Topic 3 Autoimmunity

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Topic 3 Autoimmunity

• Terry Kotrla, MS, MT(ASCP)BB
• Fall 2005

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Introduction

• Under normal circumstances immune system will not
  destroy self antigens.
• Autoimmunity can be defined as breakdown of
  mechanisms responsible for self tolerance and
  induction of an immune response against
  components of the self.
• In numerous autoimmune diseases it is well
  recognized that products of the immune system
  cause damage to the self.

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Autoimmunity
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Autoimmune Response

• Antibody directed against self, termed
  auto-antibody
• Considered abnormal but usually does not result
  in disease.
• May occur in healthy individuals.

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Autoimmune Disease

• Disorder in which tissue injury is caused by an
  immunologic reaction of the host to its own
  tissues.
• Precise mechanisms unknown.
• Classified as systemic or organ specific,
  frequently have overlap.

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Proposed Mechanisms

• Forbidden clone
• Altered antigen
• Sequestered Antigen
• Immunologic deficiency theory
• Genetic influence

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Forbidden clone

• Clone of changed or altered lymphocytes arise
  through mutation.
• Lack foreign surface antigens, not destroyed.
• Because of alteration may recognize host as
  foreign.

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Altered Antigen

• Surface antigens on host altered by chemical,
  biological or physical means.
• This new antigenic determinant may be recognized
  as foreign by the host.

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Sequestered Antigen

• Some antigens in the body are hidden from cells
  of the immune system.
• If there is damage to these organs causing
  exposure of these sequestered antigens an immune
  reaction to these antigens may occur.

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Immunologic Deficiency Theory

• Relates the increased frequency of
  auto-antibodies and increased immune system
  deficiency to age.
• Mutation or loss of immune regulatory powers
  results in the condition in which self antigens
  behave as foreign antigens.

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Genetic Influence

• It is well recognized that certain immune
  disorders predominate in females and in families.
• Determined by family studies.
• Genetic links have occurred between diseases and
  HLA antigens

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Contributing Factors

• Defects in the immune system.
• Influence of hormones
• Environmental conditions

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Classification of Autoimmune Diseases

• Systemic- the auto-immunity is directed against
  an antigen that is present at many different
  sites and can include involvement of several
  organs
• Organ specific - Organ specific means the
  auto-immunity is directed against a component of
  one particular type of organ.
• Both can get overlap

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Systemic Lupus Erythematosus

• Chronic, systemic inflammatory disease caused by
  immune complex formation.
• The word "systemic" means the disease can affect
  many parts of the body.
• Pathophysiology associated with clinical features
  secondary to immune complexes depositing in
  tissues resulting in inflammation.
• Parts of the body affected include the joints,
  skin, kidneys, heart, lungs, blood vessels, and
  brain.

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Systemic Lupus Erythematosus

• Peak age of onset is 20 to 40 years of age.
• Found more frequently in women.
• Has both genetic and environmental factors.

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SLE Clinical Signs

• Extremely diverse and nonspecific.
• Joint involvement most frequent sign
  polyarthralgia and arthritis occur in 90 of
  patients.
• Skin manifestations next most common.
• Erythematosus rash may appear.
• Most classic is butterfly rash.

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SLE Butterfly Rash

• The source of the name "lupus" is unclear. All
  explanations originate with the characteristic
  butterfly-shaped malar rash that the disease
  classically exhibits across the nose and cheeks.
• In various accounts, some doctors thought the
  rash resembled a wolf pattern. In other accounts
  doctors thought that the rash, which was often
  more severe in earlier centuries, created lesions
  that resembled wolf bites or scratches.
• Stranger still, is the account that the term
  "Lupus" didn't come from latin at all, but from
  the term for a French style of mask which women
  reportedly wore to conceal the rash on their
  faces

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SLE Clinical Signs

• Renal involvement very common.
• Caused by deposition of immune complexes in
  kidney tissue.
• Leads to renal failure, most common cause of
  death.
• Other systemic effects
• Cardiac
• Central nervous system.
• Hematologic abnormalities.

