4254235
Descripción
Fichas por Amber Jade Lewis, actualizado hace más de 1 año
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Creado por Amber Jade Lewis
hace casi 9 años
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| Pregunta | Respuesta |
| How is self tolerance generated? | Self-reactive lymphocytes are removed |
| What four criteria to autoimmune diseases follow? | 1) Demonstrate immunological reactivity to a self-antigen 2) Characterize initiating auto-antigen 3) The immunological reactivity can be induced in animal models 4) Can show the pathological changes in the appropriate organs and tissues |
| What is experimental autoimmune encephalomyelinitis (EAE)? | Mice injected with basic proteins and Frueds adjuvent develop EAE and are paralysed Disease is mediated by myelin basic protein specific Th cells and the disease is transmitted with T-cells |
| What is autoimmunity? | An immune response against a self-antigen leading to tissue damage or disturbed function, autoimmune diseases occur when tolerance breaks down |
| What gender are autoimmune diseases more prevalent with? | Females |
| Where does T-cell tolerance occur | Central Thymus - selects out the useful t-cells and destroys the others |
| How does positive selection of T-cells occur? | T-self which recognise self MHC molecules proceed to full maturation |
| How does negative selection of T-cells occur? | T-cells which do not recognise self MHC or which do but bind with high affinities are selected and die by apoptosis |
| Why is thymic education only partially successful? | Some t-cells bind with low affinities to self MHC and avade apoptosis |
| What occurs in mutations of AIRE (genes which expresses self-proteins in the thymus)? | Leads to rare autoimmune disease APECED |
| Where does central B-cell tolerance occur? | B-cells are testing for autoimmunity in the bone marrow |
| What happens to multivalent self molecules? | Removed by apoptosis |
| What happens to low affinity self reacting b-cells? | Will escape apoptsis but are generally removed by peripheral tolerance |
| What happens in somatic hypermutation of the peripherary? | Generates autoreactive immune B-cells |
| What occurs in peripheral tolerance? | Immunological ignorance Anergy Suppression |
| What is immunological ignorance? | Self-antigens and lymphs are separated by restricted routes of circulation Naive lymphs are limited to secondary lymphoid tissue and blood Debris from cell tissue is rapidly cleared and destroyed Apoptopic cell death doesn't create danger signals and cell content leakage Scavenger mechanisms are induced Anti-inflammatory environment |
| What is anergy? | Niave CD4 cells need two signals to become activated; an antigen specific signal and a non-specific costimulatory signal (CD28) If no costim signal occurs then stimulated TCR leads to either apoptosis or state of unresposiveness = ANERGY |
| What happens to anergic cells? | They are excluded from lymph nodes and eventually die |
| How are co-stimulatory signal molecules regulated? | Tightly controlled to specialised APCs |
| Where does interaction with Naive t-cells usually occur? | In the secondary lymph nodes |
| What is suppression? | Where self-reactive t-cells are actively supressed by inhibitory populations of t-cells (t-regs) |
| How do CD4+ and CD25+ cells supress? | They derive from the thymus and supress other t-cell proliferation (when depleted autoimmune diseases develop) |
| When CD4+ and CD25+ molecules are given to animal participants what diseases ameliorate? | Type 1 diabetes MS Inflammatory bowel disease |
| How is tolerance broken down? | Inappropriate access to self-Ags by APCS Innapropriate expression of co-stim molecules Aberrant MHC II expression (more common in tissue damage and inflammation) Increased activity of proteolytic enzymes in inflammatory sites can lead to high concentration of peptides being shown to t-cells Self-peptide structure altered by viruses, free radicals and radiation |
| What happens when the tolerance barrier is broken? | Becomes much easier to maintain |
| Name an example of post-translational modification? | Citrullination - Augiune to citrulline conversion |
| When does citrullemination occur? | Inflammation dependent Can lead to t-cells binding to self-antigens |
| In which diseases is citrullination seen? | Rheumatoid arthiritis MS |
| What is molecular mimicry? | Structural similarities between self-proteins and microbial antigens triggering an autoimmune response |
| When does molecular mimicry occur? | When b cells clonally expand (somatic hyper-mutation) new antibodies are generated Similarities between these antibodies and pathogen epitopes can arise |
