Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
42 Cards in this Set
- Front
- Back
|
Define autoimmunity
|
Autoimmunity is the state that is present when an individual makes an immune response against self antigens. Not all autoantibodies cause tissue damage ie autoimmunity can be present in the absence of autoimmune disease (This is common in the elderly.)
Autoimmunity can be organ specific – the target antigen is located in one organ eg thyroid peroxidise. Or non organ specific – target antigen is located in many different tissues and organs eg double stranded DNA in systemic lupus erythematous ( SLE) |
|
|
Describe autoimmune disease.
|
Autoimmune disease – a disease in which autoimmunity is thought to play a significant pathogenic role.
Autoimmune diseases can be organ specific eg hyperthyroidism or non-organ specific eg SLE. |
|
|
Describe how B1 cells are different to normal B cells.
|
B1 cells only produce IgM, do not undergo affinity maturation (somatic hypermutation and class switching) and are not affected by T cells. They produce natural antibodies which protect against certain bacteria. Some of these antibodies cross react with human antigens.
|
|
|
What are hypersensitivity reactions?
|
Hypersensitivity is exagerated forms of the normal immune response leading to tissue damage. it doesn't always involve antibodies.
hypersensitivity reactions are the mechanisms by which autoantibodies or autoreactive T cells cause tissue damage. They indicate that the processes of central tolerance are faulty, and some cells can escape the process. Peripheral tolerance is present to prevent the activation of autoreactive t and b cells but when this system breaks down, autoimmunity occurs. |
|
|
Describe celiac disease.
|
Celiac disease is a T cell mediated autoimmune disease of the small bowel in which prolamin ( alcohol soluble proteins in wheat, barley, rye and oats) intolerance causes villous atrophy and malabsorption. It is associated with HLA- DQ2 (MHC- Class II) markers. Gluten is broken down to gliadin which is deaminated by tissue transaminase, converting some glutamine groups to glutamic acid. In celiac disease deaminated gliadin becomes bound to HLA-DQ2 which presents gliadin and the bound tissue transaminase to T cells. The immune system cross reacts with small bowel tissue causing the formation of autoantibodies against tissue transaminase. The t cells react with macrophages, producing the delayed type hypersensitivity reaction of erythematic and injurated areas. This damages the intestinal villi causing atrophy of villi. The surface area of absorption of nutrients is reduced. Withdrawal of gluten however reverses the process restoring the villi back to normal and loss of autoantibodies to tissue transaminase.
other antibodies tested are anti-reticulin, anti gliadin and anti-endomysium. Also igA levels are measured as celiac patients with IgA deficiency ( the most common type) may not be able to produce the antibodies an which these tests are based ie the autoantibodies are IgA except for anti-tissue transaminase which is IgG |
|
|
Describe type 1 hypersensitivity reactions.
|
Type 1 hypersensitivity reaction are also called immediate hypersensitivity reactions. They are caused by the cross linking of antigen specific IgE on the surface of mast cells or basophils leading to the degranulation of these cells which release histamine (vasodilator) and heparin ( anticoagulant – antithrombin 3). The reactions appear within minute of antigen exposure and form the basis of common allergies eg peanut allergy. They are not usually life threatening except anaphylaxis which is a severe form of immediate hypersensitivity. It is triggered by exposure of a pre-sensitised individual to an allergen causing systemic mast cell degranulation, vasodilation, tissue oedema, airway obstruction, decreased blood pressure and shock. It is treated with intramuscular adrenalin which increases blood pressure by increasing heart rate and force of contraction. It also causes bronchodilation.
|
|
|
Describe type II hypersensitivity.
|
Type II hypersensitivity is also known as antibody-mediated hypersensitivity. They are caused by IgG binding to self antigen present on tissues or on the surface of cells. Complements then bind to the antibody or Fc receptors on phagocytic cells, leading to induction of localised inflammation and tissue damage. These reactions occur very quickly after binding of antibody to antigen but may also lead to prolonged activation of the innate immune mechanisms causing the tissue damage. Examples of type II reactions causing disease include goodpasture’s syndrome where autoantibodies attack components on basement membranes in the lungs and kidneys. Other examples include haemolytic anaemia and rhesus disease – haemolytic anaemia in new borns.
|
|
|
Describe type III hypersensitivity.
