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


Immune Response (Autoimmune diseases) Chapter 13 While hypersensitivity disorders (allergies) are caused by exaggerated adaptive responses to harmless environmental ... – PowerPoint PPT presentation

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

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.

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
  • 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.

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
  • Autoimmune diseases are caused by failures of the
    mechanisms that maintain self-tolerance (
    prevention of attack on the bodys own cells and

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

Four types of hypersensitivity reactions
0 Autoimmune diseases are never caused
by IgE
Have corresponding autoimmune disease
Type II Caused by IgM or IgG antibodies that bind
to components of cell surfaces or extra-cellular
Type III Caused by formation of soluble protein
complexes that are deposited in tissues and blood
Type IV Caused by effector T cells
Autoimmune diseases can be directed against
different tissues of the body
  • Directed against Cells (neutropenia)
  • Autoimmune Tissues/organs (Diabetes)
  • diseases
  • Systemic (Lupus)

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
  • 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

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.
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.
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.

Pathogenesis and Therapies for SLE
  • Current Therapies
  • Immunosuppressions
  • Future Therapies
  • Hormonal modulation
  • Cytokine inhibition

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.

  • 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.

  • 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
  • Treatment for type 1 diabetes includes taking
    daily insulin shots.

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.

Most rheumatological diseases are caused by
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.
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).

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.

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.

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.

Regulatory T cells protect cells and tissues from
  • 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

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.
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.

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,
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.

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
Figure 11-30
Infections associated with the start of
  • 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
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