Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosis

Beltrán, Eduardo; Gerdes, Lisa Ann; Hansen, Julia; Flierl-Hecht, Andrea; Krebs, Stefan; Blum, Helmut; Ertl‐Wagner, Birgit; Barkhof, Frederik; Kümpfel, Tania; Hohlfeld, Reinhard; Dornmair, Klaus

doi:10.1172/jci128475

Cited by 96 publications

(114 citation statements)

References 51 publications

Supporting

Mentioning

106

Contrasting

Order By: Relevance

“…2E). CD8 + T cells responding to 2 additional myelin determinants, MAG 509-517 and PLP [45][46][47][48][49][50][51][52][53] , showed nonsignificant increases in memory status in MS patients ( Fig. 2E).…”

Section: Resultsmentioning

confidence: 96%

“…1C). Using this stepwise approach, 3 HLA-A2 (MOG 181-189 , MOG 156-164 , and MAG 509-517 ) and 2 HLA-A3 (PLP [45][46][47][48][49][50][51][52][53] and CNP [54][55][56][57][58][59][60][61][62][63] ) CD8 + T cell epitopes were validated (Fig. 1C).…”

Section: Resultsmentioning

confidence: 99%

“…To our knowledge, MOG 181-189 :HLA-A2 and CNP [54][55][56][57][58][59][60][61][62][63] :HLA-A3 have not been described in humans. Of interest, MOG 181-189 was previously reported as a CD8 + T cell epitope in HLA-A2 transgenic mice (21), and both the MOG 181-189 and PLP [45][46][47][48][49][50][51][52][53] epitopes were pathogenic in humanized mouse models of EAE (21,22). A potential pathogenic role for these populations is supported by the finding that all of the isolated myelin-specific CD8 + T cell populations produced significant amounts of IFNγ, TNFα, IL-2, GM-CSF, and CD107a (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Anti-CD20 therapy depletes activated myelin-specific CD8⁺T cells in multiple sclerosis

Sabatino

Wilson

Calabresi³

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

103

View full text Add to dashboard Cite

CD8 + T cells are believed to play an important role in multiple sclerosis (MS), yet their role in MS pathogenesis remains poorly defined. Although myelin proteins are considered potential autoantigenic targets, prior studies of myelin-reactive CD8 + T cells in MS have relied on in vitro stimulation, thereby limiting accurate measurement of their ex vivo precursor frequencies and phenotypes. Peptide:MHC I tetramers were used to identify and validate 5 myelin CD8 + T cell epitopes, including 2 newly described determinants in humans. The validated tetramers were used to measure the ex vivo precursor frequencies and phenotypes of myelin-specific CD8 + T cells in the peripheral blood of untreated MS patients and HLA allele-matched healthy controls. In parallel, CD8 + T cell responses against immunodominant influenza epitopes were also measured. There were no differences in ex vivo frequencies of tetramerpositive myelin-specific CD8 + T cells between MS patients and control subjects. An increased proportion of myelin-specific CD8 + T cells in MS patients exhibited a memory phenotype and expressed CD20 compared to control subjects, while there were no phenotypic differences observed among influenza-specific CD8 + T cells. Longitudinal assessments were also measured in a subset of MS patients subsequently treated with anti-CD20 monoclonal antibody therapy. The proportion of memory and CD20 + CD8 + T cells specific for certain myelin but not influenza epitopes was significantly reduced following anti-CD20 treatment. This study, representing a characterization of unmanipulated myelin-reactive CD8 + T cells in MS, indicates these cells may be attractive targets in MS therapy. multiple sclerosis | CD8 + T cells | myelin antigen | anti-CD20 therapy

show abstract

Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Anti-CD20 therapy depletes activated myelin-specific CD8⁺T cells in multiple sclerosis

Sabatino

Wilson

Calabresi³

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

103

View full text Add to dashboard Cite

show abstract

“…Interestingly, our human CSF transcriptome analyses placed CD11c + CD88 + CD317 + cells within a population of myeloid cells that was previously defined as CSF microglia 11,[32][33][34] . We found that activated, but not naive murine microglia concomitantly express CD11c, CD88, and CD317.…”

Section: Discussionmentioning

confidence: 86%

“…Characteristic gene expression markers were employed to assign cellular identities to each cluster of myeloid populations in blood (Figure 5A) and CSF (Figure 5B). Recent studies identified myeloid cells within the CSF using scRNA-seq that resembled microglia 11,[32][33][34] , which are characterized by the expression of signature genes including CX3CR1, CSF1R, SLC2A5, MARCKS, and P2RY13 [35][36][37] .…”

Section: And Csf By Transcriptomic Profilingmentioning

confidence: 99%

CD11c⁺CD88⁺CD317⁺myeloid cells are critical mediators of persistent CNS autoimmunity

