Topic 3 Autoimmunity
Terry Kotrla, MS, MT(ASCP)BB
Fall 2007
Introduction
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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.
Autoimmunity
Autoimmune Response
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Antibody directed against “self ”, termed autoantibody
Considered abnormal but usually does not result
in disease.
May occur in healthy individuals.
Autoimmune Disease
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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.
Proposed Mechanisms
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Forbidden clone
Altered antigen
Sequestered Antigen
Immunologic deficiency theory
Genetic influence
Forbidden clone
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Clone of changed or altered lymphocytes arise
through mutation.
Lack foreign surface antigens, not destroyed.
Because of alteration may recognize host as
foreign.
Altered Antigen
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Surface antigens on host altered by chemical,
biological or physical means.
This new antigenic determinant may be
recognized as foreign by the host.
Sequestered Antigen
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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.
Immunologic Deficiency Theory
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Relates the increased frequency of autoantibodies 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.
Genetic Influence
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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
Contributing Factors
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Defects in the immune system.
Influence of hormones
Environmental conditions
Classification of Autoimmune
Diseases
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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 autoimmunity is directed against a component of
one particular type of organ.
Both – can get overlap
Systemic Lupus Erythematosus
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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.
Systemic Lupus Erythematosus
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Peak age of onset is 20 to 40 years of age.
Found more frequently in women.
Has both genetic and environmental factors.
SLE Clinical Signs
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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.
SLE Butterfly Rash
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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
SLE Clinical Signs
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Renal involvement very common.
Caused by deposition of immune complexes in
kidney tissue.
 Leads to renal failure, most common cause of death.
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Other systemic effects:
Cardiac
 Central nervous system.
 Hematologic abnormalities.
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Immunologic Findings
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Lupus Erythematosus (LE) cell, neutrophil which has
engulfed the antibody-coated nucleus of another cell.
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First classic test to aid in diagnosis.
Not utilized anymore, may still see in older references.
Over activity of B cells main immunologic
characteristic.
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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.
LE Cell
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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]
Immunologic Findings
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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.
Laboratory Diagnosis
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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.
ANA
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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
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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.
Homogeneous Pattern
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Smooth, even staining of the nucleus with or without
apparent masking of the nucleoli
Nucleolar
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23 or 46 (or some multiple of 46) bright speckles or
ovoid granules spread over the nucleus of interphase
cells
Peripheral
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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.
Speckled
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Large speckles covering the whole nucleoplasm,
interconnected by a fine fluorescent network.
Anti-nuclear antibodies detected by FANA
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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.
Anti-nuclear Antibodies by
Immunodiffusion.
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Used to determine specificity.
Ouchterlony double diffusion most frequently
used to identify antibodies to: Sm, nRNP, SSA/Ro, SS-B/La and others.
Test is not as sensitive but very specific.
Extractable Nuclear Antigen
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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).
Systemic Lupus Erythematosus
Extractable Nuclear Antigen ENA
Antiphospholipid Antibodies
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Antiphospholipid antibodies may be present and
are of two types.
Anticardiolipin.
 Lupus anticoagulant, if present, may cause
spontaneous abortion and increase
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Risk of clotting, platelet function may be
affected.
Treatment
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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%.
Rheumatoid Arthritis
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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.
Clinical Signs
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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
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Symptoms initially non-specific: malaise, fever, weight
loss, and transient joint pain.
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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
Immunologic Findings
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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.
Rheumatoid Arthritis
Diagnosis
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Diagnosis is based on:
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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
Treatment
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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.
Hashimoto's Thyroiditis
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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.
Hashimoto’s prevents the gland from producing
enough thyroid hormones for the body to work
correctly.
It is the most common form of Hypothyroidism
(underactive thyroid).
Hashimoto’s Thyroiditis
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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.
Hashimoto’s Thyroiditis
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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.
Symptoms
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The following are the most common symptoms.
However, each individual may experience symptoms
differently:
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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
Thyroid
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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).
Goiter
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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.
Laboratory Testing
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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.
Treatment
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Thyroid hormone replacement.
Spontaneous remissions have occurred.
Graves’ Disease - Thyrotoxicosis
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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.
Graves’ Disease
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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.
Exophthalmos
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Exophthalmos, also called proptosis, is a characteristic
finding in thyroid eye disease, and has been reported
to occur in 34% to 93% of patients
Signs Symptoms
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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.
Laboratory Testing
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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.
Treatment
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Medication.
Radioiodine therapy to destroy the thyroid.
Surgical removal of thyroid
Insulin Dependent Diabetes Mellitus
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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.
Complications
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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.
Laboratory Testing
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The American Diabetes Association (ADA) recommendations
for diagnosing diabetes state that patients be told they have
diabetes if any of the criteria below applies:
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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.
Indications for Laboratory Testing
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Testing should be conducted at earlier ages and carried out more
frequently in individuals who are any of the following:
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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.
Treatment
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Injected insulin.
Immunosuppressive drugs for newly diagnosed
patients.
Multiple Sclerosis
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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.
Multiple Sclerosis
Multiple Sclerosis
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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.
Damage Caused by MS
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Without the protective coating, nerve cells have
difficulty doing their job and sending signals.
The damage that MS causes can affect:
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the eyes, which have thousands of nerve fibers to carry visual
information from the retina to the brain, as well as nerve cells
controlling the eye's muscles
Muscle coordination and strength, because nerve fibers have
direct control of all muscles
speech, which is controlled by muscles in the throat, mouth
and tongue
bladder and bowel control
Multiple Sclerosis
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MS is a disease that treats each patient
differently.
Approximately 15 percent of patients experience
severe problems that can totally disable them.
 MS generally is not fatal, and most MS patients live a
normal life span.
 MS affects as many as 300,000 Americans.
 There is no cure for MS, but it is treatable.
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Diagnosis
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The basic guideline for diagnosing MS relies on two
criteria:
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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 myelin—the 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.
Laboratory Diagnosis
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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.
CSF Analysis
Treatment
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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.
Myasthenia Gravis
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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
Symptoms
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Facial weakness,
Difficulty chewing and swallowing,
Inability to maintain support of trunk, neck or
head.
Myasthenia Gravis
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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
Myasthenia Gravis
Laboratory Testing
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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 (αBTX).
Antibodies that bind to the receptor regions that are
not sterically blocked by the αBTX are detected.
Goodpasture’s Syndrome
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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.
Goodpasture’s Syndrome
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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.
Symptoms
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Symptoms include:
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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
Diagnosis
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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
Treatment
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Corticosteroids
Plasmapheresis
Dialysis
Sjogren's Syndrome
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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.
Sjogren’s Syndrome
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Chronic autoimmune disorder in which immune cells
attack and destroy the glands that produce tears and
saliva.
The hallmark symptoms of the disorder are dry mouth
and dry eyes.
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.
Laboratory Test
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ANA and RF positive
Treatment
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Nonsteroidal anti-inflammatory drugs
(NSAIDs), such as aspirin and ibuprofen
Corticosteroids
Saliva substitutes
Artificial tears or eye drops
Cyclosporine A (Restasis) eye drops
Scleroderma
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From the Greek words for 'hard' and 'skin' - 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.
Typically the skin appears reddish or scaly in
appearance. Blood vessels may also be more visible.
Where large areas are affected, fat and muscle wastage
will weaken limbs and affect appearance.
Scleroderma
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CREST syndrome
Calcinosis
 Raynaud’s Phenomena
 Esophageal dysmotility
 Sclerodactyly
 Telangiectases
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Calcinosis
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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.
Raynaud’s Phenomena
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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
Raynaud’s Phenomena
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.
Sclerodactyly

