Autoimmunity

Dr. dr. Nyoman Suci W, M.Kes, SpPK

Bagian Patologi Klinik

Fakultas Kedokteran Universitas Diponegoro
2015
 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.
 Autoimmune Response

Antibody directed against self,

termed auto-
auto-antibody
Considered abnormal but usually
does not result in disease.
May occur in healthy individuals.
 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.
 Proposed Mechanisms

Forbidden clone
Altered antigen
Sequestered Antigen
Immunologic deficiency theory
Genetic influence
 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.
 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.
 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.
 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.
 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
 Contributing Factors
Defects in the immune system.
Influence of hormones
Environmental conditions
 Classification of Autoimmune
Diseases
Systemic- the auto-
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-
auto-
immunity is directed against a component of
one particular type of organ.
Both can get overlap
 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.
 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.
 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.
 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
 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.
 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.
 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.
 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.
 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.
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.
 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%.
 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.
 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.

 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
 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.
Rheumatoid Arthritis
 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
 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.
 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).
 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.
 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.
 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
 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).
 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
(thyroidectomy).).
Small doses of iodine (Lugol's
(Lugol's or potassium iodine
solution) may help when the goiter is due to iodine
deficiency.
 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.
 Treatment
Thyroid hormone replacement.
Spontaneous remissions have
occurred.
 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.
 Graves Disease
Diagnosis may be straightforward, since
the "classic face" with its triad of
hyperthyroidism,, goiter
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
Exophthalmos, also called proptosis
Exophthalmos, proptosis,, is a
characteristic finding in thyroid eye
disease,, and has been reported to occur
disease
in 34% to 93% of patients
 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.
 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.
 Treatment
Medication.
Radioiodine therapy to destroy the
thyroid.
Surgical removal of thyroid
 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.
 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.
 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.
 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.
 Treatment
Injected insulin.
Immunosuppressive drugs for newly
diagnosed patients.
 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.
 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..
Multiple Sclerosis
 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 myelin
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.
 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
90
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
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

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
Facial weakness,
Difficulty chewing and swallowing,
Inability to maintain support of
trunk, neck or head.
 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.
Myasthenia Gravis
 Laboratory Testing
Autoantibodies to the Acetylcholine receptor
(AChRAb) can be detected in 80-80-90% of
patients with myasthenia gravis.
The assay measures antibodies that precipitate
solublized muscle AChR that has been
complexed with radiolabeled alpha-
alpha-
bungarotoxin (BTX). Antibodies that bind to
the receptor regions that are not sterically
blocked by the BTX are detected.
 Goodpastures Syndrome

An uncommon and life-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.
 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.
 Symptoms
Symptoms include:
foamy,
bloody, or dark colored urine,
decreased urine output,
cough with bloody sputum,
difficulty breathing after exertion,
weakness,
fatigue,,
fatigue
nausea or vomiting,
weight loss,
nonspecific chest pain
and/or pale skin
 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-
(anti-GBM) antibody
Enzyme immunoassay (EIA)
Antibodies to Neutrophil Cytoplasmic Antigens (ANCA)
identified by immunofluorescence
 Treatment
Corticosteroids
Plasmapheresis
Dialysis
 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.
 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.
 Laboratory Test
ANA and RF positive
 Treatment
Nonsteroidal anti-
anti-inflammatory drugs
(NSAIDs), such as aspirin and ibuprofen
Corticosteroids
Saliva substitutes
Artificial tears or eye drops
Cyclosporine A (Restasis) eye drops
 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.
 Scleroderma

CREST syndrome
Calcinosis
Raynauds

Esophageal dysmotility

Sclerodactyly

Telangiectases
 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.
 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
oe sensitivity cold
sensitivity, changes in skin color, finger pain, toe
pain, fingertip ulcers, toe ulcers
 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-

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
 Laboratory Tests
Presence of serum anti-
anti-Scl
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).
 References
Terry Kotrla
Kotrla,, MS, MT(ASCP)BB
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http://repro
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