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IMM430 - March 26, 2013.docx

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March 26, 2013 FINAL – ALL lecture notes; questions weighted 20 marks worth of questions for lectures after midterm, 10 marks for lectures before midterm; only responsible for papers AFTER the midterm Newly discovered autoimmune disorder “Brain on Fire” – Suzanna Callahan - More psychotic symptoms, seizures – more and more bizarre behaviour - Physical symptoms – passing out while in hospital – put in epilepsy ward, where videos taken Josep Dalmau – speciality in autoimmune condition that beings as tumour – instead of immune system reacting against self-antigen, reacts first against tumour and then has immune response cross-reacting against other proteins in the body In all patients seen, female – with ovarian tumour – well-differentiated tissue – Case series vs case report – if clinician seen something interesting, one then case report; if have number of patients with same symptoms, case series Immunobiology of disorder - not a lot known about this disorder Treated as autoimmune disease – nature of target antigen – teratoma expressing self-antigens What part of the immune system is responsible for causing the damage? Type 2 cateogry – where antibodies are responsible for pathology Nature of the immune response and some of the outstanding question from clinical and immunological realm Patient CSF – oligoclonal banding in some patients – high protein content also in CSF, suggesting target is central nervous system – if in CSF, antibodies that are autoreactive and bind to neuronal tissue – took CSF from patients and took rat brain sections and probed sections with patient CSF – so if had antibodies, would bind rat brains ection – used anti-humanIg conjugate to see if would bind antibodies – if positive signal, antibody ble to bind brain section See hippocampus had strong positive signal, suggesting antibodies in CSF that is binding something in hippocampus – and also faint staining in forebrain And no staining in cerebellum – negative control NMDA receptor enriched in hippocampus Able to show through both merging binding of CSF on cells and commercial antibodies susceptible to NMDA receptor – suggesting staining in the same place NMDA receptor that these antibodies were targeting – Ketamine – depressant Dose of inhibiting the receptor causes different responses NR1 receptor is target – NMDA important for memory and learning THEREFORE why Susannah unable to remember Know that NMDA receptor primarily concentrated in CNS so how does immune system able to recognize something that is normally behind the blood brain barrier? In MS, unknown this – but potentially virus could infect cell in body and maybe have epitope resembling myeline and get T cells activated – which go into brain an dstart autoimmune process Patients have teratoma – Benign tumour – contains all germ laeyrs so can form anything Chop up tumour – show neuronal antigen expressed there – did not show that NMDA receptor expressed in the tumour Autoantibodies induce NMDAR internalization – basic studies – rat hippocampal neurons incubated with patient CSF – autoantibodies purified from antibodies from patient CSF – what antibodies were doing to the receptor – causing receptor to be internalized, downregulating the expression The NMDAR being the autoantigen also makes sense in light of clinical signs – ketamine is an antagonist – lower doses cause psychotic behaviourl; high er does affects breathing, heart rate, etc. Autoantibodies – CSF > sera Presence of antibodies in CSF – higher levels of antibodies in CSF compared to serum (blood) Immune response may be in the peripheral bu thte causal cells, B plasma cells producing antibodies, have trafficked into CNS and source of antibody seems higher in brain Those with tumour have higher antibodies – showed that tumour removal helpful to the patients Biopsy from NMDAR patient – when Susannah was in hospital – got biopsy – showed that immune cells present in the brain, suggesting autoimmune disorder Vascular cuffing – lesions – T cells coming in from periphery surround blood vessels, clue that immune cells going into CNS from periphery – compared to MS, most of the immune cells CD3 0- T cells CD68 macrophages CD20 – B cells In MS, mostly T cells and macrophages, whereas this disease is B cell-mediated Autoantibodies can fix complement – can these antibodies fix complement – may
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