A Distinct Class of Antibodies May Be an Indicator of Gray Matter Autoimmunity in Early and Established Relapsing Remitting Multiple Sclerosis Patients.ASN Neuro. 2015 Oct 21;7(5). pii: 1759091415609613. doi: 10.1177/1759091415609613.
We have previously identified a distinct class of antibodies expressed by B cells in the cerebrospinal fluid (CSF) of early and established relapsing remitting multiple sclerosis (RRMS) patients that is not observed in healthy donors. These antibodies contain a unique pattern of mutations in six codons along VH4 antibody genes that we termed the antibody gene signature (AGS). In fact, patients who have such B cells in their CSF are identified as either having RRMS or developing RRMS in the future. As mutations in antibody genes increase antibody affinity for particular antigens, the goal for this study was to investigate whether AGS(+) antibodies bind to brain tissue antigens. Single B cells were isolated from the CSF of 10 patients with early or established RRMS. We chose 32 of these B cells that expressed antibodies enriched for the AGS for further study. We generated monoclonal full-length recombinant human antibodies (rhAbs) and used both immunological assays and immunohistochemistry to investigate the capacity of these AGS(+) rhAbs to bind brain tissue antigens. AGS(+) rhAbs did not recognize myelin tracts in the corpus callosum. Instead, AGS(+) rhAbs recognized neuronal nuclei and/or astrocytes, which are prevalent in the cortical gray matter. This pattern was unique to the AGS(+) antibodies from early and established RRMS patients, as AGS(+) antibodies from an early neuromyelitis optica patient did not display the same reactivity. Prevalence of CSF-derived B cells expressing AGS(+) antibodies that bind to these cell types may be an indicator of gray matter-directed autoimmunity in early and established RRMS patients.
B cells are currently the go to cells in MS, but what is it about the antibodies that they produce in MS that is distinct from those without MS? In fact we know from practice that depletion of B cells can help in RRMS, and plasmapharesis which removes circulating antibodies can help in some patients. When blood from MS patients has been added to cultures containing astrocytes, oligodendrocytes (myelin forming cells), and neurones in the lab they have resulted in damage to these cells.
Here the authors say that the characteristic of the antibody heavy chain variable regions genes in B cells predicts the development of RRMS by 85-94% accuracy. These antibody genes appear to have developed mutations in the variable regions at an excessive rate compared to normals. The authors have called this feature of the MS antibody genes AGS. When B cells in MS CSF accumulate these mutations in their antibody genes (AGS+), their antibodies have higher affinities for certain antigens, namely neuronal neuclei of cortical grey matter. Can this explain the extent of grey matter vs white matter (26.5% vs 6.5%) lesions in MS? And the dominance of grey matter atrophy in MSers with greater disease activity?
Can elimination of the AGS+ plasma cells in the CSF become a targeted therapy for slowing down cognitive decline in MSers? Do we have the technology for this?