Meningeal Tertiary Lymphoid Tissues and Multiple Sclerosis: A Gathering Place for Diverse Types of Immune Cells during CNS Autoimmunity

Abstract

Collections of leukocytes in the meningeal space have been documented in Multiple Sclerosis (MS). These meningeal aggregates, which in the context of other autoimmune diseases have often been termed tertiary lymphoid tissues (TLT), have been associated with sub-pial cortical damage and disease progression. However, the key molecular and cellular signals required for their formation and maintenance remain unclear. Herein, we review TLT structures in other disease states in order to provide a framework for understanding these structures in the MS meninges. We then assess the evidence that the meningeal compartment serves as an important nexus for immune cells as well as a location for drainage of antigen into cervical lymph nodes. Extrapolating what is known about the molecular and cellular cues that initiate the formation of leukocyte aggregates in non-lymphoid tissues, we speculate on what signals lead to the formation and maintenance of meningeal TLT structures. Referring to the animal model of MS [experimental autoimmune encephalomyelitis (EAE)], we also explore what is known about these structures in supporting B cell and T cell responses during neuroinflammation. Last, we examine the evidence that connects these structures to ongoing neuropathology. Collectively, our review points to the meningeal compartment as an important player in neuroinflammatory processes. Moreover, we hypothesize that in order to gain insights into pro- and anti-inflammatory properties of lymphocytes in MS, one must understand the cellular scaffolds that support lymphocyte retention within the meninges, thus highlighting the importance of non-immune cells (stromal cells) in the neuroinflammatory process.

Emerging Approaches for Validating and Managing Multiple Sclerosis Relapse

“…Tertiary lymphoid follicles, which are ectopic CNS lymphoid structures that attract and maintain B cells and T cells (10), have been found to reside in the meninges of some MS patients (11). Since the subarachnoid space contains the interface between cerebrospinal fluid (CSF) and vasculature, it can serve as an entry point for antigen-experienced leukocytes into the CNS.…”

Potential of Cells and Cytokines/Chemokines to Regulate Tertiary Lymphoid Structures in Human Diseases

“…In particular, increased expression of adhesion molecules such as intercellular adhesion molecule 1 (ICAM1) and chemokines such as CXCL13, CCL19 and CCL21, are critical for recruitment of hematopoietic cells (1). Thus, TLS in CNS autoimmune diseases often developed in the meninges but not in neural parenchyma; this is because stromal cells mainly reside in the meninges (28). Also, FRCs play a critical role in maintaining aberrant components in the wrong tissue at the wrong time, thereby contributing to TLS persistence in chronic inflammatory diseases (2930).…”

Activated GL7+ B cells are maintained within the inflamed CNS in the absence of follicle formation during viral encephalomyelitis

“…In addition to Ig secretion, B cells are important modulators of immune responses during CNS insults. Their functions include antigen presentation, thereby promoting CD4 T cell activities, production of pro-and antiinflammatory cytokines, and formation of follicle structures, which enhance and maintain local immune responses independent of the periphery (Claes et al, 2015;Michel et al, 2015;Owens et al, 2011;Pikor et al, 2015). B cells are effective antigen presenting cells and B cell depletion diminishes CD4 T cell numbers, reactivation, and proinflammatory cytokine production in MS patients and in experimental allergic encephalomyelitis (EAE), a rodent model of MS (Parker Harp et al, 2015;Pierson et al, 2014;Weber et al, 2010).…”

“…Irrespective of defining functions of individual B cell subsets, the broader question of their recruitment and maintenance within the CNS remains under investigation (Claes et al, 2015;Michel et al, 2015;Owens et al, 2011;Pikor et al, 2015). During MS, similar clonality among B cell subsets in the CLN and CNS suggests an axis of continual recruitment after maturation in the periphery (Bankoti et al, 2014;Palanichamy et al, 2014;Stern et al, 2014).…”