Publications by authors named "Diane E Grill"

76 Publications

Transcriptional signatures associated with rubella virus-specific humoral immunity after a third dose of MMR vaccine in women of childbearing age.

Eur J Immunol 2021 Jul 19;51(7):1824-1838. Epub 2021 Apr 19.

Department of General Internal Medicine, Mayo Clinic, Rochester, MN, 55905, USA.

Multiple factors linked to host genetics/inherent biology play a role in interindividual variability in immune response outcomes after rubella vaccination. In order to identify these factors, we conducted a study of rubella-specific humoral immunity before (Baseline) and after (Day 28) a third dose of MMR-II vaccine in a cohort of 109 women of childbearing age. We performed mRNA-Seq profiling of PBMCs after rubella virus in vitro stimulation to delineate genes associated with post-vaccination rubella humoral immunity and to define genes mediating the association between prior immune response status (high or low antibody) and subsequent immune response outcome. Our study identified novel genes that mediated the association between prior immune response and neutralizing antibody titer after a third MMR vaccine dose. These genes included the following: CDC34; CSNK1D; APOBEC3F; RAD18; AAAS; SLC37A1; FAS; and JAK2. The encoded proteins are involved in innate antiviral response, IFN/cytokine signaling, B cell repertoire generation, the clonal selection of B lymphocytes in germinal centers, and somatic hypermutation/antibody affinity maturation to promote optimal antigen-specific B cell immune function. These data advance our understanding of how subjects' prior immune status and/or genetic propensity to respond to rubella/MMR vaccination ultimately affects innate immunity and humoral immune outcomes after vaccination.
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http://dx.doi.org/10.1002/eji.202049054DOI Listing
July 2021

Contributions of cardiac dysfunction and volume status to central haemodynamics in chronic heart failure.

Eur J Heart Fail 2021 07 21;23(7):1097-1105. Epub 2021 Feb 21.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.

Aims: Elevated cardiac filling pressures producing clinical congestion in heart failure (HF) patients may be secondary to intravascular volume expansion or abnormalities in cardiac diastolic properties. The objective of this study was to assess the extent to which measures of myocardial function and intravascular volume correlate with haemodynamic abnormalities in chronic HF.

Methods And Results: Subjects underwent invasive haemodynamic assessment, measurement of total blood volume (TBV) using radiolabel indicator-dilution methodology, and echocardiography to evaluate cardiac structure and function. Patients were divided into those with hypervolaemia (defined as TBV > +8% above referenced normal volume) and normal volume ('euvolaemia') (TBV ≤ + 8%). Of 66 patients, 39 (59%) were hypervolaemic and 27 (41%) normal TBV. Central venous pressure (CVP, P = 0.01) and pulmonary capillary wedge pressure (PCWP, P < 0.001) were higher in hypervolaemic compared with euvolaemic patients; however, 15% of hypervolaemic patients displayed normal pressures. Of euvolaemic patients, 70% displayed elevated CVP and 63% elevated PCWP. PCWP was moderately correlated with TBV (r = 0.42), left ventricular diastolic function (e' velocity, r = -0.44), and left atrial strain (r = -0.47). In multivariable regression TBV, left ventricular e', and left atrial strain were independently associated with PCWP (all P < 0.05).

Conclusions: While hypervolaemic patients displayed elevations in filling pressures, a substantial proportion (15%) had normal pressures, and of all subjects with elevated filling pressures nearly one third had normal TBVs. Importantly, of patients with normal volumes, a majority (>60%) display elevated filling pressures. Combined analysis of volume, pressure, and cardiac function may be helpful to guide comprehensive assessments of HF status.
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http://dx.doi.org/10.1002/ejhf.2121DOI Listing
July 2021

The humoral immune response to high-dose influenza vaccine in persons with monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL).

Vaccine 2021 02 16;39(7):1122-1130. Epub 2021 Jan 16.

Division of General Internal Medicine and Vaccine Research Group, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.

Background: Limited data are available regarding the immunogenicity of high-dose influenza vaccine among persons with chronic lymphocytic leukemia (CLL) and monoclonal B cell lymphocytosis (MBL).

Methods: A prospective pilot study of humoral immune responses to 2013-2014 and 2014-2015 high-dose trivalent influenza vaccine (HD IIV; Fluzone® High-Dose; Sanofi Pasteur) was conducted among individuals with MBL and previously untreated CLL. Serum hemagglutination inhibition (HAI) antibody titers were measured at baseline and Day 28 after vaccination; seroprotection and seroconversion rates were determined. Memory B cell responses were assessed by B-cell enzyme-linked immune absorbent spotassays.

Results: Thirty subjects (17 CLL and 13 MBL) were included. Median age was 69.5 years. Day 28 seroprotection rates for the cohort were 19/30 (63.3%) for A/H1N1; 21/23 (91.3%) for A/H3N2; and 13/30 (43.3%) for influenza B. Those with MBL achieved higher day 28 HAI geometric mean titers (54.1 [4.9, 600.1] vs. 12.1 [1.3, 110.1]; p = 0.01) and higher Day 28 seroprotection rates (76.9% vs. 17.6%; p = 0.002) against the influenza B-vaccine strain virus than those with CLL.

Conclusions: Immunogenicity of the HD IIV3 in patients with CLL and MBL is lower than reported in healthy adults. Immunogenicity to influenza B was greater in those with MBL than CLL.
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http://dx.doi.org/10.1016/j.vaccine.2021.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189080PMC
February 2021

Diuresis-Related Weight Loss Reflects Interstitial Compartment Decongestion with Minimal Impact on Intravascular Volume Expansion or Outcomes in Post-Acute Heart Failure: Metrics of Decongestion and Volume Status.

J Card Fail 2021 04 9;27(4):445-452. Epub 2021 Jan 9.

Division of Diagnostic Radiology, Mayo Clinic, Rochester, Minnesota.

Background: Findings from heart failure (HF) studies linking diuresis-related weight loss to clinical decongestion and outcomes are mixed. Differential responses of interstitial and intravascular volume compartments to diuretic therapy and heterogeneity in volume profiles may confound the clinical interpretation of weight loss in patients with HF.

