Disruption of Healthy Tissue by the Immune Response (Autoimmune diseases) Chapter 13

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Disruption of Healthy Tissue by theImmune
Response (Autoimmune diseases)Chapter 13

• While hypersensitivity disorders (allergies) are
  caused by exaggerated adaptive responses to
  harmless environmental antigens, exaggerated
  adaptive immune response against cells and
  tissues of the body causes autoimmune diseases.
• Autoimmune diseases can be caused by antibodies
  that disrupt normal physiological function, or by
  T cells that damage healthy cells and tissues.
• About 5 of population in developed countries
  suffers some form of autoimmune disease.

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Autoimmune diseases

• When the immune system mistakes self tissues for
  non-self and mounts an inappropriate attack, the
  result is an autoimmune disease. There are many
  different autoimmune diseases. Some examples are
  multiple sclerosis, type 1 diabetes mellitus, and
  rheumatoid arthritis.
• Autoimmune diseases can each affect the body in
  different ways. For instance, the autoimmune
  reaction is directed against the brain in
  multiple sclerosis, and the gut in Crohn's
  disease. In other diseases, such as systemic
  lupus erythematosus (lupus), affected tissues and
  organs may vary among individuals with the same
  disease.
• Many autoimmune diseases are rare. As a group,
  however, they afflict millions of Americans. Most
  autoimmune diseases strike women more often than
  men, particularly affecting women of working age
  and during their childbearing years.

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Autoimmune responses

• Autoimmune diseases are caused by unwanted
  adaptive immune responses (autoimmune responses)
  against self-antigens (autoantigens).
• The effectors of adaptive immunity that recognize
  autoantigens are autoantibodies or autoimmune T
  cells.
• Autoimmune diseases are caused by failures of the
  mechanisms that maintain self-tolerance (
  prevention of attack on the bodys own cells and
  tissues).

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Three types of autoimmune diseases

• Autoimmune diseases are defined by the presence
  of autoantibodies or autoimmune T cells.
• Females are more often affected by autoimmune
  diseases than males.
• There are three types of autoimmune diseases
  they are classified according to which
  immunological mechanism is causing the diseases.
• The three types of autoimmune diseases correspond
  to the last three types of hypersensitivity
  disorders.

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Four types of hypersensitivity reactions
0 Autoimmune diseases are never caused
by IgE
Have corresponding autoimmune disease
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Type II Caused by IgM or IgG antibodies that bind
to components of cell surfaces or extra-cellular
matrix
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Type III Caused by formation of soluble protein
complexes that are deposited in tissues and blood
vessels
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Type IV Caused by effector T cells
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Autoimmune diseases can be directed against
different tissues of the body

• Directed against Cells (neutropenia)
• Autoimmune Tissues/organs (Diabetes)
• diseases
• Systemic (Lupus)

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Type II autoimmune diseases

• Autoantibodies are often directed against cell
  surface components of the blood cells
• 1. Autoimmune hemolytic anemia IgM or IgG
  antibodies bind to cell surface receptors on
  erythrocytes, thus activating complement and
  triggering erythrocyte destruction. This leads to
  a reduction in the red-cell count and anemia
  (anemia is derived from Greek words meaning
  without blood).
• 2. Neutropenia Patients produce antibodies
  against surface molecules on neutrophils this
  leads to a decreased amount of circulating
  neutrophils neutropenia (gt frequent
  infections).
• 3. Graves disease IgGs bind to the cell
  receptor of thyroid stimulating hormone, thus
  stimulating thyroid production and resulting in
  a hyperthyroid condition (heat intolerance,
  irritability, weight loss, enlargement if the
  thyroid).

