Download or read book Distinct Cytokine-defined Human B Cell Subsets in Health and Disease written by Rui Li and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Important antibody-independent pathogenic roles of B cells are emerging in autoimmune diseases including MS. The contrasting results of different treatments targeting B cells in patients (in spite of predictions of therapeutic benefit from animal models) call for a better understanding of the multiple roles that distinct human B cell subsets likely play in this illness. Cytokines expressed by B cells can be used as potential markers to define functionally distinct subsets. In spite of work carried out in mice, there remain substantial gaps in our knowledge of human cytokine-defined B cell subsets. The aim of my thesis is to better understand human cytokine-defined B cell subsets in both health and in MS, including their surface phenotype, distinct functions and the mechanisms (both external and internal) that regulate them. In the first part (Chapter 2) of my manuscript-based thesis, I identified a novel GM-CSF+ TNF[alpha]high IL-6high IL-10- effector B cell (Beff) subset that is abnormally increased, and more readily induced, in the peripheral blood of MS patients. These Beff cells strongly enhanced macrophage pro-inflammatory cytokine production through a GM-CSF-dependent mechanism. STAT5 and STAT6 were found to be important regulators of the balance between the Beff and Breg B cell subsets. Studies in patients with MS demonstrated that removal of total B cells using anti-CD20 therapy (which is very effective in limiting new MS activity) resulted in decreased myeloid cell pro-inflammatory responses. When B cells reconstituted in these patients, myeloid cells remained less inflammatory, in keeping with the lesser inflammatory profile of the reconstituting B cells. In chapter 3, I wished to investigate the impact of distinct B cell cytokine-defined subsets on T cell responses. To date, the study of B cell:T cell interactions in humans has been limited in part due to the lack of antigen specific systems to assess these interactions. I was able to establish a novel antigen-specific B-T co-culture system and used it to demonstrate that Beff cells can significantly enhance antigen-specific T cells responses to pathogens in an MHC-II restricted, CD80/CD86 and IL-6 dependent fashion. In chapter 4, I examined more closely the impact of human IL-10 expressing Breg cells on myeloid responses. I found that pro-inflammatory myeloid cell cytokine (IL-6, IL-12, TNF[alpha]) responses are significantly inhibited in co-culture with CpG-induced human Breg, an effect that was partially IL-10 dependent. CpG induced Bregs also inhibited expression of myeloid cell MHC-II and the co-stimulatory molecule CD86. Interestingly, atacicept (a TACI-Ig fusion protein) appeared to limit the induction of IL-10 expressing Bregs, providing a potential explanation for the paradoxical increase in MS disease activity seen with atacicept treatment. Together, the studies of my thesis enhance our understanding of human cytokine-defined, functionally distinct B cell subsets, both in healthy individuals and in MS patients. My results provide novel insights into the therapeutic mode of action of B cell depleting therapies in autoimmune disease, and the rational for selective targeting of distinct B cell subsets for future therapeutic approaches to both infectious and immune-mediated disease. " --