Autoimmunity Flashcards
What is tolerance?
Tolerance refers to the specific immunological non-reactivity to an antigen resulting from a previous exposure to the same antigen.
The most important form of tolerance is non-reactivity to self antigens.
Define autoimmunity
Autoimmunity can be defined as breakdown of mechanisms responsible for self tolerance and induction of an immune response against components of the self.
What is peripheral tolerance?
The immune system has devised several additional check points so that tolerance can be maintained
Peripheral tolerance is developed after T and B cells mature and enter the periphery.
These include the suppression of autoreactive cells by ‘regulatory’ T cells and the generation of hyporesponsiveness (anergy) in lymphocytes which encounter antigen in the absence of the co-stimulatory signals that accompany inflammation
What are the various theories about the etiology of autoimmunity?
Sequestered antigen
Escape of autoreactive clones
Loss of suppressor cells
Cross reactive antigens including exogenous antigens (pathogens) and altered self antigens (chemical and viral infections
What is sequestered antigen theory?
Lymphoid cells may not be exposed to some self antigens during their differentiation, because they may be late-developing antigens or may be confined to specialized organs (e.g., testes, brain, eye, etc.).
A release of antigens from these organs resulting from accidental traumatic injury or surgery can result in the stimulation of an immune response and initiation of an autoimmune disease.
Describe the theory behind escape of autoreactive clones
The negative selection in the thymus may not be fully functional to eliminate self reactive cells.
Not all self antigens may be represented in the thymus or certain antigens may not be properly processed and presented
What is lack of regulatory T cells in autoimmunity?
There are fewer regulatory T-cells in many autoimmune diseases
Describe the theory behind cross reactive antigens
Antigens on certain pathogens may have determinants which cross react with self antigens and an immune response against these determinants may lead to effector cell or antibodies against tissue antigens.
Post streptococcal nephritis and carditis, anticardiolipin antibodies during syphilis and association between Klebsiella and ankylosing spondylitis are examples of such cross reactivity
What is direct evidence of autoimmunity?
Direct evidence requires transmissibility of the characteristic lesions of the disease from human to human, or human to animal
Give examples of autoimmune diseases that fulfill the criteria for direct evidence
Idiopathic thrombocytopenic purpura
Graves’ disease
Myasthenia gravis in which there are temporary signs of disease in the infant due to transplacental transfer
Give examples of autoimmune diseases where the disease can be transmitted from humans to animals by autoantibody
Pemphigus vulgaris
Bullous pemphigoid
What is a more feasible way to demonstrate the pathological effects of autoantibody?
To reproduce the functional defects characteristic of the disease in vitro.
Give examples of how the functional defects of a disease are reproduced in vitro
Inhibition of the fixation of vitamin B12 by intrinsic factor can be produced by autoantibodies from certain patients with pernicious anemia
Overproduction of thyroid hormones can be produced by autoantibodies from patients with Graves’ disease
What is indirect evidence of autoimmunity?
Indirect evidence requires re-creation of the human disease in an animal model.
The majority of autoimmune diseases fit in this category
Give examples of autoimmune diseases that fulfill the criteria for indirect evidence
Thyroiditis and multiple sclerosis can be reproduced by immunizing the animal with an antigen analogous to the putative autoantigen of the human disease
What is the pathophysiology for Myasthenia Gravis?
Autoantibodies (IgG) develop against ACh nicotinic postsynaptic receptors .Cholinergic nerve conduction to striated muscle is impaired by a mechanical blockage of the binding site by antibodies and, ultimately, by destruction of the postsynaptic receptor.Patients become symptomatic once the number of ACh receptors is reduced to approximately 30% of normal.
The cholinergic receptors of smooth and cardiac muscle have a different antigenicity than skeletal muscle and are not affected by the disease.
What are the patterns usually seen in Myasthenia Gravis?
Female > male , Mostly in 30s
Serum IgG against AchR in post synaptic NMJ
Associated with thymic hyperplasia and thymoma
What are the findings for Myasthenia Gravis?
Weakness
Fatigability of proximal limb, ocular & bulbar muscles
Ptosis first symptom
Anti AchR antibodies found in 90%
What are the investigations done in Myasthenia Gravis?
Tensilon test - immediate improvement in muscle strength, only lasts a few minutes
Evoked potentials - Decreased
What is the treatment for Myasthenia Gravis?
Pyridostigmine, neostigmine, thymectomy, steroids, immunosuppressives
What are the patterns in Pernicious Anaemia?
Most common cause of Vit B12 deficiency
Failure of intrinsic factor(IF) production
Elderly, premature greying blue eyed women
Association with thyroid and vitiligo (auto-immune disorders)
What are the features of Pernicious Anaemia?
