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37 Cards in this Set
- Front
- Back
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Describe the role of antigen receptors in the autoimmunity
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- The role of the immune system is to recognise and eliminate 'non-self' and the adaptive arm does this via specific receptors for antigen
- These receptors (BCR, TCR) do not pre-exist, but are generated during lymphocyte development through a random recombination between gene fragments in the stem cell genome - Because of this random process, receptors to 'self' are just as likely to develop as receptors for 'non-self' - Cells bearing receptors to self are eliminated or rendered inactive = this process leads to self-tolerance, which means no response to self - However, self tolerance is never complete, and may be broken, resulting in atuoimmuntiy |
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What are the 2 mechanisms of tolerance?
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1. Central tolerance = cells bearing self-reactive receptors are eliminated during their differentiation
2. Peripheral tolerance = cells bearing self-reactive receptors mature and are released into the periphery but are (generally) unable to respond to self antigen (it is these cells that potentially generate autoimmunity) (3. Acquired tolerance) |
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Describe the generation of central tolerance of T-cells
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- Pre-T cells derived from bone marrow differentiate in the thymus to develop their unique TCR, and when mature enter the periphery
- About 98% of developing T-cells die in the thymus - Those cells that die include self-reactive cells: immature T-cells that bear TCR for self antigen undergo apoptosis when they encounter self antigens (they bind too strongly to the MHC, stimulating apoptosis) - This is referred to as negative selection or clonal deletion, because the dead cell will not proliferate to form a clone of the self-reactive T-cell - This implies that all tissue antigens are present in the thymus so that the immature cell can be eliminated by them. There is evidence that thymic epithelial cells do express the entire proteome - but recent evidence suggests that some tissue-specific proteins may not be expressed, mean that negative selection cannot take place. |
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Describe the generation of peripheral tolerance of T-cells
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- Some self-reactive cells escape deletion and enter the periphery
- These generally do not respond to self because a further set of regulatory T-cells (Treg cells CD4+CD25+) block their activation |
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Describe the generation of central tolerance of B-cells
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- B-cells are born in the bone marrow where their antigen receptors are generated but complete their maturation in the periphery
- As with T-cells, 95% of B-cells die before maturing - Immature B cells will die when they encounter their antigen, either in the BM or the periphery, without appropriate stimulation from T-cells |
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Describe the generation of peripheral tolerance in B cells
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- Absence of T-cell help means that self-reactive B cells cannot be activated
- Consequently, when they meet their Ag apoptosis is triggered |
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What is acquired tolerance?
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- If the foetus or neonate is exposed to non-self antigen (e.g. hepatitis B virus) this is treated by the immune system as self, and so no immune response develops → chronic infection
- IF the adult is given repeated small doses of an antigen tolerance may be induced e.g. desensitisation may be done for serious allergies |
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How might tolerance be broken?
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- Difficult to study the early stages as early development is silent and symptoms only develop when there is major tissue damage e.g. diabetes and pancreatic B cells
- Widely held theory is that self-reactive T cells to a particular antigen are activated and initiate some tissue damage. As this progresses, because of the inflammation and the release of tissue antigens not usually present in the EC space, more and more self-reactive clones bot of T and B cells become involved. This is known as epitope spreading - This idea is backed by the strong association between particular HLA genes and particular autoimmune diseases = there are amny HLA alleles and the protein product of some combines more specifically with particular antigens than others. Therefore, if a particular HLA is associated with a particular disease, that implies a specific triggering antigen |
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How is infection involved in autoimmunity?
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- Genetics is an important part of autoimmunity because of HLA associations but disease concordance between twins is much less that 100%, suggesting environmental factors
- Infection may trigger the breaking of tolerance in 2 ways: 1. molecular mimicry = response to a cross-reactive pathogen (i.e. pathogen antigen is similar to self antigen) 2. Bystander effect = highly inflammatory environment causes the breaking of peripheral self-tolerance - Evidence: → many infections generate self-limiting polyarthropathies → infection can exacerbate AI disease → some clear examples e.g post strep and rheumatic fever, but these are rare - However, for the common AI disease there is no clear link between infection and disease, but the triggering infection may have occurred years ago and such diseases may be rare consequences of common infections due to genetic predisposition |
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What is autoimmunity?
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An immune reaction to self
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What is autoimmune disease?
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Clinical disease/pathology resulting from autoimmunity
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What is the prevalence of autoimmune disease?
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Approximately 5% of the population - most are more common in women
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What are the 2 classifications of autoimmune disease?