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Immunologic Findings

• Lupus Erythematosus (LE) cell, neutrophil which
  has engulfed the antibody-coated nucleus of
  another cell.
• First classic test to aid in diagnosis.
• Not utilized anymore, may still see in older
  references.
• Over activity of B cells main immunologic
  characteristic.
• Antinuclear antibodies produced.
• More than 28 antibodies associated with LE have
  been identified.
• Level of antibody production correlates with
  severity of symptoms.
• Estrogen enhance B cell activation.

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LE Cell

• Here is the famous "LE cell" test which has value
  only in demonstrating how the concept of
  autoantibodies work. The pink blobs are denatured
  nuclei. Here are two, with one seen being
  phagocytozed in the center by a PMN. This test is
  not nearly as sensitive as the ANA which has
  supplanted the LE cell test. Therefore, NEVER
  order an LE cell test. Image contributed by
  Elizabeth Hammond, MD, University of Utah

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Immunologic Findings

• Decrease in absolute number of T cells
• Accumulation of immune complexes with activation
  of complement lead to kidneydamage.
• Drug induced lupus may occur, discontinue drug,
  symptoms usually disappear.

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Laboratory Diagnosis

• Screening test for anti-nuclear antibodies (ANA)
  first test done.
• Antibodies directed against nuclear material of
  cells.
• Flourescent anti-nuclear antibody (FANA) most
  widely used, extremely sensitive, low diagnostic
  specificity.
• Animal or human cells fixed to slide.
• Add patient serum and incubate.
• Wash to remove unreacted antibody.
• Add anti-human globulin labeled with fluorescent
  tag or enzyme.

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ANA

• Patterns of reactivity
• Homogenous-entire nucleus stained
• Peripheral-rim of nucleus stained
• Speckled-spots of stain throughout nucleus
• Nucleolar-nucleolus only stained
• False positives and negatives occur.
• If positive, perform profile testing.

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Antinuclear Antibody Test

• Antinuclear antibodies (ANA) are autoantibodies
  against various cell nucleus antigens and are
  found in patients with autoimmune diseases such
  as SLE.
• Some of ANA are considered to be useful for
  diagnosis of autoimmune diseases.

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Homogeneous Pattern

• Smooth, even staining of the nucleus with or
  without apparent    masking of the nucleoli

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Nucleolar

• 23 or 46 (or some multiple of 46) bright speckles
  or ovoid granules spread over the nucleus of
  interphase cells

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Peripheral

• Fluorescence is most intense at the periphery of
  the nucleus with a large ring starting from the
  internal nuclear membrane and the rest of the
  nucleus showing weaker yet smooth staining.

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Speckled

• Large speckles covering the whole nucleoplasm,
  interconnected by a fine fluorescent network.

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Anti-nuclear antibodies detected by FANA

• Double-stranded DNA (ds-DNA) antibodies are most
  specific for SLE, correlate well with disease
  activity.
• Antihistone antibody second major antibody found
  in SLE.
• Deoxyribonucleoprotein (DNP) antibody,
  responsible for LE cell phenomena and available
  as a latex agglutination test.
• Anti-Sm antibody, specific for LE.
• SS-A/Ro and SS-B/La antibodies, most common in
  patients with cutaneous manifestations.
• Anti-nRNP detected in patients with SLE as well
  as mixed connective tissue disease.
• Presence of antibodies not diagnostic, may be
  present due to other diseases.

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Anti-nuclear Antibodies by Immunodiffusion.

• Used to determine specificity.
• Ouchterlony double diffusion most frequently used
  to identify antibodies to Sm, nRNP, SS-A/Ro,
  SS-B/La and others.
• Test is not as sensitive but very specific.

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Extractable Nuclear Antigen

• This is antibody to a cytoplasmic ribonuclear
  protein complex.
• It is associated with mixed connective disease
  and SLE with particular features (arthritis,
  myositis, Raynaud's phenomenon - also association
  with HLA-DR4 and HLA-DQw8).

