Autoimmunity and Autoimmune Disease

Autoimmunity
Existence of harm-less self-reactive lymphocytes and antibodies
Potentially reversible
Incidence higher in older age
Significance unclear, possibly physiological
Autoimmune disease
Dependent on genetic viral and hormonal factors
Features of severe tissue damage
Protracted course but usually fatal
Familiar clustering
-conditions in which damage to organs or tissues results from the presence of autoantibody or autoreactive cells
Breakdown of self-tolerance
Self-tolerance is believed to be brought about by several mechanisms, including clonal deletion of relevant
effector cells and active regulation by T cells.

Central tolerance destruction of self-reactive lymphocytes in primary lymphoid organs

peripheral tolerance destruction of self-reactive lymphocytes in secondary lymphoid organs
Major histocompatibility complex (MHC) products also seem to influence antigen recognition or nonrecognition
by determining the type of peptides that can be presented t the T cells

Factors that may lead to the development of autoimmune disease

Breakdown of self-tolerance and defects in your immune system

o Defects in natural killer cells, in the secretion of cytokines, in apoptosis (or killing of cells), and in
complement components all may contribute to the loss of self-tolerance.

Genetic factors
o Familial predisposition
o Presence of HLA

Release of sequestered antigens

o Antigens that are protected from encountering the circulation are not exposed to potentially reactive
lymphocytes.
o Examples of these are myelin basic protein, normally sequestered by the bloodbrain barrier; and sperm.

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 Molecular mimicry
o viral or bacterial agents contain antigens that closely resemble self-antigens
o Exposure to such foreign antigens may trigger antibody production that in turn reacts with similar self-
antigens.
Polyclonal B-cell activation
o B-cell defects include the abnormal expression or function of key signaling molecules, dysregulation of
cytokines, and changes in B-cell developmental subsets
o One defect in particular, FC receptor polymorphisms, the receptor for antibody that normally down-regulates
antibody production,may cause continual B-cell stimulation.
Hormones
o especially estrogens, may also play a role, because they are known to affect cytokine production and may
influence which T cells, either Th1 or Th2, are more active in a particular response
Patient age - the occurrence of autoantibodies increases with age. It peaks around 60 -70 years of age
Enviroment - ultraviolet radiation, drugs,chronic disease

STRESS AND NEUROCHEMICALS IN AUTOIMMUNE DISEASE

Many instances are cited in clinical literature where patients have had a dramatic onset of autoimmune disease
following trauma or extreme stress.
Neurochemicals and hormones are thought to play a vital role in initiating disease under these circumstances

CHEMICALS AND PHARMACEUTICALS IN AUTOIMMUNE DISEASE

With the worldwide explosion of manufacturing industry and pollution, an association between exposure to certain
chemicals and the development of specific autoimmune diseases has been clearly established.
These agents may interact with tissues resulting in the expression of modified self-antigens, which are the target
for an autoimmune response. Similarly, pharmaceuticals may induce disease.

Classification of autoimmune dse

Organ specific
- Autoimmune response directed against a particular organ
Non-organ specific
Both

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Systemic lupus erythematosus (SLE)

It is a chronic systemic inflammatory disease marked by alternating exacerbations

The peak age of onset is usually between 20 and 40 years.
Women are much more likely than men to be stricken,
With earlier diagnosis and improved treatments, the 5-year survival rate has increased to greater than 90 percent
The immune response is directed against a broad range of target antigens, as the typical patient has an average
of three circulating autoantibodies.
It appears that there is an interplay between genetic susceptibility and environmental factors

Clinical signs

fatigue, weight loss, malaise, fever, and anorexia are often the first to appear.
Joint involvement seems to be the most frequently reported manifestation, because over 90 percent of patients
with SLE are subject to polyarthralgias or arthritis.
Typically, the arthritis is symmetric and involves the small joints of the hands, wrists, and knees.
The next most common signs are skin manifestations.
An erythematous rash may appear on any area of the body exposed to ultraviolet light.
Less common but perhaps more dramatic is the appearance of the classic butterfly rash across the nose and
cheeks. This is what is responsible for the name lupus, derived from the Latin term meaning wolflike.
In discoid lupus, skin lesions have central atrophy and scarring.
One-half to two-thirds of all patients exhibit evidence of renal involvement
most dangerous is diffuse proliferative glomerulonephritis (DPGN), in which there is cellular proliferation in at least
50 % of the glomeruli
20% individuals with DPGN will die or develop end-stage renal disease within 10 years of diagnosis
deposition of immune complexes in the subendothelial tissue and thickening of the basement membrane
Other systemic effect

cardiac involvement with pericarditis, tachycardia, or ventricular enlargement;

pleuritis with chest pain;
neuropsychiatric manifestations such as seizures, mild cognitive dysfunction, psychoses, or depression;
hematologic abnormalities such as anemia, leukopenia, thrombocytopenia, or lymphopenia