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Autoimmune hemolytic anemia (AIHA)
In patients with AIHA, erythrocytes are opsonized
by auto-IgGs, and destroyed by macrophages.
Erythrocytes have a normal life span of about 120
days. In AIHA, they are short-lived because they
are destroyed prematurely.
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Auto-antibodies can be transferred from mother to
the developing fetus during pregnancy
As a result, the infants will have the same
auto-antibodies as their mothers, and will suffer
from the same auto-immune diseases. As infants
grow, the maternally IgG is gradually degraded,
and the symptoms will eventually go away.
Alternatively, this can be treated by a total
exchange of the infants blood plasma.
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Type III autoimmune diseases
Caused by formation of soluble protein complexes
that are deposited in tissues

• LUPUS (Systemic Lupus Erythematosus SLE)
• Characterized by circulating autoantibodies
  (antinuclear antibodies, ANA) directed against
  constituents of all cells, especially nuclear
  antigens histones, DNA, RNA, chromatin proteins
• This initiates inflammatory reactions that lead
  to tissue destruction and inflammation. The
  released soluble antigens form immune complexes
  that become deposited in blood vessels, skin (on
  the picture), kidneys, joints and brain.
• SLE can affect all ages but most commonly begins
  from age 20 to 45 years. It is more frequent in
  women of African or Asian origin.

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Pathogenesis and Therapies for SLE

• Current Therapies
• Immunosuppressions
• Future Therapies
• Hormonal modulation
• Cytokine inhibition

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Type IV autoimmune diseases

• Mediated by effector T cells
• Insulin-Dependent Diabetes Mellitus (IDDM also
  called type 1 diabetes or "juvenile diabetes") is
  a severe autoimmune disease caused by the
  selective CD8 T cell-mediated destruction of
  insulin-producing (beta) cells in the pancreas.
• Multiple sclerosis (MS) is a chronic autoimmune
  disorder affecting movement, sensation, and
  bodily functions. It is caused by CD4 T
  cell-mediated destruction of the myelin
  insulation covering neurons in the brain and
  spinal cord.

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IDDM

• Insulin dependent diabetes mellitus (type 1) is
  an inflammatory autoimmune disease of the
  pancreas, resulting in a lack of insulin.
• Insulin is produced in the pancreas by beta cells
  of the islets of Langerhans. The main source of
  energy for all cells and especially for brain
  cells is glucose. Insulin is necessary for
  glucose to get into cells and be used for energy
  production. After eating, the glucose level in
  blood rises, which leads to insulin being
  released from the pancreas.
• In a person with IDDM, beta cells of Langerhans
  are destroyed by CD 8 T cells, leading to an
  insufficiency of insulin. The glucose level in
  blood rises and cells do not have enough energy
  for metabolism.

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IDDM

• IDDM is usually first diagnosed in children,
  teenagers, or young adults. IDDM principally
  affects population of European origin (especially
  Mediterranean) about 1 in 300 people are
  affected.
• Treatment for type 1 diabetes includes taking
  daily insulin shots.

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Multiple sclerosis

• MS is an autoimmune nerve disorder caused by
  CD4-mediated destruction of myelin, the
  insulating layer surrounding neurons in the brain
  and spinal cord. Myelin helps electrical signals
  pass quickly and smoothly between the brain and
  the rest of the body. When myelin is destroyed,
  nerve messages are sent less efficiently.

• The symptoms of MS occur when the brain and
  spinal cord nerves no longer communicate properly
  with other parts of the body. MS causes a wide
  variety of symptoms and can affect vision,
  balance, strength, sensation, coordination, and
  bodily functions.
• Multiple sclerosis affects more than a quarter
  of a million people in the US. Most people have
  their first symptoms between the ages of 20 and
  40. Women are almost twice as likely to get MS
  as men. People of northern European heritage are
  more likely to be affected than people of other
  racial backgrounds, and MS rates are higher in
  the United States, Canada, and Northern Europe
  than in other parts of the world.

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Most rheumatological diseases are caused by
autoimmunity
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Rheumatoid arthritis (RA)

• The most common of the rheumatic diseases,
  affecting 3 of the US population more frequent
  in women than in men.
• Usually starts between 20 and 40 years of age.
• Characterized by chronic inflammation of the
  joints associated with pain, swelling,
  stiffness, and loss of function in the joints. In
  addition, people with the disease may have
  fatigue, occasional fever, and a general sense of
  not feeling well (malaise).

