Transcript Bhargav

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They are also called as Non-Organ specific Auto immune
diseases.
This group includes conditions characterized by immune
response against a variety of self antigens and damage to
several organs and tissue systems.
The systemic autoimmune diseases are rheumatological
diseases. Rheumatologists specialize in their treatment.
KLEMPERER classified a number of diseases of unknown
origin with common feature of connective tissue lesions as “
Collagen Diseases”
 Rheumatoid
arthritis (RA) and Juvenile RA (JRA)
(joints; less commonly lung, skin)
 Lupus [Systemic Lupus Erythematosus] (skin, joints,
kidneys, heart, brain, red blood cells, other)
 Scleroderma (skin, intestine, less commonly lung)
 Sjögren's syndrome (salivary glands, tear glands, joints)
 Goodpasture's syndrome (lungs, kidneys)
 Wegener's granulomatosis (blood vessels, sinuses, lungs,
kidneys)
 Polymyalgia Rheumatica (large muscle groups)
 Guillain-Barre syndrome (nervous system)
This is a chronic multi system disease with
remissions ,and exacerbations, terminating
fatally.
 Patients have a variety of auto antibodies
directed against cell nuclei, intracytoplasmic cell
constituents, immunoglobulins, thyroid and
other organ- specific antigens.
 The abundance and variety of auto anti bodies
suggest a break down in control of
immunological homeostasis
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 1948
– Malcolm Hargraves discovers
the lupus erythematosus (LE) cell.
 1957 – The first anti-DNA antibody
is identified.
 LE
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CELL:
It is a neutrophil containing large ,
pale , homogenous body( LE Body) almost filling the
cytoplasm.
The LE body is the immunologically damaged nucleus
of a leukocyte.
Sometimes ,instead of being intracellular, the LE body
can be seen free, surrounded by a rosette of neutrophils .
The fact that LE cell formation is due to an antibody
(LE factor) present in SLE can be demonstrated by
incubating normal blood with serum from SLE
patients.
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The LE cell is a neutrophil
that has engulfed the
antibody-coated nucleus of
another neutrophil.
LE cells may appear in
rosettes where there are
several neutrophils vying
for an individual
complement covered
protein.
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Non-specific:
◦ Fatigue
◦ Weight loss
◦ Malaise = generally feeling ill
◦ Fever
◦ Anorexia (over time)
◦ Arthritis
 90% of patients experience arthritic symptoms
 Symmetrical
 Appears in hands, wrists, and knees mainly
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Itis a vasospastic disorder causing discoloration of the
fingers, toes, and occasionally other areas. This condition can
also cause nails to become brittle with longitudinal ridges.
Raynaud's phenomenon is an exaggeration of vasomotor
responses to cold or emotional stress. More specifically, it is a
hyperactivation of the sympathetic system causing extreme
vasoconstriction of the peripheral blood vessels, leading to
tissue hypoxia. Chronic, recurrent cases of Raynaud
phenomenon can result in atrophy of the skin, subcutaneous
tissues, and muscle. In rare cases it can cause ulceration and
ischemic gangrene
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Malar or Butterfly
Rash
Discoid Rash –
Stimulated by UV
light
Skin manifestations
only appear in 30-40%
of lupus patients.
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50-70% of all lupus patients
experience renal developments.
Most Dangerous:
◦ Glomerulonephritis where at
least 50% of the glomeruli have
cellular proliferation
 Glomeruli – capillary beds in
the kidney that filter the blood.
Renal Failure because of
Glomerulonephritis is the leading
cause of death among lupus
patients.
Normal
Glomerulonephritis
 The
plasma cells are producing antibodies
that are specific for self proteins, namely
ds-DNA
 Overactive B-cells
 Suppressed regulatory function in T-cells
 Lack of T-cells
 Activation of the Complement system
 Estrogen
is a stimulator of B-cell activity
◦Lupus is much more prevalent in females
of ages 15-45
Height of Estrogen production
 IL-10, also a B-cell stimulator is in high
concentration in lupus patient serum.