Methods And Results: Data were prospectively collected in hospitalized patients requiring diuresis. Plasma volume (PV) was measured using I-131-labelled albumin indicator-dilution methodology. The cohort was stratified by tertiles of weight loss and analyzed for interstitial fluid loss relative to changes in PV and HF-related morality or first rehospitalization. Among 92 patients, the admission PV was expanded +42% (4.7 ± 1.2 L) above normal with significant variability (14% normal PV, 18% mild-moderate expansion, and 68% with large PV expansion [>+25% above normal]). With diuresis there were proportional decreases in interstitial volume (-6.5 ± 4.4%) and PV (-7.5 ± 11%); however, absolute decreases in the PV (-254 mL, interquartile range -11 to -583 mL) were less than 10% of interstitial volume loss (-5040 mL, interquartile range -2800 to -7989 mL); greater interstitial fluid loss did not translate into better outcomes (log-rank P = .430).

Conclusions: Diuresis-related decreases in weight reflect fluid loss from the interstitial compartment with only minor changes in the PV and without an impact on outcomes. Further, the degree of PV expansion at hospital admission does not drive the magnitude of the diuresis response, even with a wide spectrum of body weights; interstitial fluid overload is preferentially targeted and PV relatively preserved. Therefore, greater interstitial fluid loss reflects clinical decongestion, but not better outcomes, and a limited association with intravascular volume profiles potentially confounding weight loss as a prognostic metric in HF.
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http://dx.doi.org/10.1016/j.cardfail.2020.12.006DOI Listing
April 2021

A prospective, blinded study of a PF4-dependent assay for HIT diagnosis.

Blood 2021 02;137(8):1082-1089

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

Heparin-induced thrombocytopenia (HIT) is a life-threatening, prothrombotic, antibody-mediated disorder. To maximize the likelihood of recovery, early and accurate diagnosis is critical. Widely available HIT assays, such as the platelet factor 4 (PF4) heparin enzyme-linked immunosorbent assay (ELISA) lack specificity, and the gold-standard carbon 14-labeled serotonin release assay (SRA) is of limited value for early patient management because it is available only through reference laboratories. Recent studies have demonstrated that pathogenic HIT antibodies selectively activate PF4-treated platelets and that a technically simpler assay, the PF4-dependent P-selectin expression assay (PEA), may provide an option for rapid and conclusive results. Based upon predefined criteria that combined 4Ts scores and HIT ELISA results, 409 consecutive adults suspected of having HIT were classified as disease positive, negative, or indeterminate. Patients deemed HIT indeterminate were considered disease negative in the primary analysis and disease positive in a sensitivity analysis. The ability of PEA and SRA to identify patients judged to have HIT was compared using receiver operating characteristic curve statistics. Using these predefined criteria, the diagnostic accuracy of PEA was high (area under the curve [AUC], 0.94; 95% confidence interval [CI], 0.87-1.0) and similar to that of SRA (AUC, 0.91; 95% CI, 0.82-1.0). In sensitivity analysis, the AUCs of PEA and SRA were also similar at 0.88 (95% CI, 0.78-0.98) and 0.86 (95% CI, 0.77-0.96), respectively. The PEA, a technically simple nonradioactive assay that uses ∼20-fold fewer platelets compared with the SRA, had high accuracy for diagnosing HIT. Widespread use of the PEA may facilitate timely and more effective management of patients with suspected HIT.
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http://dx.doi.org/10.1182/blood.2020008195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907721PMC
February 2021

Intravascular Volume Modulates the Outcome Predictive Capacity of Clinical Renal Function Biomarkers in Clinically "Euvolemic" Chronic Heart Failure Patients.

Kidney Dis (Basel) 2020 Jan 8;6(1):50-58. Epub 2019 Oct 8.

Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.

Background: Cardiorenal interconnections are complex and may in part be mediated by the extent of intravascular volume expansion. The impact of subclinical volume excess on outcomes in heart failure (HF) patients with chronic kidney disease (CKD) has not been examined previously.

Objectives: To assess the impact of volume-kidney interactions on outcomes in clinically "euvolemic" chronic HF patients (NYHA class II) with coexisting CKD.

Methods: Plasma volume (PV) was prospectively measured in 110 stable HF patients with different degrees of renal function using a standardized radiolabeled albumin indicator-dilution technique. To examine the interactive roles of volume expansion and biomarkers of CKD, the cohort was dichotomized by median PV and then further stratified by cohort median serum creatinine, eGFR, and BUN, and analyzed for outcomes of HF-related mortality and 1st hospitalization.

Results: PV was expanded above normal in 76% of the cohort. Over 1.5 years of follow-up, sCr and BUN above and eGFR below cohort median stratified higher risks for the composite endpoint only in ambulatory HF patients with a severe degree of PV expansion (median PV expansion ≥+26%; = 0.02). With less expansion (<+26% expansion), these biomarkers reflecting worse renal function did not discriminate risk ( = 0.578). The percentage of subjects experiencing composite outcome events was, however, comparable for both greater and lesser degrees of PV expansion in HF patients with stable clinical status.

Conclusions: In clinically stable chronic HF patients with coexisting CKD, substantial subclinical PV expansion is common even when patients are considered clinically to be euvolemic, and, importantly, the extent of PV expansion impacts outcomes including early HF mortality. Better kidney function appears to mitigate the effects of excess PV expansion, while less volume expansion appears to limit the risk of worse renal function as reflected by clinical biomarkers of renal function. Thus, the extent of volume expansion impacts the capacity of standard clinical biomarkers of CKD to differentiate outcome risk in ambulatory chronic (NYHA class II) HF patients.
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http://dx.doi.org/10.1159/000502210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995971PMC
January 2020

Rubella virus-specific humoral immune responses and their interrelationships before and after a third dose of measles-mumps-rubella vaccine in women of childbearing age.

Vaccine 2020 01 12;38(5):1249-1257. Epub 2019 Nov 12.

Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN 55905, USA. Electronic address:

In the U.S., measles, mumps, and rubella vaccination is recommended as two vaccine doses. A third dose of measles-mumps-rubella (MMR) vaccine is being administered in certain situations (e.g., identified seronegativity and during outbreaks). We studied rubella-specific humoral immunity (neutralizing antibody, enzyme-linked immunosorbent assay/ELISA IgG titer and antibody avidity) and the frequencies of antigen-specific memory B cells before and after a third dose of MMR-II in 109 female participants of childbearing age (median age, 34.5 years old) from Olmsted County, MN, with two documented prior MMR vaccine doses. The participants were selected from a cohort of 1117 individuals if they represented the high and the low ends of the rubella-specific antibody response spectrum. Of the 109 participants, we identified four individuals (3.67% of all study participants; 7.14% of the low-responder group) that were seronegative at Baseline (rubella-specific ELISA IgG titers <10 IU/mL), suggesting a lack of protection against rubella before receipt of a third MMR vaccine dose. The peak geometric mean neutralizing antibody titer one month following the third dose of MMR vaccine for the cohort was 243 NT (CI; 241, 245), which is expected for a cohort with two doses of MMR, and the peak geometric mean IgG titer was 150 IU/mL (CI; 148, 152) with no seronegative individuals at Day 28. One-third of all subjects (31.8% for the neutralizing antibody; 30.8% for the IgG titer) experienced a significant boost (≥4-fold) of antibody titers one month following vaccination. Antibody titers and other tested immune-response variables were significantly higher in the high-responder group compared to the low-responder group. The frequencies of rubella-specific memory B cells were modestly associated with the antibody titers. Our study suggests the importance of yet unknown inherent biologic and immune factors for the generation and maintenance of rubella-vaccine-induced humoral immune responses.
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http://dx.doi.org/10.1016/j.vaccine.2019.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992489PMC
January 2020

RITAN: rapid integration of term annotation and network resources.

PeerJ 2019 19;7:e6994. Epub 2019 Jul 19.

Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN, USA.

Background: Identifying the biologic functions of groups of genes identified in high-throughput studies currently requires considerable time and/or bioinformatics experience. This is due in part to each resource housed within separate databases, requiring users to know about them, and integrate across them. Time consuming and often repeated for each study, integrating across resources and merging with data under study is an increasingly common bioinformatics task.

Methods: We developed an open-source R software package for assisting researchers in annotating their genesets with functions, pathways, and their interconnectivity across a diversity of network resources.

Results: We present rapid integration of term annotation and network resources (RITAN) for the rapid and comprehensive annotation of a list of genes using functional term and pathway resources and their relationships among each other using multiple network biology resources. Currently, and to comply with data redistribution policies, RITAN allows rapid access to 16 term annotations spanning gene ontology, biologic pathways, and immunologic modules, and nine network biology resources, with support for user-supplied resources; we provide recommendations for additional resources and scripts to facilitate their addition to RITAN. Having the resources together in the same system allows users to derive novel combinations. RITAN has a growing set of tools to explore the relationships within resources themselves. These tools allow users to merge resources together such that the merged annotations have a minimal overlap with one another. Because we index both function annotation and network interactions, the combination allows users to expand small groups of genes using links from biologic networks-either by adding all neighboring genes or by identifying genes that efficiently connect among input genes-followed by term enrichment to identify functions. That is, users can start from a core set of genes, identify interacting genes from biologic networks, and then identify the functions to which the expanded list of genes contribute.

Conclusion: We believe RITAN fills the important niche of bridging the results of high-throughput experiments with the ever-growing corpus of functional annotations and network biology resources.

Availability: Rapid integration of term annotation and network resources is available as an R package at github.com/MTZimmer/RITAN and BioConductor.org.
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http://dx.doi.org/10.7717/peerj.6994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644632PMC
July 2019

Seroprevalence and durability of rubella virus antibodies in a highly immunized population.

Vaccine 2019 06 21;37(29):3876-3882. Epub 2019 May 21.

Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN 55905, USA. Electronic address:

Background: Although the administration of the measles-mumps-rubella (MMR) vaccine has been widespread in the United States for decades, gaps in vaccine coverage still persist for various reasons. The maintenance of herd immunity against rubella virus (RV) is important to controlling the spread and resurgence of rubella and congenital rubella syndrome.

Methods: In this study, we sought to assess the seroprevalence of RV-specific antibodies in an adult population from a defined geographic area in Olmsted County, MN, and the surrounding municipalities, with relatively high vaccine coverage and no documented evidence of circulating RV in the past 24 years. Rubella-specific IgG antibodies were measured by ELISA in a large set of serum samples (n = 1393) obtained from the Mayo Clinic Biobank. This cohort was 80.2% female and ranged from 20 to 44 years of age.

Results: In total, 97.8% of subjects were seropositive for rubella-specific IgG antibodies, with a median titer of 40.56 IU/mL, suggesting a high degree of immunization; however, 2.2% of subjects were found to be seronegative. Interestingly, 25.1% of subjects were seropositive but had titers lower than 25 IU/mL, indicating either a population of low responders or individuals that could potentially be at risk of waning immunity. No significant associations or differences were found between RV-specific titers and demographic variables such as age, sex, or body mass index (BMI).

Conclusions: A high rate of seropositivity for rubella was found among this young adult cohort, but a significant percent of the cohort had lower titers that may indicate poor initial vaccine response and potential risk if their antibody titers decline.
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http://dx.doi.org/10.1016/j.vaccine.2019.05.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934099PMC
June 2019

Sex Differences in Older Adults' Immune Responses to Seasonal Influenza Vaccination.

Front Immunol 2019 27;10:180. Epub 2019 Feb 27.

Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN, United States.

Sex differences in immune responses to influenza vaccine may impact efficacy across populations. In a cohort of 138 older adults (50-74 years old), we measured influenza A/H1N1 antibody titers, B-cell ELISPOT response, PBMC transcriptomics, and PBMC cell compositions at 0, 3, and 28 days post-immunization with the 2010/11 seasonal inactivated influenza vaccine. We identified higher B-cell ELISPOT responses in females than males. Potential mechanisms for sex effects were identified in four gene clusters related to T, NK, and B cells. Mediation analysis indicated that sex-dependent expression in T and NK cell genes can be partially attributed to higher CD4+ T cell and lower NK cell fractions in females. We identified strong sex effects in 135 B cell genes whose expression correlates with ELISPOT measures, and found that cell subset differences did not explain the effect of sex on these genes' expression. Post-vaccination expression of these genes, however, mediated 41% of the sex effect on ELISPOT responses. These results improve our understanding of sexual dimorphism in immunity and influenza vaccine response.
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http://dx.doi.org/10.3389/fimmu.2019.00180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400991PMC
January 2020

Self-reported reproductive health experiences in women with von Willebrand disease: a qualitative interview-based study.

J Obstet Gynaecol 2019 Feb 12;39(2):288-290. Epub 2018 Sep 12.

a Department of Medicine, Division of Hematology , Mayo Clinic , Rochester , MN , USA.

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http://dx.doi.org/10.1080/01443615.2018.1472223DOI Listing
February 2019

Immunization education for internal medicine residents: A cluster-randomized controlled trial.

