Topic 3

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

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.

Autoimmunity

Autoimmune Response

Antibody directed against self,

termed 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-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

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.

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]

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.

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.

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.

Homogeneous Pattern

Smooth, even staining of the nucleus with

or without apparentmasking of the
nucleoli

Nucleolar

23 or 46 (or some multiple of 46) bright

speckles or ovoid granules spread over
the nucleus of interphase cells

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.

Speckled

Large speckles covering the whole

nucleoplasm, interconnected by a fine
fluorescent network.

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.

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.

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).

Systemic Lupus
Erythematosus

Extractable Nuclear
Antigen ENA

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 antiinflammatory 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).
Small doses of iodine (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, 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, is a

characteristic finding in thyroid eye
disease, and has been reported to occur
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 (AfricanAmerican, 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 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 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 8090% of patients with myasthenia gravis.
The assay measures antibodies that
precipitate solublized muscle AChR that
has been complexed with radiolabeled
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-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,
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-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-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, t 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-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-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
Waldenstroms 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 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.

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.

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.

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.
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.

References

http://www.ucl.ac.uk/~regfjxe/Arthri
tis.htm

http://www.haps.nsw.gov.au/edrsrch/edinfo/lupus
.html

http://pathmicro.med.sc.edu/ghaffar/tolerance20
00.htm

http://repro-med.net/info/cat4.php

http://stemcells.nih.gov/info/scireport/cha
pter6.asp
http://www-ermm.cbcu.cam.ac.uk/040084