Autoimmune Disease (PowerPoint)

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					Autoimmune Disease
   Nicole D. Powell, Ph.D.
     October 13th, 2006
         Lecture Objectives
• Factors that contribute to the development of
  autoimmune disease

• Concepts & characteristics of organ-specific
  versus non-organ-specific autoimmunity

• Examples of different types of autoimmune

• Clinical and pathogenic characteristics of
  common autoimmune diseases
 The Normal Immune System
• T cells (Cell mediated responses)–
  Recognize processed antigen in the
  context of MHC to irradicate infection
  – Effector functions include cytokine production
    and release of cytotoxic factors
• B cells (Humoral responses)-Recognize
  free antigen via Ig receptor to irradicate
  – Effector functions include antibody mediated
    destruction of antigen
 What is Autoimmune Disease?
• Group of more than 80 serious, chronic
  illnesses/syndromes that can involve
  almost every organ system
  – includes diseases of the nervous,
    gastrointestinal, and endocrine systems as
    well as skin and other connective tissues,
    eyes, blood, and vasculature.
• Occurs when the immune system
  becomes dysregulated and attacks the
  very organs it was designed to protect
 What is Autoimmune Disease?
• Most of the more than 80 distinct types of
  autoimmune diseases are rare, but collectively
  they affect millions of individuals worldwide.
  – In the USA alone, 5% of the population—over 14
    million people—are affected by these debilitating
  – Autoimmune disease affects approx 2% of the global
• Mechanisms that lead to autoimmunity remain
Some factors that can predispose
     an individual to various
      autoimmune diseases
• MHC associations
• Familial concordance
• Gender
• Climate
• Chemical Agents
• Infectious Agents
• Immune Dysregulation
       Genetic Factors

•Autoimmune diseases tend to occur in families
and this concordance is largely genetic.

•Greater concordance between identical twins
for some diseases.

•Strong HLA association.
• Many autoimmune diseases affect women much
  more commonly than men
• Severity/course of autoimmune disease may
  also differ between sexes
  – Rheumatoid arthritis is typically more aggressive in
  – Multiple Sclerosis can differ in clinical course between
    females and males
     • Females tend to have a relapsing-remitting disease course
     • Males tend to exhibit a chronic progressive disease course
                                         Whitacre Nature Immunology 2, 777 - 780 (2001)

The sex distribution of the major autoimmune diseases.
The numbers above the bars refer to the total number of disease cases ( 1,000,000) in the USA1, 7.
•   Figure 2. A model for the multifactorial nature of autoimmune disease.
    Sex hormones represent an important modulatory factor in the immune and
    autoimmune response. Sex hormones include the gonadal sex steroids as well as
    other hormones that indicate differences between men and women.

                             Whitacre Nature Immunology 2, 777 - 780 (2001)
What initiates an autoimmune response???

• Incomplete deletion of self reactive cells
• Aberrant stimulation of “normally” anergic
  self reactive cells
• Altered regulation of anergic self reactive
Categories of Autoimmune Disease
• Systemic                   • Organ Specific
  – Immune cells target        – Immune cells target
    multiple organ               specific organs or
    systems and tissues          tissue
  – Thought to be due to       – Thought to be due to
    aberrant regulation of       failure of self tolerance
    many clones of               in only a few clones of
    lymphocytes                  cells which react to a
                                 limited number of
Systemic Lupus Erythematosus
(SLE) – A systemic disorder in which a   Multiple Sclerosis (MS) –
variety of autoantibodies (DNA,          Immune System targets Central
nucleoproteins, platelets,               Nervous System via myelin
lymphocytes) can cause multisystem       specific T cells
   Examples of Four Common
     Autoimmune Diseases
• Systemic Lupus Erythematosus (SLE)
• Rheumatoid Arthritis (RA)
Organ Specific
• Insulin Dependant Diabetes Mellitus
• Multiple Sclerosis m (MS)
Systemic Autoimmune Disease
           SLE Clinical Features
• Multisystem disorder characterized by a variety of
• Increased risk associated with HLA DR2 and HLA DR3
• Female/male predominance 10:1
• Initial onset of symptoms typically occurs between 15-25
  years of age
• Typical symptoms include
   –   Fatigue
   –   Fever
   –   Alopecia
   –   Mucosal ulceration
   –   Butterfly rash
   –   Joint and muscle pain
• Severe complications
   – Kidney, Heart, lung, CNS
             SLE Pathogenesis
 • Immune complex disease (type III
 • Large amounts of autoantibodies produced
   against self antigens
     – DNA
     – Nucleoproteins
     – Platelets
Fever, butterfly rash, discoid rash,
     – Lymphocytes
blood in urine complexes deposit in kidneys, joints
  • Immune
    and swollen walls
Arthritis, vessel glands, muscle aches
Severe complications: heart, kidney,
lung, CNS
              SLE Treatments
• Nonsteroidal anti-inflammatory drugs (NSAIDS) are used
  to treat arthritic symptoms of lupus