Vaccine 2018 03 26;36(14):1823-1829. Epub 2018 Feb 26.

Mayo Clinic, 200 First St SW Rochester, MN 55905, USA. Electronic address:

Purpose: The aims of this study are to evaluate the impact of a novel immunization curriculum based on the Preferred Cognitive Styles and Decision Making Model (PCSDM) on internal medicine (IM) resident continuity clinic patient panel immunization rates, as well as resident immunization knowledge, attitudes, and practices (KAP).

Methods: A cluster-randomized controlled trial was performed among 143 IM residents at Mayo Clinic to evaluate the PCSDM curriculum plus fact-based immunization curriculum (intervention) compared to fact-based immunization curriculum alone (control) on the outcomes of resident continuity clinic patient panel immunization rates for influenza, pneumococcal, tetanus, pertussis, and zoster vaccines. Pre-study and post-study immunization KAP surveys were administered to IM residents.

Results: Ninety-nine residents participated in the study. Eighty-two residents completed pre-study and post-study surveys. Influenza and pertussis immunization rates improved for both intervention and control groups. There was no significant difference in immunization rate improvement between the groups. Influenza immunization rates improved significantly by 33.4% and 32.3% in the intervention and control groups, respectively. The odds of receiving influenza immunization at the end of the study relative to pre-study for the entire study cohort was 4.6 (p < 0.0001). The odds of having received pertussis immunization at the end of the study relative to pre-study for the entire study cohort was 1.2 (p = 0.0002). Both groups had significant improvements in immunization knowledge. The intervention group had significant improvements in multiple domains that assessed confidence in counseling patients on immunizations.

Conclusions: Fact-based immunization education was useful in improving IM resident immunization rates for influenza and pertussis. The PCSDM immunization curriculum did not lead to increases in immunization rates compared with the fact-based curriculum, but it did significantly increase resident confidence in communicating with patients about vaccines.
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http://dx.doi.org/10.1016/j.vaccine.2018.02.082DOI Listing
March 2018

Colonoscopy surveillance for high risk polyps does not always prevent colorectal cancer.

World J Gastroenterol 2018 Feb;24(8):905-916

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States.

Aim: To determine the frequency and risk factors for colorectal cancer (CRC) development among individuals with resected advanced adenoma (AA)/traditional serrated adenoma (TSA)/advanced sessile serrated adenoma (ASSA).

Methods: Data was collected from medical records of 14663 subjects found to have AA, TSA, or ASSA at screening or surveillance colonoscopy. Patients with inflammatory bowel disease or known genetic predisposition for CRC were excluded from the study. Factors associated with CRC developing after endoscopic management of high risk polyps were calculated in 4610 such patients who had at least one surveillance colonoscopy within 10 years following the original polypectomy of the incident advanced polyp.

Results: 84/4610 (1.8%) patients developed CRC at the polypectomy site within a median of 4.2 years (mean 4.89 years), and 1.2% (54/4610) developed CRC in a region distinct from the AA/TSA/ASSA resection site within a median of 5.1 years (mean 6.67 years). Approximately, 30% (25/84) of patients who developed CRC at the AA/TSA/ASSA site and 27.8% (15/54) of patients who developed CRC at another site had colonoscopy at recommended surveillance intervals. Increasing age; polyp size; male sex; right-sided location; high degree of dysplasia; higher number of polyps resected; and piecemeal removal were associated with an increased risk for CRC development at the same site as the index polyp. Increasing age; right-sided location; higher number of polyps resected and sessile endoscopic appearance of the index AA/TSA/ASSA were significantly associated with an increased risk for CRC development at a different site.

Conclusion: Recognition that CRC may develop following AA/TSA/ASSA removal is one step toward improving our practice efficiency and preventing a portion of CRC related morbidity and mortality.
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http://dx.doi.org/10.3748/wjg.v24.i8.905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829154PMC
February 2018

Differential miRNA expression in B cells is associated with inter-individual differences in humoral immune response to measles vaccination.

PLoS One 2018 30;13(1):e0191812. Epub 2018 Jan 30.

Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, Minnesota, United States of America.

Background: MicroRNAs are important mediators of post-transcriptional regulation of gene expression through RNA degradation and translational repression, and are emerging biomarkers of immune system activation/response after vaccination.

Methods: We performed Next Generation Sequencing (mRNA-Seq) of intracellular miRNAs in measles virus-stimulated B and CD4+ T cells from high and low antibody responders to measles vaccine. Negative binomial generalized estimating equation (GEE) models were used for miRNA assessment and the DIANA tool was used for gene/target prediction and pathway enrichment analysis.

Results: We identified a set of B cell-specific miRNAs (e.g., miR-151a-5p, miR-223, miR-29, miR-15a-5p, miR-199a-3p, miR-103a, and miR-15a/16 cluster) and biological processes/pathways, including regulation of adherens junction proteins, Fc-receptor signaling pathway, phosphatidylinositol-mediated signaling pathway, growth factor signaling pathway/pathways, transcriptional regulation, apoptosis and virus-related processes, significantly associated with neutralizing antibody titers after measles vaccination. No CD4+ T cell-specific miRNA expression differences between high and low antibody responders were found.

Conclusion: Our study demonstrates that miRNA expression directly or indirectly influences humoral immunity to measles vaccination and suggests that B cell-specific miRNAs may serve as useful predictive biomarkers of vaccine humoral immune response.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191812PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790242PMC
March 2018

Platelet-predominate gene expression and reticulated platelets in nonvalvular atrial fibrillation: Effect of pulmonary veins isolation.

J Cardiovasc Electrophysiol 2018 03 13;29(3):412-420. Epub 2018 Feb 13.

Department of Cardiovascular Medicine, Mayo Clinic Foundation for Education and Research, Rochester, MN, USA.

Introduction: Reticulated platelet (RP) content is increased in nonvalvular atrial fibrillation (NVAF). The purpose of this study was to determine if platelet content, morphology, and RP proportion are modulated by platelet genes.

