B Cell Repertoire Diversity and Clonal Expansion in Multiple Sclerosis Brain Lesions

Abstract

Multiple sclerosis (MS) lesions in the CNS are characterized by disseminated demyelination with perivascular infiltrates of macrophages, T cells, and B cells. To investigate the origin and characteristics of the B cell population found in MS plaque tissue, we performed molecular studies in 10 MS patients and 4 non-MS control samples. Ig transcripts from the perivascular infiltrated brain lesions were analyzed by complementary-determining region 3 spectratyping to ascertain the B cell heavy chain gene rearrangement repertoire expressed in MS brains. Significant rearrangement diversity and deviation from the normal Ig heavy (H) chain repertoire was observed. The cloning and sequencing of RT-PCR products from families VH1 and VH4 showed a correlation with the profiles obtained by spectratyping. Generally, restricted spectratyping patterns concurred with repetition of in-frame complementary-determining region 3 identical sequences. The analysis of heavy chain variable (VH), diversity (D), and joining (JH) gene segments revealed the increased usage of VH1–69, VH4–34, and VH4–39. Similarly, gene segments from families D2, D3, and JH4 were over-represented. The presence of restricted patterns of rearranged Ig mRNA within the plaque lesion suggests that Ab production in the demyelinating plaque is a local phenomenon and supports the idea that in MS an Ag-driven immune response might be responsible for demyelination.

Influence of Peripheral inflammation on the progression of multiple sclerosis: Evidence from the clinic and experimental animal models

“…The presence of B cells in recent MS plaques was first described in 1980 (Esiri, 1980), since then they were found to play a significant role in the pathology of the disease (reviewed in Wootla et al, 2011). As previously said, Baranzini et al were able to prove that a germinal center-like reaction takes place during the immune attack against CNS structures, with the production of antibodies within the plaques (Baranzini et al, 1999;Bradl and Lassmann, 2009;Kutzelnigg et al, 2005). Some of the roles attributed to these cells in MS pathology are: myelin-specific antigen presentation (acute demyelination and contribution to MS progression), abnormal cytokine production (decreased production of IL-10 may be responsible for the activation of proinflammatory T cells), and the production of immunoglobulins involved in demyelination or remyelination (reviewed in Wootla et al, 2011).…”

Determinants and Biomarkers of Progression Independent of Relapses in Multiple Sclerosis

“…Supernatants from cultured B cells from MS patients were toxic and induced more significant apoptosis in cultured neurons and oligodendrocytes than supernatants from cultured B cells from healthy controls 139,140 . The same antigen‐experienced B cell clones were found in meningeal immune cell infiltrates, the CSF and perivascular parenchymal lesions 141–143 . In addition, it has been demonstrated that B cell clones are bidirectionally exchanged between the CNS and the periphery and that affinity maturation occurs on both sides of the blood–brain barrier 144 .…”

“…139,140 The same antigen-experienced B cell clones were found in meningeal immune cell infiltrates, the CSF and perivascular parenchymal lesions. [141][142][143] In addition, it has been demonstrated that B cell clones are bidirectionally exchanged between the CNS and the periphery and that affinity maturation occurs on both sides of the blood-brain barrier. 144 More recently, a study in mouse models suggested that meningeal B cells encompass multiple stages of development and may originate in calvaria and then infiltrate and maturate in the meninges via a network of channels uncoupled from the systemic circulation.…”

Pathogenic myelin-specific antibodies in multiple sclerosis target conformational proteolipid protein 1–anchored membrane domains

“…One of the earliest biochemical observations of MS was the presence of cerebrospinal fluid (CSF) oligoclonal IgG bands (4). Oligoclonal bands (OCBs) are accompanied by elevated numbers of clonally expanded B cells and plasmablasts in CSF, meninges, and brain tissue (5)(6)(7)(8)(9)(10). Deep sequencing of B cell repertoires established clonal relationships between CSF IgG OCBs and CSF B cell clones (11) and among CSF and meningeal and MS lesion B cell infiltrates (12).…”