Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood

Abstract

IntroductionB cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) directly ex vivo and after 96 h of polyclonal stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS).ResultsNine patients displayed B cells in the blood producing brain-specific antibodies directly ex vivo. Six patients were classified as B cell positive donors only after polyclonal B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly ex vivo and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40%) with a pattern II and three of 14 patients (21.4%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95% confidence interval 1.87-19.77).ConclusionsOur data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients.

Immunoglobulin free light chains in saliva: a potential marker for disease activity in multiple sclerosis

“…The reason for this change still needs to be determined, but it could be speculated that it is due to a local switch in the biosynthesis from IgA2 to IgA1 or IgG, leading to increased production of monomeric FLC. It is already known that MS flare may be preceded by T cell and B cell activity months before the clinical flare [27,28]. This finding lends further support to the view that even during clinical remission there is a subtle immunological activity, which may need special attention and perhaps certain measures for suppression.…”

“…Fifteen of 58 patients in remission continued to have higher than normal FLC indices, thus suggesting ongoing immunological activity despite perceived clinical remission. It is already known that MS flare may be preceded by T cell and B cell activity months before the clinical flare [27,28]. Whether our finding has treatment implications still needs to be investigated.…”

The brain antigen-specific B cell response correlates with glatiramer acetate responsiveness in relapsing-remitting multiple sclerosis patients

“…As previously reported, we were able to identify MS patients with a brain-reactive B cell response in the blood 24 25 . We hypothesized that the identification of brain-specific B cells in RRMS patients is as crucial at an early stage of the disease as the identification of treatment responders at the onset of GA therapy.…”

“…We have previously introduced an enzyme-linked immunospot technique (ELISPOT) assay for the ex vivo detection of brain-specific B cells 24 25 . Brain-reactive B cells were only detected in patients with clinically isolated syndrome or MS, but were absent in healthy subjects or in patients with other neurological or autoimmune diseases 24 25 . We have now used this bioassay to investigate whether GA treatment has an influence on the presence of autoreactive B cells in the blood of RRMS patients, and vice versa .…”

The Correlation between the Virus- and Brain Antigen-Specific B Cell Response in the Blood of Patients with Multiple Sclerosis

“…We have recently introduced an enzyme-linked immunospot (ELISPOT) assay for the detection of brain-specific B cells in the blood of patients with MS. These B cells only occurred in patients with clinically isolated syndrome or definite MS and were absent in healthy donors and in patients with other inflammatory and non-inflammatory neurological diseases as well as other autoimmune disorders [ 12 , 13 ]. In addition, the presence of directly ex vivo detectable brain antigen-specific B cells during relapse was associated with a significantly increased risk of the development of a subsequent relapse within the next few months [ 13 ].…”