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Systemic Lupus Erythematosus
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Extractable Nuclear Antigen ENA
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Antiphospholipid Antibodies

• Antiphospholipid antibodies may be present and
  are of two types.
• Anticardiolipin.
• Lupus anticoagulant, if present, may cause
  spontaneous abortion and increase
• Risk of clotting, platelet function may be
  affected.

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Treatment

• Aspirin and anti-inflammatories for fever and
  arthritis.
• Skin manifestations-anti-malarials or topical
  steroids.
• Systemic corticosteroids for acute fulminant
  lupus, lupus nephritis or central nervous system
  complications.
• Five year survival rate is 80 to 90.

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Rheumatoid Arthritis

• Chronic inflammatory disease primarily affecting
  the joints, but can affect heart, lung and blood
  vessels.
• Women three more times as likely as men to have
  it.
• Typically strikes at ages between 20 and 40, but
  can occur at any age.
• The three major symptoms of arthritis are joint
  pain, inflammation, and stiffness.
• Progress of disease varies.

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Clinical Signs

• Diagnosis based on criteria established by
  American College of Rheumatologists, must have at
  least 4 of the following
• Morning stiffness lasting 1 hour.
• Swelling of soft tissue around 3 or more joints.
• Swelling of hand/wrist joints.
• Symmetric arthritis.Subcutaneous nodules
• Positive test for rheumatoid factor.
• Xray evidence of joint erosion.

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Clinical Signs

• Symptoms initially non-specific malaise, fever,
  weight loss, and transient joint pain.
• Morning stiffness and joint pain improve during
  the day.
• Symmetric joint pain knees, hips, elbows,
  shoulders.
• Joint pain leads to muscle spasm, limits range of
  motion, results in deformity.
• Approximately 25 of patients have nodules over
  bones (necrotic areas), nodules can also be found
  in organs.
• Certain bacteria may trigger RA due to certain
  proteins that possess antigens similar to those
  antigens found in joint, ie, molecular mimicry

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Immunologic Findings

• Rheumatoid Factor (RF) is an IgM antibody
  directed against the Fc portion of the IgG
  molecule, it is an anti-antibody.
• Not specific for RA, found in other diseases.
• Immune complexes form and activate complement and
  the inflammatory response.
• Enzymatic destruction of cartilage is followed by
  abnormal growth of synovial cells, results in the
  formation of a pannus layer.

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Rheumatoid Arthritis
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Diagnosis

• Diagnosis is based on
• Clinical findings.
• Radiographic findings
• Laboratory testing.
• Laboratory tests involve testing patients serum
  with red blood cells or latex particles coated
  with IgG, agglutination is a positive result.
• Nephelometry and ELISA techniques are available
  to quantitate the RF.
• Erythrocyte Sedimentation Rate (ESR) used to
  monitor inflammation.
• C-Reactive protein (CRP) is utilized to monitor
  inflammation

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Treatment

• Rest and nonsteroidal anti-inflammatory drugs
  control swelling and pain.
• Substantial functional loss seen in 50 of
  patients within 5 years.
• Slow acting antirheumatic drugs are coming into
  use but have side affects.
• Joint replacement.

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Hashimoto's Thyroiditis

• Hashimoto's Thyroiditis is a type of autoimmune
  thyroid disease in which the immune system
  attacks and destroys the thyroid gland.
• The thyroid helps set the rate of metabolism -
  the rate at which the body uses energy.
• Hashimotos prevents the gland from producing
  enough thyroid hormones for the body to work
  correctly.
• It is the most common form of Hypothyroidism
  (underactive thyroid).

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Hashimotos Thyroiditis

• Organ specific disease affecting the thyroid
  gland.
• Most often seen in women 30 to 40 years old, may
  be genetic predisposition.
• Common cause of hypothyroidism.
• Causes diffuse hyperplasia in the gland resulting
  in development of a goiter.
• Thyroid autoantibodies are formed.

