Tertiary Lymphoid Organs in Central Nervous System Autoimmunity

Abstract

Multiple sclerosis (MS) is an autoimmune disease characterized by chronic inflammation in the central nervous system (CNS), which results in permanent neuronal damage and substantial disability in patients. Autoreactive T cells are important drivers of the disease; however, the efficacy of B cell depleting therapies uncovered an essential role for B cells in disease pathogenesis. They can contribute to inflammatory processes via presentation of autoantigen, secretion of pro-inflammatory cytokines, and production of pathogenic antibodies. Recently, B cell aggregates reminiscent of tertiary lymphoid organs (TLOs) were discovered in the meninges of MS patients, leading to the hypothesis that differentiation and maturation of autopathogenic B and T cells may partly occur inside the CNS. Since these structures were associated with a more severe disease course, it is extremely important to gain insight into the mechanism of induction, their precise function, and clinical significance. Mechanistic studies in patients are limited. However, a few studies in the MS animal model experimental autoimmune encephalomyelitis (EAE) recapitulate TLO formation in the CNS and provide new insight into CNS TLO features, formation, and function. This review summarizes what we know so far about CNS TLOs in MS and what we have learned about them from EAE models. It also highlights the areas that are in need of further experimental work, as we are just beginning to understand and evaluate the phenomenon of CNS TLOs.

T lymphocytes and cytotoxic astrocyte blebs correlate across autism brains

“…In some foci, CD8 + and CD4 + T lymphocytes extend individually into the white and gray matter parenchyma (not shown). The larger lymphocytic cuffs sometimes contain CD20 + B cells, presumably representing transient immature tertiary lymphoid organs as reported in multiple sclerosis, which were often separate from the sites of astrocyte debris with associated CD8 + cytotoxic T lymphocytes. The increased collagen deposition and expanded perivascular spaces with jagged contours in ASD suggest a destructive effect of the elevated cytotoxic T lymphocytes.…”

Serum Lymphocyte-Associated Cytokine Concentrations Change More Rapidly over Time in Multiple System Atrophy Compared to Parkinson Disease

“…The presence of TNFβ together with IL-7 is required for lymph node and Peyer’s patch development, and increased concentrations of both of these cytokines may contribute to the formation of tertiary lymphoid organs in chronic inflammatory diseases [28, 29]. Of note, tertiary lymphoid organs are found in meninges of patients with multiple sclerosis and in mice with experimental autoimmune encephalitis [30]. Thus, it is intriguing to speculate that chronic inflammatory conditions associated with idiopathic PD may also drive the development of tertiary lymphoid organs, and these structures might provide a local source of activated T and B cells that contribute to the spread of brain pathology.…”

Role of chemokines in ectopic lymphoid structures formation in autoimmunity and cancer

“…It has been recently described that a group of innate lymphoid cells (ILC), probably ancestrally linked to the Th17 cells, and called “adult LTi” can also contribute to the development of ectopic lymphoid tissue. This process occurs by exploiting the same downstream pathway used by the Th17 subset . Furthermore, it has lately emerged that also IL‐21‐producing and ICOS‐expressing T follicular helper (Tfh) cells may be involved in ELS generation and activities, as the organization of the GC and the production of high‐affinity immunoglobulins appear deranged in the absence of Tfh .…”

“…This process occurs by exploiting the same downstream pathway used by the Th17 subset. 33,39 Furthermore, it has lately emerged that also IL-21-producing and ICOS-expressing T follicular helper (Tfh) cells may be involved in ELS generation and activities, as the organization of the GC and the production of high-affinity immunoglobulins appear deranged in the absence of Tfh. 40 In line with that, an increased rate of circulating Tfh cells can be detected in several autoimmune conditions characterised by ELS formation.…”