Regulatory B cells in multiple sclerosis - functional characterization and therapeutic implication

• Applicant: Professor Dr. Martin Weber
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 383699619

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, in which disability can occur as acute relapses or as continuous chronic deterioration. In its pathogenesis, B cells and B cell-derived products may play a key role; in many MS patients, peripheral B cells show signs of chronic activation and pro-inflammatory differentiation. In the cerebrospinal fluid, clonally expanded plasma cells produce oligoclonal immunoglobulins, which remain a hallmark diagnostic finding. Moreover, anti-CD20-mediated depletion of B cells halted development of CNS lesions and reduced occurrence of relapses in recent clinical MS trials. Besides such evidence for their pathogenic contribution, B cells may exert anti-inflammatory properties in MS. Naïve B cells, in MS patients similar to healthy controls, are a relevant source of regulatory cytokines, such as IL-10, which dampens the activity of other immune cells. Mice deficient in releasing regulatory B cell cytokines fail to recover from an acute attack in the MS model experimental autoimmune encephalomyelitis (EAE) and instead chronically deteriorate. B cells are thus crucially involved in development of relapses caused by de novo CNS infiltration, and yet convey the potential to promote recovery and to prevent transition to chronic progression. To decrypt this apparent enigma with wide-ranging clinical implications, we will functionally characterize and possibly delineate regulatory B cell function from pathogenic B cell properties in MS. At first, we will characterize B and plasma cells in CNS tissues from MS patients. These studies are now possible by an imaging technique developed at our Institute. In conjunction with transcriptome analyses, we will investigate whether all B cells in MS lesions are uniformly pathogenic, and whether subtypes of patients or CNS lesions may vary in the extent of pathogenic versus regulatory B cells (aim 1). Second, we will determine whether MS patients differ in the relative extent of peripheral pro- and anti-inflammatory B cells. We will correlate this individual B cell phenotype to the loss of IL-10 and the relative increase of pro-inflammatory monocyte function upon anti-CD20 treatment. In perspective and correlation with the clinical outcome, these immunological parameters could develop into an urgently needed biomarker predicting the individual response to anti-CD20 treatment (aim 2). Lastly, we will investigate in EAE, whether, where and how B cells promote recovery and control chronic progression. For this purpose, we are utilizing a purely T cell-mediated EAE model, in which anti-CD20 substantially deteriorates disease severity. Using this model in combination with adoptive transfer and tracking of genetically modified B cells, we will investigate to what extent B cells can dampen CNS intrinsic circuits of inflammation, the assumed correlate of progression and which B cell property is required to mediate this effect (aim 3).

• DFG Programme: Research Grants