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1.  Vaccine-Induced Antibody Isotypes Are Skewed by Impaired CD4 T Cell and Invariant NKT Cell Effector Responses in MyD88-Deficient Mice1 
The requirement for TLR signaling in the initiation of an Ag-specific Ab response is controversial. In this report we show that a novel OVA-expressing recombinant Salmonella vaccine (Salmonella-OVA) elicits a Th1-biased cell-mediated and serum Ab response upon oral or i.p. immunization of C57BL/6 mice. In MyD88−/−mice, Th1-dependent Ab responses are greatly reduced while Th2-dependent Ab isotypes are elevated in response to oral and i.p., but not s.c. footpad, immunization. When the T effector response to oral vaccination is examined we find that activated, adoptively transferred Ag-specific CD4+ T cells accumulate in the draining lymph nodes, but fail to produce IFN-γ, in MyD88−/− mice. Moreover, CD1d tetramer staining shows that invariant NKT cells are activated in response to oral Salmonella-OVA vaccination in wild-type, but not MyD88−/−, mice. Treatment with neutralizing Ab to CD1d reduces the OVA-specific Ab response only in MyD88-sufficient wild-type mice, suggesting that both Ag-specific CD4 T cell and invariant NKT cell effector responses to Salmonella-OVA vaccination are MyD88 dependent. Taken together, our data indicate that the type of adaptive immune response generated to this live attenuated vaccine is regulated by both the presence of MyD88-mediated signals and vaccination route, which may have important implications for future vaccine design.
PMCID: PMC4454352  PMID: 19620295
2.  B-Cell Activating Factor (BAFF) is elevated in Chronic Granulomatous Disease 
Clinical immunology (Orlando, Fla.)  2013;148(2):258-264.
Chronic Granulomatous Disease (CGD) is an inherited defect in superoxide production leading to life-threatening infections, granulomas, and, possibly, abnormal immunoglobulin concentrations. We investigated whether factors controlling antibody production, such as B-cell activating factor (BAFF), were altered in CGD. CGD subjects had significantly increased mean (2.3-fold, p<0.0001) plasma concentrations of BAFF compared to healthy donors. Patients on IFN-γ treatment had significantly higher BAFF concentrations compared with CGD patients not taking IFN-γ (1.6-fold, p<0.005). Leukocytes from CGD subjects produced normal amounts of BAFF in response to IFN-γ or G-CSF in vitro. Expression of BAFF-R and TACI were significantly reduced on CGD B cells. Elevated BAFF in CGD correlated with CRP (R=0.44), ESR (R=0.49), and IgM (R=0.47) and increased rapidly in healthy subjects following intravenous endotoxin administration. These findings suggest that elevated BAFF in CGD subjects and healthy donors is a consequence of acute and chronic inflammation.
PMCID: PMC3774275  PMID: 23773925
Chronic Granulomatous Disease; B-cell activating factor; inflammation
3.  Medical students’ attitudes toward gay men 
BMC Medical Education  2012;12:71.
Healthcare providers’ attitudes toward sexual minorities influence patient comfort and outcomes. This study characterized medical student attitudes toward gay men, focusing on behavior, personhood, gay civil rights, and male toughness.
A cross-sectional web-based anonymous survey was sent to medical students enrolled at the University of California, Davis (N = 371) with a response rate of 68%.
Few respondents expressed negative attitudes toward gay men or would deny them civil rights. More negative responses were seen with respect to aspects of intimate behavior and homosexuality as a natural form of sexual expression. Men and students younger than 25 years old were more likely to endorse negative attitudes toward behavior as well as more traditional views on male toughness.
We show that an important minority of students express discomfort with the behavior of gay men and hold to a narrow construction of male identity. These findings suggest that competency training must move beyond conceptual discussions and address attitudes toward behaviors through new pedagogical approaches.
PMCID: PMC3460746  PMID: 22873668
Homosexuality; Medical students; Bias
4.  Toll-like receptor 4-mediated regulation of spontaneous Helicobacter-dependent colitis in IL-10 deficient mice 
Gastroenterology  2009;137(4):1380-1390.e3.
Background & Aims
The commensal microbiota is believed to have an important role in regulating immune responsiveness and preventing intestinal inflammation. Intestinal microbes produce signals that regulate inflammation via Toll-like receptor (TLR) signaling, but the mechanisms of this process are poorly understood. We investigated the role of the anti-inflammatory cytokine, IL-10, in this signaling pathway using a mouse model of colitis.
