Immunoglobulins are molecules produced by activated B cells and plasma cells in response to exposure to antigens. Upon antigen exposure, these molecules are secreted allowing the immune system to recognize and effectively respond to a myriad of pathogens. Immunoglobulin or antibody secreting cells are the mature form of B lymphocytes, which during their development undergo gene rearrangements and selection in the bone marrow ultimately leading to the generation of B cells, each expressing a single antigen-specific receptor/immunoglobulin molecule. Each individual immunoglobulin molecule has an affinity for a unique motif, or epitope, found on a given antigen. When presented with an antigen, activated B cells differentiate into either plasma cells (which secrete large amounts of antibody that is specific for the inducing antigen), or memory B cells (which are long-lived and elicit a stronger and faster response if the host is re-exposed to the same antigen). The secreted form of immunoglobulin, when bound to an antigen, serves as an effector molecule that directs other cells of the immune system to facilitate the neutralization of soluble antigen or the eradication of the antigen-expressing pathogen. This review will focus on the regulation of secreted immunoglobulin by long-lived normal or disease-associated plasma cells. Specifically, the focus will be on signaling and transcriptional events that regulate the development and homeostasis of long-lived immunoglobulin secreting plasma cells.

Ig secretion by terminally differentiated B cells is an important component of the immune response to foreign pathogens. Its overproduction is a defining characteristic of several B cell malignancies, including Waldenström macroglobulinemia (WM), where elevated IgM is associated with significant morbidity and poor prognosis. Therefore, the identification and characterization of the mechanisms controlling Ig secretion are of great importance for the development of future therapeutic approaches for this disease. In this study, we define a novel pathway involving the oncogenic transcription factor GLI2 modulating IgM secretion by WM malignant cells. Pharmacological and genetic inhibition of GLI2 in WM malignant cells resulted in a reduction in IgM secretion. Screening for a mechanism identified the IL-6Rα (gp80) subunit as a downstream target of GLI2 mediating the regulation of IgM secretion. Using a combination of expression, luciferase, and chromatin immunoprecipitation assays we demonstrate that GLI2 binds to the IL-6Rα promoter and regulates its activity as well as the expression of this receptor. Additionally, we were able to rescue the reduction in IgM secretion in the GLI2 knockdown group by overexpressing IL-6Rα, thus defining the functional significance of this receptor in GLI2-mediated regulation of IgM secretion. Interestingly, this occurred independent of Hedgehog signaling, a known regulator of GLI2, as manipulation of Hedgehog had no effect on IgM secretion. Given the poor prognosis associated with elevated IgM in WM patients, components of this new signaling axis could be important therapeutic targets.

Targeting IL-6 receptor reduces IgM levels and tumor growth in Waldenstrm macroglobulinemia

The interaction between tumor cells and their surrounding microenvironment is essential for the growth and persistence of cancer cells. This interaction is mediated, in part, by cytokines. Although the role of cytokines in normal and malignant cell biology is well established, many of the molecular mechanisms regulating their expression remain elusive. In this article, we provide evidence of a novel pathway controlling the transcriptional activation of CD40L in bone marrow–derived stromal cells. Using a PCR-based screening of cytokines known to play a role in the biology of bone marrow malignancies, we identified CD40L as a novel GLI2 target gene in stromal cells. CD40L plays an important role in malignant B cell biology, and we found increased Erk phosphorylation and cell growth in malignant B cells cocultured with CD40L-expressing stromal cells. Further analysis indicated that GLI2 overexpression induced increased CD40L expression, and, conversely, GLI2 knockdown reduced CD40L expression. Using luciferase and chromatin immunoprecipitation assays, we demonstrate that GLI2 directly binds and regulates the activity of the CD40L promoter. We found that the CCR3–PI3K–AKT signaling modulates the GLI2–CD40L axis, and GLI2 is required for CCR3–PI3K–AKT-mediated regulation of the CD40L promoter. Finally, coculture of malignant B cells with cells stably expressing human CD40L results in increased Erk phosphorylation and increased malignant B cell growth, indicating that CD40L in the tumor microenvironment promotes malignant B cell activation. Therefore, our studies identify a novel molecular mechanism of regulation of CD40L by the transcription factor GLI2 in the tumor microenvironment downstream of CCR3 signaling.

We show that the semigroups S_k,ℓhaving semigroup presentations are residually finite and finitely separable. Generally, these semigroups have finite separating images which are finite groups and other finite separating images which are semigroups of order-increasing transformations on a finite partially ordered set. These semigroups thus have vastly different residual and separability properties than the Baumslag–Solitar groups which contain them.

Congenital syphilis (CS) rates have increased in the United States since 2013. Management of infants exposed to syphilis during pregnancy entails a detailed clinical evaluation, followed by stratified work-up and treatment. Of the 8,280 surveillance cases which were assigned a clinical scenario, the majority (80.9%) were classified as Possible CS, of whom 60.7% received an appropriate evaluation, while 68.4% received appropriate treatment. Of those assigned to Proven or Highly Probable CS, 46.0% received an appropriate evaluation, while 82.3% received appropriate treatment. This analysis of CS clinical scenarios underscores disparities in evaluation and therapy across geographic, racial, and ethnic lines. Further research is needed to understand factors involved in the evaluation and treatment of infants affected by CS, particularly for those born in the South and to birthing parents reporting minority racial and ethnic backgrounds. All Authors: No reported disclosures