While our understanding of multiple sclerosis (MS) pathophysiology increases, the definition of the etiology of the disease remains an unmet need. As most multifactorial diseases, elusive regulome alterations are part of the problem.
Over the years we have tried to combine genetic, epidemiological and immunological information to understand how this complex picture is funneled into specific (therapeutically actionable) pathophysiological mechanism in MS. As detailed in the proposal, our data and those from other research groups, suggest that a significant part of this complex dysregulation converges on the CD40 pathway, a master regulator of B lymphocyte responses. However, key mechanistic implications of the CD40 dysregulation remain unclear. For example, the CD40 downregulation that comes along with the MS-associated CD40 risk allele appears paradoxical, distinguishes MS from many other autoimmune diseases where it goes in the opposite direction and suggests caution with respect to therapies targeting this pathway. Hence, it is urgent to expand our knowledge about these mechanisms (CD40L antagonists are progressing from phase 2 to phase 3 clinical trials).
We will investigate whether the CD40 dysregulation may be better understood taking into account possible effectors of another master regulator of the pathway (which is implicated in MS etiology), namely Epstein-Barr virus (EBV). Based on preliminary and published data we will try to understand whether and how LMP1, an EBV protein and CD40 mimic, concurs with CD40 in regulating the activity of activation-induced deaminase (AID), a major driver of acquired gene expression variability, and a master regulator of the B cell response, known to be under the control of the CD40 pathway. If confirmed, this may represent a mechanism that amplifies and sustains the regulome dysfunction in B cell response that is so relevant for MS.
The pathogenic mechanism we are going to investigate is completely new for MS. However, our hypothesis rests on a novel interpretation of solid epidemiological, genetic and immunological data. Furthermore, we have produced a substantial amount of preliminary data.
Altogether, we think that it is probable that the hypothesis, though original, will be confirmed.
If successful, our investigation will support therapeutic approaches aimed at antagonizing pathogenic loops that originate from, and are part of, the causes of the disease. It is hoped that such therapies will represent another step towards the goal of a cure that ends MS rather than just controlling it in people who are affected.
Furthermore, our results may add unprecedented information about the effects of therapies that are entering an advanced phase of clinical evaluation (hence involving a substantial number of person with MS) and may carry some risk of paradoxical effects in case of an incomplete understanding of the pathway they are targeting.