| Give an example of molecular mimicry? | DNA Heat shock protein E.coli similar to HLA-DRB chain leading to RA |
| What is epitope spreading? | Molecular mimcry can lead to epitope spreading Autoreactive t-cell responses to progressively less dominant epitopes are activated as consequence of release of other antigens |
| Name an example of epitope spreading? | MS Immunisation with a single peptide found in myelin can lead to widespread inflammation, starting immune response against MBP leads to MOG and PLP |
| Do genetic factors contribute to autoimmune diseases? | Yes, twin studeis confirm genetic contribution in all autoimmune diseases known Multiple autoimmune diseases can cluster within families, subclinical autoimmunity is common among family membranes |
| What are the strongest genetic associations? | Involved alles of HLA/MHC DR2- Risk Goodpasture syndrome DR4 - Insulin dependent diabetes |
| What mechanisms lead to autoimmune diseases? | Tissue damage Auto-immune antibodies |
| How does tissue damage lead to autoimmune disease? | Tissue damage can be mediated by antibodies, immune complexes, CD4 cells and macrophages |
| How do auto-immune antibodies lead to disease? | By binding to hormone receptors (Graves disease) and neurotransmitter receptors (they can mimic or block ligand action) |
| What is systemic lupus erythematosus (SLE)? | SLE is a disorder of immune regulation (unknown cause) charaterized by the breakdown of tolerance to self nuclear cytoplasmic and cell surface molecules (autoantibodies) |
| What does SLE result in? | Results in generalized autoimmunity manifested by multi-system chronic inflammatory disease. The antibodies are not confined to one area, some react with DNA and nuclear constituents |
| What are the pathological changes in SLE? | Widespread changes Immune complexes deposited in small membranes and blood vessels Target organs include skin (butterfly rash), glomeruli in kidneys, joints, serous membranes and blood vessels |
| Are antibodies cause or consequence of SLE? | Neutrophils clear bacterial disease and release chromatin leading to autoimmunity OR In SLE neutrophils undergo abnormal NET formation in response to antibodies Increased NET formation may result in excessive dsDNA release leading to autoimmunity |
| What is Multiple Sclerosis (MS)? | Recurrent inflammatory attacks involving CNS white matter (myelin) |
| What is the incidence of MS? | Female to Male ratio 2:1 Age of onset 20-40s 1/3 of patients present with relapsing-remitting MS and progress to chronic disabilities |
| What are the symptoms of MS? | Visual disturbance Loss of sensation and coordination Bowel and bladder incontinence Fatigue and muscle weakness |
| What is the major hallmark of MS? | Hallmark of MS is the plaque (area of myelin loss) immune infiltration and astrocytic scarring |
| What causes MS? | Exact causes unknown Immunogenic Environmental (geographic) Viral Genetic Vitamin D and possibly trauma induced |
| What happens during the inflammatory phase in MS? | Leukocytes are recruited to CNS where they target oligodendrogial cells Resident microgilia also present auto-antigens to t-cells Once blood/brain barrier breached further inflammatory cells accumulate in white matter |
| How is MS diagnosed? | MRI scans detect demyelination Oligoclonal bands in CSF (intrathecally produced antibodies) Presence of autoantibodies to nuclear proteins/ dsDNA/ cytoplasmic proteins are useful diagnostic targets |
| What is the anti-nuclear antibody test (ANA)? | Patients serum is applied to cultured human cell line (normal antibodies won't bind), bound antibodies detected using anti-human IgG linked to flurophore. Staining pattern is characteristic to target |
| Why is the staining in ANA's important? | Pattern helps identify some exact nuclear targets which constituently appear in particular diseases In some patients more than one stain will be seen due to disease crossover |
| What staining patterns are seen in SLE? | Cell nucleus stained homogenously positive in SLE patients (target dsDNA, histones and nucleosomes) ELIZA can differentiate Rarely antibodies will only stain some cells (due to antibodies to cell cycle cyclins) |
| What staining pattern is seen in Sharp syndrome? | U1 ribonucleoprotein (spliceosome) staining but no dsDNA staining |
| What staining is seen is Sjogrens Syndrome? | Presents with freckled nuclear staining of SS-A(RO) and SS-B(LA) (some staining might be indicative of SLE) |
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