It is time to start trials targeting plasma cells in MS? #ResearchSpeak #MSBlog #MSResearch
The study below is one of many in the literature fingering B-cells and immunoglobulin as being potentially behind some of the pathology of MS.
In this study Rivas and colleagues show that plasmablasts (immature plasma cells) in CISers produce highly-selected, or mutated, oligoclonal antibodies that react with neurons. Imagine these plasmablasts taking up residence in the brain and spinal cord to become long-lived plasma cells. They will then continue to produce antibodies that may be driving ongoing neuronal loss. The neuronal loss, particularly in the gray matter, is considered to be one of the drivers of progressive MS and the cognitive impairment that becomes the norm in advanced MS.
There is clearly an unmet need to try and kill these plasma cells in MS. Plasma cells are a law unto themselves; they tend to take-up living in a niche and become independent of T-cell help. They change their genetic programme, or expression profile, lose important surface markers to become little protein (immunoglobulin) factories. This makes them resistant to our biological therapies, but not necessarily all therapies.
At present none of our licensed DMTs have reliably been shown to kill plasma cells within the brain and spinal cord. Therefore, at present we are not addressing one of the core pathologies of MS with our current therapies and this may explain why none of the current treatments have convincingly been shown to prevent progressive MS or modify its course. This is why we need to think laterally and try new add-on treatments to clear the CNS of unwanted plasma cells. The latter is easier said than done. We have several ideas that we are exploring and hopefully in the next few months we will have funding to do an add-on trial of a putative anti-plasma cell treatment in MS.
I am aware that some of you don’t think, or believe, that oligoclonal IgG bands play a role in MS. The pathological evidence would suggest otherwise. There are no place for beliefs in the field of MS only hypotheses. I feel strongly about this. What we need to do is design a study to prove, or preferably disprove, the hypothesis that oligoclonal IgG bands in MS are pathogenic and responsible for driving disease progression.
Rivas et al. Peripheral VH4+ plasmablasts demonstrate autoreactive B cell expansion toward brain antigens in early multiple sclerosis patients. Acta Neuropathol. 2016 Oct 11.
Plasmablasts are a highly differentiated, antibody secreting B cell subset whose prevalence correlates with disease activity in Multiple Sclerosis (MS). For most patients experiencing partial transverse myelitis (PTM), plasmablasts are elevated in the blood at the first clinical presentation of disease (known as a clinically isolated syndrome or CIS). In this study we found that many of these peripheral plasmablasts are autoreactive and recognize primarily gray matter targets in brain tissue. These plasmablasts express antibodies that over-utilize immunoglobulin heavy chain V-region subgroup 4 (VH4) genes, and the highly mutated VH4+ plasmablast antibodies recognize intracellular antigens of neurons and astrocytes. Most of the autoreactive, highly mutated VH4+ plasmablast antibodies recognize only a portion of cortical neurons, indicating that the response may be specific to neuronal subgroups or layers. Furthermore, CIS-PTM patients with this plasmablast response also exhibit modest reactivity toward neuroantigens in the plasma IgG antibody pool. Taken together, these data indicate that expanded VH4+ peripheral plasmablasts in early MS patients recognize brain gray matter antigens. Peripheral plasmablasts may be participating in the autoimmune response associated with MS, and provide an interesting avenue for investigating the expansion of autoreactive B cells at the time of the first documented clinical event.