In order for a clinical diagnosis of lupus to be made, four of eleven specific criteria must be present:
- malar rash, - discoid rash
- Photosensitivity - oral ulcers
- arthritis, - serositis
- renal disorders - neurological disorders
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 - Hematologic disorders - immunologic disorders,
Presence of antinuclear antibodies.
antibodies to double-stranded DNA, to Smith antigen, and to phospholipids

Pathophysiology

first clue in the mystery of lupus was the discovery of the LE cell by Malcolm Hargraves in 1948.
LE cell is -a neutrophil that has engulfed the antibody-coated nucleus of another neutrophil.
Nine years after the LE cell was discovered, the first anti-DNA antibody was identified.
uncontrolled autoreactivity of T and B cells leading to the production of autoantibodies
Tregs in lupus seem to be more sensitive to apoptosis, or programmed cell death
altered FC receptors for IgG on B cells keep them from being switched off, so they continue to produce antibody
Alteration on the function of helper T cells
In particular, increased production of interleukin-10 (IL-10), which normally serves an immunosuppressive
role, correlates with increased antibody production and with disease activity. IL-10 appears to trigger an
increase in antibodies directed against DNA and stimulate production of platelet activating factor
Dysfunctional processing in the routine nonimmunologic clearing of cellular debris may also be a key to the
pathogenesis of SLE
Abnormal apoptosis of regular cells
defects in complement receptors on phagocytic cells
defects in receptors for the FC portion of immunoglobulins
deficiencies of early complement components such as C1q, C2, or C4
Drug-induced lupus:
procainamide, hydralazine, chlorpromazine, isoniazid, quinidine, anticonvulsants such as methyldopa,
and possibly oral contraceptives
usually manifested as fever, arthritis, or rashes; rarely are the kidneys involved

Laboratory Diagnosis of Systemic Lupus Erythematosus

screening test for antinuclear antibodies (ANA). Fluorescent antinuclear antibody (FANA) testing is the
most widely used and accepted test, because it detects a wide range of antibodies and is positive in about 95% of
patients with lupus
Double stranded DNA
Makes use of a purified ds-Dna reagent
One test uses the Crithidia luciliae, a hemoflagellate, as the substrate. This trypanosome has circular ds-
DNA in the kinetoplast.
A positive test is indicated by a brightly stained kinetoplast with patient serum and an antibody
conjugate
screening test for antinuclear antibodies (ANA). Fluorescent antinuclear antibody (FANA) testing is the
most widely used and accepted test, because it detects a wide range of antibodies and is positive in about 95% of
patients with lupus
Double stranded DNA
Makes use of a purified ds-Dna reagent
One test uses the Crithidia luciliae, a hemoflagellate, as the substrate. This trypanosome has circular ds-
DNA in the kinetoplast.
A positive test is indicated by a brightly stained kinetoplast with patient serum and an antibody
conjugate
A second major antibody found in lupus patients is antihistone antibody.
Histone is a nucleoprotein that is a major constituent of chromatin. It can be detected in almost all patients with
drug-induced lupus.
About 70 percent of othe patients with SLE have elevated levels of antihistone antibodies
Presence of antihistone antibody alone or combined with antibody to ss-DNA supports the diagnosis of
drug-induced lupus
typically detected by immunofluorescent assays, immunoblotting, and EIA
ANA
Patterns of reactivity:
Homogenous-entire nucleus stained
Smooth, even staining of the nucleus with or without apparent masking of the nucleoli
Peripheral-rim of nucleus stained
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-spots of stain throughout nucleus
Large speckles covering the whole nucleoplasm, interconnected by a fine fluorescent network.
Nucleolar-nucleolus only stained
23 or 46 (or some multiple of 46) bright speckles or ovoid granules spread over the nucleus of
interphase cells
False positives and negatives occur.
If positive, perform profile testing.
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 Antibodies are also stimulated by DNA complexed to histone, known as deoxyribonucleoprotein (DNP)
Immunofluorescent
Latex particles coated with DNP are used in a simple slide agglutination test for SLE
anti-Sm antibody.
Extractable nuclear antigens represent a family of small nuclear proteins that are associated with uridine-
rich RNA. T
he anti-Sm antibody is specific for lupus,
This antibody produces a coarsely speckled pattern of nuclear fluorescence on IIF.
immunodiffusion, immunoblotting, immunoprecipitation and EIA
anti-nRNP antibody
produces a coarsely speckled IIF Ribonucleoprotein (RNP) is protein complexed to a particular type of
nuclear RNA called U1-nRNP (U for uridine-rich).
detected in 20 to 40 percent of patients with SLE, it is also found at a high titer in individuals with mixed
connective tissue disease, systemic sclerosis, Sjgrens syndrome, and other autoimmune diseases.
can be measured by immunoblotting, immunoprecipitation, EIA, and IIF.
Antiphospholipid Antibodies
Antiphospholipid antibodies are a heterogeneous group of antibodies that bind to phospholipid alone or
are complexed with protein.
found in up to 60 percent of patients with lupus
The lupus anticoagulant, one of the several types of antiphospholipid antibodies, was so named because
it produces prolonged activated partial thromboplastin time (aPTT)and prothrombin time (PT).
Treatment for SLE
If fever or arthritis is the primary symptom, a high dose of aspirin or other anti-inflammatory drug may bring relief.
skin manifestations, antimalarials such as hydroxychloroquine or chloroquine and topical steroids are often
prescribed.
Systemic corticosteroids are used for acute fulminant lupus,lupus nephritis, or central nervous system
complications,because these suppress the immune response and lower antibody
Other drugs used include cyclophosphamide, azathioprine, methotrexate, and chlorambucil, but all of these may
have serious side effects such as bone marrow suppression,
Overall, the present 5-year survival rate approaches 90 percent

