Biology subjects

Segal, B. M.

Publications and source records attributed to Segal, B. M..

3 recordsLinked to original sources

bioRxiv2023

Respiratory tract Moraxella catarrhalis and Klebsiella pneumoniae can promote pathogenicity of myelin-reactive Th17 cells

The respiratory tract is home to a diverse microbial community whose influence on local and systemic immune responses is only beginning to be appreciated. The airways have been linked with trafficking of myelin-specific T cells in the pre-clinical stages of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Th17 cells are important pathogenic effectors in MS and EAE but are innocuous immediately following differentiation. Upregulation of the cytokine GM-CSF appears to be a critical step in their acquisition of pathogenic potential, but little is known about the mechanisms that mediate this process. Here, primed myelin-specific Th17 cells were transferred to congenic recipient mice prior to exposure to various human respiratory tract-associated bacteria and T cell trafficking, phenotype and the severity of resulting EAE monitored. Disease was exacerbated in mice exposed to the Proteobacteria Moraxella catarrhalis and Klebsiella pneumoniae, but not the Firmicute Veillonella parvula, and this was associated with a significant increase in GM-CSF+ and GM-CSF+IFN{gamma}+ ex-Th17-like donor CD4 T cells in the lungs and CNS of these mice. These findings support the concept that respiratory bacteria may contribute to the pathophysiology of CNS autoimmunity by modulating pathogenicity in crucial T cell subsets that orchestrate neuroinflammation.

immunology↗

bioRxiv2021

Biological Aging of CNS-Resident Cells Alters the Clinical Course and Immunopathology of Autoimmune Demyelinating Disease

Biological aging is the strongest factor associated with the clinical phenotype of multiple sclerosis (MS). Relapsing remitting MS (RRMS) typically presents in the third or fourth decade, while the mean age of presentation of progressive MS (pMS) is 45 years old. Here we show that experimental autoimmune encephalomyelitis (EAE), induced by the adoptive transfer of encephalitogenic CD4+ Th17 cells, is more severe, and less like to remit, in middle-aged compared with young adult mice. Donor T cells and neutrophils are more abundant, while B cells are relatively sparse, in central nervous system (CNS) infiltrates of the older mice. Experiments with reciprocal bone marrow chimeras demonstrate that radio-resistant, non-hematopoietic cells play a dominant role in shaping age-dependent features of the neuroinflammatory response, as well as the clinical course, during EAE. Reminiscent of pMS, EAE in middle-aged adoptive transfer recipients is characterized by widespread microglial activation. Microglia from older mice express a distinctive transcriptomic profile, suggestive of enhanced chemokine synthesis and antigen presentation. Collectively, our findings suggest that drugs that suppress microglial activation, and acquisition or expression of aging-associated properties, may be beneficial in the treatment of progressive forms of inflammatory demyelinating disease.

neuroscience↗

bioRxiv2019

The landscape of myeloid and astrocyte phenotypes in acute multiple sclerosis lesions

Activated myeloid cells and astrocytes are the predominant cell types in active multiple sclerosis (MS) lesions. Both cell types can adopt diverse functional states that play critical roles in lesion formation and resolution. In order to identify phenotypic subsets of myeloid cells and astrocytes, we profiled acute MS lesions with thirteen glial activation markers using imaging mass cytometry (IMC), a method for multiplexed labeling of histological sections. In a demyelinating lesion, we found multiple distinct myeloid and astrocyte phenotypes that populated separate lesion zones. In a post-demyelinating lesion, phenotypes were less distinct and more uniformly distributed. In both lesions cell-to-cell interactions were not random, but occurred between specific glial subpopulations and lymphocytes. Finally, we demonstrated that myeloid, but not astrocyte phenotypes were activated along a lesion rim-to-center gradient, and that marker expression in glial cells at the lesion rim was driven more by cell-extrinsic factors than in cells at the center. This proof-of-concept study demonstrates that highly multiplexed tissue imaging, combined with the appropriate computational tools, is a powerful approach to study heterogeneity, spatial distribution and cellular interactions in the context of MS lesions. Identifying glial phenotypes and their interactions at different lesion stages may provide novel therapeutic targets for inhibiting acute demyelination and low-grade, chronic inflammation.

immunology↗