◦High concentration linked to cell damage
caused by inflammation
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Fc region switch
◦ ζ  εγ
◦ Leads to malfunction in signaling and decreased IL-2 production
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Increased levels of Ca2+
◦ Leads to spontaneous apoptosis
 Complement
system is activated by the
binding of antibodies to foreign debris.
◦In this case its over activation
 RBCs lack CR1 receptor
◦Decreasing the affective removal of
complexes
 IgG
is the most “pathogenic”
because it forms intermediate sized
complexes that can get to the small
places and block them.
 ESR
 Urinalysis
 Complement
Test
◦ Tests levels of C3, C4, CH50
◦ Low levels indicates possible presence of
disease
 FANA – Fluorescent antinuclear antibody
 Ouchterlony Test – shows interactions
 Giemsa-stained
smears of blood or bone
marrow can demonstrate LE cells but its
sensitivity is so low that this test has
been replaced by other Antibody tests for
diagnosis.
 Immunofluorescent tests for antinuclear
antibodies (ANA) show different patterns
o staining such as homogenous(diffuse),
peripheral(outline), speckled and
nucleolar.
ANA tests are sensitive but not specific for SLE, as
they may be positive in many other autoimmune
conditions, viral infections, chronic inflammatory
processess , as well as in persons using certain
medicines and in the aged.
 Anti-DNA antibodies are tested by RIA or ELISA.
 Three major types of these antibodies are seen ,
those reacting with single stranded(SS),double
stranded(ds) & both ss and ds DNA.
 Of these ,high titre anti ds antibody is relatively
specific for SLE .
 Another SLE specific antibody is the anti-sm
antibody.
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ELISA Test
◦ Generally test for:
 ds-DNA antibodies
 Antihistone
antibodies
 Binds to DNA,
major
constituent of
chromatin
 Deoxyribonucleopr
otein (DNP)
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Used to determine
immunological
specificity
Rules out a false
positive
Shows the serum does
or does not have
antinuclear antibodies
 This
is a symmetric polyarthritis with muscle
wasting and subcutaneous nodules,
commonly associated with serositis,
myocarditis, vasculitis and other disseminated
lesions.
 More common in WOMEN.
 The synovial membranes of the effected joints
are swollen and edematous with dense
infiltration of lymphocytes and plasma cells.
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A striking feature is the presence of circulating autoantibody
called the “rheumatoid factor”(RF).
This is usually 19-s IgM ,though IgG and IgA RF have also
been demonstrated.
RF acts as an antibody against Fc fragment of
immunoglobulins. they combine usually with IgG though some
times of RF are directed towards other immunoglobulin classes.
RF reacts with autologous , isologous or heterologous
immunoglobulins .
RF is generally considered to be an immunoglobulin behaving
as antibody to determinants present in patients own IgG
molecules, though some configurational alteration of IgG may
be required before its reactivity with RF becomes demonstrable.
RF is detected by agglutination tests using , as
antigens, particles coated with globulins.
 In the Rose-Waaler test , the original technique for
detection of RF, sheep erythrocytes coated with a
subagglutinating dose of anti erythrocyte antibody
(amboceptor) are used as the antigen in an
agglutination test.
 In modifications of the test, latex and bentonite are
used as the carrier particles for IgG.
 Antinuclear antibodies are frequently found in
rheumatoid arthritis.
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Other, rather rare, skin associated symptoms include:
pyoderma gangrenosum, a necrotizing, ulcerative, noninfectious
neutrophilic dermatosis.
Sweet's syndrome, a neutrophilic dermatosis usually associated with
myeloproliferative disorders
drug reactions
erythema nodosum
lobular panniculitis
atrophy of digital skin
palmar erythema
diffuse thinning (rice paper skin), and skin fragility (often worsened
by corticosteroid use).
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X-rays of the hands and feet .
Other medical imaging techniques such as
magnetic resonance imaging and ultrasound
are also used in rheumatoid arthritis.