|
Type III hypersensitivity reactions are caused by deposition of immune complexes. The antibody, IgG, and antigens are usually in the same concentration and so they produce much smaller antibody antigen complexes than usual. They deposit in small blood vessels, joints and glomeruli causing rash, arthritis and nephritis. They stimulate inflammation with activation of complements and phagocytic cells but they are too small to be removed. The reactions usually occur within several hours of antigen challenge. Examples include systemic lupus erythematous , post-streptococcal glomerulonephritis and farmer’s lung in which antibodies to an airborne fungal spore form immune complexes in the lung and cause an inflammatory response.
|
|
|
Describe type IV hypersensitivity.
|
Type IV hypersensitivity is also known as delayed hypersensitivity reaction. This is mediated by activated T helper cells ( Th1) which stimulate the activation of macrophages and cytoxic T cells causing tissue damage. The reaction appears days after initially antigen challenge. Examples of delayed hypersensitivity to external antigens include tuberculoid leprosy, turberculin skin test and contact dermatitis. Delayed hypersensitivity reactions are also present in many autoimmune diseases eg insulin dependent diabetes mellitus type 1, celiac disease and multiple sclerosis.
|
|
|
Describe the classification and mechanism of hypersensitivy reactions comparing: onset time, infection, environmental cause examples, autoimmune, adaptive mechanism, innate mechanism.
|
Type 1 hypersenstivity: onset time is minutes, infection causes include parasites eg schistosomiasis ( increased risk of bladder cancer), environmental factors include house dust mites, peanuts, pollen etc. It is NOT autoimmune. Its adaptive mechanism involves IgE, triggering degranulation of mast cells. The innate mechanism components are mast cells and basophils.
Type II hypersensitivity: onset time is minutes to hours, infection causes are mycoplasma resulting in immune haemolytic anaemia, environmental causes can be drugs inducing haemolytic anaemia, autoimmune haemolytic anaemia, goodpastures syndrome, rhesus disease, the adaptive mechanism component is IgG and the innate components are complements and phagocytes. Type III hypersensitivity: onset time is hours, infection causes are post-streptococcal glomerulonephritis, environmental disease example is farmer’s lung, autoimmune example is SLE, adaptive mechanism involves IgG immune complexes and the innate components are complements and phagocytes Type IV hypersensitivity: onset time is 2-3 days, infection example is tuberculoid leprosy, environmental example is contact dermatitis, autoimmune examples are type 1 diabetes mellitus, multiple sclerosis and celiac disease. The adaptive components are T cells and the innate components are macrophages. |
|
|
How do you calculate the relative risk for an HLA allele in an autoimmune disease? At what age would diseases which show a significant bias in sex ratio, show the greatest differences between sex?
|
Compare the observed number of patients carrying the HLA allele with the number of patients that would be expected, given the prevalence of the HLA allele in the general population. HLA-CR3 and DR4 are tightly linked to HLA –DQ.
The differences in sex ratio indicate that sex hormones have an effect on the pathogenesis of the disease, so the differences in the sex ratio will be greatest at puberty when these hormones are at their highest. |
|
|
Describe mechanisms of auto-immunity and tolerance breakdown.
|
Molecular mimicry is cross reactivity between pathogen and self antigen so that an anti-pathogen immune response leads to anti-self response. Examples include celiac disease – adenovirus 12 and gliadin.
Defective immunoregulation is when there is a reduction in suppressor or regulatory t cell number or function. There may be faulty AIRE ( antigen regulatory) transcription factor produced, aberrant antigen presentation by dendritic cells. Cytokine dysregulation is where cytokines provide additional signals to activate resting or tolerised autoreactive cells. Example is autoimmune thyroid disease following IL-2 therapy. T cell bypass is when the action of T cells activating B cells is bypassed by pathogens producing super antigens, that can cause polyclonal expansion of b cells. This is seen in drug and virus induced autoimmune cytopenias. Exposure of Hidden self antigens eg sympathetic ophthamia, myelin antigens in MS, post myocardial complications |
|
|
Give examples of organ specific, intermediate/mixed and non-organ specific autoimmune diseases.
|
Organ specific autoimmune diseases include hashimotos disease, primary myxodema and thyrotoxicosis effecting the thyroid gland, chronic atrophic gastritis, pernicious anaemia, addisons disease, myasthenia gravis, diabetes melitis type 1, premature ovarian failure and male infertility.
