Project description:Somatic hypermutation (SHM) is a pivotal process in adaptive immunity that occurs in the germinal centre and allows B-cells to change their primary DNA sequence and diversify their antigen receptors. Here, we report that genome binding of Lamin B1, a component of the nuclear envelope involved in epigenetic chromatin regulation, is reduced during B cell activation and formation of lymphoid germinal centres. ChIP-Seq analysis showed that kappa and heavy variable immunoglobulin domains were released from the Lamin B1 suppressive environment when SHM was induced in B cells. RNAi-mediated reduction of Lamin B1 resulted in spontaneous SHM as well as kappa-light chain aberrant surface expression. Finally, Lamin B1 expression level was directly proportional to 5-year survival rate in chronic lymphocytic leukaemia, and was strongly involved in transformation of follicular lymphoma. In summary, here we report that Lamin B1 is a negative epigenetic regulator of SHM in normal B-cells and a "mutational gatekeeper", suppressing the aberrant mutations that drive lymphoid malignancy.
Project description:The mission of B lymphocytes is considered to reside primarily in immunoglobulin production; however, the success of B cell depletion in autoimmune diseases previously thought to be T cell-mediated suggests that some B cells fulfill other roles in autoimmunity. We examined the recently identified human B1 cell population for T cell stimulatory activity. We found two kinds of B1 cells that are distinguished by multiple surface markers and distinct transcriptomic profiles. In both umbilical cord and adult peripheral blood, the larger of the two, which is CD11b-, constitutes about 90% of B1 cells, whereas the smaller of the two, which is CD11b+, constitutes about 10% of B1 cells. These B1 cell populations differ functionally. CD11b- B1 cells spontaneously secrete much more IgM than CD11b+ B1 cells. In contrast, CD11b+ B1 cells express more CD86, and efficiently stimulate more T cell expansion, than CD11b- B1 cells. These CD11b+ B1 cells are markedly elevated in lupus patients and express increased CD86 and increased T cell stimulating activity in disease. This work distinguishes a novel, T cell-interacting B1 cell population whose expression and activity may be a reflection of, and a therapeutic target in, autoimmune disease. abstract
Project description:The mission of B lymphocytes is considered to reside primarily in immunoglobulin production; however, the success of B cell depletion in autoimmune diseases previously thought to be T cell-mediated suggests that some B cells fulfill other roles in autoimmunity. We examined the recently identified human B1 cell population for T cell stimulatory activity. We found two kinds of B1 cells that are distinguished by multiple surface markers and distinct transcriptomic profiles. In both umbilical cord and adult peripheral blood, the larger of the two, which is CD11b-, constitutes about 90% of B1 cells, whereas the smaller of the two, which is CD11b+, constitutes about 10% of B1 cells. These B1 cell populations differ functionally. CD11b- B1 cells spontaneously secrete much more IgM than CD11b+ B1 cells. In contrast, CD11b+ B1 cells express more CD86, and efficiently stimulate more T cell expansion, than CD11b- B1 cells. These CD11b+ B1 cells are markedly elevated in lupus patients and express increased CD86 and increased T cell stimulating activity in disease. This work distinguishes a novel, T cell-interacting B1 cell population whose expression and activity may be a reflection of, and a therapeutic target in, autoimmune disease. abstract Four groups each group comprising 3 samples for a total of 12 samples of human B cells were analyzed