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Chemically synthesised DMARDs:
azathioprine
ciclosporin (cyclosporine A)
D-penicillamine
gold salts
hydroxychloroquine
leflunomide
methotrexate (MTX)
minocycline
sulfasalazine (SSZ)
Cytotoxic drugs:
Cyclophosphamide
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This is a necrotising angiitis involving medium sized arteries,
ending fatally due to coronary thrombosis, cerebral hemorrhage
or gastrointestinal bleeding.
Polyarteritis is seen as a component of serum sickness and
other toxic complex diseases. Immune complexes of hepatitis B
virus antigen (Hbs Ag) in affected tissues, including kidneys
have been demonstrated in 30-40% of patients.
Though it has been suggested that polyarteritis nodosa may be
an autoimmune disease , the auto antibody responsible has not
been identified
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Scleroderma is a chronic systemic autoimmune disease
characterized by fibrosis (or hardening), vascular
alterations, and autoantibodies. There are two major forms:
Limited systemic sclerosis/scleroderma cutaneous
manifestations mainly affect the hands, arms and face.
Previously called CREST syndrome in reference to the
following complications:
Calcinosis,
Raynaud's phenomenon,
Esophageal dysfunction,
Sclerodactyly, and
Telangiectasias.
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Additionally, pulmonary arterial hypertension may occur in up
to one third of patients and is the most serious complication for
this form of scleroderma.
Diffuse systemic sclerosis/scleroderma is rapidly progressing
and affects a large area of the skin and one or more internal
organs, frequently the kidneys, esophagus, heart and lungs.
This form of scleroderma can be quite disabling. There are no
treatments for scleroderma itself, but individual organ system
complications are treated.[1][2] Other forms of scleroderma
include Systemic sine scleroderma, which lacks skin changes,
but has systemic manifestations, and two localized forms
which affect the skin, but not the internal organs: morphea,
and linear scleroderma.
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Heart: Untreated high blood pressure strains the heart; irregular heart
rhythm and enlargement of the heart lead to heart failure.
Kidney: scleroderma renal crisis in which malignant hypertension
develops and causes acute renal failure. This was once a common cause of
death, but now is easy to treat with ACE inhibitors.
Lung: Two-thirds of all patients suffer from respiratory problems such as
shortness of breath, coughing, difficulty breathing, alveolitis
(inflammation of lung air sacs), pneumonia, and cancer.
Digestive: Esophagus damage can make it difficult to swallow food, and
acid reflux is common. The stomach can develop watermelon stomach
(gastric antral vascular ectasia, GAVE) which occasionally may bleed
profusely. A sluggish intestine may cause pain & bloating; undigested
food can result in diarrhea, weight loss and anemia.
Skin and joints: Carpal tunnel syndrome is common, as are muscle
weakness, joint pain, and stiffness.[
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There is no direct cure for scleroderma. Because the exact
cause is unknown, any treatment is patient-specific and
aimed at ameliorating symptoms of the disease. For example,
patients who experience Raynaud's phenomenon may be
treated with agents to increase blood flow to the fingers,
including nifedipine, amlodipine, diltiazem, felodipine, or
nicardipine.
Fibrosis of the skin has been treated with varying degrees of
success with agents such as d-penicillamine, colchicine,
PUVA, Relaxin, and cyclosporine.
Because scleroderma is an autoimmune disease, one of the
major pillars of treatment involves the use of
immunosuppressive agents. These drugs include methotrexate,
cyclophosphamide, azathioprine, and mycophenolate
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is a triad of conjuctivitis sicca , dryness of
mouth , with or without salivary gland
enlargement , and rheumatoid arthritis.
 The syndrome may not occur in association
with other collagen diseases.
 Anti nuclear antibodies and rheumatoid factor
commonly occur in sera.
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hallmark symptoms of the disorder are dry
mouth and dry eyes (part of what are known as
sicca symptoms). In addition, Sjögren's
syndrome may cause skin, nose, and vaginal
dryness, and may affect other organs of the
body, including the kidneys, blood vessels,
lungs, liver, pancreas, peripheral nervous system
(distal axonal sensorimotor neuropathy) and
brain.
