Characterization of the B Lymphocyte Populations in Lyn-Deficient Mice and the Role of Lyn in Signal Initiation and Down-Regulation

Abstract

Lyn-deficient mice were generated to analyze the role of Lyn in B cell antigen receptor (BCR) signaling. These mice had a reduced number of peripheral B cells with a greater proportion of immature cells and a higher than normal turnover rate. Aged lyn-/- mice developed splenomegaly, produced autoantibodies, and had an expanded population of B lymphoblasts of the B1 lineage. Splenic B cells from young lyn-/- mice initiated early BCR signaling events, although in a delayed fashion. Unexpectedly, lyn-/- B cells exhibited an enhanced MAP kinase activation and an increased proliferative response to BCR engagement. Stimulation of lyn-/- B cells with intact and F(ab')2 anti-IgM revealed defects in at least two mechanisms that negatively regulate BCR signaling, one of which involves Fc gammaRIIb1.

Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

“…Although the precise mechanism(s) by which SFKs impact these functions in the HSC/P compartment are unclear, previous studies have demonstrated that these kinases in addition to both positively and negatively regulating functions in the same cell type can also antagonize the function of each other. For example, significant evidence exists to suggest that in B cells, early responses to BCR cross-linking are altered in Lyn −/− mice, supporting a role for Lyn in the initiation of signaling via the BCR [20,21,23]. Intriguingly, Lyn-deficient B cells are also hyperresponsive to anti-IgMinduced proliferation and demonstrate enhanced activation of mitogen-activated protein An alternate, but unlikely possibility to explain the increase in the number of relatively immature HSC/P cells in the BM of SFK −/− mice could be attributed to microenvironmental changes in these mice.…”

“…For example, significant evidence exists to suggest that in B cells, early responses to BCR cross-linking are altered in Lyn −/− mice, supporting a role for Lyn in the initiation of signaling via the BCR [20,21,23]. Intriguingly, Lyn-deficient B cells are also hyperresponsive to anti-IgMinduced proliferation and demonstrate enhanced activation of mitogen-activated protein kinase and sustained calcium mobilization [21][22][23]26]. Hernandez-Hansen et al [32] have shown that dysregulated signaling in Lyn-deficient mast cells is due in part to enhanced Fyn activation, and a recent study by Hong et al [33] suggested that the Src kinase Hck regulates mast cell activation by suppressing activation of Lyn.…”

“…Previous studies using Lyn-deficient mice have shown Lyn to play an essential role in maintaining signaling thresholds in B cells [21,25,26], myeloid cells, including in mast cells [14,19,[34][35][36][37]. Loss of Lyn results in reduced activation of phosphatases, such as SHIP, which results in hypersensitivity to cytokines [19,24,25].…”

“…Lyn −/− mice are hyperresponsive to myeloid growth factors and develop a myeloproliferative disorder due, in part, to loss of negative regulation through SHP-1 and SHIP phosphatases [19]. The importance of regulating Lyn activation is further demonstrated by additional pathological changes that occur in Lyndeficient mice, including lethal antibody-mediated autoimmune disease [20][21][22][23]. Lyndeficient mice succumb to autoimmune disease, and B cells from Lyn-deficient mice demonstrate hypersensitivity to B-cell receptor (BCR) stimulation.…”

Association of a four–amino acid residue insertion polymorphism of the HS1 gene with systemic lupus erythematosus: Molecular and functional analysis

“…B cells from mice deficient in Lyn (10)(11)(12), CD22 (13)(14)(15)(16), SHP-1 (17,18) exhibit a hyperreactive phenotype and produce autoantibodies. Indeed, Lyn-deficient mice demonstrate activation of autoreactive B cells and subsequent SLE-like symptoms, such as the production of anti-double-stranded DNA (anti-dsDNA) antibodies, splenomegaly, and glomerulonephritis (11,12).…”