Lymphoid chemokines in chronic neuroinflammation

Abstract

Lymphoid chemokines play an essential role in the establishment and maintenance of lymphoid tissue microarchitecture and have been implicated in the formation of tertiary (or ectopic) lymphoid tissue in chronic inflammatory conditions. Here, we review recent advances in lymphoid chemokine research in central nervous system inflammation, focusing on multiple sclerosis and the animal model experimental autoimmune encephalomyelitis. We also highlight how the study of lymphoid chemokines, particularly CXCL13, has led to the identification of intrameningeal B-cell follicles in the multiple sclerosis brain paving the way to the discovery that these abnormal structures are highly enriched in Epstein-Barr virus-infected B cells and plasma cells.

Fig. 1

CXCL13 in MS ectopic B-cell follicles and CSF. Immunostainings for the pan B-cell marker CD20 (A) and for the lymphoid chemokine CXCL13 (B) were performed on serial brain sections from a case with secondary progressive MS, as previously described (Serafini et al., 2007). An intrameningeal B-cell follicle comprising numerous CD20+ B cells (A) aggregated around a network of CXCL13+ stromal cells/follicular dendritic cells (B) is shown. In situ hybridization for EBER (C) and immunostaining for the EBV latent protein LMP1 (D) (see Serafini et al., 2007 for staining protocols) reveal enrichment in EBV-infected cells inside the same B-cell follicle shown in A, B. Original magnifications: 250× in A, C and D, 1000× in B. Panel E shows the levels of CXCL13 protein in post-mortem CSF of MS cases that were classified as EBV-high (n = 7) and EBV-low (n = 9) based on the frequency of EBV-infected cells accumulating in the meninges and in white matter lesions (Serafini et al., 2007). The levels of CXCL13 are significantly higher in the CSF of MS cases characterized by more prominent deposits of EBV infection in brain tissue. CXCL13 levels were determined with a quantitative sandwich ELISA, in accordance with manufacturer's instructions (R&D Systems, Minneapolis, MN, USA). Bars indicate median values. Between-group comparison was performed by Mann–Whitney test.