Download or read book Interactions Between B Cells and CD8+ T Cells in Multiple Sclerosis written by Ayman Rezk and published by . This book was released on 2020 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Previous studies have identified functionally distinct human B cell sub-populations based on distinct cytokine expression profiles and characterized the functional capacities of such B cell subsets to modulate T cell and myeloid cell effector functions. Such antibody-independent B cell functions have emerged as highly relevant to disease activity in multiple sclerosis (MS), as evidenced by the ability of B-cell depleting therapy to robustly reduce new relapsing disease activity while having minimal to no impact on the abnormal antibody profile within the central nervous system (CNS) of patients. While these results have been interpreted to reflect B cell:CD4+ T cell interactions, we noted that B-cell depleting therapy results in reduced effector functions of both CD4+ and CD8+ T cells, suggesting that B cells and CD8+ T cells may also interact in disease-relevant ways. It is noteworthy that in MS, CD8+ T cells are actually more abundant in the inflamed MS CNS than are CD4+ T cells. Furthermore, among the CNS-infiltrating T cells in MS, pathologists have identified presence of clonally expanded mucosal-associated invariant T cell receptor (MAIT) cells expressing pro-inflammatory effector molecules. The overall aim of my thesis is to characterize antibody-independent interactions between human B cells and CD8+ T (both MAIT and non-MAIT) cells, and their possible implication in MS pathophysiology. Chapter 1 introduces multiple sclerosis by summarizing the genetic and environmental factors associated with disease development, highlighting the roles of CD4+ T cells and B cells in disease pathogenesis and the implication of CD8+ T cells, including MAIT cells, in MS. In Chapter 2, I set out to optimize an approach for the simultaneous isolation of multiple rare cytokine-secreting viable human B cells. I demonstrate that the cytokine-secretion assay can be developed and applied for the detection and isolation of multiple highly-purified, viable, low-frequency cytokine-defined B cells (i.e. secreting GM-CSF or IL-10), and that isolated cell fractions are amenable for gene expression profiling and in vitro culture. The assay can be multiplexed, wherein up to three cytokines can be simultaneously detected on B cells, without any impact on cell purity, though a variable loss in yields requires assay optimization. Overall, this approach is a stepping-stone in enabling future investigations into the biology of these cytokine-defined B cell subsets. In chapter 3, I examine the interactions between B cells and both CD8+ MAIT and non-MAIT cells using a series of in vitro experiments complemented by deep immunophenotyping of CD8+ T cells within peripheral blood mononuclear cells obtained prior to and after B cell depletion therapy in patients with MS. I found that B cells have opposing effects on different CD8+T cell subsets, namely induction of proliferation, pro-inflammatory cytokine responses, and cytotoxicity of MAIT cells, yet suppression of non-MAIT cell proliferation and pro-inflammatory cytokine production. In vivo, B cell depletion in MS patients results in reduced counts and pro-inflammatory responses of MAIT cells. Overall, these observations provide novel insights into fundamental functions of human B cells in the modulation of CD8+ T cell effector responses, in both health and disease. They also add to our understanding of the complex cellular networks involving the balance between pro- and anti-inflammatory functions of different cell types and their interactions in the pathogenesis of multiple sclerosis by invoking a B cell:CD8+ T cell axis (and particularly the role of B cell: MAIT cell interactions), which may be therapeutically targeted by B cell depletion. Further characterization of cytokine-defined B cell responses and their interactions with CD8+ MAIT and non-MAIT cells could enable the development of more focused therapies that selectively impact these interactions for the treatment of autoimmune diseases"--