Macrophage regulation of B cell proliferation.

Unlike organized lymphoid tissue, the tumor microenvironment (TME) often includes a high proportion of immunosuppressive macrophages. We model the TME by culturing peritoneal cavity (PerC) cells that naturally have a high macrophage to lymphocyte ratio. Prior studies revealed that, following TCR ligation, PerC T cell proliferation is suppressed due to IFNγ-triggered inducible nitric oxide synthase expression. In this study we assessed the ability of PerC B cells to respond to surrogate activating signals in the presence of high numbers of macrophages. Surface IgM (BCR) ligation led to cyclooxygenase-mediated, and TLR-4 ligation to IL10-mediated, suppression of PerC B cell proliferation. In contrast, PerC B cells had a robust response to CD40 ligation, which could overcome the suppression generated by the BCR or TLR-4 response. However, the CD40 response was suppressed by concurrent TCR ligation. These results reveal the challenges of promoting B and T cell responses in macrophage-rich conditions that model the TME.

Patient Factors Impacting Baseline Motor Evoked Potentials (MEPs) in Patients Undergoing Cervical Spine Surgery for Myelopathy or Radiculopathy.

STUDY DESIGN: Retrospective review of 2532 adults who underwent elective surgery for cervical radiculopathy or myelopathy with intraoperative neuromonitoring (IONM) with motor evoked potentials (MEPs) between 2017 and 2019. OBJECTIVE: Evaluate attainability of monitorable MEPs across demographic, health history, and patient-reported outcomes measure (PROM) factors. SUMMARY OF BACKGROUND DATA: When baseline IONM responses cannot be obtained, the value of IONM on mitigating the risk of postoperative deficits is marginalized and a clinical decision to proceed must be made based, in part, on the differential diagnosis of the unmonitorable MEPs. Despite known associations with baseline MEPs and anesthetic regimen or preoperative motor strength, little is known regarding associations with other patient factors. METHODS: Demographics, health history, and PROM data were collected preoperatively. MEP baseline responses were reported as monitorable or unmonitorable at incision. Multivariable logistic regression estimated the odds of having at least one unmonitorable MEP from demographic and health history factors. RESULTS: Age [odds ratio (OR)=1.031, P <0.001], sex (male OR=1.572, P =0.007), a primary diagnosis of myelopathy (OR=1.493, P =0.021), peripheral vascular disease (OR=2.830, P =0.009), type II diabetes (OR=1.658, P =0.005), and hypertension (OR=1.406, P =0.040) were each associated with increased odds of unmonitorable MEPs from one or more muscles; a history of thyroid disorder was inversely related (OR=0.583, P =0.027). P atients with unmonitorable MEPs reported less neck-associated disability and pain ( P <0.036), but worse SF-12 physical health and lower extremity (LE) and upper extremity function ( P <0.016). Compared with radiculopathy, unmonitorable MEPs in myelopathy patients more often involved LE muscles. Cord function was monitorable in 99.1% of myelopathic patients with no reported LE dysfunction and no history of hypertension or diabetes. CONCLUSION: Myelopathy, hypertension, peripheral vascular disease, diabetes, and/or symptomatic LE dysfunction increased the odds of having unmonitorable baseline MEPs. Unmonitorable baseline MEPs was uncommon in patients without significant LE weakness, even in the presence of myelopathy.

Synthesis of Sphingolipids Impacts Survival of Porphyromonas gingivalis and the Presentation of Surface Polysaccharides.

Bacteria alter the biophysical properties of their membrane lipids in response to environmental cues, such as shifts in pH or temperature. In essence, lipid composition determines membrane structure, which in turn influences many basic functions, such as transport, secretion, and signaling. Like other members of the phylum Bacteroidetes, the oral anaerobe Porphyromonas gingivalis possesses the ability to synthesize a variety of novel membrane lipids, including species of dihydroceramides that are distinct, yet similar in structure to sphingolipids produced by the human host. The role of dihydroceramides in the physiology and pathogenic potential of the human microbiota is only beginning to be explored; yet there is increasing data indicating that these lipids play a role in human diseases, such as periodontitis and multiple sclerosis. Here, we report on the identification of a gene (PG1780) in the chromosome of P. gingivalis strain W83 encoding a putative serine palmitoyltransferase, the enzyme that catalyzes the first step in sphingolipid biosynthesis. While we were able to detect dihydroceramides in whole lipid extracts of P. gingivalis cells as well as crude preparations of outer membrane vesicles, sphingolipids were absent in the PG1780 mutant strain. Moreover, we show that the synthesis of sphingolipids plays an essential role in the long-term survival of the organism as well as its resistance to oxidative stress. Further, a PG1780 mutant displayed much lower activity of cell-associated arginine and lysine gingipains, yet slightly higher activity in the corresponding culture supernates, which we hypothesize is due to altered membrane properties and anchoring of these proteases to the cell surface. In addition, we determined that sphingolipid production is critical to the presentation of surface polysaccharides, with the mutant strain displaying less K-antigen capsule and more anionic polysaccharide (APS). Overall, we have discovered that, in addition to their role in pathogenicity, the synthesis of sphingolipids is critical to the cellular homeostasis and persistence of this important dental pathogen.