Impaired proliferation of peripheral B cells and indication of autoimmune disease in lyn-deficient mice

Nishizumi, Hirofumi; Taniuchi, Ichiro; Yamanashi, Yuji; Kitamura, Daisuke; Ilić, Duško; Mori, Shigeki; Watanabe, Takeshi; Yamamoto, Tadashi

doi:10.1016/1074-7613(95)90126-4

Cited by 442 publications

(439 citation statements)

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

“…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.…”

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

Orschell

Borneo

Munugalavadla

et al. 2008

Experimental Hematology

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Objective-Src family kinases (SFK) have been implicated in regulating growth factor and integrin-induced proliferation, migration, and gene expression in multiple cell types. However, little is known about the role of these kinases in the growth, homing, and engraftment potential of hematopoietic stem and progenitor cells.Results-Here we show that loss of hematopoietic-specific SFKs Hck, Fgr, and Lyn results in increased number of Sca-1 + Lin − cells in the bone marrow, which respond differentially to cytokine-induced growth in vitro and manifest a significant defect in the long-term repopulating potential in vivo. Interestingly, a significant increase in expression of adhesion molecules, known to coincide with the homing potential of wild-type bone marrow cells is also observed on the surface of SFK −/− cells, although, this increase did not affect the homing potential of more primitive Lin − Sca-1 + SFK −/− cells. The stem cell-repopulating defect observed in mice transplanted with SFK −/− bone marrow cells is due to the loss of Lyn Src kinase, because deficiency of Lyn, but not Hck or Fgr, recapitulated the long-term stem cell defect observed in mice transplanted with SFK −/− bone marrow cells.Conclusions-Taken together, our results demonstrate an essential role for Lyn kinase in positively regulating the long-term and multilineage engraftment of stem cells, which is distinct from its role in mature B cells and myeloid cells. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptEngraftment and reconstitution of normal hematopoiesis following transplantation of hematopoietic stem/progenitor (HSC/P) cells is the product of several important parameters, including the ability of hematopoietic stem cells (HSC) to home to, anchor within, and survive in specialized bone marrow (BM) niches, followed by timely proliferation and selfrenewal of stem cells for life-long hematopoiesis. While investigators have sought to understand the mechanisms behind each individual step, engraftment remains largely undefined.Besides homing and anchoring of HSC/P cells following transplantation, signals emanating from cytokine receptors also play a prominent role in regulating HSC/P cell growth and survival. In general, both positive and negative signals induced in response to cytokine stimulation contribute to this process. Deregulated signaling downstream from cytokine receptors can alter the growth and differentiation of these cells and, in some cases, contribute to leukemogenesis. Examples of molecules that are activated in response to hematopoietic growth factors include, but are not limited to, nonreceptor tyrosine kinases, such as Src family kinases (SFKs). SFKs function in signal transduction from growth factor receptors for granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, IL-5, stem cell factor (SCF), erythropoietin, M-CSF, G-CSF, thrombopoietin, and Flt3 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Although diverse cytokine receptors activat...

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Section: Discussionmentioning

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

Orschell

Borneo

Munugalavadla

et al. 2008

Experimental Hematology

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“…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).…”

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

Otsuka

Horiuchi

Yoshizawa

et al. 2004

Arthritis & Rheumatism

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Objective. To investigate whether polymorphism(s) or mutation(s) in the hematopoietic cellspecific Lyn substrate 1 (HS1) gene are involved in the pathogenesis of systemic lupus erythematosus (SLE).Methods. The entire coding region of the HS1 gene was analyzed by reverse transcriptase-polymerase chain reaction/single-strand conformational polymorphism analysis. HS1-transfected WEHI-231 cells or B lymphocytes from patients with SLE were studied for apoptosis, activation, and proliferation by flow cytometric analysis and MTT assay.Results. We identified a glutamic acid-prolineglutamic acid-proline insertion between codons 366 and 367 (EPEP366-367ins) and 2 amino acid substitutions (A235T and E361K). The genotype frequency among individuals homozygous for the EPEP؉ allele was 0.184 in 201 patients with SLE but only 0.098 in 184 healthy individuals (P ‫؍‬ 0.016). The allele frequency of EPEP366-367ins was 0.408 in patients with SLE; this frequency was significantly higher than that in healthy controls (0.312) (P ‫؍‬ 0.006). WEHI-231 cells transfected with EPEP؉ HS1 were 100-fold more sensitive to B cell receptor (BCR)-mediated apoptosis than were those transfected with HS1 without EPEP. B lymphocytes from SLE patients with the EPEP؉ allele were significantly more apoptotic without BCR stimulation and less activated after BCR stimulation than were those from SLE patients without the EPEP allele. Conclusion. These results suggest that HS1 with the EPEP insertion polymorphism transmits accelerated signals from BCR and is involved in the pathogenesis of SLE.Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by the presence of a variety of autoantibodies. Various genetic and environmental factors, including B cell hyperactivity, T cell dysfunction, and cytokine dysregulation, initiate immune activation in SLE that culminates in organ inflammation and damage (1-9). It has been considered that B cells are innocent bystanders that are activated secondarily by autoreactive T lymphocytes. However, recent evidence from the study of human SLE and its murine models suggests that B lymphocytes are intrinsically defective and are primarily essential for the maintenance of activated/memory T cells by presenting antigens to T cells.B cells from mice deficient in Lyn (10-12), CD22 (13-16), 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)

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“…Indeed, Lyn-deficient mice demonstrated the activation of autoreactive B lymphocytes and subsequent SLE-like symptoms, such as the production of anti-double-strand DNA antibody, splenomegaly and glomerulonephritis. 25,26 Moreover, it is shown that lupus B lymphocytes exhibit aberrant BCRmediated signal transduction. 13 These data prompted us to investigate BCR-associated signaling molecules in SLE patients.…”

Section: Introductionmentioning

confidence: 99%

Aberrant HS1 molecule in a patient with systemic lupus erythematosus

et al. 2003

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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the activation of autoreactive B lymphocytes, which are supposed to carry aberrant signal transduction after the stimulation of B-cell receptor (BCR). To investigate abnormalities in BCR-mediated signaling pathway in lupus B lymphocytes, we analyzed HS1, a molecule downstream of BCR, in 80 Japanese SLE patients. We identified 37 amino acid deletion of HS1 in a 25-year-old female patient, and the aberrant HS1 lacked a part of a functional motif. Analysis of genomic DNA revealed that the aberrant HS1 was caused by exon skipping. Family study showed that the patient as well as her father and sister are heterozygous for the abnormality. WEHI-231 cell, a mouse B cell line, transfected with the aberrant HS1 displayed a significantly increased cell death upon cross-linking of BCR. Additionally, peripheral B lymphocytes from the patient exerted increased apoptosis after BCR stimulation compared to those from control SLE patients. These data suggest that the aberrant HS1 molecule may transmit an accelerated signal after BCR stimulation and may play a role in the activation of autoreactive B lymphocytes.

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Impaired proliferation of peripheral B cells and indication of autoimmune disease in lyn-deficient mice

Cited by 442 publications

References 60 publications

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

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

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

Aberrant HS1 molecule in a patient with systemic lupus erythematosus

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