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Transient peripheral immune response and central nervous system leaky compartmentalization in a viral model for multiple sclerosis.

ABSTRACT: Theiler's virus-induced demyelination represents an important animal model to study the chronic-progressive form of multiple sclerosis (MS). The aim of the present study was to identify specific genes and pathways in the deep cervical lymph node (cLN) and spleen of experimentally infected SJL-mice, using DNA microarrays. Analyses identified 387 genes in the deep cLN and only 6 genes in the spleen of infected animals. The lymph node presented 27.4% of genes with fold changes +/-1.5 at 14 days post infection (dpi) and a reduced transcription at later time points. K-means clustering analyses resulted in five clusters. Accordingly, functional annotation revealed that the B-cell immune response pathway was the most up-regulated cluster at the early phase. Additionally, an increase of CD68- and lysozyme-positive cells in the deep cLN was observed by immunohistochemistry. Polioencephalitis was most intense at 14 dpi, and the spinal cord demyelinating leukomyelitis started at 42 dpi. In summary, early gene expression is indicative of virus-trigged immune responses in the central nervous system (CNS)-draining lymph node. The decreased gene transcription in the deep cLN during the chronic phase and the low number of spleen genes supports the hypothesis of a compartmentalized inflammation within the CNS, as described in progressive MS.

SUBMITTER: Navarrete-Talloni MJ

PROVIDER: S-EPMC8094647 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The role of innate immunity in the pathogenesis of cryptococcal meningitis is unclear. We hypothesized that natural killer (NK) cell and monocyte responses show central nervous system (CNS) compartment-specific profiles, and are altered by antifungal therapy and combination antiretroviral therapy (cART) during cryptococcal meningitis/HIV coinfection.Substudy of a prospective cohort study of adults with cryptococcal meningitis/HIV coinfection in Durban, South Africa.We used multiparametric flow cytometry to study compartmentalization of subsets, CD69 (a marker of activation), CXCR3 and CX3CR1 expression, and cytokine secretion of NK cells and monocytes in freshly collected blood and cerebrospinal fluid (CSF) at diagnosis (n = 23), completion of antifungal therapy induction (n = 19), and after a further 4 weeks of cART (n = 9).Relative to blood, CSF was enriched with CD56(bright) (immunoregulatory) NK cells (P = 0.0004). At enrolment, CXCR3 expression was more frequent among blood CD56(bright) than either blood CD56(dim) (P < 0.0001) or CSF CD56(bright) (P = 0.0002) NK cells. Antifungal therapy diminished blood (P < 0.05), but not CSF CXCR3(pos) NK-cell proportions nor CX3CR1(pos) NK-cell proportions. CD56(bright) and CD56(dim) NK cells were more activated in CSF than blood (P < 0.0001). Antifungal therapy induction reduced CD56(dim) NK-cell activation in CSF (P = 0.02). Activation of blood CD56(bright) and CD56(dim) NK cells was diminished following cART commencement (P < 0.0001, P = 0.03). Immunoregulatory NK cells in CSF tended to secrete higher levels of CXCL10 (P = 0.06) and lower levels of tumor necrosis factor ? (P = 0.06) than blood immunoregulatory NK cells. CSF was enriched with nonclassical monocytes (P = 0.001), but antifungal therapy restored proportions of classical monocytes (P = 0.007).These results highlight CNS activation, trafficking, and function of NK cells and monocytes in cryptococcal meningitis/HIV and implicate immunoregulatory NK cells and proinflammatory monocytes as potential modulators of cryptococcal meningitis pathogenesis during HIV coinfection.

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Transient peripheral immune response and central nervous system leaky compartmentalization in a viral model for multiple sclerosis.

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