HIV: Dendritic cells as embers for the infectious fire

AbstractIn people with HIV-1, most of the CD4-expressing T cells that produce virus are short-lived and vulnerable to anti-retroviral agents. But the initial ‘fire’ of HIV-1 infection may begin in, and be maintained by, cells of the dendritic cell lineage

CD22: A Regulator of Innate and Adaptive B Cell Responses and Autoimmunity

CD22 (Siglec 2) is a receptor predominantly restricted to B cells. It was initially characterized over 30 years ago and named “CD22” in 1984 at the 2nd International workshop in Boston (1). Several excellent reviews have detailed CD22 functions, CD22-regulated signaling pathways and B cell subsets regulated by CD22 or Siglec G (2–4). This review is an attempt to highlight recent and possibly forgotten findings. We also describe the role of CD22 in autoimmunity and the great potential for CD22-based immunotherapeutics for the treatment of autoimmune diseases such as systemic lupus erythematosus (SLE)

Janus Configurations, Chern-Simons Couplings, And The Theta-Angle in N=4 Super Yang-Mills Theory

We generalize the half-BPS Janus configuration of four-dimensional N=4 super Yang-Mills theory to allow the theta-angle, as well as the gauge coupling, to vary with position. We show that the existence of this generalization is closely related to the existence of novel three-dimensional Chern-Simons theories with N=4 supersymmetry. Another closely related problem, which we also elucidate, is the D3-NS5 system in the presence of a four-dimensional theta-angle.Comment: 66 p

The B Lymphocyte Adaptor Molecule of 32 kD (Bam32) Regulates B Cell Antigen Receptor Signaling and Cell Survival

The B lymphocyte–associated adaptor protein 32 kD in size (Bam32) is expressed at high levels in germinal center (GC) B cells. It has an NH2-terminal src homology 2 (SH2) domain which binds phospholipase C (PLC)γ2, and a COOH-terminal pleckstrin homology (PH) domain. Thus, Bam32 may function to integrate protein tyrosine kinase (PTK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways in B cells. To further define the role Bam32 plays in B cells, we generated Bam32-deficient DT40 cells. These Bam32−/− cells exhibited lower levels of B cell antigen receptor (BCR)-induced calcium mobilization with modest decreases in tyrosine phosphorylation of phospholipase C (PLC)γ2. Moreover, BCR-induced activation of extracellular signal-regulated kinase (ERK), c-jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) pathways was impaired in Bam32−/− cells but not the activation of Akt-related pathways. Activation of downstream transcription factors such as nuclear factor of activated T cells (NF-AT) and nuclear factor of κ binding (NF-κB) was also impaired in Bam32−/− cells. Furthermore, Bam32−/− cells were more susceptible to BCR-induced death. Taken together, these findings suggest that Bam32 functions to regulate BCR-induced signaling and cell survival most likely in germinal centers

B cell-activating factor (BAFF) from dendritic cells, monocytes and neutrophils is required for B cell maturation and autoantibody production in SLE-like autoimmune disease

Purpose and methodsB cell-activating factor (BAFF) contributes to the pathogenesis of autoimmune diseases including systemic lupus erythematosus (SLE). Although several anti-BAFF Abs and derivatives have been developed for the treatment of SLE, the specific sources of BAFF that sustain autoantibody (auto-Ab) producing cells have not been definitively identified. Using BAFF-RFP reporter mice, we identified major changes in BAFF-producing cells in two mouse spontaneous lupus models (Tlr7 Tg mice and Sle1), and in a pristane-induced lupus (PIL) model.ResultsFirst, we confirmed that similar to their wildtype Tlr7 Tg and Sle1 mice counterparts, BAFF-RFP Tlr7 Tg mice and BAFF-RFP Sle1 mice had increased BAFF serum levels, which correlated with increases in plasma cells and auto-Ab production. Next, using the RFP reporter, we defined which cells had dysregulated BAFF production. BAFF-producing neutrophils (Nphs), monocytes (MOs), cDCs, T cells and B cells were all expanded in the spleens of BAFF-RFP Tlr7 Tg mice and BAFF-RFP Sle1 mice compared to controls. Furthermore, Ly6Chi inflammatory MOs and T cells had significantly increased BAFF expression per cell in both spontaneous lupus models, while CD8- DCs up-regulated BAFF expression only in the Tlr7 Tg mice. Similarly, pristane injection of BAFF-RFP mice induced increases in serum BAFF levels, auto-Abs, and the expansion of BAFF-producing Nphs, MOs, and DCs in both the spleen and peritoneal cavity. BAFF expression in MOs and DCs, in contrast to BAFF from Nphs, was required to maintain homeostatic and pristane-induced systemic BAFF levels and to sustain mature B cell pools in spleens and BMs. Although acting through different mechanisms, Nph, MO and DC sources of BAFF were each required for the development of auto-Abs in PIL mice.ConclusionsOur findings underscore the importance of considering the relative roles of specific myeloid BAFF sources and B cell niches when developing treatments for SLE and other BAFF-associated autoimmune diseases