Methods And Results: Expression of six platelet-predominate genes impacting platelet formation and release, platelet count, and RP content was assessed in NVAF patients before and 3-4 months after pulmonary veins isolation (PVI) and compared to normal sinus rhythm (NSR) controls. RNA from isolated platelets was reverse-transcribed assayed against selected genes utilizing real-time qPCR, and expressed as mean cycle threshold (ΔCt) using beta-2-microglobulin as endogenous control. RP content was assessed by flow cytometry. A fourfold lower expression of CFL1 gene coding for nonmuscle cofilin (7.8 ± 0.9 vs. 5.7 ± 1.6, P < 0.001) and twofold lower expression of four other genes were associated with similar platelet counts but fourfold higher (28.7+7.0 vs. 6.7+5.4, P < 0.001) RP content (%) in 97 NVAF cases compared to 51 NSR controls. Three to 4 months after PVI, RP decreased by 28%, while CFL1 gene expression increased over twofold but TUBA4A gene expression decreased almost twofold; NFE2 and MYL6 gene expression remained unchanged.

Conclusions: NVAF is associated with notable downregulation of genes directing platelet production and size but increased RP content. PVI impacts the expression of many of these genes, implying a direct relationship between atrial fibrillation and platelet biogenesis.
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http://dx.doi.org/10.1111/jce.13438DOI Listing
March 2018

Transcriptomic signatures of cellular and humoral immune responses in older adults after seasonal influenza vaccination identified by data-driven clustering.

Sci Rep 2018 01 15;8(1):739. Epub 2018 Jan 15.

Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN 55905, USA.

PBMC transcriptomes after influenza vaccination contain valuable information about factors affecting vaccine responses. However, distilling meaningful knowledge out of these complex datasets is often difficult and requires advanced data mining algorithms. We investigated the use of the data-driven Weighted Gene Correlation Network Analysis (WGCNA) gene clustering method to identify vaccine response-related genes in PBMC transcriptomic datasets collected from 138 healthy older adults (ages 50-74) before and after 2010-2011 seasonal trivalent influenza vaccination. WGCNA separated the 14,197 gene dataset into 15 gene clusters based on observed gene expression patterns across subjects. Eight clusters were strongly enriched for genes involved in specific immune cell types and processes, including B cells, T cells, monocytes, platelets, NK cells, cytotoxic T cells, and antiviral signaling. Examination of gene cluster membership identified signatures of cellular and humoral responses to seasonal influenza vaccination, as well as pre-existing cellular immunity. The results of this study illustrate the utility of this publically available analysis methodology and highlight genes previously associated with influenza vaccine responses (e.g., CAMK4, CD19), genes with functions not previously identified in vaccine responses (e.g., SPON2, MATK, CST7), and previously uncharacterized genes (e.g. CORO1C, C8orf83) likely related to influenza vaccine-induced immunity due to their expression patterns.
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http://dx.doi.org/10.1038/s41598-017-17735-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768803PMC
January 2018

Characterization of rubella-specific humoral immunity following two doses of MMR vaccine using proteome microarray technology.

PLoS One 2017 16;12(11):e0188149. Epub 2017 Nov 16.

Mayo Vaccine Research Group, Mayo Clinic and Foundation, Rochester, MN, United States of America.

Introduction//background: The lack of standardization of the currently used commercial anti-rubella IgG antibody assays leads to frequent misinterpretation of results for samples with low/equivocal antibody concentration. The use of alternative approaches in rubella serology could add new information leading to a fuller understanding of rubella protective immunity and neutralizing antibody response after vaccination.

Methods: We applied microarray technology to measure antibodies to all rubella virus proteins in 75 high and 75 low rubella virus-specific antibody responders after two MMR vaccine doses. These data were used in multivariate penalized logistic regression modeling of rubella-specific neutralizing antibody response after vaccination.

Results: We measured antibodies to all rubella virus structural proteins (i.e., the glycoproteins E1 and E2 and the capsid C protein) and to the non-structural protein P150. Antibody levels to each of these proteins were: correlated with the neutralizing antibody titer (p<0.006); demonstrated differences between the high and the low antibody responder groups (p<0.008); and were components of the model associated with/predictive of vaccine-induced rubella virus-specific neutralizing antibody titers (misclassification error = 0.2).

Conclusion: Our study supports the use of this new technology, as well as the use of antibody profiles/patterns (rather than single antibody measures) as biomarkers of neutralizing antibody response and correlates of protective immunity in rubella virus serology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188149PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690594PMC
December 2017

Intra-articular injection of a substance P inhibitor affects gene expression in a joint contracture model.

J Cell Biochem 2018 02 20;119(2):1326-1336. Epub 2017 Nov 20.

Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota.

Substance P (SP), a neurotransmitter released after injury, has been linked to deregulated tissue repair and fibrosis in musculoskeletal tissues and other organs. Although SP inhibition is an effective treatment for nausea, it has not been previously considered as an anti-fibrotic therapy. Although there are extensive medical records of individuals who have used SP antagonists, our analysis of human registry data revealed that patients receiving these antagonists and arthroplasty are exceedingly rare, thus precluding a clinical evaluation of their potential effects in the context of arthrofibrosis. Therefore, we pursued in vivo studies to assess the effect of SP inhibition early after injury on pro-fibrotic gene expression and contractures in an animal model of post-traumatic joint stiffening. Skeletally mature rabbits (n = 24) underwent surgically induced severe joint contracture, while injected with either fosaprepitant (a selective SP antagonist) or saline (control) early after surgery (3, 6, 12, and 24 h). Biomechanical testing revealed that differences in mean contracture angles between the groups were not statistically significant (P = 0.27), suggesting that the drug neither mitigates nor exacerbates joint contracture. However, microarray gene expression analysis revealed that mRNA levels for proteins related to cell signaling, pro-angiogenic, pro-inflammatory, and collagen matrix production were significantly different between control and fosaprepitant treated rabbits (P < 0.05). Hence, our study demonstrates that inhibition of SP alters expression of pro-fibrotic genes in vivo. This finding will motivate future studies to optimize interventions that target SP to reduce the formation of post-traumatic joint contractures.
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http://dx.doi.org/10.1002/jcb.26256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388635PMC
February 2018

Integration of Immune Cell Populations, mRNA-Seq, and CpG Methylation to Better Predict Humoral Immunity to Influenza Vaccination: Dependence of mRNA-Seq/CpG Methylation on Immune Cell Populations.

Front Immunol 2017 21;8:445. Epub 2017 Apr 21.

Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN, USA.

