The aging process has profound effects on the immune system, including a decrease in T cell responsiveness and an increase in circulating autoantibodies. We propose to use a mouse model of autoimmune myasthenia gravis (EAMG) to address the effects of aging on immunological tolerance. Myasthenia gravis (MG) is a disease that is characterized by muscle weakness due to autoantibodies directed against the muscle acetylcholine receptor (AChR). A similar disorder, Experimental Autoimmune Myasthenia Gravis (BAMG), can be induced in rodents by immunization with AChR from the electric ray, Torpedo californica. We have shown that 1) immunization with AChR leads to loss of muscle function, 2) the B cell response is heterogeneous, but only some of the antibodies are pathogenic, and 3) there is a predominance of antibodies of the IgG1 isotype. Although this disease etiology is caused by B cells, it is T cell dependent and the T cells are unusually restricted in specificity. In humans, early onset MG differs from late onset disease (>40 years of age) both physiologically and immunologically. We now propose to ask whether changes in T or B cells that naturally occur with age will alter the ability to elicit an autoimmune reaction in mice. Mice of three different ages will be immunized with AChR and the following questions will be addressed:
Aim I. Will the age of the animal affect its susceptibility to experimental autoimmune myasthenia gravis? Aim II. Will the age of the animal affect the titer, isotype, and repertoire of auto-antibodies (B cell)? Aim III. Will the age of the animal affect the T cells avctivated by immunization with AChR, with a particular emphasis on antigenic specificity and cytokine production? The data gained from these experiments will provide novel insights into the similarities and differences in immune responses and tolerance between young and old. This information will be critical in determining whether novel immune- based therapies can be successfully implemented in MG patients of all ages.
| Stacy, Sue; Williams, Earlanda L; Standifer, Nathan E et al. (2010) Maintenance of immune tolerance to a neo-self acetylcholine receptor antigen with aging: implications for late-onset autoimmunity. J Immunol 184:6067-75 |
| Standifer, Nathan E; Stacy, Sue; Kraig, Ellen et al. (2007) Discrete T cell populations with specificity for a neo-self-antigen bear distinct imprints of tolerance. J Immunol 178:3544-50 |
