AUTOIMMUNITY

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-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

1. 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.
Peak age of onset is 20 to 40 years of age.
Found more frequently in women.
Have both genetic and environmental factors


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.
Butterfly Rash
o 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.
o 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.
o 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
Renal involvement very common.
o Caused by deposition of immune complexes in
kidney tissue.
o Leads to renal failure, most common cause of death.
Other systemic effects:
o Cardiac
o Central nervous system.
o Hematologic abnormalities.
Immunologic Findings
Lupus Erythematosus (LE) cell, neutrophil which has
engulfed the antibody-coated nucleus of another cell.
o First classic test to aid in diagnosis.
o Not utilized anymore, may still see in older
references.
Over activity of B cells main immunologic characteristic.
o Antinuclear antibodies produced.
o More than 28 antibodies associated with LE have
been identified.
o Level of antibody production correlates with severity
of symptoms.
o Estrogen enhances B cell activation.
LE Cell
o Here is the famous "LE cell" test which has value
only in demonstrating how the concept of
autoantibodies works. The pink blobs are denatured
nuclei. Here are two, with one seen being
phagocytized 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]
Decrease in absolute number of T cells
Accumulation of immune complexes with activation of
complement leads to kidney damage.
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.
Fluorescent anti-nuclear antibody (FANA) most widely
used extremely sensitive, low diagnostic specificity.
o Animal or human cells fixed to slide.
o Add patient serum and incubate.
o Wash to remove unreacted antibody.
o Add anti-human globulin labeled with fluorescent tag
or enzyme.
ANA
o Patterns of reactivity:
Homogenous-entire nucleus stained
Peripheral-rim of nucleus stained
Speckled-spots of stain throughout nucleus
Nucleolar-nucleolus only stained
o False positives and negatives occur.
o If positive, perform profile testing.
Antinuclear Antibody Test
o Antinuclear antibodies (ANA) are autoantibodies
against various cell nucleus antigens and are found in
patients with autoimmune diseases such as SLE.
o Some of ANA are considered to be useful for
diagnosis of autoimmune diseases.
o Homogeneous Pattern
Smooth, even staining of the nucleus with or
without apparent masking of the nucleoli
o Nucleolar
23 or 46 (or some multiple of 46) bright speckles
or ovoid granules spread over the nucleus of
interphase cells
o 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.
o Speckled
Large speckles covering the whole nucleoplasm,
interconnected by a fine fluorescent network.
Anti-nuclear antibodies detected by FANA
o Double-stranded DNA (ds-DNA) antibodies are most
specific for SLE, correlate well with disease activity.
o Anti-histone antibody second major antibody found
in SLE.
o Deoxyribonucleoprotein (DNP) antibody, responsible
for LE cell phenomena and available as a latex
agglutination test.
o Anti-Sm antibody, specific for LE.
o SS-A/Ro and SS-B/La antibodies, most common in
patients with cutaneous manifestations.
o Anti-nRNP detected in patients with SLE as well as
mixed connective tissue disease.
o Presence of antibodies not diagnostic may be present
due to other diseases.
Anti-nuclear Antibodies by Immunodiffusion.
o Used to determine specificity.
o Ouchterlony double diffusion most frequently used to
identify antibodies to: Sm, nRNP, SS-A/Ro, SS-B/La
and others.
o Test is not as sensitive but very specific.

o 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).

Extractable Nuclear Antigen ENA

Antiphospholipid Antibodies
o Antiphospholipid antibodies may be present and
are of two types.
Anticardiolipin.
Lupus anticoagulant, if present, may cause
spontaneous abortion and increase
o Risk of clotting, platelet function may be affected.
Treatment
o Aspirin and anti-inflammatories for fever and
arthritis.
o Skin manifestations-anti-malarials or topical
steroids.
o Systemic corticosteroids for acute fulminant lupus,
lupus nephritis or central nervous system
complications.
o Five year survival rate is 80 to 90%.

2. 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:
o Morning stiffness lasting 1 hour.
o Swelling of soft tissue around 3 or more joints.
o Swelling of hand/wrist joints
o Symmetric arthritis.Subcutaneous nodules
o Positive test for rheumatoid factor.
o Xray evidence of joint erosion.

