Children with neurodevelopmental abnormalities resulting from duplication of the methyl-CpG binding protein 2 gene (MECP2) also have impaired T-helper-cell 1 (Th1) responses, research shows.
The findings "suggest that the high frequency of pulmonary and other inflammatory complications affecting these children may be due to opportunistic pathogens," say the researchers, led by David Corry (Baylor College of Medicine, Houston, Texas, USA).
The total peripheral blood leukocyte counts of 27 children with MECP2 duplication were normal, the team reports in Science Translational Medicine. However, they had increased numbers of innate immune cells, suggestive of infection and inflammation, and also had reduced numbers of memory T and B cells and natural killer cells.
When stimulated to differentiate, T cells taken from the children with MECP2 duplication produced significantly less interferon (IFN)-γ than cells taken from 26 age-matched healthy children (controls). In addition, the number of Th1 cells generated from the patients' T cells was about a third of that generated from the control T cells, and not because of reduced proliferation.
Further analysis suggested that the MeCP2 protein directly affected IFN-γ production; overexpression of MeCP2 in a cell line resulted in reduced IFN-γ production, while inhibiting MeCP2 in T cells from the patients partly restored IFN-γ production.
Transgenic mice overexpressing MeCP2 were unable to combat infection with the intracellular protozoan parasite Leishmania major, which requires IFN-γ production from Th1 cells. By contrast, the mice were able to control infections that required them to mount a Th2-mediated immune response.
This is consistent with the susceptibility of children with MECP2 duplication to infections such as pneumonia, which are caused by intracellular pathogens, say Corry et al.
In a commentary accompanying the study, Mark Boothby and Christopher Williams (Vanderbilt University School of Medicine, Nashville, Tennessee, USA) say that the findings "strengthen the rationale for the monitoring of affected patients for infections."
They also highlight how relatively modest changes in gene expression, as seen with MECP2 duplication, can cause "devastating phenotypic outcomes."
They say: "Together with Rett syndrome patients, the new work stresses that MeCP2 must stay within a very narrow range of expression - not too much, not too little - to be functionally 'just right.' "
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