Regional CNS responses to IFN-γ determine lesion localization patterns during EAE pathogenesis

The localization of inflammatory foci within the cerebellum is correlated to severe clinical outcomes in multiple sclerosis (MS). Previous studies of experimental autoimmune encephalomyelitis (EAE), a model of MS, revealed distinct clinical outcomes correlated with the capacity of the animal to produce IFN-γ. Outcomes were linked to localization of inflammatory cells in either the spinal cord (wild type [WT]) or the cerebellum and brain stem (IFN-γ deficient). We demonstrate, using an adoptive transfer system, that the ability of the central nervous system (CNS) to sense pathogenic T cell–produced IFN-γ during EAE initiation determines the sites of CNS pathogenesis. Transfer of WT Th1 cells into IFN-γ receptor–deficient mice results in pathogenic invasion of the brain stem and cerebellum with attendant clinical symptoms, which are identical to the disease observed after transfer of IFN-γ–deficient T cells to WT hosts. Inflammation of the spinal cord associated with classical EAE is abrogated in both IFN-γ–deficient systems. Cotransfer of CNS antigen-specific WT Th1 cells with IFN-γ–deficient T cells is sufficient to restore spinal cord invasion and block cerebellar and brain stem invasion. These data demonstrate that interaction between IFN-γ and host CNS cells during the initiation of EAE can selectively promote or suppress neuroinflammation and pathogenesis

One Year Outcome of Boys With Duchenne Muscular Dystrophy Using the Bayley-III Scales of Infant and Toddler Development

BACKGROUND: The pathogenesis of Duchenne muscular dystrophy starts prior to birth. Despite this, clinical trials exclude young boys because traditional outcome measures rely on cooperation. We recently used the Bayley-III Scales of Infant and Toddler Development to study 24 infants and boys with Duchenne muscular dystrophy. Clinical evaluators at six centers were trained and certified to perform the Bayley-III. Here we report six and twelve month follow-up of two subsets of these boys. PATIENTS: Nineteen boys (1.9 ± 0.8 years) were assessed at baseline and six months. Twelve boys (1.5 ± 0.8 years) were assessed at baseline, six, and twelve months. RESULTS: Gross motor scores were lower at baseline compared to published controls (6.2 ± 1.7; normal 10 ± 3; p<.0001), and showed a further declining trend to 5.7 ± 1.7 (p =.20) at six months. Repeated measures analysis of the 12 boys followed for 12 months showed that gross motor scores, again low at baseline (6.6 ± 1.7; p<.0001), declined at six months (5.9 ± 1.8) and further at 12 months (5.3 ± 2.0) (p=0.11). Cognitive and language scores were lower at baseline compared to normal children (range p=.002 to p<0.0001) and did not change significantly at 6 or 12 months (range p=.89 to p=.09). Fine motor skills, also low at baseline, improved over one year (p=.05). CONCLUSION: Development can reliably be measured in infants and young boys with DMD across time using the Bayley-III. Power calculations using these data show that motor development may be used as an outcome measure

Association Study of Exon Variants in the NF-\u3baB and TGF\u3b2 Pathways Identifies CD40 as a Modifier of Duchenne Muscular Dystrophy

The expressivity of Mendelian diseases can be influenced by factors independent from the pathogenic mutation: in Duchenne muscular dystrophy (DMD), for instance, age at loss of ambulation (LoA) varies between individuals whose DMD mutations all abolish dystrophin expression. This suggests the existence of trans-acting variants in modifier genes. Common single nucleotide polymorphisms (SNPs) in candidate genes (SPP1, encoding osteopontin, and LTBP4, encoding latent transforming growth factor \u3b2 [TGF\u3b2]-binding protein 4) have been established as DMD modifiers. We performed a genome-wide association study of age at LoA in a sub-cohort of European or European American ancestry (n = 109) from the Cooperative International Research Group Duchenne Natural History Study (CINRG-DNHS). We focused on protein-altering variants (Exome Chip) and included glucocorticoid treatment as a covariate. As expected, due to the small population size, no SNPs displayed an exome-wide significant p value (< 1.8 7 10 126). Subsequently, we prioritized 438 SNPs in the vicinities of 384 genes implicated in DMD-related pathways, i.e., the nuclear-factor-\u3baB and TGF\u3b2 pathways. The minor allele at rs1883832, in the 5\u2032-untranslated region of CD40, was associated with earlier LoA (p = 3.5 7 10 125). This allele diminishes the expression of CD40, a co-stimulatory molecule for T cell polarization. We validated this association in multiple independent DMD cohorts (United Dystrophinopathy Project, Bio-NMD, and Padova, total n = 660), establishing this locus as a DMD modifier. This finding points to cell-mediated immunity as a relevant pathogenetic mechanism and potential therapeutic target in DMD