Department of Medicinal & Biological Chemistry : Katherine A. Wall

Institutions/Degrees

Immunology and biochemistry; molecular analysis of the autoimmune disease myasthenia gravis using a murine model system; design of immunomodulatory drugs.

Research Interests

My major research interest is in the autoimmune disease myasthenia gravis. I have focused on myasthenia gravis as a model system because the autoantigen is known (the nicotinic acetylcholine receptor) and because genetically well-defined animal models of disease susceptibility are available. During the past fifteen years, my collaborators and I have shown that the T cell response to the Torpedo acetylcholine receptor in disease-susceptible C57Bl/6 mice is limited in diversity. The response is dominated by T cells defined by a shared fine-specificity (residues 146-162 of the receptor), their use of the Vß6 gene segment to form the T cell receptor, and by common amino acids in the antigen recognition region of the T cell receptor. Elimination of these cells reduces disease susceptibility and may serve as a model for disease therapy. We have defined the requirements for peptide binding to I-Ab. Residues responsible for T cell recognition and antagonism have been identified and antagonist peptides have been made.

We have also shown that cytokines that favor a Th1 type (inflammatory) immune response enhance disease in this model. This was different than what was predicted for an antibody-mediated autoimmune disease. We have recently shown that inflammatory cytokines such as interleukin-12 and interferon-gamma can affect how muscle tissue responds to antibody attack. We are currently examining the mechanism of cytokine enhancement of disease in passive transfer models of myasthenia. Detailed knowledge of these processes may provide another avenue for therapeutic intervention.

Representative Publications

1. A disease-related epitope of Torpedo acetylchone receptor: residues involved in IAb binding, self-nonself discrimination, and TCR antagonism. K. A. Wall, J.-y. Hu, P. Currier, S. Southwood, A. Sette, and A. J. Infante. J. Immunol. 152:4526-4536, 1994.
   
   
2. Restricted T cell receptor repertoire for acetylcholine receptor in murine myasthenia gravis. E. Kraig, J. L. Pierce, K. Z. Clarkin, N. E. Standifer, P. Currier, K. A. Wall, and A. J. Infante.. J. Neuroimmunol. 71: 87-95, 1996.
   
   
3. Inhibition of the intrinsic NAD+ glycohydrolase activity of CD38 by carbocyclic NAD analogues. K. A. Wall, M. Klis, J. Kornet, D. Coyle, J.-C. Amé, M. K. Jacobson, and J. T. Slama. Biochemical J. 335: 631-636, 1998.
   
   
4. Interleukin-12 enhances clinical experimental autoimmune myasthenia gravis in susceptible but not resistant mice. S. Sitaraman, D. W. Metzger, R. J.Belloto, Jr., A. J.Infante, and K. A. Wall. J. Neuroimmunol. 107: 73-82, 2000.
   
   
5. Split tolerance in a novel transgenic model of autoimmune myasthenia gravis. S. Stacy, B. Gelb, B. A. Koop, J. J. Windle, K. A. Wall, K. A. Krolick, A. J. Infante, and E. Kraig. J. Immunol. 169: 6570-6579, 2002.
   
   
6. Recall immune memory: A new tool for generating late onset autoimmune myasthenia gravis. S. Stacy, A. J.Infante, K. A. Wall, K. Krolick, and E. Mechanisms of Ageing and Development 124: 931-940, 2003.
   
   
7. Passive experimental autoimmune myasthenia gravis with mAb35 is enhanced by IL-12 and requires IFN-?. S. Yim, M. Klis, A. J. Infante, and K. A. Wall. Submitted, 2004.