ch14 autoimmunity (4)

Clinical Immunology & SerologyA Laboratory Perspective, Third Edition

Autoimmunity

Chapter Fourteen

Autoimmunity Autoimmune diseases are conditions in

which damage to organs or tissues results

from the presence of autoantibody or

autoreactive cells.

This is thought to be caused by the loss or

breakdown of self-tolerance; believed to be

brought about by several mechanisms,

including clonal deletion of relevant effector

cells and active regulation by T reg cells.

Autoimmunity Thus, in the secondary lymphoid organs,

peripheral tolerance is maintained by a delicate

balance between the T helper cell type 1 (Th1)

and T helper cell type 2 (Th2) populations.

Recent findings indicate that regulatory T cells

(Tregs) play a central role in maintaining this

balance and eliminating harmful autoimmune

responses. Also recall the roles of IL-10 and TGF-

Autoimmunity Major histocompatibility complex (MHC)

products also seem to influence antigen

recognition or nonrecognition by determining

the type of peptides that can be presented to

the T cells.

The expression of class II molecules on cells

where they are not normally found may result

in the presentation of self-antigens for which

no tolerance has been established.

Autoimmunity The strongest link found to date between

certain HLA molecules and specific diseases is

between HLA-B27 and ankylosing spondylitis.

Several other mechanisms are thought be

contribute to autoimmunity: release of

sequestered antigens, molecular mimicry, and

polyclonal B-cell activation due to abnormal

expression or function of cytokines and/or

receptors

Autoimmunity Autoimmune diseases can be classified as

systemic or organ specific.

Organ specific disorders for thyroid,adrenal

cortex, pancreas, nervous tissue

Autoimmunity Systemic lupus erythematosus (SLE) is a

chronic systemic inflammatory disease

marked by alternating exacerbations and

remissions.

The immune response is directed against a

broad range of target antigens, as the typical

patient has an average of three circulating

autoantibodies.

Autoimmunity – SLE It appears that there is an interplay between

genetic susceptibility and environmental

factors in the development of the disease.

In whites, there is a strong association with

human leukocyte antigens (HLA) DR and DQ.

Lupus has been associated with inherited

deficiencies of complement components C1q,

C2, and C4.

Autoimmunity – SLE Abnormalities of Fc γ receptors on B cells,

macrophages, dendritic cells, and neutrophils that

bind IgG and prevent excessive immune

reactions have also been found.

Environmental factors include exposure to

ultraviolet light, certain medications, and

infectious agents.

Hormones, especially estrogen. These disorders

occur 10 times more often in women; onset in the

30-40s.

Autoimmunity – SLE The clinical signs of SLE are extremely

diverse, and nonspecific symptoms such as

fatigue, weight loss, malaise, fever, and

anorexia are often the first to appear.

Joint involvement seems to be the most

frequently reported manifestation, presenting

as a symmetric arthritis that involves the small

joints of the hands, wrists, and knees.

Autoimmunity – SLE After joint involvement, the next most

common signs are skin manifestations.

A classic butterfly rash across the nose and

cheeks may develop.

Autoimmunity – SLE One-half to two-thirds of all patients exhibit

evidence of renal involvement, with diffuse

proliferative glomerulonephritis (DPGN),

deposition of immune complexes in the

subendothelial tissues and thickening of the

basement membranes.

All of these can lead to renal failure, the most

frequent cause of death in patients with SLE.

Autoimmunity – SLE For a clinical diagnosis of lupus to be made, 4

of 11 specific criteria must be present: malar

rash, discoid rash, photosensitivity, oral ulcers,

arthritis, serositis, renal disorder, neurological

disorder, hematologic disorder, immunologic

disorder, and presence of antinuclear

antibodies.

Autoimmunity – SLE SLE is associated with more than 25

autoantibodies.

Some of the more common autoantibodies are

listed in Table 14-2.

The large number of possible autoantibodies

reflects a generalized dysregulation of the

immune system in SLE.

Autoimmunity – SLE The constant presence of antigenic material

triggers polyclonal activation of B cells.

There is an accompanying alteration in the

function of both Th1 and Th2 helper cells,

resulting in enhanced production of certain

cytokines that contribute to up-regulation of

antibody production by B cells (eg. IL-4 and

IL-6).

Autoimmunity – SLE Drug-induced lupus differs from the more

chronic form of the disease in that symptoms

usually disappear once the drug is

discontinued.

Typically, this is a milder form of the disease,

usually manifested as fever, arthritis, or

rashes; the kidneys are rarely involved.