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1. Organ specific: immune response directed against local antigens e.g.Grave's disease
2. Systemic - multisystem: immune response directed against widespread target antigens e.g. RA |
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What is Graves disease?
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- Autoimmunity to the thyroid gland
- Antibodies to TSH receptors stimulates thyroid gland and produces proptosis |
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What parts of the immune system are involved in autoimmunity?
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- B cells = autoantibodies
- T cells = auto-reactive T cells - Cytokines = activate other cells of the immune system - Complement = hereditary complement. Deficiencies associated with autoimmunity (rare) |
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What is the evidence that B-cells are involved in autoimmune disease?
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1. Antibodies transfer disease to infants of affected mothers e.g. neonatal lupus = usually cleared from baby's circulations and rash disappears ~8 weeks
2. Antibodies can be identified at sites of damage e.g. SLE-renal biopsies |
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What is the evidence that T-cells are involved in autoimmune disease?
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1. CD4 lymphocytes identified at sites of tissue damage
2. HLA associations of autoimmune disease 3. Actions of immunosuppressive drugs (and subsequent alleviation of symptoms) |
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Describe 4 mechanisms of autoimmunity
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1. Inappropriate triggering of immune response →
- inappropriate access of self-antigens to APCs - inappropriate local expression of co-stimulatory molecules - alterations in the way self-molecules are presented to the immune system - e.g polyclonal activation, EBV (glandular fever), or hepatitis C infection 2. Molecular mimicry → structural similarity between self-proteins and those from micro-organisms may trigger an AI response e.g. rheumatic fever 3. Failure to delete/supress auto-reactive cells e.g. failure of apoptosis in SLE 4. 'Immune privilege' → hidden antigens behind anatomical barriers e.g. blood-brain barrier, eye = penetrating injury to the eye can result in a immune reaction to the other unaffected eye 1-2 weeks after injury ('sympathetic ophthalmia') |
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Describe 3 environmental factors involved in autoimmunity
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1. Infection
- AI disease may be triggered by an infection e.g. rheumatic fever - Pre-existing AI diseases may be aggravated or reactivated by infection - But not everyone who gets an infection gets AI disease 2. Hormones - Most AI disease are more prevalent in women, often during their reproductive years - But men also get AI disease 3. Drugs - Structural alteration to self antigen - E.g. halothane = anaesthetic agent. Metabolic products of halethane bind to liver enzymes, resulting in the formation of a neoantigen which stimulates B and T cells and causes hepatic necrosis |
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Describe the genetic factors associated with AI disease
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- HLA genes have strong associations with AI diseases
- Class II antigens expressed on APCs - Class II associations with diseases e.g. rheumatoid arthritis = HLA DR1 and DR4, ankylosing spondylitis = HLAB27 in 97% |
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Give an example of when autoimmunity can be beneficial
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- Accumulating evidence that autoimmune reaction to tumour cells may play a role in controlling/killing cancer cells e.g. malignant melanoma
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Describe the features of rheumatoid arthritis
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- A systemic chronic inflammatory disease affecting the joints = usually symmetrical
- Present in ~1% of the population - Female to Male 3:1 - Age onset peak 20-50 years - Associated with HLA DR4 and DR1 - 75% present with rheumatoid factor = an autoantibody - Pathological damage to tissues by the immune system - Suppression of the immune system improves the disease |
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Describe the aetiology of rheumatoid arthritis
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1. Genetic
- HLA associations - 90% patients with RA have 'shared epitope' - HLA region chromosome 6, DR1 or DR4 → predisposition - However, only 4% of non-identical twins both get RA, suggesting that must be environmental factors 2. Environment - Hormones - female sex (but males do get it too) - May be virus induced |
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Describes the investigations for suspected rheumatoid arthritis
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'Inflammatory markers'
1. Erythrocyte sedimentation rate (ESR) = will raise both in infections and in AI disease 2. C-reactive protein 3. Rheumatoid factor |
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What is rheumatoid factor?
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- IgM directed against the Fc portion of IgG molecule → autoantibody
- RF presents in ~75% of patients with RA - Presence of RF associated with more severe disease - However, 10% of the asymptomatic population also present with RF, and is far more likely to present if elderly so may only be truely useful in the young - Also, RF may present in infections e.g. endocarditis, hepatitis, and tuberculosis, and in lung diseases e.g. chronic bronchitis, silicosis |
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Describe the 4 stages of rheumatoid arthritis pathogenesis
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1. Antigen presentation to T-cells = no symptoms and X-rays normal
2. T and B cell proliferation and angiogenesis in the synovium - Symptoms: malaise, mild joint stiffness, swelling - Findings: swelling or pain of small joints, wrists and knees. Normal X-rays 3. Synovial fluid (SF) polymorphic neutrophils (PMN) accumulation and synovial cell proliferation - Symptoms: Joint pain, swelling, AM stiffness, malaise and weakness - Findings: Warm, swollen joints including SF, soft tissue proliferation, limited range of movement, nodules, soft tissue swelling on X-ray 4. Synovial proliferation - Symptoms: loss of function - Findings: Erosions on X-rays |
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Other than the joints, where else may rheumatoid arthritis effect?
