Clonal expansion and somatic hypermutation of V(H) genes of B cells from cerebrospinal fluid in multiple sclerosis.

Qin, Yingzhi; Duquette, Pierre; Zhang, Yiping; Talbot, Pierre J.; Poole, Robin; Antel, Jack P.

doi:10.1172/jci3568

Cited by 300 publications

(181 citation statements)

References 43 publications

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“…B cells, which are found in the CNS compartment, display a limited heavy chain repertoire and also contain dominant clonotypes. These cells show extensive replacement mutations in the B cell receptor genes compatible with repeated antigenic challenges (6)(7)(8)(9)(10). Oligoclonal IgG bands (OCBs) are observed in the lesions and CSF but either to a much lesser extent or not at all in the serum of these MS patients (11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis

Cepok¹,

Zhou²,

Srivastava³

et al. 2005

J. Clin. Invest.

176

156

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MS is a chronic inflammatory and demyelinating disease of the CNS with as yet unknown etiology. A hallmark of this disease is the occurrence of oligoclonal IgG antibodies in the cerebrospinal fluid (CSF). To assess the specificity of these antibodies, we screened protein expression arrays containing 37,000 tagged proteins. The 2 most frequent MS-specific reactivities were further mapped to identify the underlying high-affinity epitopes. In both cases, we identified peptide sequences derived from EBV proteins expressed in latently infected cells. Immunoreactivities to these EBV proteins, BRRF2 and EBNA-1, were significantly higher in the serum and CSF of MS patients than in those of control donors. Oligoclonal CSF IgG from MS patients specifically bound both EBV proteins. Also, CD8 + T cell responses to latent EBV proteins were higher in MS patients than in controls. In summary, these findings demonstrate an increased immune response to EBV in MS patients, which suggests that the virus plays an important role in the pathogenesis of disease.

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Section: Introductionmentioning

confidence: 99%

Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis

Cepok¹,

Zhou²,

Srivastava³

et al. 2005

J. Clin. Invest.

176

156

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“…The intrathecal B cell expansion seems to occur early, or even prior to the disease [35,36], and established B cell clones are maintained for several years [37]. The V H genes from intrathecal B cells have undergone somatic hypermutation [38][39][40][41][42], which could favor T cell recognition of Ig Id. The high frequency of mutations, and the predominance of the IgG1 isotype [43], imply that the intrathecal B cell response in MS is antigen-driven and T cell dependent.…”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal fluid T cell clones from patients with multiple sclerosis: recognition of idiotopes on monoclonal IgG secreted by autologous cerebrospinal fluid B cells

Holmøy¹,

Fredriksen²,

Thompson³

et al. 2005

Eur. J. Immunol.

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Due to somatic recombination and hypermutation, Ig variable heavy (V H ) and light (V L ) regions contain unique immunogenic determinants, idiotopes (Id), which can stimulate T cells. To address the relevance of this in a human disease, monoclonal IgG (mAb)-secreting B cell clones were established from the cerebrospinal fluid (CSF) of two patients with multiple sclerosis (MS). HLA-DR-restricted CD4 + T cell lines and clones from CSF of both patients specifically recognized autologous CSF mAb. The CSF T cell clones produced IFN-c; some also produced TNF-a, IL-10 and IL-5. V H and V L on the monoclonal IgG derived from CSF B cells expressed amino acid replacements due to somatic mutations. A T cell epitope was mapped to a V H framework region, where an amino acid replacement was critical for the T cell recognition. The finding of Id-specific T cells and Id-bearing B cells in the CSF indicates that they coexist within the diseased organ, and provide a basis for the study of Id-driven T-B cell collaboration in a human autoimmune disease.

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“…In humans, the compartmentalisation of the immune response in CNS is underscored by the perpetual intrathecal synthesis of oligoclonal IgG in MS, CNS infections and other immune mediated neurological diseases, including SPS (Owens 2006;). CSF T and B cells from MS patients have been reported to be clonally expanded (Oksenberg 1990;Wucherpfennig 1992;Qin 1998;Colombo 2000;Owens 1998Owens , 2003Obermeier 2008) One of the major issues in understanding the pathophysiology of human autoimmune diseases is to identify the target antigens that drive the clonal expansion of autoreactive T cells. In paper II we showed that the synthesis of GAD65 IgG antibodies in SPS is oligoclonal and mediated by a stable population of affinity maturated B cell clones, suggesting that these antibodies are produced by B cells having received T cell help.…”

Section: The Relevance Of Csf Lymphocytes In the Studies Of Ms And Spsmentioning

confidence: 99%

MS and clinically isolated syndromes: Shared specificity but diverging clonal patterns of virus‐specific IgG antibodies produced in vivo and by CSF B cells in vitro

Skorstad

Vandvik

Vartdal

et al. 2009

Euro J of Neurology

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Background: Intrathecal synthesis of oligoclonal IgG antibodies against measles virus (MeV), varicella zoster virus (VZV) and herpes simplex virus type‐1 (HSV‐1) is a characteristic feature multiple sclerosis (MS). Methods: We have used isoelectric focusing‐immunoblot to define the clonal patterns of IgG and of IgG antibodies to MeV, VZV and HSV‐1 in supernatants of in vitro cultures of peripheral blood lymphocytes (PBL) and cerebrospinal fluid (CSF) cells and in sera and CSF from three patients with MS and three patients with clinically isolated syndromes (CIS) suspective of demyelinating disease. Results: In vitro synthesis of IgG by PBL was not detected in any patient. In contrast, in vitro synthesis by CSF cells of oligoclonal IgG and oligoclonal IgG antibodies to one or two of the three viruses tested was observed in all six patients. The clonal patterns of the in vitro synthesized IgG and virus specific IgG differed to varying extent from those synthesized intrathecally in vivo. However, in each patient, the in vitro and in vivo intrathecally produced antibodies displayed specificity for the same viruses. The addition of B cell activating factor (BAFF) had no effect on the amounts or clonal patterns of either total IgG or virus‐specific IgG produced by CSF cells in vitro. Conclusion: Virus specific B cells capable of spontaneous IgG synthesis are clonally expanded in the CSF of patients with MS. The B‐cell repertoire in CSF samples is only partially representative of the intrathecal B‐cell repertoire.

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Clonal expansion and somatic hypermutation of V(H) genes of B cells from cerebrospinal fluid in multiple sclerosis.

Cited by 300 publications

References 43 publications

Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis

Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis

Cerebrospinal fluid T cell clones from patients with multiple sclerosis: recognition of idiotopes on monoclonal IgG secreted by autologous cerebrospinal fluid B cells

MS and clinically isolated syndromes: Shared specificity but diverging clonal patterns of virus‐specific IgG antibodies produced in vivo and by CSF B cells in vitro

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