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AUTO IMMUNITY
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”
Systemic 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)
Examples..
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
Systemic lupus erythematosus
1948 – Malcolm Hargraves discovers the lupus erythematosus (LE) cell.
1957 – The first anti-DNA antibody is identified.
History
LE 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.
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.
LE Cell
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
Symptoms
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
Raynaud's phenomenon
Secondary Raynaud's (syndrome)
Decreasing TEMPERATURE
Skin Manifestations
Malar or Butterfly Rash
Discoid Rash – Stimulated by UV light
Skin manifestations only appear in 30-40% of lupus patients.
Renal (Kidney) Manifestations
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-cellsSuppressed regulatory function in T-cells
Lack of T-cellsActivation of the Complement system
Main Pathology
Estrogen is a stimulator of B-cell activity◦Lupus is much more prevalent in females of ages 15-45Height 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
Overactive B-cells
Fc region switch◦ ζ εγ◦ Leads to malfunction in signaling and decreased
IL-2 production Increased levels of Ca2+
◦ Leads to spontaneous apoptosis
T-cell Malfunctions
T-cell Signal Transduction
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
Activation of Complement System
IgG is the most “pathogenic” because it forms intermediate sized complexes that can get to the small places and block them.
Ig-G Pathogen
ESRUrinalysisComplement Test◦Tests levels of C3, C4, CH50◦Low levels indicates possible presence of disease
FANA – Fluorescent antinuclear antibody
Ouchterlony Test – shows interactions
Testing
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.
FANA ELISA Test
◦Generally test for: ds-DNA
antibodies Antihistone
antibodies Binds to
DNA, major constituent of chromatin
Deoxyribonucleoprotein (DNP)
ANA Antibodies in SLE
Ouchterlony Test
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.
Rheumatoid Arthritis
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.
MECHANISM
MECHANISM
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.
In BREIF - sumMARY
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).
X-rays of the hands and feet . Other medical imaging techniques such as
magnetic resonance imaging and ultrasound are also used in rheumatoid arthritis.
DIAGNOSIS
SYNOVIAL FLUID
Chemically synthesised DMARDs: azathioprine ciclosporin (cyclosporine A) D-penicillamine gold salts hydroxychloroquine leflunomide methotrexate (MTX) minocycline sulfasalazine (SSZ)
Cytotoxic drugs: Cyclophosphamide
TREATMENT
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
Polyarteritis nodosa
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.
Scleroderma
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.
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.[
Severe complications
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
Treatment
This 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.
Sjogren’s syndrome
The 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.
Signs and symptoms
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.
Treatment
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 medium-size blood vessels.
WEGNERS GRANULOMATOSIS
]
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.
Signs and symptoms
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
Diagnosis
Immunofluorescence pattern produced by binding of ANCA from a patient with Wegener's Granulomatosis to ethanol-fixed neutrophils
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.
Transitory Auto Immune Response
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.
Pathogenesis Of AutoImmune Disease
A 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
