MeCP2-duplication/triplication syndrome is a devastating neurodevelopmental disorder mostly affecting boys and is caused by duplication (or triplication) of the region in the X-chromosome containing the gene encoding MeCP2 (methyl-CpG-binding protein 2). MeCP2 binds to methylated CpG sites on DNA and recruits transcription complexes to modulate gene expression. Because MeCP2 modulates a multitude of genes, it is not surprising that pinpointing specific functions has proven difficult. In additio to MeCP2-duplication syndrome, loss-of-function mutations in MeCP2 account for about 96% of Rett Syndrome cases, another devastating neurodevelopmental disorder that is typically seen in girls. Because of the strong neurologic component seen in both Rett and MeCP2-duplication syndromes, MeCP2 was long assumed to be primarily important for neurons. However, recent studies have shown that other cells, such as astrocytes and microglia in Rett syndrome, and T cells in MeCP2-duplication syndrome, also play a significant role. This understanding opens up the possibility for treatment modalities beyond direct neuronal intervention, which has been a problematic approach due to the complexity and risk involved in any manipulation of neurons themselves. Here, we propose to test the hypothesis that MeCP2 overexpression causes defects of adaptive immunity that lead to excessive, pathologic innate inflammation, ultimately contributing to morbidity and mortality. Preliminary data in MeCP2Tg3 mice, which overexpress MeCP2 at 3-5 fold normal levels, reveals that as disease progresses, peripheral organs undergo significant weight loss associated with gross pathologic appearance and immune infiltrates. However, immune-privileged organs (brain and testes) are protected from these changes. This suggests that a peripheral destructive immune process is contributing to pathology in MeCP2Tg3 mice. In addition, MeCP2Tg3 mice have significantly increased mortality from influenza infection. In an influenza model, MeCP2Tg3 mice exhibit a deficient CD8+ T cell response and excessive innate inflammation without an apparent defect in viral clearance;we intend to test the hypothesis that CD8+ T cell defects result in a compensatory increased innate response, which causes pathology leading to increased death.
The first aim i s to test the hypothesis that dendritic cell malfunction contributes to defects of the adaptive immune response using both in vitro and in vivo assessment of antigen presentation and T cell activation.
The second aim i n this proposal will test the hypothesis that a deficient CD8+ T cell response contributes to increased mortality in MeCP2Tg3 mice via an excessive innate immune response. This will be tested by in vitro assessment of CD8+ T cell function and in vivo assessment of CD8+ T cell response to influenza.
The third aim i s to ameliorate death from influenza in MeCP2Tg3 mice via either bone marrow transplant or suppression of the excessive innate inflammation. Ultimately, results obtained from this work may lead to immune-based treatment strategies for patients with MeCP2-duplication syndrome.

Public Health Relevance

Recurrent infections are a major cause of suffering and death in MeCP2-duplication syndrome patients, the majority of whom are young boys. Treating these infections is difficult, and the reason for this is poorly understood. This project is focused on understanding why MeCP2-duplication syndrome patients are at risk for life-threatening infections and inflammation, and will potentially lead to immune-based treatments for these patients

National Institute of Health (NIH)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Prograis, Lawrence J
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University of Virginia
Schools of Medicine
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Cronk, James C; Derecki, Noel C; Litvak, Vladimir et al. (2016) Unexpected cellular players in Rett syndrome pathology. Neurobiol Dis 92:64-71
Cronk, James C; Derecki, Noël C; Ji, Emily et al. (2015) Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli. Immunity 42:679-91