The development of a humoral immune response to influenza vaccines occurs on a multisystems level. Due to the orchestration required for robust immune responses when multiple genes and their regulatory components across multiple cell types are involved, we examined an influenza vaccination cohort using multiple high-throughput technologies. In this study, we sought a more thorough understanding of how immune cell composition and gene expression relate to each other and contribute to interindividual variation in response to influenza vaccination. We first hypothesized that many of the differentially expressed (DE) genes observed after influenza vaccination result from changes in the composition of participants' peripheral blood mononuclear cells (PBMCs), which were assessed using flow cytometry. We demonstrated that DE genes in our study are correlated with changes in PBMC composition. We gathered DE genes from 128 other publically available PBMC-based vaccine studies and identified that an average of 57% correlated with specific cell subset levels in our study (permutation used to control false discovery), suggesting that the associations we have identified are likely general features of PBMC-based transcriptomics. Second, we hypothesized that more robust models of vaccine response could be generated by accounting for the interplay between PBMC composition, gene expression, and gene regulation. We employed machine learning to generate predictive models of B-cell ELISPOT response outcomes and hemagglutination inhibition (HAI) antibody titers. The top HAI and B-cell ELISPOT model achieved an area under the receiver operating curve (AUC) of 0.64 and 0.79, respectively, with linear model coefficients of determination of 0.08 and 0.28. For the B-cell ELISPOT outcomes, CpG methylation had the greatest predictive ability, highlighting potentially novel regulatory features important for immune response. B-cell ELISOT models using only PBMC composition had lower performance (AUC = 0.67), but highlighted well-known mechanisms. Our analysis demonstrated that each of the three data sets (cell composition, mRNA-Seq, and DNA methylation) may provide distinct information for the prediction of humoral immune response outcomes. We believe that these findings are important for the interpretation of current omics-based studies and set the stage for a more thorough understanding of interindividual immune responses to influenza vaccination.
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http://dx.doi.org/10.3389/fimmu.2017.00445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399034PMC
April 2017

Impact of atrial fibrillation on platelet gene expression.

Eur J Haematol 2017 Jun 20;98(6):615-621. Epub 2017 Apr 20.

Mayo Clinic and Foundation for Education and Research, Rochester, MN, USA.

Aims: Platelets retain cytoplasmic messenger RNA and are capable of protein biosynthesis. Several diseases are known to impact the platelet transcriptome but the effect of non-valvular atrial fibrillation (NVAF) on platelet RNA transcript is essentially unknown. The aim of this study was to evaluate the impact of NVAF on platelet RNA transcript by measuring platelet genes expression in consecutive NVAF patients before and 3-4 months after pulmonary vein isolation (PVI) and compared to normal sinus rhythm controls (NSR).

Methods And Results: RNA from isolated platelets were reverse transcribed, assayed against 15 genes using real-time qPCR, and expressed as mean cycle threshold (ΔCt) using beta-2-microglobulin as endogenous control. Expression of all evaluated genes, except cathepsin A gene, was significantly lower (higher ΔCt) in 103 NVAF patients compared to 55 NSR controls. Insulin-like growth factor binding protein acid labile subunit gene (IGFALS) had expression more than 16 fold-lower (17.0±2.8 vs 12.5±3.8, P<.001), follow by genes encoding for prostacyclin receptor, and for von Willebrand factor which had fourfold lower expression compared to NSR controls. Gender, type of atrial fibrillation, heart failure, hypertension, prior stroke, diabetes mellitus, and atherosclerosis were associated with different gene expression. Following PVI, expression of four genes significantly increased, particularly IGFALS gene (increased 256-fold) and ADAMT gene increased 16-fold); expression of three genes significantly decreased, and expression of eight genes has not changed.

Conclusions: Platelets are capable to respond to the circulatory environment of NVAF by altering transcript and changing prothrombotic status. This shows platelet potential for molecular "reprogramming" possibly induced by flow disturbances of NVAF.
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http://dx.doi.org/10.1111/ejh.12879DOI Listing
June 2017

Genome-wide associations of CD46 and IFI44L genetic variants with neutralizing antibody response to measles vaccine.

Hum Genet 2017 04 13;136(4):421-435. Epub 2017 Mar 13.

Mayo Clinic Vaccine Research Group, Mayo Clinic, Guggenheim 611C, 200 First Street SW, Rochester, MN, 55905, USA.

Population-based studies have revealed 2-10% measles vaccine failure rate even after two vaccine doses. While the mechanisms behind this remain unknown, we hypothesized that host genetic factors are likely to be involved. We performed a genome-wide association study of measles specific neutralizing antibody and IFNγ ELISPOT response in a combined sample of 2872 subjects. We identified two distinct chromosome 1 regions (previously associated with MMR-related febrile seizures), associated with vaccine-induced measles neutralizing antibody titers. The 1q32 region contained 20 significant SNPs in/around the measles virus receptor-encoding CD46 gene, including the intronic rs2724384 (p value = 2.64 × 10) and rs2724374 (p value = 3.16 × 10) SNPs. The 1q31.1 region contained nine significant SNPs in/around IFI44L, including the intronic rs1333973 (p value = 1.41 × 10) and the missense rs273259 (His73Arg, p value = 2.87 × 10) SNPs. Analysis of differential exon usage with mRNA-Seq data and RT-PCR suggests the involvement of rs2724374 minor G allele in the CD46 STP region exon B skipping, resulting in shorter CD46 isoforms. Our study reveals common CD46 and IFI44L SNPs associated with measles-specific humoral immunity, and highlights the importance of alternative splicing/virus cellular receptor isoform usage as a mechanism explaining inter-individual variation in immune response after live measles vaccine.
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http://dx.doi.org/10.1007/s00439-017-1768-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433429PMC
April 2017

Immunosenescence-Related Transcriptomic and Immunologic Changes in Older Individuals Following Influenza Vaccination.

Front Immunol 2016 2;7:450. Epub 2016 Nov 2.

Mayo Clinic Vaccine Research Group, Department of General Internal Medicine, Mayo Clinic , Rochester, MN , USA.

