example of an autoimmune disorder in
which Beta cells of the pancrease show
destruction.
Graves diseases
Addison disease
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Endocrine
Type I (insulin -dependent) diabetes
(pancreatic beta-cell autoreactive T cells and
autoantibodies)
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Graves Disease
Graves Disease is an autoimmune condition that
strikes more women than men at a rate of 71. It
affects the functioning of the thyroid and causes
hyperthyroidism, but it can also affect the
tissue surrounding the eyes.
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Rheumatology
SLE
RA
Progressive systemic sclerosis is an example of
an autoimmune disorder in which skin cells show
extensive dermal fibrosis.
Systemic Scelerosis
Dermatomyocytis
Ankylosing spondylitis
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SLE is the most commonly known autoimmune
disorder. This characteristic butterfly rash
is made worse by exposure to sunlight. Lupus is
a potentially fatal autoimmune disease that
strikes 1 in 2,000 Americans and 10 times as many
women as men.
Malar rash
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Rheumatoid arthritis
Among the most serious and disabling types of
arthritis, 2.1 million Americans live with
rheumatoid arthritis.
About one out of seven Americans exhibit some
form of arthritis.
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A Genetic Connection?
Many chronic inflammatory diseases have been
shown to occur preferentially in individuals
carrying certain variants of MHC (major
histocompatibility complex) genes.
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MHC Genes
There are two classes of HLA antigens
class I antigens (HLA A, B, Cw) class II
antigens (HLA DR and DQ DP) There are
22 different HLA A antigens 42 different B
antigens 9 different Cw antigens 18
different DR antigens
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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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Ankylosing spondylitis (Bechterew's
Disease), a joint inflammation mainly affecting
the spine, occurs only in individuals carrying a
certain variant of MHC molecule (HLA-B27). Much
evidence suggests that molecules derived from
microorganisms interact with the B27 molecule in
causing the destructive immune reactions
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Multiple sclerosis (MS)
Individuals with the DR2, DR3 variant of MHC
genes are most susceptible to MS.
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Multiple sclerosis (MS)
Some populations, such as
Gypsies, Eskimos, and Bantus, never get MS.
However, for susceptible populations, if one
person in a family has MS, that person's
first-degree relatives -- parents, children, and
siblings -- have a one to three percent chance of
getting the disease.
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MS In MS, tumor necrosis factor-alpha (TNFa),
interLeukin (IL)-2, and IL-6 lead to the
activation of most peripheral T-Cells (mainly CD4
memory) by promoting a persistent intracellular
calcium increase via two independent signaling
pathways.
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Family members with autoimmune diseases may
inherit and share a set of abnormal genes,
although they may develop different autoimmune
diseases.
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Other genetic connections
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Antiphospholipid antibody
(APL), traditionally associated with rheumatic
autoimmune diseases such as SLE (lupus
anticoagulant) APL has been identified as a
"common thread" in families where at least one
member suffers from an autoimmune disorder.
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• Antiphospholipid antibody syndrome
• (APS) is associated with recurrent clotting
  events (thrombosis)
• premature stroke CVA
• repeated miscarriages
• Phlebitis
• Venous thrombosis (clot in the vein)
• pulmonary thromboembolism
• Also associated with low platelet or blood
  elements that prevent bleeding.

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How to establish the Diagnosis

• History characteristic symptoms
• Classical physical findings and signs
• Laboratory
• General CBC, ?ESR, ?CRP, C3, ?C4, ?IgG
• Specific auto-antibodies
• Hormonal assay
• Radiological
• ? HLA

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What are some of the treatments for autoimmune
diseases?
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Diminishing of the activity of the immune
system
This necessitates a delicate balance, controlling
the disorder while maintaining the body's ability
to fight disease in general.
Drugs most commonly used are corticosteroid
drugs.
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Cyclosporin A (CsA) inhibits a signal
transmission pathway in T lymphocyte cells.
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Treatment

• 1- Metabolic control
• a. Graves disease antithyroid drugs, surgical,
  radiation
• b. Hashimotos thyroiditis Thyroxin.
• c. Pernicious anemia vitamin B12.
• d. IDDM insulin
• 2- Antiinfalamtory and cytotxic drugs
• Nonsteroidal antiinflamatory (NSAID)
• Corticosteroids
• Cytotoxic drugs Cyclophosphamide, Azothioprine,
  Cyclosporin
• 3- Thymectmy
• Myasthenia gravis after anticholinesterase
• 4- Plasmapheresis or Plasma exchange
• GBS, SLE, Goodpastures
• 5- Spleenectomy
• Hemolytic anemia, ITP
• 6- Intravenous Gammaglobulin therapy
• GBS, Dermatomyositis
• 7- Cytokines and inhibitors anti-TNF

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Intravenous immunoglobulin IVIG therapy is used
in the treatment of various autoimmune
diseases to reduce circulating immune complexes.
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Another treatment approach is to manipulate
immune system messenger molecules called
cytokines.
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Cytokines Are low molecular mass proteins,
secreted by lymphocytes, which activate other
immune system cells to regulate Cell Growth,
Cell Activation, Inflammation, Immunity,
Tissue Repair, Fibrosis and Morphogenesis.
examples Interferons and InterLeukins
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Some cytokines (for example, IL-8) are also
chemotactic for specific cell types, and are
called chemokines.
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Example of inflammation and cytokines Tumor
necrosis factor-a TNF-a Released by macrophages,
increases vascular permeability, adhesion
molecule expression on blood vessel endothelium,
increases MHC expression, platelet activation
(clots keep infection from the blood, and direct
products to the lymphatic system).

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If the infection reaches the blood, TNF-a causes
septic shock and death. Release into joints leads
to Rheumatoid arthritis.
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New treatments Use a chimeric monoclonal
antibody against TNF-a, or a new drug,
Etanercept, which is a recombinant protein with
TNF receptor and the constant region of an
antibody. Blocking TNF-a shows great promise as a
new treatment for RA.
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• Thanks