Autoimmunity and autoimmune diseases dr. ihsan alsaimary

AUTOIMMUNITY
&
AUTOIMMUNE DISEASES
prof.dr.ihsan edan alsaimary
department of microbiology –
college of medicine – university of basrah

AUTOIMMUNITY
 Ability of immune system to differentiate
between self and non-self antigens
 Immune system response against self
antigens

AUTOIMMUNITY
 Autoimmunity appears normal part of
immune system
 Healthy people have low concentration
of autoantibodies in serum and tissue
 Auto-antibodies may form antigen-
antibody complex removed by
macrophages as part of tissue damage
removal

Definitions
 Auto-antigens
– Self antigens
 Immunologic tolerance
– No immune response to a specific
antigen

T Cells Mature
in Thymus
Stem Cells
of the Bone
Marrow
Identify
Antigens
B Cells Replicate
to form
Plasma cells
B Memory
Cells
Released into
blood, spleen,
lymph
Macrophages
carry foreign
cells to T
Helper cells
T Helper cells (Th)
produce proteins
Secrete
Interleukins
Secrete
lymphokines
Release
Antibodies
Stimulates
Phagocytosis
Effector Tc
Cells
Tm Memory
Cells
B Cells Mature
in Marrow
Replicate
Cytotoxic (killer)
T (Tc) Cells
Antibody Mediated
Immunity
Cell Mediated
Immunity
Lymphocyte
Maturation

Autoimmune Diseases
 Autoimmune Diseases
 What is an autoimmune disease?

Autoimmune Diseases
 When the immune system attacks the
body's own cells, it produces an
autoimmune disease.

Autoimmune Diseases
 Some examples of autoimmune
diseases include:
 Type I diabetes attacks insulin-producing cells.
 Rheumatoid arthritis attacks connective tissues
around joints.
 Myasthenia gravis attacks neuromuscular
junctions.
 Multiple sclerosis (MS) destroys functions of
brain and spinal cord neurons.

Autoimmune Diseases
 Some autoimmune diseases are treated
with medications that alleviate specific
symptoms.

Immunological Problems & Diseases
There are several ways in which the immune system may fail:
 When the pathogen is too violent (multiplies too fast, causes
too much damage), or evades the immune system (e.g., via
mutation). Solution: vaccination or medication.
 Immune deficiencies: inherited or acquired.
 Improper response to foreign (non-pathogenic) antigens:
Hypersensitivity and Allergy.
 Improper response to self: Autoimmune diseases.
 Rejection of transplanted tissues.
 Failure to detect cancers.
 [Cancer of immune cells.]

Immune Deficiencies
 Inherited:
 Cellular - when the defective gene is only in T cells;
 Humoral - when the defective gene is only in B cells;
 Combined - when the defect is in a gene common to all
lymphocytes, e.g., RAGs (recombination activation genes).
 Acquired - due to:
 Hemopoietic diseases;
 Treatments: chemotherapy, irradiation;
 Infection: AIDS - caused by the Human Immunodeficiency
Virus (HIV) which attacks helper T cells. The virus gradually
kills more T cells than the body can produce, the immune
system fails, and the patient dies from infections that are
normally not dangerous.

Immune Hypersensitivity
 Hypersensitivity is an improperly strong response.
 Immediate hypersensitivity:
 Mediated by antibodies.
 Types:
 allergy - up to anaphylactic shock.
 Induction of antibody-mediated cytotoxicity.
 Sickness due to accumulation of immune complexes.
 Delayed hypersensitivity:
 Mediated by T cells.
 Hyper-activity of CTLs and macrophages.
 Contact sensitivity.

Allergy
 Allergy is an immune response
to harmless antigens.
 Mechanism: IgE bind Fce
receptors on mast cells and
basophils, and causes release
of granules with inflammatory
agents.
 The “real” role of IgE is
probably to fight parasites such
as helminths. (In developing
countries, people hardly ever
suffer from allergies.)