Intermediate autoimmune diseases include goodpastures syndrome ( autoantibodies attack BM in lung and kidneys), primary biliary cirrhosis, autoimmune haemolytic disease and ulcerative colitis. Non organ specific autoimmune diseases include SLE, RA, progesive systemic sclerosis, sjogren’ s syndrome. |
|
|
List the autoantibody targets of the following diseases: hashimotos thyroiditis, graves disease, atrophic gastritis, pernicious anaemia and celiac disease.
|
Hashimotos thyroiditis: thyroid peroxidise is attacked
Graves disease: TSH receptor is stimulated -> thyroid hormone release Atrophic gastritis: gastric parietal cell Pernicious anaemia: gastric parietal cell and intrinsic factor -> blocks vitamin B12 uptake Celiac disease: tissue transglutaminase |
|
|
List the autoantibody targets of the following diseases: myasthenia gravis, diabetes type 1 mellitus, goodpasture’s syndrome, addisons disease, systemic vasculitis, primary biliary cirrhosis, RA, SLE, bullous skin disease.
|
Myasthenia gravis: aceylcholine receptor – blocks neuromuscular junction/damages receptor
Diabetes: islet b cell Goodpastures syndrome: anti-glomerular basement membrane -> type II hypersensitivity in kidney and lung Addisons disease: adrenal corex -> reduced mineralcorticoids and glucocorticoids -> skin pigmentation Systemic vasculitis: anti-neutrophil cytoplasmic antibody (ANCA) Primary billary cirrhosis: mitochondrial Rheumatoid arthritis: rheumatoid factor SLE: double stranded DNA Bullous skin disease: skin autoantibodies |
|
|
HLA- B27, DR2, DQ2,DR3,DR4 and DR5 increase risk of which diseases.
|
HLA-B27 – Ankylosing spondylitis
HLA – DR2 – goodpastures syndrome and multiple sclerosis HLA – DQ2 – celiac disease HLA- DR3 – grave’s disease, myasthenia gravis, SLE, type 1 diabetes mellitus HLA –DR4 –type 1 diabetes mellutis, RA, pemphigus vulgaris HLA – DR5- hashimotos disease |
|
|
Define immunotherapy
|
Immunotherapy is the manipulation of the immune response to treat disease. It can either enhance immunity as in vaccination or suppress immune responses as in treatment of allergic or autoimmune diseases.
|
|
|
Describe antihistamines.
|
Antihistamines are used to treat type I hypersensitivity reactions eg nut allergy and treat urticaria and angioedema. They are H1 histamine receptor antagonists which lead to inhibition of increased vascular permeability and smooth muscle contraction and reduced exocrine secretions and sensory nerve stimulation (itching and sneezing).
Older antihistamines have sedating affects eg chlorphenamine ( piriton) and alimemazine ( vallergan) New antihistamines are non-sedating and have longer lasting activity. Eg cetirizine, terfandine and loratidine. |
|
|
Describe allergen desensitisation.
|
Allergen desensitisation is carried out in patients who have severe allergies that result in anaphylaxis or chronic allergies that are not maintained well with antihistamines. The individual is given regular subcutaneous injections over a period of weeks or months. It works by switching the allergen specific t cell response to TH1 instead of TH2, by inducing allergen specific regulatory t cells that suppress the allergic response and by inducing IgG antibodies to the antigen that have a blocking effect. IgE levels are reduced due to t cell response switch to TH1.
|
|
|
Describe the treatments of asthma..
|
The major pathogenic effect in asthma is bronchoconstriction which is treated with b2 agonists ag salbutamol. There is sometimes also an inflammatory or allergic component that can be treated by corticosteroids or leukotriene receptor antagonists.
|
|
|
Describe the use of corticosteroids to treat asthma. How are they given? Define leukocyte trafficking and their functional effects.
|
Corticosteroids are given topically by inhaler, creams or drops or systemically– becotide, pulmicort and flixotide. They are anti-inflammatory and immunosuppressive drugs. They block or suppress function of non specific inflammatory cells eg monocytes, macrophages, granulocytes or proinflammory mediators.
