Polygenic Autoimmune Traits: Lyn, CD22, and SHP-1 Are Limiting Elements of a Biochemical Pathway Regulating BCR Signaling and Selection

Cornall, Richard J.; Cyster, Jason G.; Hibbs, Margaret L.; Dunn, Ashley R.; Otipoby, Kevin L.; Clark, Edward A.; Goodnow, Christopher C.

doi:10.1016/s1074-7613(00)80554-3

Cited by 412 publications

(357 citation statements)

References 49 publications

Supporting

Mentioning

329

Contrasting

Unclassified

Order By: Relevance

“…Under these circumstances, some of the factors causing a breakdown in tolerance could be antigen independent. Lyn-deficient B cells expressing Ig transgenes for hen egg lysozyme show increased differentiation to plasma cells even in the absence of lysozyme, which is consistent with a polyclonal B cell activation [29,54]. This process could be driven to affinity maturation and isotype class switching by antigen and TLR-dependent signals or by nonspecific activation of DC and hypersecretion of cytokines, such as IL-6.…”

Section: Discussionsupporting

confidence: 58%

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

et al. 2007

View full text Add to dashboard Cite

Recent evidence suggests that systemic autoimmune disease depends on signals from TLR ligands, but little is known about how TLR-dependent pathways lead to the loss of self tolerance in vivo. To address this, we have examined the role of TLR signaling in Lyndeficient mice, which develop an autoimmune disease similar to SLE. We found that absence of the TLR signaling adaptor molecule MyD88 suppresses plasma cell differentiation of switched and unswitched B cells, and prevents the generation of antinuclear IgG antibodies and glomerulonephritis. In mixed chimeras the increased IgM and IgG antibody secretion in Lyn-deficient mice is at least partially due to B cellindependent effects of Lyn. We now show that MyD88 deficiency blocks the expansion and activation of DC in which Lyn is also normally expressed, and prevents the hypersecretion of proinflammatory cytokines IL-6 and IL-12 by Lyn-deficient DC. These findings further highlight the important role of TLR-dependent signals in both lymphocyte activation and autoimmune pathogenesis. IntroductionOur understanding of the pathways leading to autoantibody (autoAb) production in systemic lupus erythematosus (SLE) has been greatly enhanced by studies of murine SLE models, including mice with single targeted mutations to negative regulators of BCR signaling, e.g., the src-family protein tyrosine kinase Lyn [1][2][3], phosphatase SHP-1 [4] and coreceptor CD22 [5, 6]. Lyn deficiency manifests as the hypersecretion of IgM, IgA and IgG autoAb, which, by 17-20 weeks of age, develop specificity to nuclear components such as dsDNA, are deposited as immune complexes (IC) in the kidneys and lead to lethal proliferative glomerulonephritis [1][2][3]. Following BCR stimulation, Lyn-deficient B cells have greater and more prolonged intracellular calcium flux, more MAPK activation and hyperproliferate in comparison to WT B cells [1, 7, 8]. These findings, together with the fact that the expression of Lyn is limited to B, NK and myeloid cells [9], have led to the suggestion that B cell intrinsic effects are the main cause of SLE-like autoimmune disease. Growing support for the central role B cells play in the development of autoimmune disease (reviewed in [10]) and the discovery of lower levels of Lyn in B cells of human SLE patients have helped strengthen this idea [11].However, the development of high-affinity pathogenic autoAb, which are targeted at nuclear antigens and potentially damaging to organs including kidneys, depends on somatic hypermutation in the germinal center and collaboration between cells of the adaptive and innate immune systems. T cells play an important role in this process and autoantigen-specific T cells are required for secretion of IgG autoAb specific for nuclear components and end-organ damage in the spontaneous murine models, MRL-lpr/lpr and (NZBÂNZW)F 1 [18]. Disease in the gp96 transgenic mice is dependent on MyD88, an adaptor molecule required for signaling by all TLR except TLR3, which binds dsRNA, and TLR4, which also signals by a MyD88-independent pa...

