The c-Myb transcription factor is required for normal adult hematopoiesis. However, the embryonic lethality of Myb-null mutations has been an impediment to identifying roles for c-Myb during ...lymphocyte development. We have used tissue-specific inactivation of the Myb locus in early progenitor cells to demonstrate that c-Myb is absolutely required for the differentiation of CD19(+) B-lineage cells and B cell differentiation is profoundly blocked beyond the pre-pro-B cell stage in Myb(f/f) Mb1-cre mice. We demonstrate that c-Myb is required for the intrinsic survival of CD19(+) pro-B cells as well as the proper expression of the alpha-chain of the IL-7 receptor (CD127) and Ebf1. However, survival of c-Myb-deficient CD19(+) pro-B cells cannot be rescued by transduction with CD127-producing retrovirus, suggesting that c-Myb controls a survival pathway independent of CD127. Furthermore, c-Myb-deficient progenitor cells inefficiently generate CD19(+) B-lineage cells during stromal cell culture but this process can be partially rescued with exogenous Ebf1. Thus, c-Myb does not appear to be required for commitment to B cell differentiation but is crucial for B cell differentiation to the CD19(+) pro-B cell stage as well as survival of CD19(+) pro-B cells. Surprisingly, forced c-Myb expression in lymphoid-primed multipotent progenitors favors differentiation toward the myeloid lineage, suggesting that proper c-Myb expression is crucial for B-lineage development.
Antiviral Abs, for example those produced in response to influenza virus infection, are critical for virus neutralization and defense against secondary infection. While the half-life of Abs is short, ...Ab titers can last a lifetime due to a subset of the Ab-secreting cells (ASCs) that is long lived. However, the mechanisms governing ASC longevity are poorly understood. Here, we have identified a critical role for extrinsic cytokine signals in the survival of respiratory tract ASCs in a mouse model of influenza infection. Irradiation of mice at various time points after influenza virus infection markedly diminished numbers of lung ASCs, suggesting that they are short-lived and require extrinsic factors in order to persist. Neutralization of the TNF superfamily cytokines B lymphocyte stimulator (BLyS; also known as BAFF) and a proliferation-inducing ligand (APRIL) reduced numbers of antiviral ASCs in the lungs and bone marrow, whereas ASCs in the spleen and lung-draining lymph node were surprisingly unaffected. Mice deficient in transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), a receptor for BLyS and APRIL, mounted an initial antiviral B cell response similar to that generated in WT mice but failed to sustain protective Ab titers in the airways and serum, leading to increased susceptibility to secondary viral challenge. These studies highlight the importance of TACI signaling for the maintenance of ASCs and protection against influenza virus infection.
A 3 yr old spayed female boxer weighing 22.8 kg was presented for severe, acute vomiting and tenesmus. Tachycardia, tachypnea, dehydration, and abdominal pain were present on physical examination. ...Abdominal radiographs showed a foreign object (golf ball) in the fundus of the stomach, and a larger, round, soft-tissue opacity mass in the region of the pylorus. Endoscopic removal of the foreign object was unsuccessful. A large soft-tissue mass (duodenogastric intussusception) was visualized with endoscopy, but was not correctly diagnosed until surgery. A midline exploratory celiotomy was performed and the duodenogastric intussusception was diagnosed and manually reduced. Severe pyloric wall edema and minimal bruising were present. A routine fundic gastrotomy was performed and the foreign object was removed. A right-sided incisional gastropexy and duodenopexy were performed in attempt to prevent recurrence of the intussusception. The dog was discharged from the hospital 38 hrs after surgery, and was normal on follow-up 1 yr after surgery. The dog in this report is the sixth documented case of duodenogastric/pylorogastric intussusception in the veterinary literature. This is the first reported case with a concurrent gastric foreign body and endoscopic visualization of the intussusception.
Peripheral B cell subsets Allman, David; Pillai, Shiv
Current opinion in immunology,
04/2008, Letnik:
20, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Our understanding of the origins and the biological functions of different peripheral B cell subsets continues to evolve. Some understanding has been obtained regarding the synergy between ...BCR-derived signals and other receptors and signaling pathways that drive the development of follicular, marginal zone, and B-1 B cells, but this remains a complex and poorly understood issue. More recent information regarding the origins of B-1 and B-2 B cells, the ability of follicular B cells to mature both in the bone marrow and the spleen, the existence of a definable precursor for MZ B cells, and the ability of follicular B cells to occupy two distinct niches are all highlighted in this review.
Little is known about the signals that promote early B lineage differentiation from common lymphoid progenitors (CLPs). Using a stromal-free culture system, we show that interleukin (IL)-7 is ...sufficient to promote the in vitro differentiation of CLPs into B220(+) CD19(+) B lineage progenitors. Consistent with current models of early B cell development, surface expression of B220 was initiated before CD19 and was accompanied by the loss of T lineage potential. To address whether IL-7 receptor (R) activity is essential for early B lineage development in vivo, we examined the frequencies of CLPs and downstream pre-pro- and pro-B cells in adult mice lacking either the alpha chain or the common gamma chain (gamma(c)) of the IL-7R. The data indicate that although gamma(c)(-/-) mice have normal frequencies of CLPs, both gamma(c)(-/-) and IL-7R(alpha)(-/-) mice lack detectable numbers of all downstream early B lineage precursors, including pre-pro-B cells. These findings challenge previous notions regarding the point in B cell development affected by the loss of IL-7R signaling and suggest that IL-7 plays a key and requisite role during the earliest phases of B cell development.