Autoimmunity – SLE When SLE is suspected, the first test

typically done is a screening test for

antinuclear antibodies (ANA).

Fluorescent antinuclear antibody (FANA)

testing is the most widely used and accepted

test, because it detects a wide range of

antibodies and is positive in about 95 percent

of patients with SLE.

Autoimmunity – SLE This is an extremely sensitive test and relatively

easy to perform, but it has low diagnostic

specificity, because many of the antibodies are

associated with other autoimmune diseases.

Approximately 2 percent of healthy individuals

and up to 75 percent of older individuals yield

false-pos. results.

Autoimmunity – SLE Conversely, up to 5 percent of SLE patients

yield false-negative results.

It is now common practice to screen with a

1:80 dilution (or 1:160 if the patient is over 65)

to avoid low positive titers in the normal

population.

A diagram of the possible fluorescent patterns

is shown in Figure 14-2 (see also Color Plate

10 in the text).

Autoimmunity – SLE Double-stranded DNA (ds-DNA) antibodies

are the most specific for SLE, because they

are mainly seen only in patients with lupus,

and levels correlate with disease activity.

The presence of these antibodies is

considered diagnostic for SLE, especially

when they are found in combination with low

levels of complement C3.

Autoimmunity – SLE Antibodies to ds-DNA typically produce a

peripheral or a homogeneous staining

pattern on FANA testing.

Other assays that can be used to detect

antibodies to ds-DNA include immunodiffusion,

particle agglutination and enzyme

immunoassay (EIA).

Autoimmunity – SLE A second major antibody found in lupus

patients is antihistone antibody.

Histone is a nucleoprotein that is a major

constituent of chromatin.

Presence of antihistone antibody alone or

combined with antibody to ss-DNA supports

the diagnosis of drug-induced lupus.

Autoimmunity – SLE Antihistone and anti-DNP antibodies are also

found in lupus but are not diagnostic as they

may be seen in rheumatoid arthritis (RA) and

primary biliary cirrhosis, but the levels are

usually lower.

Autoimmunity – SLE On FANA, either a homogeneous pattern is

seen, representing fluorescence of the entire

nucleus, or staining of the periphery of the

nucleus occurs.

Autoimmunity – SLE Figure 14-2

Autoimmunity – SLE Antibody to a preparation of extractable

nuclear antigen (small nuclear proteins that

associated with uridine-rich RNA) was first

described in a patient named Smith, hence the

name anti-Sm antibody.

The anti-Sm antibody is specific for SLE,

because it is not found in other autoimmune

diseases.

Autoimmunity – SLE This and other antibodies produce a coarsely

speckled pattern of nuclear fluorescence on

Other ANA patterns include

nucleolar, seen in systemic sclerosis and RA

centromere,seen in CREST syndrome

mitochondrial

Autoimmunity Antiphospholipid antibodies are a

heterogeneous group of antibodies that bind to

phospholipid alone or lipoprotein.

They can affect every organ in the body, but

they are especially associated with deep-vein

and arterial thrombosis and with morbidity in

pregnancy.

Autoimmunity The lupus anticoagulant, one of the several

types of antiphospholipid antibodies, was so

named because it produces prolonged

activated partial thromboplastin time (aPTT)

and prothrombin time (PT).

The lupus anticoagulant may also cause false-

positive results for the VDRL test for syphilis.

Autoimmunity Patients with this antibody have an increased

risk of clotting and spontaneous abortion.

Platelet function may also be affected.

There are several EIA methods for

antiphospholipid antibodies that are sensitive

and relatively simple to perform.

Autoimmunity Rheumatoid arthritis (RA) is another

example of a systemic autoimmune

disorder.

RA can be characterized as a chronic,

symmetric, and erosive arthritis of the

peripheral joints that can also affect multiple

organs such as the heart and the lungs.

Autoimmunity – RA In addition to a decline in functional ability,

there is a reduced life expectancy.

As in SLE, there appears to be an association

of RA with certain MHC class II genes.

The strongest association appears with certain

DR4 alleles.

This “shared epitope” on the HLA class II β

chain may act to facilitate antigen presentation

to Th cells and to B cells.

Autoimmunity – RA Key symptoms: morning stiffness around the

joints lasting at least 1 hour; swelling of the

soft tissue around three or more joints;

swelling of the proximal interphalangeal,

metacarpophalangeal, or wrist joints;

symmetric arthritis; subcutaneous nodules; a

positive test for rheumatoid factor (RF); and

radiographic evidence of erosions in the joints

of the hands, the wrists, or both.

