Topic 3 Topic 3 AutoimmunityAutoimmunity

Terry Kotrla, MS, Terry Kotrla, MS, MT(ASCP)BBMT(ASCP)BB

Fall 2005Fall 2005

IntroductionIntroduction

Under normal circumstances immune Under normal circumstances immune system will not destroy self antigens.system will not destroy self antigens.

Autoimmunity can be defined as Autoimmunity can be defined as breakdown of mechanisms responsible breakdown of mechanisms responsible for self tolerance and induction of an for self tolerance and induction of an immune response against components of immune response against components of the self. the self.

In numerous autoimmune diseases it is In numerous autoimmune diseases it is well recognized that products of the well recognized that products of the immune system cause damage to the self. immune system cause damage to the self.

AutoimmunityAutoimmunity

Autoimmune Autoimmune ResponseResponse

Antibody directed against “self”, Antibody directed against “self”, termed auto-antibodytermed auto-antibody

Considered abnormal but usually Considered abnormal but usually does not result in disease.does not result in disease.

May occur in healthy individuals.May occur in healthy individuals.

Autoimmune Autoimmune DiseaseDisease

Disorder in which tissue injury is Disorder in which tissue injury is caused by an immunologic reaction caused by an immunologic reaction of the host to its own tissues.of the host to its own tissues.

Precise mechanisms unknown.Precise mechanisms unknown. Classified as systemic or organ Classified as systemic or organ

specific, frequently have overlap.specific, frequently have overlap.

Proposed MechanismsProposed Mechanisms

Forbidden cloneForbidden clone Altered antigenAltered antigen Sequestered AntigenSequestered Antigen Immunologic deficiency theoryImmunologic deficiency theory Genetic influenceGenetic influence

Forbidden cloneForbidden clone

Clone of changed or altered Clone of changed or altered lymphocytes arise through mutation.lymphocytes arise through mutation.

Lack foreign surface antigens, not Lack foreign surface antigens, not destroyed.destroyed.

Because of alteration may recognize Because of alteration may recognize host as foreign.host as foreign.

Altered AntigenAltered 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 AntigenSequestered 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 Immunologic Deficiency TheoryTheory

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 InfluenceGenetic 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 FactorsContributing Factors

Defects in the immune system. Influence of hormones Environmental conditions

Classification of Classification of Autoimmune DiseasesAutoimmune Diseases

Systemic- the auto-immunity is the auto-immunity is directed against an directed against an antigenantigen that is that is present at many different sites and can present at many different sites and can include involvement of several organs include involvement of several organs

Organ specific - Organ specific means Organ specific means the auto-immunity is directed against the auto-immunity is directed against a component of one particular type of a component of one particular type of organ.organ.

Both – can get overlap

Systemic Lupus Systemic Lupus ErythematosusErythematosus

Chronic, systemic inflammatory disease Chronic, systemic inflammatory disease caused by immune complex formation.caused by immune complex formation.

The word "systemic" means the disease can The word "systemic" means the disease can affect many parts of the body. 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, Parts of the body affected include: the joints, skin, kidneys, heart, lungs, blood vessels, and skin, kidneys, heart, lungs, blood vessels, and brain. brain.

Systemic Lupus Systemic Lupus ErythematosusErythematosus

Peak age of onset is 20 to 40 years of age.

Found more frequently in women. Has both genetic and environmental

factors.

SLE Clinical SignsSLE 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 RashSLE Butterfly Rash The source of the name "lupus" The source of the name "lupus"

is unclear. All explanations is unclear. All explanations originate with the characteristic originate with the characteristic butterflybutterfly-shaped malar rash -shaped malar rash that the disease classically that the disease classically exhibits across the nose and exhibits across the nose and cheeks. cheeks.

In various accounts, some In various accounts, some doctors thought the rash doctors thought the rash resembled a wolf pattern. In resembled a wolf pattern. In other accounts doctors thought other accounts doctors thought that the rash, which was often that the rash, which was often more severe in earlier centuries, more severe in earlier centuries, created lesions that resembled created lesions that resembled wolf bites or scratches. wolf bites or scratches.

