Contribution of viral infection to risk for cancer in systemic lupus erythematosus and multiple sclerosis.

Patients with autoimmune disorders (AD) have altered cancer risks compared to the general population. Systemic lupus erythematosus and multiple sclerosis lead to a heightened risk for hematological malignancies and decreased risk for breast, ovarian, and prostate malignancies. Often patients with autoimmune disease have dysregulated antiviral immune responses, including against oncogenic viruses. To uncover the relationship between viral incidence and cancer risk in the context of autoimmune disease, we extracted electronic health records (EHR) from Vanderbilt University. ICD-9/10 codes and laboratory values were collected for hematological, lung, anal-vaginal, thyroid, hepatobiliary, bladder, prostate, and breast cancers; and viruses including Epstein Barr virus (EBV), Human papilloma virus (HPV), and Hepatitis A/B/C (Hep). Only viral infections that led to a physician visit or laboratory test were entered into the EMR; therefore, only clinically relevant cases were noted and considered positive in this study. The relationship between virus infection and cancer in an SLE cohort (SLE-cases n = 2,313, and SLE-controls n = 5,702) and an MS cohort (MS-case n = 7,277, MS-control n = 7,277) was examined by multilinear logistic regression. Viral infection was strongly associated with increased risk for cancer overall. SLE and MS patients were more susceptible to all viral infections. MS patients trended toward increased risk for cancers overall, while decreased risk for hormone-based cancers in SLE patients non-significantly reduced their risk for overall cancer. Both SLE and MS patients had increased clinically relevant EBV infection, which was associated with risk for hematological cancers. Preventing viral infections by vaccination may be especially helpful in controlling risk for cancer in SLE and MS patients.

CD4 Inhibits Helper T Cell Activation at Lower Affinity Threshold for Full-Length T Cell Receptors Than Single Chain Signaling Constructs.

CD4+ T cells are crucial for effective repression and elimination of cancer cells. Despite a paucity of CD4+ T cell receptor (TCR) clinical studies, CD4+ T cells are primed to become important therapeutics as they help circumvent tumor antigen escape and guide multifactorial immune responses. However, because CD8+ T cells directly kill tumor cells, most research has focused on the attributes of CD8+ TCRs. Less is known about how TCR affinity and CD4 expression affect CD4+ T cell activation in full length TCR (flTCR) and TCR single chain signaling (TCR-SCS) formats. Here, we generated an affinity panel of TCRs from CD4+ T cells and expressed them in flTCR and three TCR-SCS formats modeled after chimeric antigen receptors (CARs) to understand the contributions of TCR-pMHCII affinity, TCR format, and coreceptor CD4 interactions on CD4+ T cell activation. Strikingly, the coreceptor CD4 inhibited intermediate and high affinity TCR-construct activation by Lck-dependent and -independent mechanisms. These inhibition mechanisms had unique affinity thresholds dependent on the TCR format. Intracellular construct formats affected the tetramer staining for each TCR as well as IL-2 production. IL-2 production was promoted by increased TCR-pMHCII affinity and the flTCR format. Thus, CD4+ T cell therapy development should consider TCR affinity, CD4 expression, and construct format.

Combating Vaccine Hesitancy with Vaccine-Preventable Disease Familiarization: An Interview and Curriculum Intervention for College Students.

In 2019, the World Health Organization (WHO) listed vaccine hesitancy in its top ten threats to global health. Vaccine hesitancy is a "delay in acceptance or refusal to vaccinate despite availability of vaccination services". Urban areas with large amounts of vaccine hesitancy are at risk for the resurgence of vaccine-preventable diseases (VPDs). Many vaccine-hesitant (VH) parents may be unfamiliar with the consequences of VPDs, and thus might be swayed when confronted with the symptoms and dangers of VPDs. As such, we sought to educate college students (future parents) in an urban vaccine-hesitant hotspot by assigning them to interview family or community members who had experienced a VPD. Student vaccine attitudes were assessed by surveys before and after the interviews. Vaccine-hesitant students who conducted a VPD interview but received no additional vaccine educational materials were significantly more likely (interaction term p < 0.001) to become pro-vaccine (PV) (68%) than students who conducted an autoimmune interview and received no additional educational materials. Additionally, students whose interviewees experienced intense physical suffering or physical limitations or students who were enrolled in a course with intensive VPD and vaccine curriculum had significantly increased vaccine attitudes. This suggests that introducing students to VPDs can decrease vaccine hesitancy.

The nuclear variant of bone morphogenetic protein 2 (nBMP2) is expressed in macrophages and alters calcium response.

