T cells from multiple sclerosis patients recognize immunoglobulin G from cerebrospinal fluid

Abstract

Idiotopic sequences are created after V, D and J recombinations and by somatic mutations during affinity maturation of immunoglobulin (Ig) molecules, and may therefore be potential immunogenic epitopes. Idiotope-specific T cells are able to activate and sustain the B cells producing such idiotopes. It is therefore possible that idiotope-specific intrathecal T cells could help maintain the persisting intrathecal synthesis of oligoclonal IgG observed in patients with multiple sclerosis (MS). This study was undertaken to examine T-cell responses to cerebrospinal fluid (CSF) IgG. Peripheral blood mononuclear cells (PBMC) from 14 of 21 MS patients and four of 17 control patients with other neurological diseases proliferated upon stimulation with autologous CSF IgG, while five and three, respectively, responded to serum IgG. By comparison, responses to myelin basic protein were recorded in only four MS and three control patients. Data from a limited number of patients indicate that the CSF IgG responsive cells were CD4+ and human leucocyte antigen DR restricted, that PBMC also respond to CSF IgG from other MS patients and that the CSF may contain T cells responding to autologous CSF IgG. This suggests that CSF IgG, or substances bound to this IgG, may represent T-cell immunogens, which could contribute to the intrathecal immune response in MS.

The idiotype connection: linking infection and multiple sclerosis

“…Experimental support of the hypothesis In agreement with the proposed hypothesis, most MS patients display proliferative T cell responses against autologous CSF IgG [46]. Further, Id + B cells and Id-specific CD4 + T cells have been cloned from the CSF of MS patients, and EBV transformed CSF B cells were shown to activate CSF CD4 + T cells in an Id-specific manner [47,48].…”

“…31 No.2 Our studies suggest that Id-specific CSF T cells have a predominant Th1 phenotype, that they kill oligodendrocytes in vitro, and that they are quite prevalent in the CSF of MS patients [43,46,47]. Their pathogenicity in vivo is, however, difficult to establish in humans.…”

“…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].…”

T Cell Tolerance to Germline-Encoded Antibody Sequences in a Lupus-Prone Mouse

“…Several groups have reported evidence in support of receptor presentation in autoimmunity (27,30,31,(35)(36)(37)(38)(39)(40). In a preceding study, we conducted a genealogical analysis of somatic mutations within an autoreactive B cell lineage obtained from a spontaneously diseased SNF 1 mouse.…”

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

“…We have previously demonstrated that CD4 + T cells from the majority of MS patients recognize autologous CSF IgG [44]. However, it could not be excluded that the T cells actually recognized an antigen complexed to the IgG.…”