show abstract

Section: Discussionsupporting

confidence: 58%

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

et al. 2007

View full text Add to dashboard Cite

show abstract

“…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].…”

Section: Discussionmentioning

confidence: 99%

“…Loss of Lyn results in reduced activation of phosphatases, such as SHIP, which results in hypersensitivity to cytokines [19,24,25]. In both B cells as well as mast cells, loss of Lyn results in hyperactivation of AKT and the mitogen-activated protein kinase extracellular signal-regulated kinase.…”

Section: Discussionmentioning

confidence: 99%

“…Lyndeficient mice succumb to autoimmune disease, and B cells from Lyn-deficient mice demonstrate hypersensitivity to B-cell receptor (BCR) stimulation. In the B-cell compartment, in addition to positively contributing to BCR-induced ty-rosine phosphorylation, Lyn also plays an essential nonredundant role in phosphorylating specific tyrosine residues present in the immunoreceptor tyrosine-based inhibitory motifs in the cytoplasmic domains of inhibitory receptors, such as CD22 [24,25] and FcγRIIB [22,26]. …”

Section: Author Manuscriptmentioning

confidence: 99%

See 1 more Smart Citation

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

Orschell

Borneo

Munugalavadla

et al. 2008

Experimental Hematology

View full text Add to dashboard Cite

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...

show abstract

“…In keeping with this notion, studies of compound heterozygote mice have revealed the importance of threshold levels of proteins in controlling immune responses. 8,9 The phosphatidylinositol 3-kinase (PI3K) pathway which is activated following BCR and TCR stimulation 10,11 is well poised to regulate immune responses through antigen receptor signalling via the generation of phosphatidylinositol (3,4) bisphosphate (PIP 2 ) and phosphatidylinositol (3,4,5) trisphosphate (PIP 3 ). These reaction products allow translocation of multiple pleckstrin homology (PH) domain-containing proteins to the membrane, and these in turn regulate downstream events such as proliferation, apoptosis, protein synthesis, and cell shape (reviewed in Chan et al 12 and Martin 13 ).…”

Section: Introductionmentioning

confidence: 99%

Loss of a single allele of SHIP exacerbates the immunopathology of Pten heterozygous mice

et al. 2003

View full text Add to dashboard Cite

Phosphatidylinositol 3-kinase (PI3K) has emerged as a critical component of multiple immune system intracellular signalling pathways. The levels and relative ratios of PI3K products, phosphatidylinositol (3,4) bisphosphate (PI(3,4)P 2 ) and phosphatidylinositol (3,4,5) trisphosphate (PIP 3 ), are regulated by inositol phosphatases such as Pten and SHIP. Interestingly, mice heterozygous for Pten, a 3 0 -inositol phosphatase, develop a progressive lymphoproliferative syndrome with autoimmune features. Given the importance of PIP 3 species in regulating immune responses, we hypothesized that heterozygosity for the 5 0 -inositol phosphatase SHIP might exacerbate the autoimmune phenotype of Pten +/À mice. In keeping with this, mice heterozygous for both Pten and SHIP developed lymphoproliferation, hypergammaglobulinaemia, autoantibody titres and renal pathology that were more severe than that of Pten +/À mice. These results suggest that the relative levels of phosphatidylinositol phosphatases are likely critical to immune system homeostasis and they also highlight the potential for gene dosage effects in regulating susceptibility and/or severity of autoimmunity.

show abstract

Polygenic Autoimmune Traits: Lyn, CD22, and SHP-1 Are Limiting Elements of a Biochemical Pathway Regulating BCR Signaling and Selection

Cited by 412 publications

References 49 publications

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

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

Loss of a single allele of SHIP exacerbates the immunopathology of Pten heterozygous mice

Contact Info

Product

Resources

About