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Hashimotos Thyroiditis

• Hashimoto's thyroiditis is the most common cause
  of hypothyroidism.
• It is also most prevalent in elderly women and
  tends to run in families.
• Hashimoto's thyroiditis occurs eight times more
  often in women than men.
• Certain chromosomal abnormalities include
  Hashimoto's thyroiditis as a symptom.

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Symptoms

• The following are the most common symptoms.
  However, each individual may experience symptoms
  differently
• goiter (enlarged thyroid gland which may cause a
  bulge in the neck)
• other endocrine disorders such as diabetes, an
  underactive adrenal gland, underactive
  parathyroid glands, and other autoimmune
  disorders
• fatigue
• muscle weakness
• weight gain

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Thyroid

• Thyroid hormones are produced by the thyroid
  gland. This gland is located in the lower part of
  the neck, below the Adam's apple.
• The gland wraps around the windpipe (trachea) and
  has a shape that is similar to a butterfly -
  formed by two wings (lobes) and attached by a
  middle part (isthmus).

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Goiter

• This enlargement is due to the inflammatory cells
  which destroy thyroid cells, resulting in long
  term scarring. When the cells are damaged they
  cease thyroid hormone production, resulting in
  hypothyroidism
• A goiter only needs to be treated if it is
  causing symptoms.
• The enlarged thyroid can be treated with
  radioactive iodine to shrink the gland or with
  surgical removal of part or all of the gland
  (thyroidectomy).
• Small doses of iodine (Lugol's or potassium
  iodine solution) may help when the goiter is due
  to iodine deficiency.

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Laboratory Testing

• The diagnosis of Hashimoto's thyroiditis is
  simply diagnosed by two blood tests.
• Routine thyroid function tests to confirm that a
  patient has an underactive thyroid gland.
• Anti-microsomal and anti-thyroglobulin antibodies
  are immune cells which the body produces to
  attack specific portions of the thyroid cells
  which pinpoint Hashimoto's thyroiditis as the
  cause of the hypothyroidism.
• The anti-microsomal antibody test is much more
  sensitive than the anti-thyroglobulin, therefore
  some doctors use only the former blood test.
• These thyroid autoantibodies blood tests are high
  in about 95 of patients with Hashimoto's
  thyroiditis, but are not diagnostic.

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Treatment

• Thyroid hormone replacement.
• Spontaneous remissions have occurred.

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Graves Disease - Thyrotoxicosis

• Characterized by HYPERTHYROIDISM.
• Nervousness, insomnia, depression, weight loss,
  heat intolerance, breathlessness, fatigue,
  cardiac dysrhythmias, and restlessness.
• Women more susceptible, occurs most frequently
  between 30 and 40 years of age.
• Genetic link suspected.

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Graves Disease

• Diagnosis may be straightforward, since the
  "classic face" with its triad of hyperthyroidism,
  goiter, and exophthalmos is easily recognized.
• Goiter is usually symmetric, smooth, and
  nontender
• The hyperthyroid state, which is by far the most
  common component of Graves' disease, can cause a
  wide variety of multisystem derangements that
  often result in diagnostic confusion.

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Exophthalmos

• Exophthalmos, also called proptosis, is a
  characteristic finding in thyroid eye disease,
  and has been reported to occur in 34 to 93 of
  patients

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Signs Symptoms

• Nervousness and increased activity, Grave's
  disease patients may suffer a fast heartbeat,
  fatigue, moist skin, increased sensitivity to
  heat, shakiness, anxiety, increased appetite,
  weight loss, and sleep difficulties.
• They also have at least one of the following an
  enlargement of the thyroid gland (goiter),
  bulging eyes, or raised areas of skin over the
  shins.

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Laboratory Testing

• Presence of thyroid-stimulating hormone receptor
  antibody, causes release of thyroid hormones.
• Key findings are elevated total and free T3
  (triiodothyronine) and T4 (thyroxine), the
  thyroid hormones.
• Thyroid stimulating hormone (TSH) is reduced due
  to antibody stimulation of the thyroid.

