Selective emergence of antibody-secreting cells in the multiple sclerosis brain

Bogers, Laurens; Engelenburg, Hendrik J.; Janssen, Malou; Unger, Peter-Paul A.; Melief, Marie-José; Wierenga‐Wolf, Annet F.; Hsiao, Cheng-Chih; Mason, Matthew R. J.; Hamann, Jörg; Langelaar, Jamie van; Smolders, Joost; Luijn, Marvin M. van

doi:10.1016/j.ebiom.2023.104465

Cited by 21 publications

(14 citation statements)

References 79 publications

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“…Moreover, we found that tissue containing microglia nodules in MS had significant upregulated immunoglobulin genes (IGKC, IGHG1, IGHG2, and IGKV3-15), which was absent in tissue containing stroke nodules. This corresponds with the characteristic high prevalence of intrathecal unique oligoclonal IgG production in MS and the presence of B cells in MS NAWM 61 . Previously, we have shown that microglia in the NAWM are immunosuppressed 62 , and that immunoglobulins can break this immune tolerance of microglia cells through Fcγ receptors and thereby potentiate inflammation by microglia 63 .…”

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confidence: 60%

“…Previously, we showed MS NAWM to be enriched for perivascular B cells and T cells 57,59 . These lymphocytes may produce soluble factors contributing to lesion formation as cytokines and immunoglobulins 44,60,61 . Therefore, as we show lymphocytes in close proximity to microglia nodules in MS, they may be contributing to the inflammatory environment in which microglia nodules reside.…”

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confidence: 99%

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Profiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation

van den Bosch,

van der Poel,

Fransen

et al. 2023

Preprint

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Clusters of ramified HLA-DR+ cells, known as microglia nodules, are associated with brain pathology. Here we investigated if microglia nodules in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) are different from microglia nodules in white matter (WM) in stroke and whether they may relate to the start of demyelinating MS lesions. We studied the relation between microglia nodules and pathological severity in an MS autopsy cohort (n=167), and we compared frequency, size, and gene expression of microglia nodules in MS (n=7) and stroke (n=7). MS donors with microglia nodules (64%) had a higher lesion load and a higher proportion of active lesions compared to donors without microglia nodules (36%). We found altered expression of genes in microglia nodules in MS compared to stroke, including genes previously shown to be upregulated in MS lesions. Genes associated with lipid metabolism, presence and proliferation of T and B cells, production of and response to immunoglobulins and cytokines (specifically TNF and IFN), activation of the complement cascade, and metabolic stress were upregulated. Using immunohistochemistry, we confirmed that in MS, more than in stroke, microglia nodules are associated with membrane attack complexes, have phagocytosed oxidized phospholipids, and have a tubular mitochondrial network reflecting increased metabolic activity. Furthermore, in MS, some nodules encapsulated partially demyelinated axons. Taken together, we propose that activation of some microglia nodules in MS by pro-inflammatory cytokines and immunoglobulins in combination with phagocytosis of oxidized phospholipids may lead to a volatile phenotype prone to form MS lesions.

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confidence: 60%

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confidence: 99%

Profiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation

van den Bosch,

van der Poel,

Fransen

et al. 2023

Preprint

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“…CXCR3 is a chemokine receptor that is involved in the recruitment of distinct types of bone marrow-derived monocytic cells, such as plasmacytoid monocytes [38], synovial tissue monocytes [39], and dendritic cells [40]. In the brain, CXCR3-expressing cells have been implicated in Alzheimer’s disease and other age-dependent cognitive dysfunctions [41] [42], multiple sclerosis [43], epilepsy [44], and stoke [45]. However, no previous study has evaluated CXCR3 in the hypothalamus in the context of obesity.…”

Section: Discussionmentioning

confidence: 99%

CXCR3-expressing myeloid cells recruited to the hypothalamus protect against diet-induced body mass gain and metabolic dysfunction

Mendes,

Zanesco,

Aguiar

et al. 2024

Preprint

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Microgliosis is an important component of diet-induced hypothalamic inflammation in obesity. A few hours after the introduction of a high-fat diet, the mediobasal hypothalamus resident microglia undergo morphological and functional changes toward an inflammatory phenotype. If the consumption of large amounts of dietary fats persists for long periods, bone marrow-derived myeloid cells are recruited and integrated into a new landscape of hypothalamic microglia. However, it is currently unknown what are the transcriptional signatures and specific functions exerted by either resident or recruited subsets of hypothalamic microglia. Here, the elucidation of the transcriptional signatures revealed that resident microglia undergo only minor changes in response to dietary fats; however, under the consumption of a high-fat diet, there are major transcriptional differences between resident and recruited microglia with a major impact on chemotaxis. In addition, in recruited microglia, there are major transcriptional differences between females and males with an important impact on transcripts involved in neurodegeneration and thermogenesis. The chemokine receptor CXCR3 emerged as one of the components of chemotaxis with the greatest difference between recruited and resident microglia, and thus, was elected for further intervention. The hypothalamic immunoneutralization of CXCL10, one of the ligands for CXCR3, resulted in increased body mass gain and reduced energy expenditure, particularly in females. Furthermore, the chemical inhibition of CXCR3 resulted in a much greater change in phenotype with increased body mass gain, reduced energy expenditure, increased blood leptin, glucose intolerance, and reduced insulin. Thus, this study has elucidated the transcriptional differences between resident and recruited hypothalamic microglia in diet-induced obesity, identifying chemokines as a relevant subset of genes undergoing regulation. In addition, we showed that a subset of recruited microglia expressing CXCR3 has a protective, rather than a detrimental role in the metabolic outcomes promoted by the consumption of a high-fat diet, thus, establishing a new concept in obesity-associated hypothalamic inflammation.

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“…5 B cells also receive signals such as IFN-γ from interacting CD4 + T cells to induce expression of transcription factor T-bet and chemokine receptor CXCR3, which can be potentiated by EBV and guides their entry into the CNS. To drive MS pathology, the accumulation of EBV-infected CXCR3 + B cells in the perivascular space of people with MS may also give rise to clones that produce autoantibodies or posttranslationally modified (myelin) peptides that can form toxic amyloid-like aggregates, 8,9 yet this hypothesis needs to be further tested. Although CD8 + T cells are enriched in the MS brain, their exhausted features in risk HLA (and their cytotoxic capacity in protective HLA) carriers could further promote local B-cell maturation and persistence.…”

Section: Alternative Viewmentioning

confidence: 99%