The neonatal CNS is not conducive for encephalitogenic Th1 T cells and B cells during experimental autoimmune encephalomyelitis

Cravens, Petra D.; Kieseier, Bernd C.; Hussain, Rehana Z.; Herndon, Emily; Arellano, Benjamine; Ben, Li Hong; Timmons, Brenda C.; Castro-Rojas, Cyd; Hartung, Hans Peter; Hemmer, Bernhard; Weber, Martin; Zamvil, Scott S.; Stüve, Olaf

doi:10.1186/1742-2094-10-67

Cited by 14 publications

(14 citation statements)

References 36 publications

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“…Our data, in agreement with these studies, show that the gene expression profile of neonatal microglia significantly differed from adult homeostatic microglia and in addition from that seen during EAE, showing myelin‐ and neurogenic in neonates versus an immune response signature in EAE. In line with the fact that neonatal mice have been shown to be resistant or to have delayed onset of EAE in comparison with adult mice (Smith et al , ; Cravens et al , ), our findings suggest that the neurosupportive capacity of microglia decreases with aging.…”

Section: Discussionsupporting

confidence: 87%

A novel microglial subset plays a key role in myelinogenesis in developing brain

et al. 2017

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Microglia are resident macrophages of the central nervous system that contribute to homeostasis and neuroinflammation. Although known to play an important role in brain development, their exact function has not been fully described. Here, we show that in contrast to healthy adult and inflammation‐activated cells, neonatal microglia show a unique myelinogenic and neurogenic phenotype. A CD11c+ microglial subset that predominates in primary myelinating areas of the developing brain expresses genes for neuronal and glial survival, migration, and differentiation. These cells are the major source of insulin‐like growth factor 1, and its selective depletion from CD11c+ microglia leads to impairment of primary myelination. CD11c‐targeted toxin regimens induced a selective transcriptional response in neonates, distinct from adult microglia. CD11c+ microglia are also found in clusters of repopulating microglia after experimental ablation and in neuroinflammation in adult mice, but despite some similarities, they do not recapitulate neonatal microglial characteristics. We therefore identify a unique phenotype of neonatal microglia that deliver signals necessary for myelination and neurogenesis.

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Section: Discussionsupporting

confidence: 87%

A novel microglial subset plays a key role in myelinogenesis in developing brain

et al. 2017

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“…In MS and EAE, DCs are readily detectable in the brain [42–48]. Fischer and Reichmann showed that CNS inflammation in EAE and toxoplasmic encephalitis was associated with the proliferation of CD11b + CD11c + cells [49].…”

Section: The Innate Immune System In Cns Immune Surveillancementioning

confidence: 99%

Immune surveillance of the central nervous system in multiple sclerosis — Relevance for therapy and experimental models

Hussain

Hayardeny

Cravens

et al. 2014

Journal of Neuroimmunology

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Treatment of central nervous system (CNS) autoimmune disorders frequently involves the reduction, or depletion of immune-competent cells. Alternatively, immune cells are being sequestered away from the target organ by interfering with their movement from secondary lymphoid organs, or their migration into tissues. These therapeutic strategies have been successful in multiple sclerosis (MS), the most prevalent autoimmune inflammatory disorder of the CNS. However, many of the agents that are currently approved or in clinical development also have severe potential adverse effects that stem from the very mechanisms that mediate their beneficial effects by interfering with CNS immune surveillance. This review will outline the main cellular components of the innate and adaptive immune system that participate in host defense and maintain immune surveillance of the CNS. Their pathogenic role in MS and its animal model experimental autoimmune encephalomyelitis (EAE) is also discussed. Furthermore, an experimental model is introduced that may assist in evaluating the effect of therapeutic interventions on leukocyte homeostasis and function within the CNS. This model or similar models may become a useful tool in the repertoire of pre-clinical tests of pharmacological agents to better explore their potential for adverse events.

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“…This delayed onset compared to other studies was likely due to injection of the encephalitogen into ~5 week old C57BL/6J mice rather than older C57BL/6J mice used in other studies [6, 19]. After disease onset, the progression of clinical scores appeared to advance more rapidly in the EAE mice administered omeprazole compared to saline, but the differences did not achieve significance (Figure 3A).…”

Section: Resultsmentioning

confidence: 68%

The effect of omeprazole on the development of experimental autoimmune encephalomyelitis in C57BL/6J and SJL/J mice

et al. 2014

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BackgroundGastric disturbances such as dyspepsia are routinely encountered by multiple sclerosis (MS) patients, and these conditions are often treated with gastric acid suppressors such as proton pump inhibitors, histamine H2 receptor antagonists, or antacids. The proton pump inhibitor omeprazole can alter the gut flora and immune responses, both of which can influence the course of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The objective of the current study was to examine the effect of omeprazole treatment on the development of EAE. Bacterial microbiome analysis of mouse fecal pellets was determined in C57BL/6J EAE mice chronically treated with omeprazole, and spleen immune cell content, clinical scores, weight, rotarod latency, and histopathology were used as outcome measures in C57BL/6J and SJL/J mice with EAE.ResultsOmeprazole treatment resulted in decreases in Akkermansia muciniphila and Coprococcus sp. and an increase in unidentified bacteria in the family S24-7 (order Bacteroidales) in C57BL/6J mice with EAE. Omeprazole did not alter spleen immune cell content compared to vehicle in EAE mice, but differences independent of treatment were observed in subsets of T cells between early and advanced disease in C57BL/6J mice as well as between the two strains of mice at an advanced disease stage. Omeprazole caused no difference in clinical scores in either strain, but significantly lowered weight gain compared to vehicle in the C57BL/6J mice with EAE. Omeprazole also did not alter rotarod behavior or hindbrain inflammatory cell infiltration compared to vehicle in both strains of mice with EAE. Rotarod latency did reveal a negative correlation with clinical scores during active disease in both mouse strains, but not during clinical remission in SJL/J mice, suggesting that rotarod can detect disability not reflected in the clinical scores.ConclusionsDespite alterations in the gut microbiota and weight gain in the C57BL/6J EAE model, omeprazole had no effect on multiple measures of disease activity in C57BL/6J and SJL/J mice with EAE, supporting the notion that omeprazole does not substantially influence disease activity in MS patients.Electronic supplementary materialThe online version of this article (doi:10.1186/1756-0500-7-605) contains supplementary material, which is available to authorized users.

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The neonatal CNS is not conducive for encephalitogenic Th1 T cells and B cells during experimental autoimmune encephalomyelitis

Cited by 14 publications

References 36 publications

A novel microglial subset plays a key role in myelinogenesis in developing brain

A novel microglial subset plays a key role in myelinogenesis in developing brain

Immune surveillance of the central nervous system in multiple sclerosis — Relevance for therapy and experimental models

The effect of omeprazole on the development of experimental autoimmune encephalomyelitis in C57BL/6J and SJL/J mice

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