The goal of annual influenza vaccination is to reduce mortality and morbidity associated with this disease through the generation of protective immune responses. The objective of the current study was to examine markers of immunosenescence and identify immunosenescence-related differences in gene expression, gene regulation, cytokine secretion, and immunologic changes in an older study population receiving seasonal influenza A/H1N1 vaccination. Surprisingly, prior studies in this cohort revealed weak correlations between immunosenescence markers and humoral immune response to vaccination. In this report, we further examined the relationship of each immunosenescence marker (age, T cell receptor excision circle frequency, telomerase expression, percentage of CD28 CD4 T cells, percentage of CD28 CD8 T cells, and the CD4/CD8 T cell ratio) with additional markers of immune response (serum cytokine and chemokine expression) and measures of gene expression and/or regulation. Many of the immunosenescence markers indeed correlated with distinct sets of individual DNA methylation sites, miRNA expression levels, mRNA expression levels, serum cytokines, and leukocyte subsets. However, when the individual immunosenescence markers were grouped by pathways or functional terms, several shared biological functions were identified: antigen processing and presentation pathways, MAPK, mTOR, TCR, BCR, and calcium signaling pathways, as well as key cellular metabolic, proliferation and survival activities. Furthermore, the percent of CD4 and/or CD8 T cells lacking CD28 expression also correlated with miRNAs regulating clusters of genes known to be involved in viral infection. Integrated (DNA methylation, mRNA, miRNA, and protein levels) network biology analysis of immunosenescence-related pathways and genesets identified both known pathways (e.g., chemokine signaling, CTL, and NK cell activity), as well as a gene expression module not previously annotated with a known function. These results may improve our ability to predict immune responses to influenza and aid in new vaccine development, and highlight the need for additional studies to better define and characterize immunosenescence.
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http://dx.doi.org/10.3389/fimmu.2016.00450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089977PMC
November 2016

Taxa of the Nasal Microbiome Are Associated with Influenza-Specific IgA Response to Live Attenuated Influenza Vaccine.

PLoS One 2016 19;11(9):e0162803. Epub 2016 Sep 19.

Mayo Vaccine Research Group, Mayo Clinic, Rochester, MN, 55905, United States of America.

Live attenuated influenza vaccine (LAIV) has demonstrated varying levels of efficacy against seasonal influenza; however, LAIV may be used as a tool to measure interactions between the human microbiome and a live, replicating virus. To increase our knowledge of this interaction, we measured changes to the nasal microbiome in subjects who received LAIV to determine if associations between influenza-specific IgA production and the nasal microbiome exist after immunization with a live virus vaccine. The anterior nares of 47 healthy subjects were swabbed pre- (Day 0) and post- (Days 7 and 28) LAIV administration, and nasal washes were conducted on Days 0 and 28. We performed next-generation sequencing on amplified 16s rRNA genes and measured mucosal influenza-specific IgA titers via enzyme-linked immunosorbent assay (ELISA). A significant increase in alpha diversity was identified (Observed, CHAO, and ACE) between Days 7 vs 0 (p-values = 0.017, 0.005, 0.005, respectively) and between Days 28 vs 0 (p-values = 0.054, 0.030, 0.050, respectively). Several significant associations between the presence of different microbial species, including Lactobacillus helveticus, Prevotella melaninogenica, Streptococcus infantis, Veillonella dispar, and Bacteroides ovatus, and influenza-specific H1 and H3 IgA antibody response were demonstrated. These data suggest that LAIV alters the nasal microbiome, allowing several less-abundant OTUs to establish a community niche. Additionally, specific alterations in the nasal microbiome are significantly associated with variations in influenza-specific IgA antibody production and could be clinically relevant.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162803PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5028048PMC
August 2017

Whole Transcriptome Profiling Identifies CD93 and Other Plasma Cell Survival Factor Genes Associated with Measles-Specific Antibody Response after Vaccination.

PLoS One 2016 16;11(8):e0160970. Epub 2016 Aug 16.

Mayo Clinic Vaccine Research Group-Department of Medicine, Mayo Clinic and Foundation, Rochester, MN, United States of America.

Background: There are insufficient system-wide transcriptomic (or other) data that help explain the observed inter-individual variability in antibody titers after measles vaccination in otherwise healthy individuals.

Methods: We performed a transcriptome(mRNA-Seq)-profiling study after in vitro viral stimulation of PBMCs from 30 measles vaccine recipients, selected from a cohort of 764 schoolchildren, based on the highest and lowest antibody titers. We used regression and network biology modeling to define markers associated with neutralizing antibody response.

Results: We identified 39 differentially expressed genes that demonstrate significant differences between the high and low antibody responder groups (p-value≤0.0002, q-value≤0.092), including the top gene CD93 (p<1.0E-13, q<1.0E-09), encoding a receptor required for antigen-driven B-cell differentiation, maintenance of immunoglobulin production and preservation of plasma cells in the bone marrow. Network biology modeling highlighted plasma cell survival (CD93, IL6, CXCL12), chemokine/cytokine activity and cell-cell communication/adhesion/migration as biological processes associated with the observed differential response in the two responder groups.

Conclusion: We identified genes and pathways that explain in part, and are associated with, neutralizing antibody titers after measles vaccination. This new knowledge could assist in the identification of biomarkers and predictive signatures of protective immunity that may be useful in the design of new vaccine candidates and in clinical studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160970PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987012PMC
July 2017

Gene signatures related to HAI response following influenza A/H1N1 vaccine in older individuals.

Heliyon 2016 May 6;2(5):e00098. Epub 2016 May 6.

Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN 55905, USA.

To assess gene signatures related to humoral response among healthy older subjects following seasonal influenza vaccination, we studied 94 healthy adults (50-74 years old) who received one documented dose of licensed trivalent influenza vaccine containing the A/California/7/2009 (H1N1)-like virus strain. Influenza-specific antibody (HAI) titer in serum samples and next-generation sequencing on PBMCs were performed using blood samples collected prior to (Day 0) and at two timepoints after (Days 3 and 28) vaccination. We identified a number of uncharacterized genes (ZNF300, NUP1333, KLK1 and others) and confirmed previous studies demonstrating specific genes/genesets that are important mediators of host immune responses and that displayed associations with antibody response to influenza A/H1N1 vaccine. These included interferon-regulatory transcription factors (IRF1/IRF2/IRF6/IRF7/IRF9), chemokine/chemokine receptors (CCR5/CCR9/CCL5), cytokine/cytokine receptors (IFNG/IL10RA/TNFRSF1A), protein kinases (MAP2K4/MAPK3), growth factor receptor (TGFBR1). The identification of gene signatures associated with antibody response represents an early stage in the science for which further research is needed. Such research may assist in the design of better vaccines to facilitate improved defenses against new influenza virus strains, as well as better understanding the genetic drivers of immune responses.
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http://dx.doi.org/10.1016/j.heliyon.2016.e00098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946173PMC
May 2016

Transcriptional signatures of influenza A/H1N1-specific IgG memory-like B cell response in older individuals.