When the fingers become tight, stretched, wax-like, and
hardened
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
CREST
Treatment


Those who suffer from scleroderma, a chronic
autoimmune disease, may have hope in a new
drug being tested at Wayne State University
School of Medicine.
Phase II clinical studies of relaxin, a naturally
occurring hormone, show that the drug may
reverse skin thickening, which is a clinical
measure of the progression of scleroderma.
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).
Immunoproliferative Disease


Malignant and pre-malignant proliferation of
cells.
Broadly classified as leukemias and lymphomas.
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.
Plasma Cell Dyscrasias

Include several related syndromes:
Multiple myeloma
 Waldenstrom’s macroglobulinemia
 Light-chain disease
 Heavy-chain disease
 Monoclonal gammopathy of undetermined
significance.

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.
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.

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.

Clinical Manifestations

Hematologic related to failure of bone marrow to produce
normal number of hematopoeitic 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.
Multiple Myeloma

Bone Marrow –
Malignant plasma cells

Peripheral smear –
pathologic rouleaux
Waldenstrom’s 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 patient’s extremities in cold weather.
Leads to skin sores and necrosis of fingers and toes.
Waldenstrom’s Macroglobulinemia

Cryoglobulins detected in blood or plasma by placing
the sample in a refrigerator in the clinical laboratory.



Precipitate forms at low temperatures (4C).
Dissolves upon rewarming.
May be associated with a cold red cell autoantibody directed
against the I antigen on the patient’s own red blood cells, may
result in hemolytic anemia.
Waldenstrom’s Macroglobulinemia

Patients with stable production of monoclonal
IgM without infiltration of marrow or lymphoid
tissue are considered to have cold agglutinin
syndrome.
Clinical Symptoms

Clinical symptoms:
Anemia
 Bleeding
 Hyperviscosity


Median survival 5 years versus multiple
myeloma, 3 years.
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.
Laboratory Diagnosis




Immunoelectrophoresis used to evaluate monoclonal
gammopathies detected by SPE.
Immunofixation electrophoresis also used to evaluate
monoclonal gammopathies.
Serum viscosity measurements useful for
Waldenstrom’s 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.
References

http://www.ucl.ac.uk/~regfjxe/Arthritis.htm


http://www.haps.nsw.gov.au/edrsrch/edinfo/lupus.html
http://pathmicro.med.sc.edu/ghaffar/tolerance2000.htm

http://repro-med.net/info/cat4.php


http://stemcells.nih.gov/info/scireport/chapter6.asp
http://www-ermm.cbcu.cam.ac.uk/04008427h.htm

http://www.biotest.de/ww/en/pub/folder_pharma/fields_of_use/autoimmune_disease.htm

http://72.14.203.104/search?q=cache:H7KcpVQ4xkYJ:www.peppypaws.com/Glossary.html+Forbidden+clone+theory&hl=en&client=firefox-a