Symptoms initially non-specific: malaise, fever, weight
loss, and transient joint pain.
o Morning stiffness and joint pain improve during the
day.
o Symmetric joint pain: knees, hips, elbows, shoulders.
o 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.

Diagnosis
Diagnosis is based on:
o Clinical findings.
o Radiographic findings
o 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 anti-rheumatic drugs are coming into use but
have side effects.
Joint replacement.

3. 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).
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.
Symptoms
The following are the most common symptoms. However,
each individual may experience symptoms differently:
o 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
o fatigue
o 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.

4. 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.
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 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
5. 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:
o Fasting plasma glucose is above 126 mg/dl;
o Diabetes symptoms exist and casual plasma glucose
is equal to or above 200 mg/dl; or
o 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:
o obese;
o have a first degree relative with diabetes;
o are members of a high-risk ethnic population
(African-American, Hispanic, Native American,
Asian);
o have delivered a baby weighing more than 9 pounds;
o have had gestational diabetes;
o are hypertensive;
o have HDL cholesterol levels equal to or less than 35
mg/dl or triglyceride levels equal to or greater than
250 mg/dl;
o or who, on previous testing had impaired glucose
tolerance or impaired fasting glucose.
Treatment
Injected insulin.
Immunosuppressive drugs for newly diagnosed patients.


6. 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.
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.


Diagnosis
The basic guideline for diagnosing MS relies on two
criteria:
o 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.
o 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.






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.

7. 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
o Antibody mediated damage to acetylcholine receptors
in skeletal muscles leading to progressive muscle
weakness.
o Acetylcholine released from nerve endings to
generate muscle contraction.
o Antibody combines with receptor site, blocking
acetylcholine binding.
o Receptors destroyed by action of antibody and
complement.

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

8. 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.
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
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

9. 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.
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

10. 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.
CREST syndrome
o Calcinosis
o Raynauds
o Esophageal dysmotility
o Sclerodactyly
o Telangiectases

A. 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.
B. 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
C. 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.
D. Sclerodactyly
When the fingers become tight, stretched, wax-like,
and hardened
E. 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

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

Plasma Cell Dyscrasias
Include several related syndromes:
o Multiple myeloma
o Waldenstroms macroglobulinemia
o Light-chain disease
o Heavy-chain disease
o Monoclonal gammopathy of undetermined
significance.

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






MULTIPLE MYELOMA
Malignancy of mature plasma cells.
o Most serious and common of plasma cell
dyscrasias.
o Age of diagnosis 40 t0 70 years, found in blacks
twice as frequently as whites, and men twice as
likely as women.
o Have excess of plasma cells in the bone marrow.
o Level of normal immunoglobulin decreased in
proportion to abnormal immunoglobulin.
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.
o Abnormal production of free immunoglobulin light
chains, kappa or lambda.
o 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
o High levels of immunoglobulins lead to rouleaux
formation being noted on blood smear.
o High levels of abnormal plasma cells lead to
deficiency in normal immunoglobulin levels.
o Myeloma involves bone leading to lytic lesions, bone
pain and fractures.
o Deposition of antibody derived material leads to
organ dysfunctions, with kidneys most commonly
involved.
o Hyperviscosity develops when protein levels are
high, especially with IgM producing tumors.
o Hemorrhage can occur due to thrombocytopenia and
paraprotein interferes in normal hemostasis


WALDENSTROMS MACROGLOBULINEMIA
Malignant proliferation of IgM producing lymphocytes
o Malignant cells more immature than plasma cells,
with appearance being between small lymph and
plasma cell.
o Plasmacytoid lymphs infiltrate bone marrow, spleen
and lymph nodes.
Some IgM paraproteins behave as cryoglobulins,
precipitate at cold temperatures.
o Occlude small vessels in patients extremities in cold
weather.
o Leads to skin sores and necrosis of fingers and toes
Cryoglobulins detected in blood or plasma by placing the
sample in a refrigerator in the clinical laboratory.
o Precipitate forms at low temperatures.
o Dissolves upon rewarming.
o 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:
o Anemia
o Bleeding
o 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.