Autoimmune diseases
 Normally, the immune system does not attack the self.
 This is ensured by elimination of auto-reactive lymphocytes
during their development (negative selection).
 However, there is a large group of diseases in which the
immune system does attack self-cells: autoimmune diseases.
 The attack can be either humoral (by auto-antibodies) or
cellular (by auto-reactive T cells).
 The attack can be directed either against a very specific
tissue, or to a large number of tissues (systemic autoimmune
disease), depending on the self-antigen which is attacked.

Autoimmune diseases
 Specific:
 Juvenile diabetes (attacks insulin-producing cells)
 Multiple sclerosis (attacks myelin coating of nerve axons)
 Myasthenia gravis (attacks nerve-muscle junction)
 Thyroiditis (attacks the thyroid)
 …
 Systemic: Immune complexes accumulate in many tissues and
cause inflammation and damage.
 Systemic Lupus Erythematosus (anti-nuclear antibodies):
harms kidneys, heart, brain, lungs, skin…
 Rheumatoid Arthritis (anti-IgG antibodies): joints, hearts,
lungs, nervous system…
 Rheumatic fever: cross-reaction between antibodies to
streptococcus and auto-antibodies.

What could cause the immune
system to attack the self?
 Changes in self-antigens, that make them look like non-self to
the immune system, due to:
 Viral or bacterial infection
 Irradiation
 Medication
 Smoking …
 Changes in the immune system:
 Normal auto-antibodies exist; mutations in B cells producing
them may create pathogenic auto-antibodies.
 Problems with control of lymphocyte development and
differentiation.

Transplant Rejection
 The T lymphocyte repertoire is selected to tolerate cells
expressing self-MHC-I + self-peptide complexes, and attack
non-self (altered) complexes.
 Normally, altered complexes would be the result of infection
or transformation of the cell expressing the MHC, that is, the
peptide will be non-self.
 However, transplantation of tissues from a non-MHC-matched
donor will present to the immune system a non-self-MHC
(with self-peptides, usually).
 The immune system will react vigorously against this “altered
self”.
 Prevention: finding a matched donor or immune suppression.

Failure to detect Cancer cells
 Cancer is uncontrolled proliferation of self-cells. Cancer cells
have lost the mechanisms of cell cycle control, dependence
on resources or cell density, etc. Later on, some of the
tumor cells may migrate to other body sites (metastasis).
 Transformation from normal to cancerous cells involves many
genetic, biochemical, metabolic changes in the cells.
 The immune system sometimes recognizes these changes
and regards the transformed cells as “ altered self ” to be
attacked.
 When will the immune system fight cancer:
 When it’s different enough from self,
 When the quantity of non-self cells is large enough,
 When the system functions well, and is not suppressed.

Development of
Autoimmune Disease
 Autoimmune disease occurs as a result of breakdown
in tolerance to self
 Autoimmune disease is characterized by immune
system “attack” against self antigens that lead to
tissue damage
– Inflammation and hypersensitivity reactions
 Mediated by B-lymphocytes that produce antibodies
to self antigens
And / or
 T-lymphocytes with T-cell receptors that recognize
selfantigens
– Autoreactive CD4 Th and autoreactive CD8
cytotoxic T cells

Mechanisms of tissue injury
 Auto-antibodies circulating in blood or
at site of tissue injury
 Autoreactive B and T cells in blood and
at site of tissue injury
 Hypersensitivity reactions occurring at
sites of tissue injury
 Histology- chronic inflammation
 Pathway for cell death- apoptosis

TYPES OF HYPERSENSITIVITY
 Type II
– Autoimmune hemolytic anemias
– Anti-insulin receptor antibody (insulin-
dependent diabetes mellitus )
 Type III
– Systemic lupus erythematosus (SLE)
– Rheumatoid arthritis

SYSTEMIC LUPUS
ERYTHEMATOSUS (SLE)
 Chronic systemic autoimmune disease
 Cause unknown
 Affects almost any organ(s)
 Characterized by chronic inflammation

SYSTEMIC LUPUS
ERYTHEMATOSUS (SLE)
 Auto-antibodies formed against variety of self
antigens
 Anti-double stranded DNA,RNA and histones
 Antibodies against cell surface antigens on
RBC’s and/or platelets
 Tissue damage caused by Type III
hypersensitivity reactions
 Immune circulating complexes formed
against self deposit on tissues
 Vasculitis, synovitis, glomerulonephritis

Systemic lupus
erythematosis is the most
commonly known
autoimmune disorder. This
characteristic “butterfly”
rash is made worse by
exposure to sunlight.
Lupus is a potentially fatal
autoimmune disease that
strikes 1 in 2,000
Americans and 10 times as
many women as men.

