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 apparent    masking 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 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.
• Hashimoto’s prevents the gland from producing enough thyroid hormones for the body to work correctly.
• It is the most common form of Hypothyroidism (underactive thyroid).

Hashimoto’s Thyroiditis�

• Organ specific disease affecting the thyroid gland.
• Most often seen in women 30 to 40 years old, may be genetic predisposition.
• Common cause of hypothyroidism.
• Causes diffuse hyperplasia in the gland resulting in development of a goiter.
• Thyroid autoantibodies are formed.

​

Hashimoto’s Thyroiditis

• 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 (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—the sheath that surrounds and protects nerve fibers. The damage to myelin must have occurred at more than one point in time and not have been caused by any other disease that can cause demyelination or similar neurologic symptoms.

​

Laboratory Diagnosis

• 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 80-90% of patients with myasthenia gravis.
• The assay measures antibodies that precipitate solublized muscle AChR that has been complexed with radiolabeled alpha- bungarotoxin (αBTX). Antibodies that bind to the receptor regions that are not sterically blocked by the αBTX are detected.

Goodpasture’s Syndrome�

• An uncommon and life-threatening hypersensitivity disorder believed to be an autoimmune process related to antibody formation in the body.
• Goodpasture's syndrome is characterized by renal (kidney) disease and lung hemorrhage.

Goodpasture’s Syndrome

• 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.

Sjogren’s 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
• Raynaud’s
• 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.

Raynaud’s 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

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
• Waldenstrom’s macroglobulinemia
• Light-chain disease
• Heavy-chain disease
• Monoclonal gammopathy of undetermined significance.

​

Plasma Cell Dyscrasias

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

​

Multiple Myeloma�

• Malignancy of mature plasma cells.
• Most serious and common of plasma cell dyscrasias.
• Age of diagnosis 40 t0 70 years, found in blacks twice as frequently as whites, and men twice as likely as women.
• Have excess of plasma cells in the bone marrow.
• Level of normal immunoglobulin decreased in proportion to abnormal immunoglobulin.

​

Multiple Myeloma�

• Immunoglobulin produced by malignant clone, can be of any class, IgG most common.
• Important diagnostic feature is presence of Bence Jones protein in the urine.
• Abnormal production of free immunoglobulin light chains, kappa or lambda.
• Can be detected by immunoelectrophoresis or heat precipitation.

​

Clinical Manifestations

• Hematologic related to failure of bone marrow to produce normal number of 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.

​

Waldenstrom’s Macroglobulinemia�

• Malignant proliferation of IgM producing lymphocytes
• Malignant cells more immature than plasma cells, with appearance being between small lymph and plasma cell.
• Plasmacytoid lymphs infiltrate bone marrow, spleen and lymph nodes.
• Some IgM paraproteins behave as cryoglobulins, precipitate at cold temperatures.
• Occlude small vessels in patient’s extremities in cold weather.
• Leads to skin sores and necrosis of fingers and toes.

​

Waldenstrom’s Macroglobulinemia�

• Cryoglobulins detected in blood or plasma by placing the sample in a refrigerator in the clinical laboratory.
• Precipitate forms at low temperatures.
• Dissolves upon rewarming.
• May be associated with a cold red cell autoantibody directed against the I antigen on the patient’s own red blood cells, may result in hemolytic anemia.
• 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 Waldenstrom’s macroglobulinemia or high levels of IgG or IgA paraproteins.
• Bone marrow biopsy to establish diagnosis of lymphoproliferative disorder and determine extent of bone marrow replacement by malignancy.

​

References

• http://www.ucl.ac.uk/~regfjxe/Arthritis.htm
• http://www.haps.nsw.gov.au/edrsrch/edinfo/lupus.html
• http://pathmicro.med.sc.edu/ghaffar/tolerance2000.htm
• http://repro-med.net/info/cat4.php
• http://stemcells.nih.gov/info/scireport/chapter6.asp
• http://www-ermm.cbcu.cam.ac.uk/04008427h.htm
• http://www.biotest.de/ww/en/pub/folder_pharma/fields_of_use/autoimmune_disease.htm
• http://72.14.203.104/search?q=cache:H7KcpVQ4xkYJ:www.peppypaws.com/Glossary.html+Forbidden+clone+theory&hl=en&client=firefox-a

​

​

​

​