A CD19-Dependent Signaling Pathway Regulates Autoimmunity in Lyn-Deficient Mice

When a BCR on a mature B cell is engaged by its ligand, the cell becomes activated, and the Ab-mediated immune response can be triggered. The initiation of BCR signaling is orchestrated by kinases of the Src and Syk families. However, the proximal BCR-induced phosphorylation remains incompletely understood. According to a model of sequential activation of kinases, Syk acts downstream of Src family kinases (SFKs). In addition, signaling independent of SFKs and initiated by Syk has been proposed. Both hypotheses lack sufficient evidence from relevant B cell models, mainly because of the redundancy of Src family members and the importance of BCR signaling for B cell development. We addressed this issue by analyzing controlled BCR triggering ex vivo on primary murine B cells and on murine and chicken B cell lines. Chemical and Csk-based genetic inhibitor treatments revealed that SFKs are required for signal initiation and Syk activation. In addition, ligand and anti-BCR Ab–induced signaling differ in their sensitivity to the inhibition of SFKs.

Section: Discussionmentioning

confidence: 99%

Nonredundant Roles of Src-Family Kinases and Syk in the Initiation of B-Cell Antigen Receptor Signaling

Štěpánek

Dráber

Drobek

et al. 2013

“…B cells play a major role in the development of autoimmune disease in Lyn-deficient mice. Lyn-deficient mice lacking B cells fail to develop autoimmune disease (23), as do Lyn 2/2 mice with null mutations in molecules essential for early B cell activation such as Btk and CD19 (24)(25)(26). Although few studies have investigated the role of other hematopoietic cells and the contribution of cytokines, a recent report has shown that disruption of TLR signaling in Lyn 2/2 MyD88 2/2 mice prevented the production of pathogenic auto-Abs and associated glomerulonephritis, and has suggested a role for proinflammatory cytokine secretion by dendritic cells (DCs) in disease pathogenesis (27).…”

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confidence: 99%

Autoimmune Disease in Lyn-Deficient Mice Is Dependent on an Inflammatory Environment Established by IL-6

Tsantikos

Oracki

Quilici

et al. 2009

122

Lyn-deficient mice develop Ab-mediated autoimmune disease resembling systemic lupus erythematosus where hyperactive B cells are major contributors to pathology. In this study, we show that an inflammatory environment is established in Lyn−/− mice that perturbs several immune cell compartments and drives autoimmune disease. Lyn−/− leukocytes, notably B cells, are able to produce IL-6, which facilitates hyperactivation of B and T cells, enhanced myelopoiesis, splenomegaly, and, ultimately, generation of pathogenic autoreactive Abs. Lyn−/− dendritic cells show increased maturation, but this phenotype is independent of autoimmunity as it is reiterated in B cell-deficient Lyn−/− mice. Genetic deletion of IL-6 on a Lyn-deficient background does not alter B cell development, plasma cell accumulation, or dendritic cell hypermaturation, suggesting that these characteristics are intrinsic to the loss of Lyn. However, hyperactivation of B and T cell compartments, extramedullary hematopoiesis, expansion of the myeloid lineage and autoimmune disease are all ameliorated in Lyn−/−IL-6−/− mice. Importantly, our studies show that although Lyn−/− B cells may be autoreactive, it is the IL-6–dependent inflammatory environment they engender that dictates their disease-causing potential. These findings improve our understanding of the mode of action of anti–IL-6 and B cell-directed therapies in autoimmune and inflammatory disease treatment.

“…Btk activation and membrane localization requires Src family PTK and phosphatidylinositol 3-kinase (PI3-kinase) activation (10, 11, 38 -40), with Btk activation contributing to phospholipase C␥ activation and [Ca 2ϩ ] i mobilization (13,41). A major function for CD19 is the regulation of Src family PTK activity (42)(43)(44). Lyn is the primary PTK to initially phosphorylate CD19 (43), while phosphorylated CD19, in turn, amplifies Src family PTK activity through events termed "processive amplification" (27,43).…”

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confidence: 99%

Complementary Roles for CD19 and Bruton’s Tyrosine Kinase in B Lymphocyte Signal Transduction

Fujimoto

Poe

Satterthwaite

et al. 2002

Self Cite

CD19 and Bruton’s tyrosine kinase (Btk) may function along common signaling pathways in regulating intrinsic and B cell Ag receptor (BCR)-induced signals. To identify physical and functional interactions between CD19 and Btk, a CD19-negative variant of the A20 B cell line was isolated, and CD19-deficient (CD19−/−) and CD19-overexpressing mice with the X-linked immunodeficient (Xid; Btk) mutation were generated. In A20 cells, Btk physically associated with CD19 following BCR engagement. CD19 and Btk interactions were not required for initial Btk phosphorylation, but CD19 expression maintained Btk in an activated state following BCR engagement. In primary B cells, CD19 signaling also required downstream Btk function since CD19-induced intracellular Ca2+ ([Ca2+]i) responses were modest in Xid B cells. In addition, CD19 overexpression did not normalize the Xid phenotype and most phenotypic and functional hallmarks of CD19 overexpression were not evident in these mice. However, CD19 and Btk also regulate independent signaling pathways since their combined loss had additive inhibitory effects on BCR-induced [Ca2+]i responses and CD19 deficiency induced a severe immunodeficiency in Xid mice. Thus, CD19 expression amplifies or prolongs Btk-mediated signaling, rather than serving as a required agent for Btk activation. Consistent with this, phosphatidylinositol 3-monophosphate kinase and Akt activation were normal in CD19−/− B cells following IgM engagement, although their kinetics of activation was altered. Thus, these biochemical and compound gene dosage studies indicate that Btk activation and [Ca2+]i responses following BCR engagement are regulated through multiple pathways, including a CD19/Src family kinase-dependent pathway that promotes the longevity of Btk signaling.