Glossitis
Angular stomatitis
Mild jaundice
Subacute combined degeneration of cord (weakness, ataxia, visual defects, paraplegia dementia)
What are the findings for Pernicious Anaemia?
Increased MCV (Mean red blood cell volume) Hypersegmented neutrophils Low serum B12 Low red cell folate Anti parietal cell antibodies Anti IF antibodies Increased unconjugated bilirubin
What investigation is performed for suspected Pernicious Anaemia?
Schilling Test - Shows low B12 absorption in Pernicious Anaemia
What is the treatment for Pernicious Anaemia?
B12 injections
Oral B12 preparations which can be used to distinguish between malabsorption and malnutrition by trial therapy
What is the pathophysiology for Pernicious Anaemia?
Vitamin B-12 cannot be produced by the human body, and must therefore be obtained from diet.
Dietary vitamin B-12 can only be absorbed by the ileum when it is bound by the intrinsic factor produced by parietal cells of the gastric mucosa.
In pernicious anemia, this process is impaired because of loss of parietal cells, resulting in insufficient absorption of the vitamin, which over a prolonged period of time ultimately leads to vitamin B-12 deficiency and thus megaloblastic anemia.
This anemia is due to the inability to produce DNA in sufficient quantities for blood cell synthesis, due to interruption of a biochemical pathway that is dependent on vitamin B-12 and/or folic acid as cofactors, which synthesizes thymine, a DNA component
Classic pernicious anemia is caused by the failure of gastric parietal cells to produce sufficient IF to permit the absorption of adequate quantities of dietary vitamin B-12
Autoantibodies are directed against parietal cells (resulting in their loss) as well as against the intrinsic factor itself (rendering it unable to bind vitamin B-12)
What is the pathophysiology of autoimmune haemolytic anaemia (AHA)?
Anti RBC antibodies become fixed onto the RBC surface and activates complement causing cell destruction by lysis and/or by opsonization.
What are the clinical features of warm haemolytic anaemia?
Can occur at any age, in either sex, and presents as haemolytic anaemia of varying severity
Enlarged spleen
Tends to remit and relapse
May occur alone, or with other diseases, or occur in some patients as a result of methyldopa therapy
When associated with idiopathic thrombocytopenic purpura (ITP), which is a similar condition affecting platelets, it is known as Evans’ Syndrome
When secondary to systemic lupus erythematosus, the cells are typically coated with immunoglobulin and complement
What are the laboratory findings for warm autoimmune haemolytic anaemia?
The haemotological and biochemical findings are typical of an extravascular haemolytic anaemia with spherocytosis (sphere shaped red blood cells) prominent in the peripheral blood
Positive Coombs’ test as a result of IgG, IgG and complement, or IgA on the cells and, in some cases, the autoantibody shows specificity within the rhesus system
The antibodies, both on the cell surface and free in the sserum are best detected at 37C
What are the symptoms of warm autoimmune haemolytic anaemia?
Symptoms of warm antibody haemolytic anaemia tend to be due to the anemia.
If the disorder is severe, fever, chest pain, syncope, or heart failure may occur.
Mild splenomegaly is typical.
What is the etiology of warm haemolytic anaemia?
Warm antibody hemolytic anemia is the most common form of autoimmune hemolytic anemia (AIHA); it is more common among women. Autoantibodies in warm antibody hemolytic anemia generally react at temperatures ≥ 37° C.
The autoantibodies may occur:
Spontaneously
In association with certain disorders (SLE, lymphoma, chronic lymphocytic leukemia)
After use of certain drugs
Some drugs stimulate production of autoantibodies against Rh antigens (α-methyldopa-type of AIHA). Other drugs stimulate production of autoantibodies against the antibiotic–RBC-membrane complex as part of a transient hapten mechanism; the hapten may be stable or unstable
In warm antibody haemolytic anemia, haemolysis occurs primarily in the spleen. It is often severe and can be fatal. Most of the autoantibodies in warm antibody haemolytic anemia are IgG. Most are panagglutinins and have limited specificity.
What drugs can cause warm autoimmune haemolytic anaemia by autoantibodies to Rh antigens?
Cephalosporins Diclofenac Ibuprofen Interferon-α Levodopa Mefenamic acid α-Methyldopa Procainamide Teniposide Thioridazine Tolmetin
What are the mechanisms for drug induced warm autoimmune haemolytic anaemia?
Autoantibody to Rh antigens
Stable hapten
Unstable hapten
Unknown mechanism
What drugs can cause warm autoimmune haemolytic anaemia by stable hapten?