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Treatment

• Medication.
• Radioiodine therapy to destroy the thyroid.
• Surgical removal of thyroid

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Insulin Dependent Diabetes Mellitus

• Autoimmune process causes destruction of cells in
  the pancreas resulting in insufficient insulin
  production.
• Occurs before age 20, peak onset between 10 and
  14 years.
• Inherited susceptibility.
• Environmental influences include possibility of
  viral infections.

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Complications

• With its complications, diabetes is the seventh
  leading cause of death in the United States.
• Diabetes is the leading cause of new blindness in
  people 20-74 years of age.
• Ten to twenty-one percent of all people with
  diabetes develop kidney disease.
• People with diabetes are 2-4 times more likely to
  have heart disease.
• About 60-70 of people with diabetes have mild
  to severe forms of diabetic nerve damage, which,
  in severe forms, can lead to lower limb
  amputations.

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Laboratory Testing

• The American Diabetes Association (ADA)
  recommendations for diagnosing diabetes state
  that patients be told they have diabetes if any
  of the criteria below applies
• Fasting plasma glucose is above 126 mg/dl
• Diabetes symptoms exist and casual plasma glucose
  is equal to or above 200 mg/dl or
• Plasma glucose is equal to or above 200 mg/dl
  during an oral glucose tolerance test.
• The ADA now also recommends that all individuals
  age 45 and above be tested for diabetes, and if
  the test is normal, they should be re-tested
  every three years.
• If genetic predisposition is suspected perform
  testing to detect antibodies to pancreatic islet
  cells.
• Antibodies to insulin detected by RIA or ELISA
  methods.

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Indications for Laboratory Testing

• Testing should be conducted at earlier ages and
  carried out more frequently in individuals who
  are any of the following
• obese
• have a first degree relative with diabetes
• are members of a high-risk ethnic population
  (African-American, Hispanic, Native American,
  Asian)
• have delivered a baby weighing more than 9
  pounds
• have had gestational diabetes
• are hypertensive
• have HDL cholesterol levels equal to or less than
  35 mg/dl or triglyceride levels equal to or
  greater than 250 mg/dl
• or who, on previous testing had impaired glucose
  tolerance or impaired fasting glucose.

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Treatment

• Injected insulin.
• Immunosuppressive drugs for newly diagnosed
  patients.

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Multiple Sclerosis

• Multiple sclerosis (MS) is a chronic, potentially
  debilitating disease that affects the brain and
  spinal cord (central nervous system).
• Destruction of myelin sheath of axons results in
  formation of lesions (plaques) in white matter of
  brain and spinal cord.
• Causes inflammation and injury to the sheath and
  ultimately to the nerves.
• The result may be multiple areas of scarring
  (sclerosis).
• Cause may include genetic and environmental
  factors.
• Most often seen between ages of 20 and 50.

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Multiple Sclerosis

• Because the myelin is damaged, messages moving
  along the nerve are transmitted more slowly or
  not at all which slows or blocks muscle
  coordination, visual sensation and other nerve
  signals.

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Multiple Sclerosis
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Diagnosis

• The basic guideline for diagnosing MS relies on
  two criteria
• There must have been two attacks at least one
  month apart. An attack, also known as an
  exacerbation, flare, or relapse, is a sudden
  appearance of or worsening of an MS symptom or
  symptoms which lasts at least 24 hours.
• There must be more than one area of damage to
  central nervous system myelinthe sheath that
  surrounds and protects nerve fibers. The damage
  to myelin must have occurred at more than one
  point in time and not have been caused by any
  other disease that can cause demyelination or
  similar neurologic symptoms.

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Laboratory Diagnosis

• Cerebrospinal fluid (CSF) is tested for levels of
  certain immune system proteins and for the
  presence of oligoclonal bands.
• These bands indicate an abnormal autoimmune
  response within the central nervous system,
  meaning the body is producing an immune response
  against itself.
• Oligoclonal bands are found in the spinal fluid
  of about 90-95 of people with MS, but since they
  are present in other diseases as well, they
  cannot be relied on as positive proof of MS. They
  may also take some years to develop.