Immunosuppressive effects: - Leukocyte trafficking: increased neutrophils but reduced lymphocytes and monocytes - Functional effects: inhibition of NFkB intracellular signalling pathway(reducing inflammatory response), reduced cytokine release, impaired lymphocyte proliferation, suppressed phagocytosis and bacteriocidal activity, impaired antigen presentation, reduced arachidonic acid metabolism. |
|
|
Describe the side effects of corticosteroid drug.
|
Glucocorticoid effects(zone fasculata): diabetes, cushings syndrome adrenal suprresion, osteoporosis – avascular necrosis of head of femur, mental disturbances
- Due to adrenal suppressive effects of steroids, they should be withdrawn gradually in patients who have received long term systemic therapy to avoid acute adrenal insufficiency. Mineralcorticoid effects ( zona glomerulosa): hypertension, sodium and water retension, potassium loss. Immunosuppressive effect: increased susceptibility to infections, impaired would healing, Also obesity and muscle wasting and growth arrest in children. CUSHINGOID: - Cataracts - Ulcers - Skin: striae, thinning, bruising - Hypertension, hyperglycaemia, hirtuism - Infections - Necrosis, avascular negrosis of femoral head - Glycosurea - Osteoporosis, obesity( moon face and central adiposity) - Immunosuppresion - Diabetes |
|
|
Describe NSAIDS.
|
NSAIDS have analgesic and anti-inflammatory effects. They inhibit cyclooxygenase in the production of prostaglandins from arachydonic acid. The major side effect of NSAIDS is gastrointestinal toxicity as prostaglandins are needed to promote protective mucus and alkali release from the columnar epithelium lining the stomach. However, COX-2 inhibitors don’t have this effect.
|
|
|
Describe COX 2 inhibitors.
|
COX-2 inhibitors target the COX-2 enzyme in the arachydonic mechanism that produces ‘bad prostaglandins’ – The ones causing pain and inflammation and so don’t cause GI toxicity as the ‘good prostaglandins’ which are needed for gastric protection or formed by COX-1.
However cox 2 inhbitors have cardiovascular effects and should not be used in patients with ischaemic heart disease or cerebrovascular disease. Cox 2 inhibitors include celocoxib and etoricoxib. |
|
|
Give examples of NSAIDS. Which NSAID is originally derived from willow bark?
|
Aspirin ( salicylic acid), ibuprofen ( propionic acid derivatives), indomethacin ( non-propionic derivatives), celocoxib and etoricoxib ( selective COX2 inhibitors).
aspirin derives from willow bark |
|
|
Describe TNF alpha antagonists. What is the main side effect?
|
TNF- alpha is a pro-inflammatory cytokine that plays a central role in many autoimmune diseases including rheumatoid arthritis and crohn’s disease. Biological therapies are used to neutrilise the effects of TNF-alpha.
Infliximab is a humanised monoclonal antibody against TNF-alpha. Etanercept is a soluble, recombinant, human TNF-alpha receptor fusion protein. Both have been successful in treating severe rheumatoid arthritis in patients who have failed to respond to normal disease modifying drugs. Infliximab has also been shown to be beneficial in crohn’s disease. The main side effect is reactivation of latent TB as TNF-alpha is very important in protection against TB. |
|
|
Describe cytotoxic and anti-proliferative agents .
|
Originally cytoxic and anti-proliferative agents were used solely for the treatment of cancer however they are now used to treat autoimmune diseases and to inhibit organ transplant rejection. The drugs are not specific to cells of the immune system but affect all proliferating cell types causing potential side effects of cytopenias, gi toxicities and reduced fertility.
|
|
|
Name the main 4 cytotoxic drugs.
|
Cyclophosphamide – toxic at all phases but mainly actively cycling than relaxing cells.
- Azathioprine – S phase - Methotrexate – S phase - Mycophenolate mofetil – blocks synthesis of guanine molecules - fairly specific for lymphocytes as they rely heavily on de novo generation of guanine whereas other cell types can syntehsise guanine via purine salvage pathways. |
|
|
List the immunological diseases treated for by cytotoxic drugs.
|
Organ transplant rejection, SLE, RA, systemic vasculiti, Wegener’s granulomatosis, polymyositis, membranous and membranoproliferative glomerulonephritis, inflammatory bowel disease.
|
|
|
Describe t cell selective immunosuppressants.
|
Cyclosporine and tacrolimus act as calcineurin inhibitors. Calcineurin is a phosphatase which activates the transription facto NFAT by dephosphorylation. The transcription factor then translocates to the nucleus where it stimuates the increases synthesis of IL-2 which is needed for T cell activation. Calcineurin inhibitors work by blocking the activity of nuclear factor of activated T cells ( NFAT), leading to the inhibition of transcription of the IL-2 gene and therefore inhibiting helper T cell responses. They are effective in inhibiting organ transplant rejection and in treating t cell mediated autoimmune diseases.