Clinical, histopathological and functional parameters of intestinal inflammation were evaluated in TLR4-/-, IL-10-/- and TLR4 -/- x IL-10 -/- mice that were free of specific pathogens and in TLR4-/- x IL-10-/- mice following eradication and reintroduction of Helicobacter hepaticus. Regulatory T-cell (Treg) function was evaluated by crossing each of the lines with transgenic mice that express green fluorescent protein (GFP) under control of the endogenous regulatory elements of Foxp3. Apoptotic cells in the colonic lamina propria were detected by a TUNEL assay.
TLR4-mediated signals have 2 interrelated roles in promoting inflammation in TLR4-/- x IL-10-/- mice. In the absence of TLR4-mediated signals, secretion of proinflammatory and immunoregulatory cytokines is dysregulated. Tregs (Foxp3+) that secrete IFN-© and IL-17 accumulate in the colonic lamina propria of TLR4-/- x IL-10-/- mice and do not prevent inflammation. Aberrant control of epithelial-cell turnover results in the persistence of antigen presenting cells that contain apoptotic epithelial fragments in the colonic lamina propria of Helicobacter-infected TLR4-/- mice.
In mice that lack both IL-10 and TLR4 mediated signals, aberrant regulatory T cell function and dysregulated control of epithelial homeostasis combine to exacerbate intestinal inflammation.
PMCID: PMC2757440  PMID: 19596011
5.  VEGF and TGF-β are required for the maintenance of the choroid plexus and ependyma 
Although the role of vascular endothelial growth factor (VEGF) in developmental and pathological angiogenesis is well established, its function in the adult is less clear. Similarly, although transforming growth factor (TGF) β is involved in angiogenesis, presumably by mediating capillary (endothelial cell [EC]) stability, its involvement in quiescent vasculature is virtually uninvestigated. Given the neurological findings in patients treated with VEGF-neutralizing therapy (bevacizumab) and in patients with severe preeclampsia, which is mediated by soluble VEGF receptor 1/soluble Fms-like tyrosine kinase receptor 1 and soluble endoglin, a TGF-β signaling inhibitor, we investigated the roles of VEGF and TGF-β in choroid plexus (CP) integrity and function in adult mice. Receptors for VEGF and TGF-β were detected in adult CP, as well as on ependymal cells. Inhibition of VEGF led to decreased CP vascular perfusion, which was associated with fibrin deposition. Simultaneous blockade of VEGF and TGF-β resulted in the loss of fenestrae on CP vasculature and thickening of the otherwise attenuated capillary endothelium, as well as the disappearance of ependymal cell microvilli and the development of periventricular edema. These results provide compelling evidence that both VEGF and TGF-β are involved in the regulation of EC stability, ependymal cell function, and periventricular permeability.
PMCID: PMC2271023  PMID: 18268040
6.  Effect of Vitamin B6 Availability on Serine Hydroxymethyltransferase in MCF-7 Cells 
Folate-activated one-carbon units are derived from serine through the activity of the pyridoxal-phosphate (PLP)-dependent isozymes of serine hydroxymethyltransferase (SHMT). The effect of vitamin B6 availability on the activity and expression of the human mitochondrial and cytoplasmic SHMT isozymes was investigated in human MCF-7 cells. Cells were cultured for 6 months in vitamin B6 replete (4.9 μM pyridoxine) minimal essential medium (αMEM) or vitamin B6-deficient medium containing 49 nM, 4.9 nM or 0.49 nM pyridoxine. Total cellular PLP levels and SHMT activity were reduced 72% and 7% respectively when medium pyridoxine was decreased from 4.9 μM to 49 nM. Cells cultured in medium containing 4.9 nM pyridoxine exhibited 75%, 27% and 60% reduced levels of PLP, SHMT activity and S-adenosylmethionine, respectively compared to cells cultured in αMEM. Cytoplasmic SHMT activity and protein levels, but not mRNA levels, were decreased in cells cultured in vitamin B6 deficient medium, whereas mitochondrial SHMT activity and protein levels were less sensitive to vitamin B6 availability. PLP bound to cytoplasmic SHMT with a Kd = 850 nM, a value two orders of magnitude lower than previously reported for the bovine cytoplasmic SHMT isozyme. Collectively, these data indicate that vitamin B6 restriction decreases the activity and stability of SHMT, and that the cytoplasmic isozyme is more sensitive to vitamin B6 deficiency than the mitochondrial isozyme in MCF-7 cells.
PMCID: PMC1976282  PMID: 17482557
serine hydroxymethyltransferase; vitamin B6; pyridoxal-phosphate; one-carbon metabolism; homocysteine; folate

Results 1-6 (6)