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CSF Analysis
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Treatment

• The treatment of MS focuses mainly on decreasing
  the rate and severity of relapse, reducing the
  number of MS lesions, delaying the progression of
  the disease, and providing symptomatic relief for
  the patient.
• Several different drugs have been developed to
  treat the symptoms of MS.
• Drug treatment depends on the stage of the
  disease as well as other factors.

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Myasthenia Gravis

• It is a chronic autoimmune neuromuscular disease
  characterized by varying degrees of weakness of
  the skeletal (voluntary) muscles of the body.
• It is the most common primary disorder of
  neuromuscular transmission

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Symptoms

• Facial weakness,
• Difficulty chewing and swallowing,
• Inability to maintain support of trunk, neck or
  head.

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Myasthenia Gravis

• Antibody mediated damage to acetylcholine
  receptors in skeletal muscles leading
  toprogressive muscle weakness.
• Acetylcholine released from nerve endings to
  generate muscle contraction.
• Antibody combines with receptor site, blocking
  acetylcholine binding.
• Receptors destroyed by action of antibody and
  complement.

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Myasthenia Gravis
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Laboratory Testing

• Autoantibodies to the Acetylcholine receptor
  (AChRAb) can be detected in 80-90 of patients
  with myasthenia gravis.
• The assay measures antibodies that precipitate
  solublized muscle AChR that has been complexed
  with radiolabeled alpha- bungarotoxin (aBTX).
  Antibodies that bind to the receptor regions that
  are not sterically blocked by the aBTX are
  detected.

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Goodpastures Syndrome

• An uncommon and life-threatening hypersensitivity
  disorder believed to be an autoimmune process
  related to antibody formation in the body.
• Goodpasture's syndrome is characterized by renal
  (kidney) disease and lung hemorrhage.

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Goodpastures Syndrome

• Antibodies react with antigens in the glomerular
  basement membrane of the kidney, results in
  severe necrosis.
• Antigen in kidney is similar to antigen found in
  lungs, resulting in antibody reacting with lung
  tissue resulting in pulmonary hemorrhage.
• Specific anti-basement antibodies can be
  demonstrated.

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Symptoms

• Symptoms include
• foamy,
• bloody, or dark colored urine,
• decreased urine output,
• cough with bloody sputum,
• difficulty breathing after exertion,
• weakness,
• fatigue,
• nausea or vomiting,
• weight loss,
• nonspecific chest pain
• and/or pale skin

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Diagnosis

• Complete blood count (CBC)
• Blood urea nitrogen (BUN) and creatinine levels
• Urinalysis will be done to check for damage to
  the kidneys.
• Sputum test to look for specific antibodies.
• Chest x ray to assess the amount of fluid in the
  lung tissues.
• Lung needle biopsy and a kidney biopsy will show
  immune system deposits.
• Kidney biopsy can also show the presence of the
  harmful antibodies that attack the lungs and
  kidneys
• Antiglomerular basement membrane (anti-GBM)
  antibody Enzyme immunoassay (EIA)
• Antibodies to Neutrophil Cytoplasmic Antigens
  (ANCA) identified by immunofluorescence

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Treatment

• Corticosteroids
• Plasmapheresis
• Dialysis

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Sjogren's Syndrome

• Sjogren's syndrome is an autoimmune disease,
  characterized by the abnormal production of extra
  antibodies in the blood that are directed against
  various tissues of the body.
• This particular autoimmune illness is caused by
  inflammation in the glands of the body.
• Inflammation of the glands that produce tears
  (lacrimal glands) leads to decreased water
  production for tears and eye dryness.
• Inflammation of the glands that produce the
  saliva in the mouth (salivary glands, including
  the parotid glands) leads to mouth dryness.