Rheumatoid arthritis (RA)

systemic autoimmune disorder.
Women are three times as likely to be affected as men.
strikes individuals between the ages of 35 and 50,
Characterized as a chronic, symmetric, and erosive arthritis of the peripheral joints that can also affect multiple
organs such as the heart and the lungs.
In addition to a decline in functional ability, there is a reduced life expectancy.
Key symptoms are morning stiffness around the joints lasting at least 1 hour; swelling of the soft tissue around
three or more joints; swelling of the proximal interphalangeal, metacarpophalangeal, or wrist joints; symmetric
arthritis; subcutaneous nodules
Presence with positive Rheumatoid Factor
Radiographic evidence of erosions in the joints of the hands, the wrists, or both.
At least four of this must be present within 6 weeks
Symptoms
malaise, fatigue, fever, weight loss, and transient joint pain that begins in the small joints of the hands and feet
Morning stiffness and joint pain usually improve during the day.
Joint involvement progresses to the larger joints in a symmetric fashion, often affecting the knees, hips, elbows,
shoulders, and cervical spine
About 20 percent of patients have nodules over the bones.
Nodules can also be found in the myocardium, pericardium, heart valves, pleura, lungs, spleen, and larynx
Feltys syndrome is a combination of several of these symptoms: chronic RA coupled with neutropenia,
splenomegaly, and possibly thrombocytopenia
Immunologic Findings
Pannus organize mass of cells that accumulate in the joints.
an infiltration of mononuclear cells, mostly CD4 T lymphocytes. CD8 T cells B cells and antibody
producing plasma cells.
Macrophages and neutrophils are attracted to the area,
Proinflammatory cytokines found in synovial fluid that contribute to inflammation are interleukin-1 (IL-1),
interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-15 (IL-15), interleukin-18 (IL-18), and tumor necrosis factor-
alpha (TNF-)
Collagenase enzymes are also released
IgM class that is directed against the Fc of IgG
Antibodies present:
IgM class that is directed against the Fc of IgG
antiperinuclear antibody, antifilaggrin, and anti-Sa antibody.
All of these antibodies are directed against citrullinated proteins, which are generated by
modification of proteinbound arginine by the enzyme peptidylarginine deiminase.
Made a much more specific marker

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Lab Dx
radiographic findings
Laboratory testing
antibody that is most often tested for to aid in making the initial diagnosis
RF: one using sheep red blood cells coated with IgG and the other using latex particles coated with the
same antigen.
Testing for two other antibody classes of RF, IgG or IgA, tends to be more specific
A new rapid anti-CCP2 test on the market appears to be valid and reliable and may help to simplify testing
Treatment
Traditional therapy for RA has included anti-inflammatory drugs such as salicylates and ibuprofen to control local
swelling and pain
Disease-modifying antirheumatic drugs (DMARDS)such as methotrexate, hydroxychloroquine,sulfasalazine,
leflunomide, and penicillamineare now prescribed if disease activity persists after 4 to 6 weeks of treatment with
nonsteroidal anti-inflammatory drugs
Corticosteroids such as prednisone can be used in longterm, but they are given in short oral courses for disease
flare-ups.

AUTOIMMUNE THYROID DISEASES

Encompass several different clinical conditions, the most notable of which are Hashimotos thyroiditis and Graves
disease.
Both interfere with thyroid function.
Hashimoto's Thyroiditis
Most often seen in women 30 to 40 years old
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:
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
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 Diagnosis
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.
The anti-microsomal antibody test is much more sensitive than the anti-thyroglobulin,
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.
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
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.
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 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
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 Test
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.
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.
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:
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.
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.
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
Antibody mediated damage to acetylcholine receptors in skeletal muscles leading to progressive 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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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 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.
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 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
characterized by the abnormal production of extra antibodies in the blood that are directed against various tissues
of the body.
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

Scleroderma
A rare, chronic disease characterized by excessive deposits of collagen.

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 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.
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.
Where large areas are affected, fat and muscle wastage will weaken limbs and affect appearance.
CREST syndrome
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
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

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
Telangiectases
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 Test
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
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.
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.
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 Manifestation

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 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.
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.
Clincial 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.

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