Identification of the Occipito-Pontine Tract Using Diffusion-Tensor Fiber Tracking in Adult-Onset Adrenoleukodystrophy with Topographic Disorientation

X-linked adrenoleukodystrophy is a severe and progressive neurodegenerative disease caused by the peroxisomal transporter ATP-binding cassette, subfamily D, member 1 gene mutations. The defect of this gene product results in accumulation of very-long-chain fatty acids in organs and serum, central demyelination, and peripheral axonopathy. Although there are different magnetic resonance (MR) findings which reflect various phenotypes in adrenoleukodystrophy, some cases present with specific symmetrical occipital white-matter lesions. We describe a patient with adult-onset X-linked adrenoleukodystrophy with topographic disorientation, whose brain MR images revealed T2-signal hyperintensity along the occipito-pontine tract and lateral lemnisci, but not in the cortico-spinal tract in the brainstem. The occipito-pontine tract and lateral lemnisci were clearly detected using diffusion-tensor fiber tracking, suggesting that the topographic disorientation of this patient might be related to the occipito-pontine tract. MR tractography can effectively identify the occipito-pontine tract and may help to localize the fibers associated with clinical symptoms

A Splice Switch in SIGIRR Causes a Defect of IL-37-Dependent Anti-Inflammatory Activity in Cystic Fibrosis Airway Epithelial Cells

Cystic fibrosis (CF) is a hereditary disease typically characterized by infection-associated chronic lung inflammation. The persistent activation of toll-like receptor (TLR) signals is considered one of the mechanisms for the CF hyperinflammatory phenotype; however, how negative regulatory signals of TLRs associate with CF inflammation is still elusive. Here, we showed that the cell surface expression of a single immunoglobulin interleukin-1 receptor (IL-1R)-related molecule (SIGIRR), a membrane protein essential for suppressing TLRs- and IL-1R-dependent signals, was remarkably decreased in CF airway epithelial cells compared to non-CF cells. Notably, CF airway epithelial cells specifically and highly expressed a unique, alternative splice isoform of the SIGIRR that lacks exon 8 (Δ8-SIGIRR), which results in the production of a C-terminal truncated form of the SIGIRR. Δ8-SIGIRR was expressed intracellularly, and its over-expression abolished the cell surface expression and function of the full-length SIGIRR (WT-SIGIRR), indicating its dominant-negative effect leading to the deficiency of anti-inflammatory activity in CF cells. Consistently, IL-37, a ligand for the SIGIRR, failed to suppress viral dsRNA analogue poly(I:C)-dependent JNK activation and IL-8 production, confirming the reduction in the functional WT-SIGIRR expression in the CF cells. Together, our studies reveal that SIGIRR-dependent anti-inflammatory activity is defective in CF airway epithelial cells due to the unique splicing switch of the SIGIRR gene and provides the first evidence of IL-37-SIGIRR signaling as a target of CF airway inflammation