Autoimmunity – RA Other systemic symptoms of RA may include

anemia, pericarditis, lymphadenopathy,

splenomegaly, interstitial lung disease, or

vasculitis.

For many years, there has been a search for

an infectious agent or agents that may be

involved in the cause of RA, but a causal

relationship has not been established.

Autoimmunity – RA The earliest lesions in rheumatoid joints

show an increase in cells lining the synovium

and an infiltration of mononuclear cells, CD4+

and CD8+ T lymphocytes, B cells, plasma

cells, macrophages, and neutrophils.

The balance between proinflammatory and

anti-inflammatory cytokines appears to be

tipped toward continual inflammation.

Autoimmunity – RA Proinflammatory cytokines found in synovial

fluid include interleukins, and tumor necrosis

factor-alpha (TNF-α).

Collagenase and other tissue-degrading

enzymes are also released from cells that line

the joint cavity.

Autoimmunity – RA The end result is destruction of connective

tissue, cartilage, and bone.

Approximately 75 percent of patients with RA

have the rheumatoid factor antibody (RF).

It is most often of the IgM class and is directed

against the FC portion of IgG.

However, this antibody is not specific for RA,

as it is found in 5 percent of healthy individuals

and in 10–20 percent of those over 65.

Autoimmunity – RA In RA, IgM antibodies combine with IgG, and

these immune complexes become deposited

in the joints, resulting in a type III (or immune

complex) hypersensitivity reaction.

The complement protein C1 binds to the

immune complexes, activating the classical

complement cascade.

Autoimmunity – RA C3a and C5a are generated, which act as

chemotactic factors for neutrophils and

macrophages.

Other autoantibodies found include antikeratin

antibody, antiperinuclear antibody, antifilaggrin

(nucleolar staining in FANA), and anti-Sa

antibody.

Autoimmunity – RA All of these antibodies are directed against

citrullinated proteins.This family of antibodies

is detected using cyclic citrullinated peptides

(CCP); hence, the antibodies are called anti-

Autoimmunity – RA Anti-CCP is now the lead marker for

detection of RA, because it is much more

specific than RF. EIA shows 74% sensitivity

and specificity of 96%; precedes symptoms by

several years

In addition, low titers of antinuclear antibodies

are present in about 40 percent of patients.

The pattern most identified is the speckled

pattern directed against ribonucleoprotein.

Autoimmunity - RAOther nonspecific indicators of

inflammation:

ESR, CRP, and complement components

Treatment: NSAIDs, injectable cortisone,

anti-TNF and anti-TNF receptor, and anti-

CD20 on B cells

Autoimmunity Autoimmune thyroid diseases (AITDs),

including Hashimoto’s thyroiditis and Graves’

disease, are examples of organ-specific

autoimmune diseases.

Although these conditions have distinctly

different symptoms, they do share some

antibodies in common, and both interfere with

thyroid function.

Autoimmunity – AITD Follicles within the thyroid are filled with

material called colloid.

The primary constituent of colloid is

thyroglobulin, a large iodinated glycoprotein,

which is the storage form of the thyroid

hormones triiodothyronine (T3) and thyroxine

Autoimmunity – AITD Under normal conditions, thyrotropin-releasing

hormone (TRH) is secreted by the

hypothalamus to initiate the process that

eventually causes release of hormones from

the thyroid.

TRH acts on the pituitary to induce release of

thyroid-stimulating hormone (TSH).

Autoimmunity – AITD TSH, in turn, binds to receptors on the cell

membrane of the thyroid gland, causing

thyroglobulin to be broken down into

secretable T3 and T4.

Production of autoantibodies interferes with

this process and causes under- or overactivity

of the thyroid.

Autoimmunity – AITD Hashimoto’s thyroiditis, also known as

chronic autoimmune thyroiditis, is most

often seen in middle-aged women, although it

may occur anywhere from childhood up to

about 70 years of age.

Patients develop a combination of goiter (or

enlarged thyroid), hypothyroidism, and thyroid

autoantibodies.

Autoimmunity – AITD Symptoms of hypothyroidism include dry

skin, decreased sweating, puffy face with

edematous eyelids, weight gain, and dry and

brittle hair.

The thyroid shows hyperplasia with an

increased number of lymphocytes, altering the

cellular architecture of the thyroid.

Antibodies to thyroglobulin predominate,

progressively destroying thyroglobulin.