Mechanism 80 of patients with RA make
antibodies against the Fc region of human IgG
these anti-immunoglobulin autoantibodies are
called rheumatoid factor.
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Mechanisms associated with RA

• In affected joints, there is an infiltration of
  leukocytes T cells, B cells producing the
  Rheumatoid Factor, and neutrophils and
  macrophages releasing pro-inflammatory mediators
  (TNF, IL-1, prostaglandins, leukotrienes, CRP)
  and proteases that degrade the tissue.
• RA is treated with anti-inflammatory (aspirin,
  Advil) and immunosuppressive (glucocorticoids)
  therapy. New therapies include anti-TNF
  antibodies (Remicade).

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Genetic and environmental factors that predispose
to autoimmune disease

• Most of the time, during development of the
  immune system, multiple control mechanisms
  prevent attack on healthy cells and tissues,
  resulting in self-tolerance of the immune system.
• All autoimmune diseases involve a breach of one
  of these mechanisms controlling self-tolerance.
• The loss of self-tolerance is determined by both
  genetic and environmental factors.

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All autoimmune diseases involve T-cells

• During development, most of the self-reactive B
  cells and T cells are deleted and die.
• In T-cell mediated autoimmune diseases, the
  mechanisms controlling elimination of
  self-reactive T cells are dys-regulated.
• Since production of antibodies requires
  activation of T cells, also the autoimmune
  diseases mediated by antibodies are dependent on
  T-cell tolerance.

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Incomplete deletion of self-reactive T cells in
the thymus causes autoimmune diseases

• Thymic selection of T cells provides the
  foundation for immunological self-tolerance.
• During T cell development, negative selection
  removes T cells that respond to self-peptides
  presented by MHC molecules.
• Defects in the negative selection of T cells
  result in autoimmune diseases.

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Regulatory T cells protect cells and tissues from
autoimmunity

• Treg are critical for the maintenance of
  self-tolerance in mice and humans. Mice that fail
  to develop Treg show early signs of T cell
  autoreactivity.

IL-4 IL-10 TGFb
Treg cells are also able to inhibit established
autoimmune disease. For example, Treg have been
shown to reverse inflammatory bowel disease in a
mouse model system.
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HLA is one of the main genetic factors affecting
susceptibility to autoimmune diseases

• Different HLA isotypes are associated with
  different disease susceptibility.
• HLA molecules account for about half of the
  genetic predisposition to autoimmune diseases.

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Senescence of the T cell population can
contribute to autoimmunity
Thymus begins shrinking 1 year after birth. By
age 50, the capacity to produce new T cells is
limited to 20, and by age 60, to 0. When the
thymus can no longer produce new naïve T cells,
the immune system compensates by expanding the
population of existing T cells, and altering
properties of some T cells, resulting in the
production of large amounts of autoreactive T
cells. Patients with RA have a high number of
expanded clones of autoreactive CD4 T cells,
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Infections can trigger autoimmune disease

• Most autoimmune diseases are triggered by some
  sort of infection.
• One of the best studied examples is rheumatic
  fever, which involves inflammation of the heart,
  kidneys and joints.
• Rheumatic fever can follow 2-3 weeks after a
  strep-throat infection antibodies specific
  against the Streptococcus bacteria can attack
  heart, joints and kidney tissue.
• The antibody binding to the heart and kidney
  tissues activates complement and results in
  widespread inflammation rheumatic fever which
  can sometimes cause a heart failure.
• The incidence of rheumatic fever has greatly
  decreased after the Strep infections began to be
  treated with antibiotics.

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Antibodies against streptococcal cell wall
antigens cross-react with antigens on heart
tissue, resulting in the rheumatic fever
Antibodies cross-reacting with the heart
(yellow) Antibodies not reacting with the heart
(blue)
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Figure 11-30
Infections associated with the start of
autoimmunity
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SUMMARY

• The successful adaptive immunity is based on the
  specific recognition of foreign antigens while
  sustaining tolerance towards self-antigens.
• The self-tolerance is ensured by clonal deletion
  and inactivation of potentially auto-reactive B
  cells and T cells.
• Failure of these protective mechanisms results in
  autoimmune diseases.
• There are three types of autoimmune diseases II,
  III and IV, corresponding to the last three types
  of hypersensitivity reactions.
• Susceptibility to autoimmune diseases is
  determined by both genetic and environmental
  factors.