Stranger still, is the account Stranger still, is the account that the term "Lupus" didn't that the term "Lupus" didn't come from latin at all, but from come from latin at all, but from the term for a French style of the term for a French style of mask which women reportedly mask which women reportedly wore to conceal the rash on wore to conceal the rash on their faces their faces

SLE Clinical SignsSLE 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 FindingsImmunologic 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 CellLE Cell Here is the famous "LE cell" test which has value only Here is the famous "LE cell" test which has value only

in demonstrating how the concept of autoantibodies in demonstrating how the concept of autoantibodies work. The pink blobs are denatured nuclei. Here are work. The pink blobs are denatured nuclei. Here are two, with one seen being phagocytozed in the center by two, with one seen being phagocytozed in the center by a PMN. This test is not nearly as sensitive as the ANA a PMN. This test is not nearly as sensitive as the ANA which has supplanted the LE cell test. Therefore, which has supplanted the LE cell test. Therefore, NEVER order an LE cell test. [Image contributed by NEVER order an LE cell test. [Image contributed by Elizabeth Hammond, MD, University of Utah] Elizabeth Hammond, MD, University of Utah]

Immunologic FindingsImmunologic 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 DiagnosisLaboratory 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.

ANAANA

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 Antinuclear Antibody TestTest

Antinuclear antibodies Antinuclear antibodies (ANA) are (ANA) are autoantibodies autoantibodies against various cell against various cell nucleus antigens and nucleus antigens and are found in patients are found in patients with autoimmune with autoimmune diseases such as SLE. diseases such as SLE.

Some of ANA are Some of ANA are considered to be considered to be useful for diagnosis of useful for diagnosis of autoimmune diseases.autoimmune diseases.

Homogeneous PatternHomogeneous Pattern

Smooth, even staining of the nucleus with Smooth, even staining of the nucleus with or without apparent    masking of the or without apparent    masking of the nucleolinucleoli

NucleolarNucleolar

23 or 46 (or some multiple of 46) bright 23 or 46 (or some multiple of 46) bright speckles or ovoid granules spread over speckles or ovoid granules spread over the nucleus of interphase cells the nucleus of interphase cells

PeripheralPeripheral

Fluorescence is most intense at the Fluorescence is most intense at the periphery of the nucleus with a large ring periphery of the nucleus with a large ring starting from the internal nuclear starting from the internal nuclear membrane and the rest of the nucleus membrane and the rest of the nucleus showing weaker yet smooth staining. showing weaker yet smooth staining.

SpeckledSpeckled

Large speckles covering the whole Large speckles covering the whole nucleoplasm, interconnected by a fine nucleoplasm, interconnected by a fine fluorescent network. 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 Extractable Nuclear Antigen Antigen

This is antibody to a cytoplasmic This is antibody to a cytoplasmic ribonuclear protein complex. ribonuclear protein complex.

It is associated with mixed It is associated with mixed connective disease and SLE with connective disease and SLE with particular features (arthritis, particular features (arthritis, myositis, Raynaud's phenomenon - myositis, Raynaud's phenomenon - also association with HLA-DR4 and also association with HLA-DR4 and HLA-DQw8). HLA-DQw8).

Systemic Lupus Systemic Lupus ErythematosusErythematosus

Extractable Nuclear Extractable Nuclear Antigen ENAAntigen 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 SignsClinical 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 SignsClinical 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 FindingsImmunologic 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 ArthritisRheumatoid Arthritis

DiagnosisDiagnosis 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

TreatmentTreatment

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 ThyroiditisHashimoto's Thyroiditis Hashimoto's Thyroiditis is a type of Hashimoto's Thyroiditis is a type of

autoimmune thyroid disease in which the autoimmune thyroid disease in which the immune system attacks and destroys the immune system attacks and destroys the thyroid gland. thyroid gland.

The thyroid helps set the rate of metabolism The thyroid helps set the rate of metabolism - the rate at which the body uses energy. - the rate at which the body uses energy.

Hashimoto’s prevents the gland from Hashimoto’s prevents the gland from producing enough thyroid hormones for the producing enough thyroid hormones for the body to work correctly. body to work correctly.

It is the most common form of It is the most common form of Hypothyroidism (underactive thyroid). 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 Hashimoto's thyroiditis is the most common cause of hypothyroidism.common cause of hypothyroidism.

It is also most prevalent in elderly It is also most prevalent in elderly women and tends to run in families.women and tends to run in families.

