UTSW

Author Of 1 Presentation

Pathogenesis – Immunology Poster Presentation

P0947 - CD11c+CD88+CD317+ myeloid cells are critical mediators of persistent CNS autoimmunity (ID 1199)

Abstract

Background

Natalizumab, 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).

Objectives

We intended to invesigate the effects of α4-integrin antagonism among CD11c+ cells on the clinical outcomes in a mouse model of EAE.

Methods

We generated CD11c.Cre+/-ITGA4fl/fl C57BL/6 mice to selectively delete α4-integrin in CD11c+ cells. Active immunization and adoptive transfer EAE models were employed and compared with wild type controls. Multi-parameter flow cytometry was utilized to immunophenotype leukocyte subsets. Results from murine model analyses were reconfirmed via single-cell RNA sequencing (scRNA-seq) of human blood and cerebrospinal fluid (CSF) samples to profile individual cells

Results

In our mouse model α4-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 clinical EAE onset, CD11c+CD88+ cells appeared in the CNS and expressed CD317+. In adoptive transfer experiments, CD11c.Cre+/-ITGA4fl/fl mice had ameliorated clinical disease phenotype associated with significantly diminished numbers of CNS CD11c+CD88+CD317+ cells. In human CSF from subjects with neuroinflammation, microglia-like cells display coincident expression of ITGAX (CD11c), C5AR1 (CD88), and BST2 (CD317). In mice, we show that only activated, but not naïve microglia expressed CD11c, CD88, and CD317. Finally, anti-CD317 treatment prior to clinical EAE substantially enhanced recovery in mice.

Conclusions

CD11c+CD88+CD317+ myeloid cells in the CNS promote inflammatory damage with direct temporal correlation with the clinical phase of the disease in EAE model in mice. Transcriptional analysis identifies ITGAX (CD11c) C5AR1 (CD88) BST2 (CD317) expressing cells as a distinct myeloid subset in human CSF collected from patients with neuroinflammation. The disease-propagating effects of these cells in EAE can be effectively antagonized using anti-CD317 mAb therapy.

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