The immunobiology of autoantibody-mediated diseases of the central nervous system. (360G-Wellcome-104079_Z_14_Z)
The last five years have seen a dramatic increase in the number of patients diagnosed with autoantibody-mediated encephalitis. These diseases appear partially immunotherapy-responsive. The two commonest antibody targets are leucine-rich-glioma-inactivated-1 (LGI1) and the NMDA-receptor. LGI1-antibodies respond well to glucocorticoids over several months, whereas NMDAR-antibodies may only fall over several years despite multiple immunotherapies. The time-course of these reductions parallel the ra tes of clinical improvement. These differences are likely to be determined by the relative persistence of different antibody-secreting cell (ASC) populations. However, this hypothesis has not been addressed. First, this fellowship will use multicolour flow-cytometry to identify baseline and longitudinal populations of total, and antigen-specific, memory B-cell and ASC populations in patients with LGI1- and NMDAR-antibodies. This will establish their relative baseline characteristics in viv o, susceptibility to immunotherapies and relationships of these measures to clinical outcomes. Second, these cells will be cultured to determine which populations produce LGI1- and NMDAR-antibodies and, subsequently, which factors modulate antibody production and ASC survival. Finally, the plasma membrane proteomic profiles of the ASCs will be studied to identify surface markers which may be potential ASC-specific drug targets. Results should inform future B-cell therapeutics, trial de sign of autoantibody-mediated illnesses and the biology of multiple antibody-mediated diseases.
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Grant Details
Amount Awarded | 834107 |
Applicant Surname | Irani |
Approval Committee | Clinical Interview Committee |
Award Date | 2014-05-14T00:00:00+00:00 |
Financial Year | 2013/14 |
Grant Programme: Title | Intermediate Clinical Fellowship |
Internal ID | 104079/Z/14/Z |
Lead Applicant | Prof Sarosh Irani |
Partnership Value | 834107 |
Planned Dates: End Date | 2022-02-01T00:00:00+00:00 |
Planned Dates: Start Date | 2014-11-03T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | South East |
Sponsor(s) | Prof Angela Vincent, Prof Kevin Talbot, Prof Peter Rothwell |