DETERMINANTS OF DISEASE IN EXPERIMENTAL MYASTHENIA GRAVI

Project: Research project

Project Details

Description

DESCRIPTION: Experimental autoimmune myasthenia gravis (EAmyasthenia gravis) in Lewis rats involves a neuromuscular impairment caused by a T cell dependent antibody response against the post-junctional acetylcholine receptor (AChR). The result is weakness and rapid onset fatigue in the rats very similar to AChR symptoms observed in human patients with myasthenia gravis (myasthenia gravis). However, although anti-AChR antibodies appear to be the direct cause of neuromuscular dysfunction in human patients, it has been observed that there is a disturbing lack of correlation between the titer of circulating antibody and the severity of symptoms demonstrated. Thus, in order to identify more useful relationships between anti-AChR antibody and disease, the overall goal of the proposed study is to define, in the EAmyasthenia gravis model system, those parameters that dictate when autoimmunity translates into pathology. Advantage will be taken of two rat strains that appear to mimic the human scenario in which high antibody titer in one individual translates into severe disease, while high antibody titer in another individual translates into mild or no disease. In other words, the principal investigator intends to ask why, even though both Lewis and Wistar Furth rat strains are equally efficient at producing such antibodies, is disease susceptibility observed on the one hand (in Lewis rats) and disease-resistance observed on the other hand (in Wistar Furth rats). The basic premise of this research proposal is that some, but not all, anti-AChR antibodies can cause disease (perhaps related to differences of the exact binding specificity of the antibodies produced). Therefore, the primary goal of the proposed study is to develop means by which past observations made by the principal investigator's laboratory can be clarified indicating that disease severity in EAmyasthenia gravis in Lewis rats is directly determined by the responsiveness of a small subset of the total population of AChR-responsive B cells. Thus far, the disease-causing subset of rat B cells has been found to be associated, at least in part, with an idiotypic determinant recognized by a monoclonal anti-Id antibody (11E10) recently prepared in this laboratory. Identifying and characterizing 1) specific clonotypic/idiotypic subsets of anti-AChR antibody that are most directly responsible for inducing disease symptoms in EAmyasthenia gravis and 2) the influence of immunodominant subsets of regulating helper T cells may point to more direct strategies for diagnosing and monitoring disease in humans, and may also provide new, more selective, targets for future immunotherapies.
StatusFinished
Effective start/end date5/1/974/30/02

Funding

  • National Institutes of Health: $174,692.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $183,315.00
  • National Institutes of Health: $11,789.00

ASJC

  • Medicine(all)
  • Neuroscience(all)

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