In multiple sclerosis (MS), the immune system attacks the brain and the spinal cord. However, the relevant immune cell subsets driving the attack and their molecular targets are not known. This hampers our understanding of the disease and prevents us from developing better diagnostic test and more focused therapies.
In this project, we will test the hypothesis that a subgroup of MS patients is defined by a genetically determined immune cell response against specific molecular targets in the central nervous system. This hypothesis is based on our recent, pioneering results showing that approximately half of MS patients have a population of B cells in the cerebrospinal fluid characterized by a certain variant of the B cell receptor. So far, we have found that these B cells and their B cell receptors harbor certain patterns that is shared across MS patients, indicating that the same molecule(s) are triggering these immune cells. This could be exogenous molecules, such as viruses, or endogenous molecules that are present in the adult nervous system. The results of our study may change the way we define MS and yield fundamental new insights into B cell biology.
Multiple sclerosis (MS) typically afflict young people in their twenties, when they start a career and establish a family. The disease thus imposes a severe impact on quality of life and heavy economic burdens on society. Critical barriers to progress in the field are the lack of knowledge of relevant immune cell subsets driving the pathology and the targets of the immune response within the central nervous system. In this project, we will test the hypothesis that a subgroup of MS patients is defined by a genetically determined B cell response against specific antigenic epitopes. The hypothesis is based on our recent, pioneering results showing that approximately half of MS patients have a restricted population of B cells in the cerebrospinal fluid defined by polymorphisms in the constant heavy-chain of the immunoglobulin B cell receptor, the G1m1 allotype. Here, we aim to characterise the G1m1 B cells, to disentangle the genetic basis of the B cell response, and to identify the molecular targets. Preliminary results from single-cell RNA-sequencing experiments show that the G1m1 B cells express a specific pattern of immunoglobulin variable heavy-/light-chain combinations that is shared across the patients. This suggests that the G1m1 allele and genetic polymorphisms in the variable region genes could be linked. It also indicates that the G1m1 B cells recognise the same antigenic structures (epitopes). To explore the former possibility, we will do phased sequencing of the complete immunoglobulin heavy (IGH) locus and connect the germline repertoire to the functional B cell response in the cerebrospinal fluid. To define the molecular targets, we will carefully select signature B cell receptors, express them as recombinant IgG and IgM, apply next-generation peptide microarrays, and perform affinity purification experiments. The results may change the way we define MS and yield fundamental new insights into B cell biology.