Autoimmunity – AITD Graves’ disease is characterized by

hyperthyroidism and is the most prevalent

aotimmune disease in the US.

The disease is manifested as thyrotoxicosis, with

an enlarged goiter, accompanied by nervousness,

insomnia, depression, weight loss, heat

intolerance, sweating, rapid heartbeat,

palpitations, breathlessness, fatigue, cardiac

dysrhythmias, and restlessness.

Autoimmunityn – AITD

The major antibodies found in Graves’

disease include thyroid-stimulating hormone

receptor antibody (TSHRab) and antibodies to

thyroid peroxidase.

Strong association with DR3

Autoimmunity – AITD When antigen–antibody combination occurs, it

mimics the normal action of TSH and results in

receptor stimulation, with the release of thyroid

hormones to produce the symptoms of

hyperthyroidism.

Autoimmunity – AITD The three major thyroid autoantibodies

present are antibodies to thyroglobulin,

thyroid peroxidase, and TSH receptors.

Antibodies to thyroglobulin can be detected

in 90% of patients with Hashimoto’s thyroiditis.

Healthy individuals may have a low titer of

antithyroglobulin antibody, but in patients with

Hashimoto’s thyroiditis, the titer is

considerably higher.

Autoimmunity – AITD Antibodies to thyroglobulin can be

demonstrated by indirect immunofluorescent

assays (IIF), passive agglutination, and EIA.

Since antithyroglobulin antibodies are not

found in all patients, a negative test result

does not necessarily rule out Hashimoto’s

disease.

Autoimmunity – AITD Antibodies to peroxidase are most commonly

measured by EIA, although IIF and particle

agglutination assays are also used.

These antibodies can be found in

approximately 90 percent of patients with

Hashimoto’s disease and 80 percent of

patients with Graves’ disease, so the two

cannot be distinguished on the basis of

this test.

Autoimmunity – AITD The third major autoantibody, anti-TSHR

antibody, is typically associated with

Graves’ disease.

Elevation of the thyroid hormones and free

triiodothyronine (T3) and thyroxine (T4) is

checked first if this disease is suspected.

TSH levels are low because of antibody

stimulation of the thyroid.

Autoimmunity - AITD

Anti-TSHR found in Hashimoto's

disease binds to a different epitope,

preventing the binding of TSH,

leading to reduced T3 and T4

Autoimmunity Autoimmune diabetes mellitus, now termed

type IA diabetes, is a chronic autoimmune

disease that occurs in genetically susceptible

individuals as a result of environmental

factors.

Approximately 10 percent of patients with

diabetes mellitus have the immune-mediated

form of the disease.

Autoimmunity – DM This form of diabetes mellitus is characterized

by insufficient insulin production caused by

selective destruction of the beta cells of the

pancreas, located in clusters called the islets

of Langerhans.

Family studies indicate that there is an

inherited genetic susceptibility to the disease,

probably attributable to multiple genes within

the HLA system.

Autoimmunity – DM Environmental influences include the

possibility of viral infections and early

exposure to cow’s milk.

Antibody production could possibly be initiated

as a result of molecular mimicry, with a virus

as the stimulating antigen triggering antibody

production against a self-antigen.

Autoimmunity – DM Progressive inflammation of the islets of

Langerhans in the pancreas leads to fibrosis

and destruction of most beta cells.

The subclinical period may last for years, and

only when 80 percent or more of the beta cells

are destroyed does hyperglycemia become

evident.

Autoimmunity – DM The generalized inflammation that results is

responsible for the destruction of beta cells.

It is apparent that autoantibody production

precedes the development of type IA diabetes

mellitus by up to several years.

Autoimmunity – DM Among the antibodies found are antibodies

to two tyrosine phosphatase-like

transmembrane proteins called insulinoma

antigen 2 (IA-2 or ICA 512) and IA-2βA

(phogrin); anti-insulin antibodies; antibodies to

the enzyme GAD; and antibodies to various

other islet cell proteins, called islet cell

antibodies (ICAs).

Autoimmunity Multiple sclerosis (MS) is an inflammatory

autoimmune disorder of the central nervous

system.

It is characterized by the formation of lesions

called plaques in the white matter of the brain

and spinal cord, resulting in the progressive

destruction of the myelin sheath of axons.

Autoimmunity – MS As is the case for most other autoimmune

diseases, a combination of genetic and

environmental factors is responsible for

development of MS.

Once initiated, the immune response becomes

directed against self-antigens that are

indistinguishable from the original foreign

antigen.

