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

Abstract

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.

Systemic Autoimmune Disease Caused by Autoreactive B Cells That Receive Chronic Help from Ig V Region-Specific T Cells

“…Moreover, Id-specific T cells have been suggested to exist in SLE patients (8,9), and have been convincingly described in autoimmune BWF 1 mice (6) as well as in CD95 mutant lpr mice (7). Furthermore, it has very recently shown the coexistence of Id ϩ B cells and Idspecific T cells in the cerebral spinal fluid of patients with multiple sclerosis (11). Further studies on patients with autoimmune diseases are clearly warranted, to establish what contribution, if any, Id-driven T-B collaboration has in the pathogenesis of disease in humans.…”

“…Idspecific CD4 ϩ T cells have been found in mice with lupus (5-7) and in humans (8 -10) suffering from autoimmune diseases like systemic lupus erythematosus (SLE) 3 (8,9), arthritis (10), and multiple sclerosis (11). B lymphoma cells (4,12), B cells from Ig L chain transgenic mice (13)(14)(15), and normal B cells (15) spontaneously display endogenous V region Id peptides on their MHC class II molecules and activate Id-specific T cells.…”

The idiotype connection: linking infection and multiple sclerosis

“…Idspecific T cells have been found in lupus-prone mouse strains [19,61]. In humans, Id-specific CD4 + T cells have been identified in the blood of patients with systemic lupus erythematosus (SLE) and Wegener's granulomatosis [52][53][54][55], in the synovial fluid from patients with rheumatoid arthritis (RA) [56], and in the blood and CSF from patients with MS [46,47]. Furthermore, modulating Idspecific T cell responses by injecting inhibitory Id-peptide analogues can perturb the development of SLE in mice and humans [62,63].…”

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

“…An alternative approach would be to use monoclonal antibodies with distinct epitope specificities. CSF B cells have previously been cloned from the CSF of MS patients in our laboratory (Holmøy 2005). Yet the limited number of antigen specific B cells has so far precluded the cloning of human GAD65 specific CSF B cells.…”