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There is neither a known cure for Sjögren's syndrome nor a
specific treatment to permanently restore gland secretion.
Instead, treatment is generally symptomatic and supportive.
Moisture replacement therapies such as artificial tears may
ease the symptoms of dry eyes (some patients with more severe
problems use goggles to increase local humidity or have punctal
plugs inserted to help retain tears on the ocular surface for a
longer time).
Cyclosporin
Nonsteroidal anti-inflammatory drugs may be used to treat
musculoskeletal symptoms.
Wegener's granulomatosis is a form of vasculitis
(inflammation of blood vessels) that affects the lungs,
kidneys and other organs. Due to its end-organ
damage.
 Wegener's granulomatosis is part of a larger group of
vasculitic syndromes, all of which feature an
autoimmune attack by an abnormal type of
circulating antibody termed ANCAs (antineutrophil
cytoplasmic antibodies) against small and mediumsize blood vessels.
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Kidney: rapidly progressive glomerulonephritis (75%), leading to chronic renal failure
Upper airway, eye and ear disease:
◦ Nose: pain, stuffiness, nosebleeds, rhinitis, crusting, saddle-nose deformity due to a
perforated septum
◦ Ears: conductive hearing loss due to auditory tube dysfunction, sensorineural hearing loss
(unclear mechanism)
◦ Oral cavity: strawberry gingivitis, underlying bone destruction with loosening of teeth,
non-specific ulcerations throughout oral mucosa
◦ Eyes: pseudotumours, scleritis, conjunctivitis, uveitis, episcleritis
Trachea: subglottal stenosis
Lungs: pulmonary nodules (referred to as "coin lesions"), infiltrates (often interpreted as
pneumonia), cavitary lesions, pulmonary hemorrhage causing hemoptysis, and rarely
bronchial stenosis.
Arthritis: Pain or swelling (60%), often initially diagnosed as rheumatoid arthritis
Skin: nodules on the elbow, purpura, various others (see cutaneous vasculitis)
Nervous system: occasionally sensory neuropathy (10%) and rarely mononeuritis multiplex
Heart, gastrointestinal tract, brain, other organs: rarely affected.
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Wegener's granulomatosis is usually suspected only
when a patient has had unexplained symptoms for a
long period of time. Determination of ANCAs can aid
in the diagnosis, but positivity is not conclusive and
negative ANCAs are not sufficient to reject the
diagnosis. Cytoplasmic staining ANCAs that react
with the enzyme proteinase 3 (cANCA) in neutrophils
(a type of white blood cell) are associated with
Wegener's
This includes conditions such as anemia ,
thrombocytopenia or nephritis that follow certain
infections or drug therapy.
 The infecting agent or drug induces antigenic
alteration in some self antigens.
 The immune response set- up causes tissue damage.
 The disease is transient and undergoes spontaneous
cure when infection is controlled or the drug is
withdrawn.
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Many diseases are considered to be auto immune in
origin , based on their association with cellular or
humoral immune response against self antigens.
 Auto antibodies are more easily detected than cellular
autosensitisation.
 However , the presence of auto antibodies during the
course of a disease does not prove their causative role.
 Auto antibody formation may be a result of tissue
injury and the antibody may help in promoting immune
elimination of damaged cell or tissue elements.
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typical example is lepromatous leprosy in
which large amounts of auto antibodies are
regularly found.
 It has been said that but for lepra bacillus,
lepromatous leprsoy may have been proposed
as an auto immune disease.
 Antibodies may cause damage by the
cytolytic or cytotoxic(type2) and toxic
complex (type 3) reactions.
 They are obviously important in
hemocytolytic auto immune diseases.
Another mechanism of auto immune tissue damage is by
sensitised T lymphocytes ( type 4 reaction ).
 It is likely that humoral and cellular immune responses
may act synergistically in production of some auto
immune diseases.
 For example, experimental orchitis can be induced only
when both types of immune responses are operative.
 Once initiated, most auto immune responses tend to be
self perpetuating.
 Their progress can be arrested by immuno suppressive
therapy, though the degree of response to such therapy
varies in different diseases
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