Cephalosporins Fluorescein sodium Penicillins Tetracycline Tolbutamide
What drugs can cause warm autoimmune haemolytic anaemia by unstable hapten or unknown mechsanisms?
p-Aminosalicylic acid Amphotericin B Antazoline Cephalosporine Chlorpropamide Diclofenac Diethylstilbestrol Doxepin Hydrochlorothiazide Isoniazid Probenecid Quinidine Quinine Rifampin Sulfonamides Thiopental Tolmetin
How is warm autoimmune haemolytic anaemia treated?
High dose prednisolone
Splenectomy
How is cold autoimmune haemolytic anaemia treated?
Avoid cold weather.
Treat the underlying lymphoma.
No cold drinks, all drinks should be on normal temperature.
Requires Heater to maintain temperature in cold places.
Treatment with rituximab has been described
What is the platelet count for thrombocytopaenia?
<150 x 10^9 l
What are the features of Idiopathic thromocytopenic purpura (ITP)?
Bruising Petechiae Epistaxis Menorrhagia (chronic) Afebrile No splenomegaly
What are the clinical types of ITP?
Acute
Chronic
Drug induced
Describe the features of acute ITP
Often in children
Usually self limiting with spontaneous resolution
May be post infective - e.g. Measles
Describe the features of chronic ITP
Usually in adults
Mainly idiopathic, but occasionally related to chronic lymphocytic leukaemia (CLL) or lymphoma
May occur in association with another autoimmune disease
What autoimmune diseases may chronic ITP occur in association with?
Rheumatoid arthritis SLE (Systemic Lupus Erythromatosus) CLL HIV NHL (non Hodgkin's lymphoma) HD
What is the treatment for ITP?
Steroids Platelet transfusion IVIg Splenectomy Immunosuppressives
What is the most common cause of hyperthyroidism?
Graves’ disease
What are the features of hyperthyroidism?
Increased appetite but weight loss Irritability Hyperkinesis Sweating Palpitations Tachycardia (atrial fibrillation) Tremor Diarrhoea
What are the feature of hyperthyroidism seen only in Graves’ disease?
Exophthalmos (protruding eyes)
Acropachy (clubbing of fingers and toes with soft tissue swelling)
Pretibial Myxoedema (waxy discoloured hardening of the skin)
Describe the pathogenesis of Graves’ disease
IgG binds to THS receptor causing prolonged stimulation of the thyroid (lasting as long as 12 hours)
The autoantibdy binds at a different site to the hormone-binding locus and is termed TSH-receptor autoantibody (TRAb)
What is the treatment for Graves’ disease?
Carbimazole
Radioactive iodine
Surgery
Propanolol for initial control of the symptoms
What is the clinical presentation of Bullous pemphigoid?1
Large, tense blisters commonly appear on the limbs, trunk and flextures (occasionally localised to one site, often the lower leg)
Oral lesions occur in 10% of cases
Urticarial eruption may precede the onset of blstering
What causes Bullous pemphigoid?
IgG antibodies are deposited at the basement membrane
Inflammatory cells, attracted by complement activation, release proteolytic enzymes, resulting in bullae formation, which tend to remain intact
What is the treatment for Bullous pemphigoid?
The disease is self limiting in about 50% of cases and is managed with systemic steroids and other immunosuppressants
What are the features of Multiple Sclerosis (MS)?
Multiple demylelinations (relapsing and remitting episodes) within brain and spinal cord (optic nerves, periventricular regions, brainstem, cerebellum, C Spinal cord (corticospinal tracts and posterior column))
Female>male
Early adulthood onset
Rare in tropics
What are the symptoms of MS?
Early Symptoms
- Blurring of vision
- Incoordination
- Abnormal Sensation
Late Symptoms
- Blindness
- Paraplegia
- Incontinence
- Ataxia
- Intellectual Dysfunction
What are the findings in MS?
Optic nerve inflammation - blurred vision/unilateral eye pain
Optic neuritis and atrophy
Diplopia (double vision)
Vertigo
Dysphagia (swallowing problems)
Nystagmus (continuous involuntary eye movement)
Paraesthesia (pins and needles)
Spastic paraparesis (progressive stiffness and contraction of the lower limbs)
What are the investigations are performed to confirm MS?
MRI Evoked potentials (extended) CSF (WBC, IgG raised, oligoclonal bands)
What are evoked potentials?
The time it takes nerves to respond to stimulation
This time is extended in MS, due to the destruction of the myelin sheath
How is MS treated?
Steroids
Interferon-β (reduces relapse rate)
Physiotherapy natalizumab