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Sjogrens Syndrome

• Sjogren's syndrome classically features a
  combination of dry eyes, and dry mouth .
• Most often occurs secondary to RA, SLE or other
  autoimmune disorders
• Dry eyes and mouth due to damage to secretory
  ducts.
• 90 of cases found in women.

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Laboratory Test

• ANA and RF positive

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Treatment

• Nonsteroidal anti-inflammatory drugs (NSAIDs),
  such as aspirin and ibuprofen
• Corticosteroids
• Saliva substitutes
• Artificial tears or eye drops
• Cyclosporine A (Restasis) eye drops

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Scleroderma

• A rare, chronic disease characterized by
  excessive deposits of collagen.
• Causes skin thickening and tightening, and can
  involve fibrosis and other types of damage to
  internal body organs.
• This condition, thought to be an autoimmune
  disease, affects both adults and children, most
  commonly adult women.
• he most evident symptom is the hardening of the
  skin and associated scarring.
• Typically the skin appears reddish or scaly in
  appearance. Blood vessels may also be more
  visible. W
• here large areas are affected, fat and muscle
  wastage will weaken limbs and affect appearance.

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Scleroderma

• CREST syndrome
• Calcinosis
• Raynauds
• Esophageal dysmotility
• Sclerodactyly
• Telangiectases

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Calcinosis

• The buildup of calcium deposits in the tissues.
• It may occur under the skin of the fingers, arms,
  feet, and knees, causing pain and infection if
  the calcium deposits pierce the surface of the
  skin.

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Raynauds Phenomena

• is a problem of poor blood flow to fingers and
  toes.  
• Blood flow decreases because blood vessels in
  these areas become narrow for a short time, in
  response to cold or to emotional stress.  
• Results in finger sensitivity, toe sensitivity
  cold sensitivity, changes in skin color, finger
  pain, toe pain, fingertip ulcers, toe ulcers

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Esophageal Dysmotility

• The digestive system includes the mouth,
  esophagus, stomach, and bowels.  
• Scleroderma can weaken the esophagus and the
  bowels.  
• It can also build-up of scar tissue in the
  esophagus, which narrows the tube.  

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Sclerodactyly

• When the fingers become tight, stretched,
  wax-like, and hardened

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Telangiectasias

• Telangiectasias are small enlarged blood vessels
  near the surface of the skin, usually they
  measure only a few millimetres.
• They can develop anywhere on the body but
  commonly on the face around the nose, cheeks and
  chin

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CREST
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Laboratory Tests

• Presence of serum anti-Scl-70 antibodies
• Antinuclear antibody (ANA or FANA)
• Rheumatoid Factor (RF)
• Antibody to single stranded DNA (ssDNA)
• Soluble interleukin 2 receptor level (sIL 2 r).

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Immunoproliferative Disease

• Malignant and pre-malignant proliferation of
  cells.
• Broadly classified as leukemias and lymphomas.

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Immunoproliferative Disease

• B-cell immunoproliferative disorders most
  commonly evaluated.
• B-cell lineage develop into plasma cells
• Urine antibodies used to diagnose and evaluate
  certain B-cell proliferations
• B-cells produce one antibody specificity
  (monoclonal).
• Persistent presence of large amounts of a single
  immunoglobulin suggests malignancy.
• Increase in total amount of one specific clone
  characteristic of benign reactive
  immunoproliferative disease.

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Plasma Cell Dyscrasias

• Include several related syndromes
• Multiple myeloma
• Waldenstroms macroglobulinemia
• Light-chain disease
• Heavy-chain disease
• Monoclonal gammopathy of undetermined
  significance.

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Plasma Cell Dyscrasias

• Characteristic is over production of a single
  immunoglobulin component.
• Paraprotein or myeloma protein.
• Diagnosis and monitoring dependent on detecting
  and quantitating the paraprotein.
• Screening and confirmatory tests performed in
  most clinical laboratories.