BAFF regulates B cell survival by downregulating the BH3-only family member Bim via the ERK pathway

The B cell activating factor belonging to the tumor necrosis factor family (BAFF) is required for B cell survival and maturation. The mechanisms by which BAFF mediates B cell survival are less understood. We found that BAFF and a proliferation-inducing ligand (APRIL), which are related, block B cell antigen receptor (BCR)–induced apoptosis upstream of mitochondrial damage, which is consistent with a role for Bcl-2 family proteins. BCR ligation strongly increased expression of the proapoptotic Bcl-2 homology 3–only Bcl-2 protein Bim in both WEHI-231 and splenic B cells, and increases in Bim were reversed by BAFF or APRIL. Small interfering RNA vector–mediated suppression of Bim blocked BCR-induced apoptosis. BAFF also induced Bim phosphorylation and inhibited BCR-induced association of Bim with Bcl-2. BAFF induced delayed but sustained stimulation of extracellular signal–regulated kinase (ERK) and its activators, mitogen-activated protein kinase/ERK activating kinase (MEK) and c-Raf, and MEK inhibitors promoted accumulation and dephosphorylation of Bim. These results suggest that BAFF inhibits BCR-induced death by down-regulating Bim via sustained ERK activation, demonstrating that BAFF directly regulates Bim function. Although transitional immature type 1 (T1) B cell numbers are normal in Bim−/− mice, T2 and follicular mature B cells are elevated and marginal zone B cells are reduced. Our results suggest that mature B cell homeostasis is maintained by BAFF-mediated regulation of Bim

Comparison of Three Aspirin Formulations in Human Volunteers

<p>Introduction: The treatment of acute coronary syndrome (ACS) includes the administration of aspirin. Current guidelines recommend chewing aspirin tablets to increase absorption. While this is intuitive, there are scant data supporting this recommendation. The purpose of this study is to assess which of 3 different aspirin formulations is most rapidly absorbed after ingestion.</p> <p>Methods: A prospective, open-label, 3-way crossover volunteer study at a tertiary university medical center with human subjects 18 years or older. Fasted subjects were randomly assigned to receive aspirin 1,950 mg as (1) solid aspirin tablets swallowed whole, (2) solid aspirin tablet chewed then swallowed, or (3) a chewable aspirin formulation chewed and swallowed. Serum salicylate measurements were obtained over a period of 180 minutes. Pharmacokinetic parameters were determined.</p> <p>Results: Thirteen males and 1 female completed all 3 arms of study. Peak serum salicylate concentrations were seen at 180 minutes in all groups. Mean peaks were 10.4, 11.3, and 12.2 mg/dL in groups 1, 2, and 3, respectively. Mean area under the time concentration was 1,153, 1,401, and 1,743 mg-min/dL in groups 1, 2, and 3, respectively. No measurable salicylate concentrations were seen in 6 subjects in group 1 at 60 minutes as compared to 1 subject in group 2. All subjects in group 3 had measurable levels at 45 minutes. There were no adverse effects in any of the subjects during the study period.</p> <p>Conclusion: Our data demonstrate that the chewable aspirin formulation achieved the most rapid rate of absorption. In addition, the chewable formulation absorption was more complete than the other formulations at 180 minutes. These data suggest that in the treatment of ACS, a chewable aspirin formulation may be preferable to solid tablet aspirin, either chewed or swallowed. [West J Emerg Med. 2011;12(4):381–385.]</p