Vaccine 2016 07 20;34(34):3993-4002. Epub 2016 Jun 20.

Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN 55905, USA. Electronic address:

Background: Studies suggest that the recall-based humoral immune responses to influenza A/H1N1 originates from activated memory B cells. The aim of this study was to identify baseline, early and late blood transcriptional signatures (in peripheral blood mononuclear cells/PBMCs) associated with memory B cell response following influenza vaccination.

Methods: We used pre- and post-vaccination mRNA-Seq transcriptional profiling on samples from 159 subjects (50-74years old) following receipt of seasonal trivalent influenza vaccine containing the A/California/7/2009/H1N1-like virus, and penalized regression modeling to identify associations with influenza A/H1N1-specific memory B cell ELISPOT response after vaccination.

Results: Genesets and genes (p-value range 7.92E(-08) to 0.00018, q-value range 0.00019-0.039) demonstrating significant associations (of gene expression levels) with memory B cell response suggest the importance of metabolic (cholesterol and lipid metabolism-related), cell migration/adhesion, MAP kinase, NF-kB cell signaling (chemokine/cytokine signaling) and transcriptional regulation gene signatures in the development of memory B cell response after influenza vaccination.

Conclusion: Through an unbiased transcriptome-wide profiling approach, our study identified signatures of memory B cell response following influenza vaccination, highlighting the underappreciated role of metabolic changes (among the other immune function-related events) in the regulation of influenza vaccine-induced immune memory.
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http://dx.doi.org/10.1016/j.vaccine.2016.06.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520794PMC
July 2016

Recursive Indirect-Paths Modularity (RIP-M) for Detecting Community Structure in RNA-Seq Co-expression Networks.

Front Genet 2016 9;7:80. Epub 2016 May 9.

Tandy School of Computer Science, University of TulsaTulsa, OK, USA; Department of Mathematics, University of TulsaTulsa, OK USA.

Clusters of genes in co-expression networks are commonly used as functional units for gene set enrichment detection and increasingly as features (attribute construction) for statistical inference and sample classification. One of the practical challenges of clustering for these purposes is to identify an optimal partition of the network where the individual clusters are neither too large, prohibiting interpretation, nor too small, precluding general inference. Newman Modularity is a spectral clustering algorithm that automatically finds the number of clusters, but for many biological networks the cluster sizes are suboptimal. In this work, we generalize Newman Modularity to incorporate information from indirect paths in RNA-Seq co-expression networks. We implement a merge-and-split algorithm that allows the user to constrain the range of cluster sizes: large enough to capture genes in relevant pathways, yet small enough to resolve distinct functions. We investigate the properties of our recursive indirect-pathways modularity (RIP-M) and compare it with other clustering methods using simulated co-expression networks and RNA-seq data from an influenza vaccine response study. RIP-M had higher cluster assignment accuracy than Newman Modularity for finding clusters in simulated co-expression networks for all scenarios, and RIP-M had comparable accuracy to Weighted Gene Correlation Network Analysis (WGCNA). RIP-M was more accurate than WGCNA for modest hard thresholds and comparable for high, while WGCNA was slightly more accurate for soft thresholds. In the vaccine study data, RIP-M and WGCNA enriched for a comparable number of immunologically relevant pathways.
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http://dx.doi.org/10.3389/fgene.2016.00080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861003PMC
May 2016

The composition of immune cells serves as a predictor of adaptive immunity in a cohort of 50- to 74-year-old adults.

Immunology 2016 07 17;148(3):266-75. Epub 2016 May 17.

Mayo Vaccine Research Group, Rochester, MN, USA.

Influenza causes significant morbidity and mortality annually. Although vaccination offers a considerable amount of protection, it is far from perfect, especially in aging populations. This is due to age-related defects in immune function, a process called immunosenescence. To date, there are no assays or methods to predict or explain variations in an individual's level of response to influenza vaccination. In this study, we measured levels of several immune cell subsets at baseline (Day 0) and at Days 3 and 28 post-vaccination using flow cytometry. Statistical modelling was performed to assess correlations between levels of cell subsets and Day 28 immune responses - haemagglutination inhibition (HAI) assay, virus neutralizing antibody (VNA) assay, and memory B cell ELISPOT. Changes in several groups of cell types from Day 0 to Day 28 and Day 3 to Day 28 were found to be significantly associated with immune response. Baseline levels of several immune cell subsets, including B cells and regulatory T cells, were able to partially explain variation in memory B-cell ELISPOT results. Increased expression of HLA-DR on plasmacytoid dendritic cells after vaccination was correlated with increased HAI and VNA responses. Our data suggest that the expression of activation markers (HLA-DR and CD86) on various immune cell subsets, as well as the relative distribution of cell subsets, both have value in predicting immune responses to influenza vaccination in older individuals.
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http://dx.doi.org/10.1111/imm.12599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913285PMC
July 2016

Impaired innate, humoral, and cellular immunity despite a take in smallpox vaccine recipients.

Vaccine 2016 06 11;34(28):3283-90. Epub 2016 May 11.

Mayo Vaccine Research Group, Mayo Clinic, Rochester, MN, USA; Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.

Smallpox vaccine is highly effective, inducing protective immunity to smallpox and diseases caused by related orthopoxviruses. Smallpox vaccine efficacy was historically defined by the appearance of a lesion or "take" at the vaccine site, which leaves behind a characteristic scar. Both the take and scar are readily recognizable and were used during the eradication effort to indicate successful vaccination and to categorize individuals as "protected." However, the development of a typical vaccine take may not equate to the successful development of a robust, protective immune response. In this report, we examined two large (>1000) cohorts of recipients of either Dryvax(®) or ACAM2000 using a testing and replication study design and identified subgroups of individuals who had documented vaccine takes, but who failed to develop robust neutralizing antibody titers. Examination of these individuals revealed that they had suboptimal cellular immune responses as well. Further testing indicated these low responders had a diminished innate antiviral gene expression pattern (IFNA1, CXCL10, CXCL11, OASL) upon in vitro stimulation with vaccinia virus, perhaps indicative of a dysregulated innate response. Our results suggest that poor activation of innate antiviral pathways may result in suboptimal immune responses to the smallpox vaccine. These genes and pathways may serve as suitable targets for adjuvants in new attenuated smallpox vaccines and/or effective antiviral therapy targets against poxvirus infections.
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http://dx.doi.org/10.1016/j.vaccine.2016.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528000PMC
June 2016
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