University of Pennsylvania

Author Of 1 Presentation

Pathogenesis – Immunology Poster Presentation

P0962 - Expression of Bruton’s tyrosine kinase in B cell-rich meningeal infiltrates in two models of progressive MS (ID 1391)

Speakers
Presentation Number
P0962
Presentation Topic
Pathogenesis – Immunology

Abstract

Background

The success of anti-CD20 therapies has emphasized the important contribution of B cells to the disease process in MS. Indeed, B cells sequestered in the central nervous system (CNS), including the ones forming organized leptomeningeal aggregates, are suspected to be a source of underlying progressive disease activity in MS. Their presence, when associated with adjacent subpial cortical pathology, is predictive of an aggressive disease course with rapid, unrelenting progression of disability. Yet CNS B cells are protected from the direct effects of anti-CD20 therapies. An alternative approach is to target the inflammatory process in the CNS by inhibiting Bruton’s tyrosine kinase (BTK), an enzyme critically involved in B cell activation and survival, but also expressed by macrophages and microglia. BTK inhibitors are small molecules potentially able to enter the CNS, that have the capacity to restrict peripheral and CNS-compartmentalized B cell responses.

Objectives

Here, we investigated the expression pattern of BTK in brain tissue from a spontaneous naturally-occurring canine neuroinflammatory disease (granulomatous meningoencephalomyelitis, GME), and from a murine experimental autoimmune encephalomyelitis (EAE) model, with both recapitulating determining aspects of progressive MS pathology.

Methods

To this end, we studied CNS samples from GME (n=9) and EAE (n=6) cases by immunofluorescent/confocal analysis of leptomeningeal and parenchymal areas affected by the neuroinflammatory process.

Results

Our analysis reveals both models are characterized by prominent B cell infiltrates in the leptomeninges that associate with submeningeal injury in the underlying parenchymal tissue. These injurious changes are reminiscent of the subpial neuropathology characteristic of MS. In both models, we found robust BTK expression within CD20+ B cell-rich leptomeningeal infiltrates. Meningeal B cell infiltration extended into the parenchymal tissue via the Virchow Robin spaces of penetrating vessels. BTK expression was also detected in B cells within these spaces and in cells moving from the perivascular space into the parenchymal tissue. In GME, BTK was also detected in microglia/macrophages in leptomeningeal infiltrates and in the neighboring parenchyma.

Conclusions

The prominent expression of BTK in leptomeningeal and perivascular B-cell rich infiltrates underscores its value as a potential candidate to target CNS compartmentalized immune responses thought to drive the progression of disability seen in MS.

Collapse