Hashimoto's thyroiditis occurs eight Hashimoto's thyroiditis occurs eight times more often in women than men.times more often in women than men.

Certain chromosomal abnormalities Certain chromosomal abnormalities include Hashimoto's thyroiditis as a include Hashimoto's thyroiditis as a symptom.symptom.

SymptomsSymptoms The following are the most common The following are the most common

symptoms. However, each individual may symptoms. However, each individual may experience symptoms differently: experience symptoms differently: goiter (enlarged thyroid gland which may goiter (enlarged thyroid gland which may

cause a bulge in the neck) cause a bulge in the neck) other endocrine disorders such as diabetes, an other endocrine disorders such as diabetes, an

underactive adrenal gland, underactive underactive adrenal gland, underactive parathyroid glands, and other autoimmune parathyroid glands, and other autoimmune disorders disorders

fatigue fatigue muscle weakness muscle weakness weight gain weight gain

ThyroidThyroid Thyroid hormones are produced by the thyroid gland. Thyroid hormones are produced by the thyroid gland.

This gland is located in the lower part of the neck, This gland is located in the lower part of the neck, below the Adam's apple. below the Adam's apple.

The gland wraps around the windpipe (trachea) and has The gland wraps around the windpipe (trachea) and has a shape that is similar to a butterfly - formed by two a shape that is similar to a butterfly - formed by two wings (lobes) and attached by a middle part (isthmus). wings (lobes) and attached by a middle part (isthmus).

GoiterGoiter

This enlargement is due to the inflammatory cells which This enlargement is due to the inflammatory cells which destroy thyroid cells, resulting in long term scarring. destroy thyroid cells, resulting in long term scarring. When the cells are damaged they cease thyroid hormone When the cells are damaged they cease thyroid hormone production, resulting in hypothyroidism production, resulting in hypothyroidism

A goiter only needs to be treated if it is causing A goiter only needs to be treated if it is causing symptoms. symptoms.

The enlarged thyroid can be treated with radioactive The enlarged thyroid can be treated with radioactive iodine to shrink the gland or with surgical removal of iodine to shrink the gland or with surgical removal of part or all of the gland (thyroidectomy). part or all of the gland (thyroidectomy).

Small doses of iodine (Lugol's or potassium iodine Small doses of iodine (Lugol's or potassium iodine solution) may help when the goiter is due to iodine solution) may help when the goiter is due to iodine deficiency. deficiency.

Laboratory TestingLaboratory 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.

TreatmentTreatment

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

DDiagnosis may be straightforward, since the iagnosis may be straightforward, since the "classic face" with its triad of "classic face" with its triad of hyperthyroidismhyperthyroidism, , goitergoiter, and , and exophthalmosexophthalmos is easily recognized. is easily recognized.

Goiter is usually symmetric, smooth, and Goiter is usually symmetric, smooth, and nontender nontender

The hyperthyroid state, which is by far the The hyperthyroid state, which is by far the most common component of Graves' disease, most common component of Graves' disease, can cause a wide variety of multisystem can cause a wide variety of multisystem derangements that often result in diagnostic derangements that often result in diagnostic confusion. confusion.

ExophthalmosExophthalmos

ExophthalmosExophthalmos, also called proptosis, is a , also called proptosis, is a characteristic finding in thyroid eye characteristic finding in thyroid eye diseasedisease, and has been reported to occur , and has been reported to occur in 34% to 93% of patients in 34% to 93% of patients

Signs SymptomsSigns Symptoms

Nervousness and increased activity, Nervousness and increased activity, Grave's disease patients may suffer a Grave's disease patients may suffer a fast heartbeat, fatigue, moist skin, fast heartbeat, fatigue, moist skin, increased sensitivity to heat, increased sensitivity to heat, shakiness, anxiety, increased appetite, shakiness, anxiety, increased appetite, weight loss, and sleep difficulties. weight loss, and sleep difficulties.

They also have at least one of the They also have at least one of the following: an enlargement of the following: an enlargement of the thyroid gland (goiter), bulging eyes, thyroid gland (goiter), bulging eyes, or raised areas of skin over the shins. 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.

TreatmentTreatment

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.