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- Eyes: scleritis, dry eyes (secondary Sjogren’s syndrome);
- Lungs: pulmonary fibrosis, rheumatoid pulmonary nodules, pleural effusions; - Skin: rheumatoid nodules, leg ulcers, vasculitis; - Haematological system:, Chronic anaemia, Spleen-enlargement (Felty’s syndrome); - Central nervous system: cervical cord compression due to subluxation/dislocation at upper cervical spine segments (C1/C2, atlanto-axial dislocation); - Skeletal system: osteoporosis. |
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Describe the management of rheumatoid arthritis
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- Treat symptoms with anti-inflammatory drugs e.g. diclofenac
- Treat with immunosuppressive drugs → corticosteroids = suppress all cells of the immune system e.g. prednisolone → Methotrexate and azathioprine = inhibits cell proliferation → BIological agents: MAbs to TNF = inhibit TNF actions, powerful immunosuppressive |
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What is TNF and how can anti-TNFs aid RA treatment?
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- Tumour necrosis factor
- Pro-inflammatory cytokine produced by macrophages - TNF activates macrophages, neutrophils and T-cells - Blockade of TNF suppresses inflammatory response - Anti-TNFs improve pain, stiffness and joint erosion in RA, and halts bone erosion on x-ray - However, costs £9000 per patient per year |
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What is Type I diabetes mellitus?
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- An organ specific autoimmune disease
- A state of chronic hyperglycaemia sufficient to cause long-term damage to specific tissues, notably the retina, kidney, nerves and arteries - T cell destruction of the beta cells of the pancreas resulting in insulin deficiency - Onset juvenile/young adult - Median age 12 |
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What evidence is there that type I diabetes mellitus is autoimmune?
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- Pancreas of newly diagnosed patients infiltrated by Tc cells
- Circulating Abs to islet cell - 85% newly diagnosed patients - HLA associations = HLA DR3 or DR4 present in >90% of patients with type I DM (but also present in 35% of the population) - Association with other autoimmune diseases e.g. Addison's diseases (autoimmune destruction of the adrenal gland) |
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Describe the theories of pathogenesis of type-1 diabetes mellitus
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- Infectious or environmental agent damages pancreas
- In genetically susceptible individuals = autoimmune - T and B cell response to B cells - Irreversible destruction of B cells → insulin deficiency - Subsequent tissue damage e.g. renal, nerves resulting from chronic hypoerglycaemia |
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Describe the management of Type-1 diabetes
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- Only presents once the damage has occured = 95% of pancreas must be knocked out before hypoerglycaemia
- Too late for immunosuppression - some evidence that ciclosporin ( a T cell suppressor) may slow disease progression in early disease - Replace insulin = complex and variable - Tight control of glucose levels to prevent tissue damage |
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What is multiple sclerosis?
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- A chronic inflammatory process of the central nervous system resulting in demyelination and loss of function
- Damage to the nervous tissue by inflammatory cells - May be an organ specific inflammatory disease = immune response to CNS tissue - MR scans of brain and spinal cord of MS patients show white-matter plaques = scarring of long-term inflammation |
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Describe the aetiology of MS
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1. Genetic
- Identical twins = 35% prevalence - HLA assocation DR 15 and DQ6 2. Environmental - Found in Northern Europe (perhaps due to lack of sunlight and vitamin D?) - No infection organisms identified |
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Describe the theories of pathogenesis of MS
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- Occurs in the brain of MS patients
1. Plaques - Infiltration of T cells (Th (CD4) and Tc (CD8)), B cells/plasma cells and monocytes/macrophages 2. CSF - Elevated levels of immunoglobulins - mostly IgG (indicating that must have been stimulated). - Used as investigation of MS (oligoclonal bands = 4-5 antibodies produced) |
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Describe the management of MS
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- Depends on the subtype of MS
- Relapsing/remitting disease → immuno-manipulation - Corticosteroids - Cytokines e.g. beta-interferon controversial - Anti-TNF seems to worsen MS |