Rheumatoid Arthritis
 Systemic autoimmune disease
 Genetic factors (HLA-DR1, HLA-DR4)
 Autoreactive B-cells synthesize auto antibody
against Fc portion of IgG
 Rheumatoid factor (RF)
 Chronic inflammation of synovial joints
 Proliferation of synovial lining cells
 Erosion of articular cartilage and adjacent
bone

Rheumatoid arthritis (RA)
affects peripheral joints and
may cause destruction of
both cartilage and bone. The
disease affects mainly
individuals carrying the DR4
variant of MHC genes.
This fact can lead to better
prognoses and in aiding
efforts to change immune
reactions that involve the
DR4 variant while leaving
other reactions intact.

 The antibody is 4 polypeptides forming
a Y-shaped structure.
 Each side of the Y is composed of one
light chain and 1 heavy chain.
 The 2 arms (Fab regions) contain
antigen binding sites.
 The stem of the Y is the Fc region.

Allergies
Exaggerated immune responses to otherwise
benign substances
What happens when the immune system
malfunctions?

malfunctions?
1. Antibodies are produced

malfunctions?
2. Stems of antibodies
attach to mast cells,
especially in the respiratory
tract

malfunctions?
2. Stems of antibodies
attach to mast cells,
especially in the respiratory
tract
3. When
antibodies
attached to mast
cells bind antigens, the mast
cells release histamine, which causes inflammation

Autoimmune diseases
The immune system lacks or loses its ability to
distinguish self vs. non-self molecules, i.e., it
loses its self-tolerance and produces anti-self
antibodies
malfunctions?
Rheumatoid arthritis (cartilage of joints)
Multiple sclerosis (mylein sheaths of
neurons)
Insulin-dependent diabetes mellitus (insulin-
secreting cells of the pancreas)

malfunctions?
Severe Combined Immunodeficiency (SCID)
An inherited disorder
Acquired Immunodeficiency Syndrome (AIDS)
Caused by retroviruses (Human
Immunodeficiency Viruses – HIV) that
especially infect helper T cells
Immunodeficiency diseases
Inhibit effective immune response; either
inherited or acquired

Lymphocytes recognize and respond to particular
microbes and foreign molecules, i.e.,
they display specificity
A foreign molecule
that induces an
immune response
is known as an
antigen
RECOGNITION

RECOGNITION
Multiple antibodies may recognize the same antigen
by different epitopes (small accessible portions
of the larger molecule)

B cells produce antibodies, that are either secreted
out of the cells or remain embedded in the B cell
membranes, and that bind to antigens
RECOGNITION

B cells produce antibodies, that are either secreted
out of the cells or remain embedded in the B cell
membranes, and that bind to antigens
T cells have T-cell receptors, embedded in their
cell membranes, that bind to antigens
RECOGNITION

RECOGNITION
Secreted antibodies con-
stitute a group of proteins
called immunoglobulins
Antibodies have 2
heavy chain and 2 light
chain subunits
Each subunit has a
constant region and a
variable region
The variable region can
bind to an antigen

Construction of antibodies
(and T-cell receptors)
Millions of antigens are recognized by randomly
combining the protein products of hundreds of genes
RECOGNITION of non-self molecules
Card analogy: although there are only 52 cards in the
deck, random combinations can produce an
enormous number of different hands

In a healthy immune system, as B and T cells mature
they are destroyed by apoptosis if they attack self
molecules
RECOGNITION of self molecules
Healthy, mature B and T cells then have the capacity
to distinguish self from non-self molecules

Almost all cells in an individual human’s body have
major histocompatibility complex (MHC)
glycoproteins embedded in their cell membranes
Class I MHC molecules are found on
almost every nucleated cell
Class II MHC molecules are restricted to a few
specialized cells, including macrophages,
dendritic cells, B cells, etc.