TreatmentTreatment

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 SclerosisMultiple 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 SclerosisMultiple Sclerosis

DiagnosisDiagnosis The basic guideline for diagnosing MS relies The basic guideline for diagnosing MS relies

on two criteria:on two criteria: There must have been two attacks at least one There must have been two attacks at least one

month apart. An attack, also known as an month apart. An attack, also known as an exacerbation, flare, or relapse, is a sudden exacerbation, flare, or relapse, is a sudden appearance of or worsening of an MS symptom or appearance of or worsening of an MS symptom or symptoms which lasts at least 24 hours. symptoms which lasts at least 24 hours.

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

Laboratory DiagnosisLaboratory Diagnosis Cerebrospinal fluid (CSF) Cerebrospinal fluid (CSF) is tested for levels is tested for levels

of certain immune system proteins and for the of certain immune system proteins and for the presence of oligoclonal bands. presence of oligoclonal bands.

These bands indicate an abnormal These bands indicate an abnormal autoimmune response within the central autoimmune response within the central nervous system, meaning the body is nervous system, meaning the body is producing an immune response against itself. producing an immune response against itself.

Oligoclonal bands are found in the spinal fluid Oligoclonal bands are found in the spinal fluid of about 90-95% of people with MS, but since of about 90-95% of people with MS, but since they are present in other diseases as well, they are present in other diseases as well, they cannot be relied on as positive proof of they cannot be relied on as positive proof of MS. They may also take some years to MS. They may also take some years to develop.develop.

CSF AnalysisCSF Analysis

TreatmentTreatment

The treatment of MS focuses mainly on The treatment of MS focuses mainly on decreasing the rate and severity of decreasing the rate and severity of relapse, reducing the number of MS relapse, reducing the number of MS lesions, delaying the progression of the lesions, delaying the progression of the disease, and providing symptomatic disease, and providing symptomatic relief for the patient. relief for the patient.

Several different drugs have been Several different drugs have been developed to treat the symptoms of MS. developed to treat the symptoms of MS.

Drug treatment depends on the stage of Drug treatment depends on the stage of the disease as well as other factors. the disease as well as other factors.

Myasthenia Gravis

It is a chronic autoimmune It is a chronic autoimmune neuromuscular disease neuromuscular disease characterized by varying degrees of characterized by varying degrees of weakness of the skeletal (voluntary) weakness of the skeletal (voluntary) muscles of the body. muscles of the body.

It is the most common primary It is the most common primary disorder of neuromuscular disorder of neuromuscular transmission transmission

SymptomsSymptoms

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 TestingLaboratory Testing Autoantibodies to the Acetylcholine Autoantibodies to the Acetylcholine

receptor (AChRAb) can be detected in receptor (AChRAb) can be detected in 80-90% of patients with myasthenia 80-90% of patients with myasthenia gravis. gravis.

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

Goodpasture’s Syndrome

An uncommon and life-threatening An uncommon and life-threatening hypersensitivity disorder believed to hypersensitivity disorder believed to be an autoimmune process related to be an autoimmune process related to antibody formation in the body. antibody formation in the body.

Goodpasture's syndrome is Goodpasture's syndrome is characterized by renal (kidney) characterized by renal (kidney) disease and lung hemorrhage. 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.

SymptomsSymptoms Symptoms include:Symptoms include:

foamy, foamy, bloody, or dark colored urine, bloody, or dark colored urine, decreased urine output, decreased urine output, coughcough with bloody sputum, with bloody sputum, difficulty breathing after exertion, difficulty breathing after exertion, weakness, weakness, fatiguefatigue, , nausea or vomiting, nausea or vomiting, weight loss, weight loss, nonspecific chest nonspecific chest painpain and/or pale skin and/or pale skin

DiagnosisDiagnosis Complete Complete blood countblood count (CBC) (CBC) Blood urea nitrogen (BUN) and creatinine levels Blood urea nitrogen (BUN) and creatinine levels UrinalysisUrinalysis will be done to check for damage to the will be done to check for damage to the

kidneys. kidneys. Sputum test to look for specific antibodies.Sputum test to look for specific antibodies. Chest x rayChest x ray to assess the amount of fluid in the lung to assess the amount of fluid in the lung

tissues. tissues. Lung needle biopsy and a Lung needle biopsy and a kidney biopsykidney biopsy will show will show

immune system deposits. immune system deposits. Kidney biopsy can also show the presence of the Kidney biopsy can also show the presence of the

harmful antibodies that attack the lungs and kidneys harmful antibodies that attack the lungs and kidneys Antiglomerular basement membrane (anti-GBM) Antiglomerular basement membrane (anti-GBM)

antibody Enzyme immunoassay (EIA) antibody Enzyme immunoassay (EIA) Antibodies to Neutrophil Cytoplasmic Antigens Antibodies to Neutrophil Cytoplasmic Antigens

