Citations

ObjectiveThis study was undertaken to explore the gene expression profile of primary central nervous system vasculitis (PCNSV).MethodsBrain specimens of 4 patients with granulomatous vasculitis (GV), 5 with lymphocytic vasculitis (LV), 4 with amyloid β‐related angiitis (ABRA), and 4 normal controls were studied. RNA‐sequencing was performed using the Illumina Hiseq‐4,000 platform and the Illumina TruSeq Total‐RNA library. Student t test and false discovery rate tests were performed for each of the differentially expressed transcripts. Ingenuity Pathway Analysis was used for the pathway expression analysis. CIBERSORT was used to estimate the abundances of different immune cell subsets in the tissues based on gene expression data.ResultsTranscripts differentially expressed between PCNSV and normal brain indicated that endosomal, mitochondrial, and ribosome dysfunction, alterations in protein synthesis, and noncoding RNAs might be involved in PCNSV. Pathway analysis revealed the activation of dendritic cell maturation and antigen processing as well as neuroinflammation in PCNSV versus normal brain, whereas oxidative phosphorylation was inhibited. CIBERSORT estimation of immune cell subsets suggested that activated NK cells, M1 macrophages, memory B cells, and follicular helper T cells were likely to be more prevalent in PCNSV samples. Naïve CD4 T cells and monocytes were mainly estimated to be present in GV and ABRA. Plasma cell and γδ T‐cell signatures were mainly found in LV and normal brain. GV showed higher levels of genes associated with macrophage activities and T cells. ABRA showed higher levels of long noncoding RNAs and miR‐616. LV showed higher levels of genes encoding immunoglobulins.InterpretationRNA sequencing confirmed PCNSV heterogeneity. ANN NEUROL 2023;93:120–130

Abstract Neuromyelitis optica is an autoimmune inflammatory disorder targeting aquaporin-4 water channels in CNS astrocytes. Histopathological descriptions of astrocytic lesions reported in neuromyelitis optica so far have emphasized a characteristic loss of aquaporin-4, with deposition of IgG and complement and lysis of astrocytes, but sublytic reactions have been underappreciated. We performed a multi-modality study of 23 neuromyelitis optica autopsy cases (clinically and/or pathologically confirmed; 337 tissue blocks). By evaluating astrocytic morphology, immunohistochemistry and AQP4 RNA transcripts, and their associations with demyelinating activity, we documented a spectrum of astrocytopathy in addition to complement deposition, microglial reaction, granulocyte infiltration and regenerating activity. Within advanced demyelinating lesions, and in periplaque areas, there was remarkable hypertrophic astrogliosis, more subtle than astrocytic lysis. A degenerative component was suggested by ‘dystrophic’ morphology, cytoplasmic vacuolation, Rosenthal fibres and associated stress protein markers. The abundance of AQP4 mRNA transcripts in sublytic reactive astrocytes devoid of aquaporin-4 protein supported in vivo restoration following IgG-induced aquaporin-4 endocytosis/degradation. Astrocytic alterations extending beyond demyelinating lesions speak to astrocytopathy being an early and primary event in the evolving neuromyelitis optica lesion. Focal astrocytopathy observed without aquaporin-4 loss or lytic complement component deposition verifies that astrocytic reactions in neuromyelitis optica are not solely dependent on IgG-mediated aquaporin-4 loss or lysis by complement or by IgG-dependent leucocyte mediators. We conclude that neuromyelitis optica reflects a global astrocytopathy, initiated by binding of IgG to aquaporin-4 and not simply definable by demyelination and astrocytic lysis. The spectrum of astrocytic morphological changes in neuromyelitis optica attests to the complexity of factors influencing the range of astrocytic physiological responses to a targeted attack by aquaporin-4-specific IgG. Sublytic astrocytic reactions are no doubt an important determinant of the lesion’s evolution and potential for repair. Pharmacological manipulation of the astrocytic stress response may offer new avenues for therapeutic intervention.

A rare APOE variant APOE3 -Jac reduces self-aggregation and promotes healthy brain aging.