Manouchehri

Hussain

Cravens

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundNatalizumab, a humanized monoclonal antibody (mAb) against α4-integrin, reduces the number of dendritic cells (DC) in cerebral perivascular spaces in multiple sclerosis (MS). Selective deletion of α4-integrin in CD11c+ cells should curtail their migration to the CNS and ameliorate experimental autoimmune encephalomyelitis (EAE).MethodsWe generated CD11c.Cre+/-ITGA4fl/fl C57/Bl6 mice to selectively delete α4-integrin in CD11c+ cells. Active immunization and adoptive transfer EAE models were employed. Multi-parameter flow cytometry was utilized to immunophenotype leukocytes. Single-cell RNA sequencing (scRNA-seq) was used to profile individual cells.Resultsα4-integrin expression by CD11c+ cells was significantly reduced in primary and secondary lymphoid organs in CD11c.Cre+/-ITGA4fl/fl mice. In active EAE, a delayed disease onset was observed in CD11c.Cre+/-ITGA4fl/fl mice, during which CD11c+CD88+ cells were sequestered in the blood. Upon EAE onset, CD11c+CD88+ cells accumulated in the CNS and expressed CD317+. In adoptive transfer experiments, CD11c.Cre+/-ITGA4fl/fl mice had ameliorated clinical disease associated with diminished numbers of CNS CD11c+CD88+CD317+ cells. The transcription profile of CD11c+CD88+CD317+ cells placed them within previously defined microglia-like cells in human CSF. We show that activated, but not naïve microglia expressed CD11c, CD88, and CD317. Finally, anti-CD317 treatment prior to clinical EAE substantially enhanced recovery.ConclusionCD11c+CD88+CD317+ cells in the CNS promote inflammatory damage. Transcriptional analysis identifies CD11c+CD88+CD317+ cells as a unique myeloid subset in human CSF. The disease-propagating effects of these cells can be antagonized using anti-CD317 mAb.

show abstract

SETD8^C302R Mutation Revealed from Myofibroblastoma‐Discordant Monozygotic Twins Leads to p53/p21 Deficit and WEE1 Inhibitor Sensitivity

Wang²,

Liao

et al. 2020

Advanced Science

View full text Add to dashboard Cite

High-throughput gene sequencing has identified various genetic variants as the culprits for some common hereditary cancers. However, the heritability of a substantial proportion of cancers remains unexplained, which may result from rare deleterious mutations hidden in a myriad of nonsense genetic variations. This poses a great challenge to the understanding of the pathology and thus the rational design of effective treatments for affected patients. Here, whole genome sequencing is employed in a representative case in which one monozygotic twin is discordant for lung inflammatory myofibroblastoma to disclose rare tumor-related mutations. A missense single nucleotide variation rs61955126 T>C in the lysine methyltransferase SETD8 (accession: NM_020382, SETD8 C302R) is exposed. It is shown that SETD8 is vital for genomic integrity by promoting faithful DNA replication, and its C302R mutation downregulates the p53/p21 pathway. Importantly, the SETD8 C302R mutation significantly increases the sensitivity of cancer cells to WEE1 inhibition. Given that WEE1 inhibitors have shown great promise for clinical approval, these results impart a potential therapeutic approach using WEE1 inhibitor for cancer patients carrying the same mutation, and indicate that genome sequencing and genetic functional studies can be integrated into individualized therapies.

show abstract

Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosis

Cited by 96 publications

References 51 publications

Anti-CD20 therapy depletes activated myelin-specific CD8⁺T cells in multiple sclerosis

Anti-CD20 therapy depletes activated myelin-specific CD8⁺T cells in multiple sclerosis

CD11c⁺CD88⁺CD317⁺myeloid cells are critical mediators of persistent CNS autoimmunity

SETD8^C302R Mutation Revealed from Myofibroblastoma‐Discordant Monozygotic Twins Leads to p53/p21 Deficit and WEE1 Inhibitor Sensitivity

Contact Info

Product

Resources

About

Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosis

Cited by 96 publications

References 51 publications

Anti-CD20 therapy depletes activated myelin-specific CD8+T cells in multiple sclerosis

Anti-CD20 therapy depletes activated myelin-specific CD8+T cells in multiple sclerosis

CD11c+CD88+CD317+myeloid cells are critical mediators of persistent CNS autoimmunity

SETD8C302R Mutation Revealed from Myofibroblastoma‐Discordant Monozygotic Twins Leads to p53/p21 Deficit and WEE1 Inhibitor Sensitivity

Contact Info

Product

Resources

About

Anti-CD20 therapy depletes activated myelin-specific CD8⁺T cells in multiple sclerosis

Anti-CD20 therapy depletes activated myelin-specific CD8⁺T cells in multiple sclerosis

CD11c⁺CD88⁺CD317⁺myeloid cells are critical mediators of persistent CNS autoimmunity

SETD8^C302R Mutation Revealed from Myofibroblastoma‐Discordant Monozygotic Twins Leads to p53/p21 Deficit and WEE1 Inhibitor Sensitivity