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Multiple Myeloma

• Malignancy of mature plasma cells.
• Most serious and common of plasma cell
  dyscrasias.
• Age of diagnosis 40 t0 70 years, found in blacks
  twice as frequently as whites, and men twice as
  likely as women.
• Have excess of plasma cells in the bone marrow.
• Level of normal immunoglobulin decreased in
  proportion to abnormal immunoglobulin.

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Multiple Myeloma

• Immunoglobulin produced by malignant clone, can
  be of any class, IgG most common.
• Important diagnostic feature is presence of Bence
  Jones protein in the urine.
• Abnormal production of free immunoglobulin light
  chains, kappa or lambda.
• Can be detected by immunoelectrophoresis or heat
  precipitation.

99
Clinical Manifestations

• Hematologic related to failure of bone marrow to
  produce normal number of hematoopoeitic cells,
  leads to anemia, thrombocytopenia and neutropenia
• High levels of immunoglobulins lead to rouleaux
  formation being noted on blood smear.
• High levels of abnormal plasma cells leads to
  deficiency in normal immunoglobulin levels.
• Myeloma involves bone leading to lytic lesions,
  bone pain and fractures.
• Deposition of antibody derived material leads to
  organ dysfunctions, with kidneys most commonly
  involved.
• Hyperviscosity develops when protein levels are
  high, especially with IgM producing tumors.
• Hemorrhage can occur due to thrombocytopenia and
  paraprotein interferes in normal hemostasis.

100
Waldenstroms Macroglobulinemia

• Malignant proliferation of IgM producing
  lymphocytes
• Malignant cells more immature than plasma cells,
  with appearance being between small lymph and
  plasma cell.
• Plasmacytoid lymphs infiltrate bone marrow,
  spleen and lymph nodes.
• Some IgM paraproteins behave as cryoglobulins,
  precipitate at cold temperatures.
• Occlude small vessels in patients extremities in
  cold weather.
• Leads to skin sores and necrosis of fingers and
  toes.

101
Waldenstroms Macroglobulinemia

• Cryoglobulins detected in blood or plasma by
  placing the sample in a refrigerator in the
  clinical laboratory.
• Precipitate forms at low temperatures.
• Dissolves upon rewarming.
• May be associated with a cold red cell
  autoantibody directed against the I antigen on
  the patients own red blood cells, may result in
  hemolytic anemia.
• Patients with stable production of monoclonal IgM
  without infiltration of marrow or lymphoid tissue
  are considered to have cold agglutinin syndrome.

102
Clinical Symptoms

• Clinical symptoms
• Anemia
• Bleeding
• Hyperviscosity
• Median survival 5 years versus multiple myeloma,
  3 years.

103
Laboratory Diagnosis

• Measurement of immunoglobulin levels in serum.
• Serum protein electrophoresis to separate and
  detect abnormal levels, myelomas which produce
  only light chains may be missed.
• Immunoelectrophoresis used to evaluate monoclonal
  gammopathies detected by SPE.
• Immunofixation electrophoresis also used to
  evaluate monoclonal gammopathies.
• Serum viscosity measurements useful for
  Waldenstroms macroglobulinemia or high levels of
  IgG or IgA paraproteins.
• Bone marrow biopsy to establish diagnosis of
  lymphoproliferative disorder and determine extent
  of bone marrow replacement by malignancy.

104
References

• http//www.ucl.ac.uk/regfjxe/Arthritis.htm
• http//www.haps.nsw.gov.au/edrsrch/edinfo/lupus.ht
  ml
• http//pathmicro.med.sc.edu/ghaffar/tolerance2000.
  htm
• http//repro-med.net/info/cat4.php
• http//stemcells.nih.gov/info/scireport/chapter6.a
  sp
• http//www-ermm.cbcu.cam.ac.uk/04008427h.htm
• http//www.biotest.de/ww/en/pub/folder_pharma/fiel
  ds_of_use/autoimmune_disease.htm
• http//72.14.203.104/search?qcacheH7KcpVQ4xkYJw
  ww.peppypaws.com/Glossary.htmlForbiddenclonethe
  oryhlenclientfirefox-a