Grant: Project Grant

B cells contribute to multiple sclerosis (MS) and other autoimmune diseases in a variety of ways (e.g. by producing antibodies); depleting them improves clinical outcomes. However, current treatments deplete most B cells, including regulatory B cells (Bregs) with beneficial anti-inflammatory properties. Studying Bregs could lead to more specific and safer therapies. In preliminary work, we found compelling evidence that another type of blood cells, the neutrophil, acts as a brake on a novel subset of Bregs expressing the protein Foxp3. This was observed in a new B cell-dependent form of experimental autoimmune encephalomyelitis (EAE), an improved mouse model for MS. In this project, our general goals are to: 1) determine the nature, anatomical distribution and function of these Foxp3+ Bregs; and 2) elucidate how neutrophils suppress their development. Our hypothesis is that Foxp3+ Bregs develop in lymph nodes, then migrate to the nervous system and restrain inflammation (e.g. via anti-inflammatory molecules); however, neutrophils counteract these Bregs by inhibiting their development via proinflammatory mediators, thereby promoting EAE. To test this, we will use state-of-the-art techniques to: 1) clarify the nature and fate of Foxp3+ Bregs in two forms of EAE; 2) validate that neutrophils suppress the development of Foxp3+ Bregs and elucidate the underlying mechanism; and 3) determine the ability of Foxp3+ Bregs to attenuate EAE when altered by genetic manipulations or when transplanted into EAE mice. Results will be confirmed in human. This project will unveil the existence of a neutrophil-Breg connection of great clinical relevance. For example, this connection offers a mechanism by which neutrophils may contribute to MS without entering the brain. This project will also help to identify new biomarkers and therapeutic strategies (e.g. anti-inflammatory drugs, autologous transplantation of Bregs) for MS and other immune conditions.