To determine the effects of propofol or etomidate on induction quality, arterial blood pressure, blood gases, and recovery quality in normal dogs.
Randomized, blinded trial.
Eighteen purpose-bred ...adult Beagles.
Dogs were randomly assigned to receive propofol at 8 mg kg−1 or etomidate at 4 mg kg−1 intravenously (IV) administered to effect. Midazolam was administered at 0.3 mg kg−1 IV as pre-medication at least 1 minute prior to induction. Direct arterial blood pressure, arterial blood gases, and heart rate were obtained at baseline, before induction, after induction, and for every 5 minutes afterwards until the dog began to swallow and the trachea was extubated. The dogs were allowed to breathe room air with the endotracheal tube in place.
The systolic arterial pressure (SAP) was higher in the etomidate group compared with the propofol group after induction. The SAP and mean arterial pressure (MAP) were higher in the etomidate group compared with the propofol group at 5 minutes. The recovery quality and ataxia score were worse in the etomidate group compared with the propofol group. Time from extubation to sternal recumbency and sternal recumbency to standing was longer in the etomidate group compared with the propofol group. The heart rate, PaCO2, and HCO3 were higher in the propofol group compared with the etomidate group after induction. The PaO2 and SaO2 were lower in the propofol group compared with the etomidate group after induction. The SAP and MAP were lower in the propofol group at 5 minutes compared with baseline.
Propofol caused a decrease in SAP and MAP which was not observed with etomidate. Etomidate caused longer and poorer recoveries than propofol.
Abstract
The efficiency with which B cells respond to activation signals varies depending on the subset. Whereas marginal zone (MZ) B cells exhibit rapid activation kinetics following stimulation, ...follicular (FO) B cells adopt delayed effector programs. The development and maintenance of MZ B cells uniquely requires signaling through transmembrane receptor family member Notch2, but whether this signal underlies distinctive response patterns among B cell subsets is not known. To examine the functional consequences of Notch2 signals on B cells with no Notch requirement, we cultured FO B cells on Notch2-ligand expressing OP9 stromal cells and subsequently stimulated them. Notch2-experienced FO B cells displayed a marked enhancement of several aspects of proliferation, including two-fold more rounds of division. Further, sensitivity to BCR cross-linking was enhanced by this signal, enabling cell cycle entry earlier and in response to lower concentrations of anti-BCR. Additionally, Notch2 signals modified responses to TLR stimuli Poly(I:C) and LPS by amplifying the time to first division and the propensity to become a plasma cell. Intriguingly, TLR3 responsiveness appeared to be an entirely Notch2-dependant mechanism. Employing a published mathematical model for dividing lymphocytes, we found Notch2 amplified the division destiny of both graded and quantal patterns of B cell responses. We next examined the timing and magnitude of Myc induction, a mitotic regulator and known Notch target. Remarkably, Myc levels prior to the first division appeared to be a direct predictor of division destiny. Together these observations highlight a novel role for Notch2 in modifying two distinct response patterns and their respective outcomes for B cells.
Supported by grants from NIH (T32-AI00763,R01 AI139123,T R01 AI154932)
Positive Selection of Natural Autoreactive B Cells Hayakawa, Kyoko; Asano, Masanao; Shinton, Susan A. ...
Science (American Association for the Advancement of Science),
07/1999, Letnik:
285, Številka:
5424
Journal Article
Recenzirano
Lymphocyte development is critically influenced by self-antigens. T cells are subject to both positive and negative selection, depending on their degree of self-reactivity. Although B cells are ...subject to negative selection, it has been difficult to test whether self-antigen plays any positive role in B cell development. A murine model system of naturally generated autoreactive B cells with a germ line gene-encoded specificity for the Thy-1 (CD90) glycoprotein was developed, in which the presence of self-antigen promotes B cell accumulation and serum autoantibody secretion. Thus, B cells can be subject to positive selection, generated, and maintained on the basis of their autoreactivity.
Notch1 signalling is essential for the commitment of multipotent lymphocyte precursors towards the αβ T-cell lineage and plays an important role in regulating β-selection in CD4−CD8− double-negative ...(DN) thymocytes. However, the role played by Notch in promoting the development of CD4+CD8+ double-positive (DP) thymocytes is poorly characterized. Here, we demonstrate that the introduction of a constitutively active Notch1 (ICN1) construct into RAG−/− lymphocyte precursors resulted in the generation of DP thymocytes in in vitro T-cell culture systems. Notably, developmental rescue was dependent not only on the presence of an intact Notch1 RAM domain but also on Delta-like signals, as ICN1-induced DP development in RAG−/− thymocytes occurred within an intact thymus or in OP9-DL1 co-cultures, but not in OP9-control co-cultures. Interestingly, ICN1 expression in SLP-76−/− precursors resulted in only a minimal developmental rescue to the immature CD8+ single-positive stage, suggesting that Notch is utilizing the same signalling pathway as the pre-TCR complex. In support of this, ICN1 introduction resulted in the activation of the ERK–MAPK-signalling cascade in RAG−/− thymocytes. Taken together, these studies demonstrate that constitutive Notch signalling can bypass β-selection during early T-cell development by inducing pre-TCR-like signals within a T-cell-promoting environment.
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