We previously identified a nuclear variant of bone morphogenetic protein 2 (BMP2), named nBMP2, that is translated from an alternative start codon. Decreased nuclear localization of nBMP2 in the nBmp2NLStm mouse model leads to muscular, neurological, and immune phenotypes-all of which are consistent with aberrant intracellular calcium (Ca2+) response. Ca2+ response in these mice, however, has yet to be measured directly. Because a prior study suggested impairment of macrophage function in nBmp2NLStm mutant mice, bone marrow derived (BMD) macrophages and splenic macrophages were isolated from wild type and nBmp2NLStm mutant mice. Immunocytochemistry revealed that nuclei of both BMD and splenic macrophages from wild type mice contain nBMP2, while the protein is decreased in nuclei of nBmp2NLStm mutant macrophages. Live-cell Ca2+ imaging and engulfment assays revealed that Ca2+ response and phagocytosis in response to bacterial supernatant are similar in BMD macrophages isolated from naïve (uninfected) nBmp2NLStm mutant mice and wild type mice, but are deficient in splenic macrophages isolated from mutant mice after secondary systemic infection with Staphylococcus aureus, suggesting progressive impairment as macrophages respond to infection. This direct evidence of impaired Ca2+ handling in nBMP2 mutant macrophages supports the hypothesis that nBMP2 plays a role in Ca2+ response.

Common gut microbial metabolites of dietary flavonoids exert potent protective activities in ß-cells and skeletal muscle cells.

Flavonoids are dietary compounds with potential anti-diabetes activities. Many flavonoids have poor bioavailability and thus low circulating concentrations. Unabsorbed flavonoids are metabolized by the gut microbiota to smaller metabolites, which are more bioavailable than their precursors. The activities of these metabolites may be partly responsible for associations between flavonoids and health. However, these activities remain poorly understood. We investigated bioactivities of flavonoid microbial metabolites [hippuric acid (HA), homovanillic acid (HVA), and 5-phenylvaleric acid (5PVA)] in primary skeletal muscle and ß-cells compared to a native flavonoid [(-)-epicatechin, EC]. In muscle, EC was the most potent stimulator of glucose oxidation, while 5PVA and HA simulated glucose metabolism at 25 µM, and all compounds preserved mitochondrial function after insult. However, EC and the metabolites did not uncouple mitochonndrial respiration, with the exception of 5PVA at10 µM. In ß-cells, all metabolites more potently enhanced glucose-stimulated insulin secretion (GSIS) compared to EC. Unlike EC, the metabolites appear to enhance GSIS without enhancing ß-cell mitochondrial respiration or increasing expression of mitochondrial electron transport chain components, and with varying effects on ß-cell insulin content. The present results demonstrate the activities of flavonoid microbial metabolites for preservation of ß-cell function and glucose utilization. Additionally, our data suggest that metabolites and native compounds may act by distinct mechanisms, suggesting complementary and synergistic activities in vivo which warrant further investigation. This raises the intriguing prospect that bioavailability of native dietary flavonoids may not be as critical of a limiting factor to bioactivity as previously thought.

T Cell Calcium Signaling Regulation by the Co-Receptor CD5.

Calcium influx is critical for T cell effector function and fate. T cells are activated when T cell receptors (TCRs) engage peptides presented by antigen-presenting cells (APC), causing an increase of intracellular calcium (Ca2+) concentration. Co-receptors stabilize interactions between the TCR and its ligand, the peptide-major histocompatibility complex (pMHC), and enhance Ca2+ signaling and T cell activation. Conversely, some co-receptors can dampen Ca2+ signaling and inhibit T cell activation. Immune checkpoint therapies block inhibitory co-receptors, such as cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed death 1 (PD-1), to increase T cell Ca2+ signaling and promote T cell survival. Similar to CTLA-4 and PD-1, the co-receptor CD5 has been known to act as a negative regulator of T cell activation and to alter Ca2+ signaling and T cell function. Though much is known about the role of CD5 in B cells, recent research has expanded our understanding of CD5 function in T cells. Here we review these recent findings and discuss how our improved understanding of CD5 Ca2+ signaling regulation could be useful for basic and clinical research.

Continuous Periosteal Strapping Sutures for Stabilization of Osseous Grafts With Resorbable Membranes for Buccal Ridge Augmentation: A Technique Report.

Alveolar bone loss occurs after extraction with loss of a premolar or anterior tooth; the residual supporting alveolar bone loss averages 1.53 mm of crestal bone height and 3.87 mm of buccolingual width, with most of the bone loss occurring at the facial plate. Socket preservation does not completely preserve the original ridge contours but can be an effective means of reducing bone loss following extraction. Attempts to rebuild the alveolar ridge structure after tooth loss often employ the concept of guided bone regeneration, a technique-sensitive procedure that routinely involves placement of particulate bone with or without fixation screws and either a resorbable or a nonresorbable membrane. We present a novel technique for stabilizing a resorbable membrane and underlying particulate graft allowing for predictable bone grafting across multiple edentulous sites.

Treatment of amalgam tattoo with a subepithelial connective tissue graft and acellular dermal matrix.

A 54-year-old female was referred for management of a large amalgam tattoo involving the alveolar mucosa between teeth #6 and #9. The lesion had been present for over 20 years following endodontic treatment of teeth #7 and #8. A two-stage surgical approach was used to remove the pigmentation, beginning with removal of amalgam fragments from the underlying bone and placement of a subepithelial connective tissue graft and acellular dermal matrix to increase soft tissue thickness subadjacent to the amalgam. Following 7 weeks of healing, gingivoplasty was performed to remove the overlying pigmented tissue. At the 21-month follow-up appointment, the patient exhibited naturally appearing soft tissue with no evidence of amalgam tattoo.