• Corticosteroid creams are used to treat skin rashes

• Antimalarial drugs sometimes used for skin and arthritis

• Corticosteroid therapy or cytotoxic (anti-proliferative)
  drugs may be used in severe or life-threatening
  manifestations of the disease

• Kidney transplant indicated for advanced Lupus nephritis
              RA Clinical Features
• Chronic inflammatory disease
   – Primarily affects the joints and surrounding tissues
   – Membranes lining the blood vessels, heart, and lung may also be
• Increased risk associated with HLA DR4
• Female predominance approx 3:1 (more common and
  more aggressive in women)
• Peak incidence is between the ages of 25 – 55
• Approximately 1-2% of the total population is affected.
• Symptoms include
   –   Pain and swelling of joints
   –   Morning aches/stiffness
   –   Loss of motion of the affected joints
   –   Loss of muscle strength
   –   Fatigue and malaise
   –   Low-grade fever
   –   Deformity of your joints over time
RA Pathogenesis

• Believed to be autoimmune in nature
• Immune cells/complexes infiltrate synovial fluid
• Chronic inflammation of the synovium and
  subsequent cytokine and antibody production
  results in
  – thickening of the synovium
  – damage to cartilage, bone, tendons and ligaments
  – loss of shape and alignment of joint over time
              RA Treatments

• Disease-modifying anti-rheumatic drugs (DMARDs)

• Anti-inflammatory agents

• Tumor necrosis factor (TNF) inhibitors

• IL-1 receptor antagonists

• Immunosupressants
Organ Specific Autoimmune
        IDDM Clinical Features
• Deficient insulin production
• Requirement for exogenous insulin
• Onset usually occurs in childhood
• Strong association with HLA DR3 and HLA DR4
  (especially with both alleles present)
• Slightly higher incidence in males
• Symptoms include
    – Increased urine volume
    – Weight loss in spite of
      increase in appetite
    – Excessive thirst
    – weakness
IDDM Pathogenesis

• Inflammation of the islets of Langerhans leading
  to fibrosis and specific destruction of the beta
• Other islet cells left intact
• Predominance of CD8+ T cell infiltrates in the
• Antibodies to islet cell antigens precede beta cell
           IDDM Treatments
•   Insulin
•   Controlled diet
•   Physical activity
•   Blood glucose monitoring
          MS Clinical Features
• The most common inflammatory disorder of the central nervous
• Increased risk associated mainly with HLA DR2
• Female/male predominance is 3:2
• Those affected can exhibit a relapsing-remitting or a chronic
  progressive disease
• Pathologic hallmark is the CNS plaque with loss of myelin and
  depletion of oligodendrocytes with or without axon loss
• Typical onset
   – women of childbearing years
   – In men onset is typically >40 years of age
• Symptoms include
   –   Impaired vision (optic neuritis)
   –   Ataxia
   –   Spasticity
   –   Bladder dysfunction
   –   Weakness/Paralysis of one or more limbs
   –   Sensitivity to temperature
   –   Cognitive impairment
            MS Pathogenesis
• T cell mediated autoimmune disease in which T cells
  are specific for components of the myelin sheath
• Also evidence of macrophage and microglial cell
  involvement in myelin degradation
• Damage to/loss of myelin impairs nerve conduction
           MS Treatments
• Immunomodulatory Drugs

• Corticosteroids

• Immunosupressive therapy
          Spectrum of autoimmune diseases

    organ-specific                         non-organ-specific

An individual may develop more than one autoimmune disease.
There can be overlaps between diseases at each end of the spectrum.
         Critical Questions
What are some possible mechanisms by
 which infections promote autoimmunity?

What are some contributing factors in the
 development of autoimmune disease?

What are important clinical and pathological
 characteristics of organ specific and
 systemic autoimmunity?

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