MHC glycoproteins migrate to the cell
membrane after they are produced
MHC glycoproteins pick up molecules from the cytosol
that are presented at the cell’s surface
T cells bind to MHC glycoproteins and
the molecules they present
An individual’s own MHC glycoproteins, and
molecules of its own body that the MHC
glycoproteins present, are treated as self

Helper T cells bind to cells that carry
Class II MHC glycoproteins
RECOGNITION of non-self molecules

ATTACK & MEMORY
The B and T cells that first recognize a given foreign
antigen are short lived, whereas immune memory
cells can have long lifetimes
Illustrated here
for B cells, but
the process for
T cells is similar

Introduction
 Under normal circumstances immune system
will not destroy self antigens.
 Autoimmunity can be defined as breakdown of
mechanisms responsible for self tolerance and
induction of an immune response against
components of the self.
 In numerous autoimmune diseases it is well
recognized that products of the immune system
cause damage to the self.

Autoimmune Response
 Antibody directed against “self”, termed auto-
antibody
 Considered abnormal but usually does not result
in disease.
 May occur in healthy individuals.

Autoimmune Disease
 Disorder in which tissue injury is caused by an
immunologic reaction of the host to its own
tissues.
 Precise mechanisms unknown.
 Classified as systemic or organ specific,
frequently have overlap.

Proposed Mechanisms
 Forbidden clone
 Altered antigen
 Sequestered Antigen
 Immunologic deficiency theory
 Genetic influence

Forbidden clone
 Clone of changed or altered lymphocytes arise
through mutation.
 Lack foreign surface antigens, not destroyed.
 Because of alteration may recognize host as
foreign.

Altered Antigen
 Surface antigens on host altered by chemical,
biological or physical means.
 This new antigenic determinant may be
recognized as foreign by the host.

Sequestered Antigen
 Some antigens in the body are hidden from cells
of the immune system.
 If there is damage to these organs causing
exposure of these sequestered antigens an
immune reaction to these antigens may occur.

Immunologic Deficiency Theory
 Relates the increased frequency of auto-
antibodies and increased immune system
deficiency to age.
 Mutation or loss of immune regulatory powers
results in the condition in which self antigens
behave as foreign antigens.

Genetic Influence
 It is well recognized that certain immune
disorders predominate in females and in
families.
 Determined by family studies.
 Genetic links have occurred between diseases
and HLA antigens

Contributing Factors
 Defects in the immune system.
 Influence of hormones
 Environmental conditions

Classification of Autoimmune
Diseases
 Systemic- the auto-immunity is directed against
an antigen that is present at many different sites
and can include involvement of several organs
 Organ specific - Organ specific means the auto-
immunity is directed against a component of
one particular type of organ.
 Both – can get overlap

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]

 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).

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

 Rheumatoid Factor (RF) is an IgM antibody
directed against the Fc portion of the IgG
molecule, it is an anti-antibody.
 Not specific for RA, found in other diseases.
 Immune complexes form and activate
complement and the inflammatory response.
 Enzymatic destruction of cartilage is followed by
abnormal growth of synovial cells, results in the
formation of a pannus layer.

Diagnosis
 Diagnosis is based on:
 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.

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.

 Cerebrospinal fluid (CSF) is tested for levels of certain
immune system proteins and for the presence of
oligoclonal bands.
 These bands indicate an abnormal autoimmune
response within the central nervous system, meaning
the body is producing an immune response against
itself.
 Oligoclonal bands are found in the spinal fluid of about
90-95% of people with MS, but since they are present
in other diseases as well, they cannot be relied on as
positive proof of MS. They may also take some years to
develop.

Treatment
 The treatment of MS focuses mainly on
decreasing the rate and severity of relapse,
reducing the number of MS lesions, delaying the
progression of the disease, and providing
symptomatic relief for the patient.
 Several different drugs have been developed to
treat the symptoms of MS.
 Drug treatment depends on the stage of the
disease as well as other factors.

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.

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

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.

 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

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