Myasthenia gravis (MG) is a progressive autoimmune disorder in which patients develop severe muscle weakness which worsens with fatigue. The symptoms are due to autoantibodies directed against acetylcholine receptors (AChR) located at the neuromuscular junctions. For many MG patients (40-60%), disease onset occurs after the age of 40. In addition, thymus cellular abnormalities and/or thymomas (tumors) are found in more than 70% of MG patients, suggesting that the thymus plays a role in disease progression as well. Since the thymus is the site of T cell maturation and is responsible for eliminating 'self' reactive T cells, it is possible that MG arises due to thymic deficiencies in maintaining immune tolerance. Given that the thymus involutes with aging, we hypothesize that immune dysregulation associated with the loss of thymic controls may play a role in late onset MG and in other autoimmune disorders in the elderly. The current application is focused on assessing why immunity and autoimmunity are differentially affected by aging, determining the role of the thymus in establishing and maintaining tolerance to self AChR, and testing potential therapeutic targets in a novel late-onset model of MG. Experiments in Aim I will focus on antibody responses to self versus foreign determinants in the murine model of MG. Using previously collected sera from mice immunized with the acetylcholine receptor from Torpedo californica, ELISAs will be used to assess the titers of antibodies that recognize 'self', mouse AChR, relative to reactivities to the foreign protein, Torpedo AChR.
In Aim II, we will ask directly whether the thymus is required for generating tolerance to AChR. Thymic grafts will be performed onto nude (athymic) mice in order to generate animals which express the TAChR transgene only in thymus, only in muscle, in both tissues, or in neither. These chimeric animals will be immunized and the level of T cell tolerance (lack of proliferation) will be measured. We will also focus on AIRE, the autoimmune regulator, a transcription factor that controls expression of peripheral antigens in the thymus. We will determine whether AIRE is involved in the regulation of AChR, and if so, whether AIRE knock-out mice are more susceptible to autoimmune MG.
Aim III is designed to test therapeutic approaches previously explored in young mice in our novel late onset MG model. We will be able to ask, for the first time, whether immunotherapies for MG will be effective in older individuals. In summary, we are uniquely positioned to elucidate the effects of aging on tolerance and immunity to AChR, the autoantigen in MG. The results of the proposed studies may provide novel insights into other autoimmune disorders with late onset disease etiologies, including Sjogren syndrome, idiopathic inflammatory myopathy, and pernicious anemia. Using both the novel TAChR transgenic mouse model and the first model of late-onset Myasthenia gravis (MG), our laboratory is uniquely positioned to elucidate the effects of aging on tolerance and immunity to AChR, the autoantigen in MG. ? ? The results of the proposed studies may provide novel insights into other autoimmune disorders with late onset disease etiologies, including Sjogren syndrome, idiopathic inflammatory myopathy, and pernicious anemia. Understanding the mechanisms of tolerance to self proteins and the disruption of these processes by thymic involution and/or age-associated immune dysregulation is a crical first step in developing novel therapeutic approaches. ? ? ?
| 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 |