Autoimmunity – MS Within the plaques, T cells and macrophages

predominate, and they are believed to

orchestrate demyelination.

Antibody binds to the myelin membrane and

may initiate the immune response, stimulating

macrophages and specialized phagocytes

called microglial cells.

Autoimmunity – MS The cascade of immunologic events results in

acute inflammation, injury to axons and glia,

structural repair with recovery of some

function, and then postinflammatory

neurodegeneration. (relapse, remission

pattern)

Activated T cells must penetrate into the

central nervous system to begin the response.

Autoimmunity – MS The two most common tests for diagnosis

of MS are oligoclonal banding and the CSF

IgG index.

Oligoclonal bands are increased in the spinal

fluid in 75–90 percent of patients with MS,

producing several distinct bands on protein

electrophoresis that are not seen in the serum.

Autoimmunity Myasthenia gravis (MG) is an autoimmune

disease that affects the neuromuscular

junction. It is characterized by weakness and

fatigability of skeletal muscles.

Antibody-mediated damage to the

acetylcholine (ACH) receptors in skeletal

muscle leads to this progressive muscle

weakness.

Autoimmunity – MG Early signs are drooping of the eyelids and the

inability to retract the corners of the mouth,

often resulting in a snarling appearance.

Other symptoms may include difficulty in

speaking, chewing, and swallowing and

inability to maintain support of the trunk, the

neck, or the head.

If respiratory muscle weakness occurs, it can

be life threatening.

Autoimmunity – MG MG is often associated with the presence of

other autoimmune diseases, such as SLE, RA,

pernicious anemia, and thyroiditis.

MG is also associated several HLA antigen

abnormalities.

Approximately 80–85 percent of patients have

antibody to ACH receptors; this appears to be

the main contributor to the pathogenesis of the

disease.

Autoimmunity – MG Normally, ACH is released from nerve endings

to generate an action potential that causes the

muscle fiber to contract.

When the antibody combines with the receptor

site, binding of ACH is blocked, and the

receptors are destroyed because of the action

of antibody and complement (see Fig. 14-5).

Autoimmunity – MG Figure 14-5

Autoimmunity Goodpasture’s syndrome is characterized by

the presence of autoantibody to glomerular,

renal tubular, and alveolar basement

membranes.

Signs of renal involvement include gross or

microscopic hematuria, proteinuria, decreased

creatinine clearance, and increased BUN and

creatinine levels.

Autoimmunity – GS Pulmonary symptoms include hemorrhage,

dyspnea, weakness, fatigue, and cough.

Severe necrosis of the glomerulus is triggered

by an antibody that has specificity for a

specific region of collagen.

Immune deposits accumulate, and

complement fixation causes injury because of

the release of oxygen species and proteolytic

enzymes.

Autoimmunity – GS This syndrome differs from glomerulonephritis

as a result of the nonspecific accumulation of

circulating immune complexes found in other

autoimmune diseases.

In Goodpasture’s syndrome, specific

antibasement antibodies can be demonstrated

by the formation of a smooth, linear ribbonlike

pattern on direct immunofluorescent assay of

patient glomerular basement membrane.

Autoimmunity – Crohn’s disease An inflammatory GI disease appearing anywhere

between the mouth and the anus, mostly in the

large intestine; may present with bloody stools;

may be triggered by an undefined microbe

Leads to malabsorption and malnutrition

Therapy includes corticosteroids and antiTNF

Should be distinguished from celiac disease (due

to gluten) and irritable bowel syndrome (due to

gas production in the bowel; often linked to stress

and anxiety)

Autoimmunity - Scleroderma Primarily in the skin but may involve multiple

organs

Breakdown of parenchymal tissue with

replacement by rapidly dividing fibroblasts.

Leads to excess collagen production and

stiffening or hardening of the tissue

Trigger for initial damage is unknown but ANA

(anti-centromere pattern) may be detected

Autoimmunity – Sjorgren’s syndrome Clinically presents as dry eyes , dry mouth, dry

nasal passages, and vaginal dryness

50% of patients have other systemic

autoimmune disorders (SLE,RA, scleroderma)

Autoantibodies, including anti-RNP, and T cells

are involved in destruction of exocrine glands;

75% have RF.

Usually have leucopenia and elevated ESR

Autoimmmunity – Addison’s disease Autoimmune destruction of the parenchyma of

the adrenal cortex, resulting in reduced

production of glucocorticoids and

mineralocorticoids

Often syptom-free until majority of organ is

destroyed

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