B cell repertoire expansion occurs in meningeal ectopic lymphoid tissue
Klaus Lehmann-Horn, Sheng-zhi Wang, Sharon A. Sagan, Scott S. Zamvil, H.-Christian von Büdingen
Klaus Lehmann-Horn, Sheng-zhi Wang, Sharon A. Sagan, Scott S. Zamvil, H.-Christian von Büdingen
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Research Article

B cell repertoire expansion occurs in meningeal ectopic lymphoid tissue

Abstract

Ectopic lymphoid tissues (ELT) can be found in multiple sclerosis (MS) and other organ-specific inflammatory conditions. Whether ELT in the meninges of central nervous system (CNS) autoimmune disease exhibit local germinal center (GC) activity remains unknown. In an experimental autoimmune encephalomyelitis model of CNS autoimmunity, we found activation-induced cytidine deaminase, a GC-defining enzyme, in meningeal ELT (mELT) densely populated by B and T cells. To determine GC activity in mELT, we excised meningeal lymphoid aggregates using laser capture microscopy and evaluated B cell repertoires in mELT and secondary lymphoid organs by next-generation immune repertoire sequencing. We found immunoglobulin heavy chain variable region sequences that were unique to mELT and had accumulated functionally relevant somatic mutations, together indicating localized antigen-driven affinity maturation. Our results suggest that B cells in mELT actively participate in CNS autoimmunity, which may be relevant to mELT in MS and ELT in other chronic inflammatory conditions.

Authors

Klaus Lehmann-Horn, Sheng-zhi Wang, Sharon A. Sagan, Scott S. Zamvil, H.-Christian von Büdingen

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Figure 5

SHM in IgG but not IgM transcripts from mELT occurs in an antigen-driven fashion and exhibits a profile distinct from that in other, peripheral immune compartments.

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SHM in IgG but not IgM transcripts from mELT occurs in an antigen-driven...
(A–D) The frequency of aa mutations in an 81-aa portion of the VDJ region, starting with the first aa of the CDR1 (IMGT position 28) and extending to the last aa of the CDR3 (IMGT position 115), is plotted. Only IgG sequencing reads are included. Data from the blood (A), an inguinal LN (B), the spleen (C), and mELT (D) from one representative Th×2D2 EAE mouse are shown (n = 5 mice). CDR1, CDR2, and CDR3 according to IMGT are highlighted in green. (E and F) Cumulative mutation counts in the CDRs (CDR1, CDR2, and CDR3 together) and the framework regions (FR2 and FR3 together) were normalized separately for their respective length and plotted against each other. Data from the blood, LN, spleen and mELT are shown from (E) 5 Th×2D2 EAE mice or (F) 4 Th×2D2 EAE mice (for mELT, only 2 data points were available), respectively. Data points located to the right of the black line indicate overrepresentation of SHM in the CDRs compared with the FRs, suggesting an antigen-driven process. ns, not significant; *P ≤ 0.05; paired 2-tailed t test adjusted for multiple comparison using the Benjamini-Hochberg method. SHM, somatic hypermutation; mELT, meningeal ectopic lymphoid tissue; CDR, complementarity determining region; LN, lymph node; EAE, experimental autoimmune encephalomyelitis; IMGT, International ImMunoGeneTics; FR, framework region.