Rapamycin blocks a cellular protein called mTOR which inhibits IL-2 production. Rapamycin also has anti-proliferative effects and can be used to treat some cancers. |
|
|
What is IF-alpha used to treat?
|
Chronic myelogenous leukaemia, hairy cell leukaemia, follicular lymphoma, AIDS related karposi’s sarcoma, and in chronic infections with hepatitis B AND C
|
|
|
What is IF-beta used to treat?
|
Relapsing multiple sclerosis
|
|
|
What is IL-2 used to treat?
|
Metastatic renal cancer. However high concentrations can cause cytokine dysregulation resuling in capillary leak syndrome or autoimmune thryoid disease as they activate resting autroreactive cells
|
|
|
What is granulocyte colongy stimulating factor used to treat?
|
GCSF is used to mobilise granulocytes in neutropenia, or to increase bone marrow progenitor cells in the blood for harvesting prior to stem cell transplantation.
|
|
|
Describe the use of human gamaglobulin from pooled plasma donations.
|
Human gammaglobulin from pooled plasma donations can be used as replacement immunoglobulin therapy for patients with primary and secondary antibody deficiencies. (intravenous or subcutaneous injections of IgG). It can also be given intravenously to treat diseases that fail to respond to other forms of immunotherapy including Kawasaki disease, idiopathic thrombocytopenia, guillain-barre syndrome, chronic inflammatory demyelinating polyneuropathy.
|
|
|
Describe monoclonal antibodies
|
Monoclonal antibodies where originally created by fusing an antigen specific b cell clone with an immortalised plasma cell line producing large quantities of antigen specific antibodies in tissue culture. They were produced by hyper-immunizing mice with an antigen and then havesting and fusing splenic B cells. However the mice proteins were seen as foreign and destroyed so the monoclonal antibodies needed to be made unrecognisable by the host immune system. This is achieved by determining the amino acid residues that confer the antigen specificity of the monoclonal antibody and genetically engineering these into the relevant sites of a human antibody – humanized monoclonal antibody.
. |
|
|
Describe the differences between traditional pharmacological agents and monoclonal antibodies.
|
Traditional pharcological agents are small, non-specific, short acting, species independent, taken orally, given by GP, non-immunogenic and cheap.
Monoclonal antibodies are large, highly specific, act over a long period of time, species dependent, taken parenteral administration that involves piercing the skin or mucous membrane, given in hospital, potentialy immunogenic – provoke immune response an expensive. |
|
|
What T cell subsets are present in the blood?
|
T helper cells – TH1, th2
T cytotoxic cells Regulatory T cells |
|
|
Describe the mechanism of anaphylaxic shock.
|
Anaphylaxis is a severe form of type I hypersensitivity reactions. A presensitised individual is exposed to the antigen which causes high levels of IgE to bind to mast cells and cross link to cause degranulation. Systemic degranulation occurs, releasing histamine causing vasodilation, tissue oedema, airway obstruction, fall in blood pressure and shock. Adrenalin in an epipen must be injected into the thigh immediately
|
|
|
What is the typical autoantibody found in most patients with rheumatoid arthritis and what is its target antigen?
|
Rheumatoid factor is the autoantibody that targets the Fc region of IgG immunoglobulins which form immune complexes. It is only present in 70-80% of RA sufferers, so 30-20% are seronegative ( NO RF). It is not a specific marker because RF can be present without the patient suffering from rheumatoid arthritis.
It is more helpful to check for inflammatory markers. |
|
|
Describe leukotriene receptor antagonists.
|
Leukotrienes may contribute to asthma by induction of smooth muscle contraction, production of mucus, recruitment of inflammatory cells, promotion of inflammation and modulation of cytokine production. Leukotriene receptor antagonists include montelukast and zafirlukast and are used to treat asthma.
|
|
|
Describe sodium cromoglicate.
|
Sodium cromoglicate helps to stabilize the mast cell membrane, preventing mast cell degranulation. It may work by disruption calcium ion flux and or chloride ion transport across the cell membrane. Leukotriene receptor antagonists have replaced it as main non corticosteriodal treatment for asthma
|