(ANCA) identified by immunofluorescence (ANCA) identified by immunofluorescence

TreatmentTreatment

CorticosteroidsCorticosteroids PlasmapheresisPlasmapheresis Dialysis Dialysis

Sjogren's SyndromeSjogren's Syndrome Sjogren's syndrome is an autoimmune disease, Sjogren's syndrome is an autoimmune disease,

characterized by the abnormal production of characterized by the abnormal production of extra antibodies in the blood that are directed extra antibodies in the blood that are directed against various tissues of the body. against various tissues of the body.

This particular autoimmune illness is caused This particular autoimmune illness is caused by inflammation in the glands of the body. by inflammation in the glands of the body.

Inflammation of the glands that produce tears Inflammation of the glands that produce tears (lacrimal glands) leads to decreased water (lacrimal glands) leads to decreased water production for tears and eye dryness. production for tears and eye dryness.

Inflammation of the glands that produce the Inflammation of the glands that produce the saliva in the mouth (salivary glands, including saliva in the mouth (salivary glands, including the parotid glands) leads to mouth dryness. 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 TestLaboratory Test

ANA and RF positive

TreatmentTreatment

Nonsteroidal anti-inflammatory Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and drugs (NSAIDs), such as aspirin and ibuprofen ibuprofen

Corticosteroids Corticosteroids Saliva substitutes Saliva substitutes Artificial tears or eye drops Artificial tears or eye drops Cyclosporine A (Restasis) eye drops Cyclosporine A (Restasis) eye drops

Scleroderma

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

Causes skin thickening and tightening, and can involve Causes skin thickening and tightening, and can involve fibrosis and other types of damage to internal body fibrosis and other types of damage to internal body organs. organs.

This condition, thought to be an autoimmune disease, This condition, thought to be an autoimmune disease, affects both adults and children, most commonly adult affects both adults and children, most commonly adult women. women.

he most evident symptom is the hardening of the skin he most evident symptom is the hardening of the skin and associated scarring. and associated scarring.

Typically the skin appears reddish or scaly in Typically the skin appears reddish or scaly in appearance. Blood vessels may also be more visible. Wappearance. Blood vessels may also be more visible. W

here large areas are affected, fat and muscle wastage here large areas are affected, fat and muscle wastage will weaken limbs and affect appearance. 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 PhenomenaRaynaud’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 oe sensitivity cold sensitivity, changes in sensitivity cold sensitivity, changes in skin color, finger pain, toe pain, fingertip skin color, finger pain, toe pain, fingertip ulcers, toe ulcers 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, When the fingers become tight, stretched, wax-like, and hardened wax-like, and hardened

TelangiectasiasTelangiectasias TelangiectasiasTelangiectasias are small enlarged blood are small enlarged blood

vessels near the surface of the skin, usually they vessels near the surface of the skin, usually they measure only a few millimetres. measure only a few millimetres.

They can develop anywhere on the body but They can develop anywhere on the body but commonly on the face around the nose, cheeks commonly on the face around the nose, cheeks and chin and chin

CRESTCREST

Laboratory TestsLaboratory Tests

Presence of serum anti-Scl-70 Presence of serum anti-Scl-70 antibodies antibodies

Antinuclear antibody (ANA or FANA)Antinuclear antibody (ANA or FANA) Rheumatoid Factor (RF)Rheumatoid Factor (RF) Antibody to single stranded DNA Antibody to single stranded DNA

(ssDNA)(ssDNA) Soluble interleukin 2 receptor level Soluble interleukin 2 receptor level

(sIL 2 r). (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 DyscrasiasPlasma 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 ManifestationsClinical 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 SymptomsClinical Symptoms

Clinical symptoms: Anemia Bleeding Hyperviscosity

Median survival 5 years versus multiple myeloma, 3 years.

Laboratory DiagnosisLaboratory 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.

ReferencesReferences

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