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1.  Disruption of macrophage pro-inflammatory cytokine release in Crohn's disease is associated with reduced optineurin expression in a subset of patients 
Immunology  2014;144(1):45-55.
Crohn's disease (CD) is a complex and highly heterogeneous chronic inflammatory disorder, primarily affecting the gastrointestinal tract. Genetic and functional studies have highlighted a key role for innate immunity in its pathogenesis. Profound systemic defects in innate immunity and acute inflammation are understood to result in markedly delayed clearance of bacteria from the tissues, leading to local chronic granulomatous inflammation and compensatory adaptive immunological changes. Macrophages, key orchestrators of acute inflammation, are likely to play an important role in the initial impaired innate immune response. Monocyte-derived macrophages from CD patients stimulated with Escherichia coli were shown to release attenuated levels of tumour necrosis factor and interferon-γ with normal secretion of interleukin-8 (IL-8), IL-10 and IL-6. In controls, the secretion of these cytokines was strongly positively correlated, which was not seen with CD macrophages. The transcriptomes of CD and control macrophages were examined in an attempt to understand the molecular basis of this defect. There were no differentially expressed genes identified between the two groups, consistent with genetic heterogeneity; however, a number of molecules were found to be under-expressed in subgroups of CD patients. The most common of these was optineurin (OPTN) which was under-expressed in approximately 10% of the CD patients. Reduced OPTN expression coincided with lower intracellular protein levels and diminished cytokine secretion after bacterial stimulation both in the patients and with small interfering RNA knockdown in THP-1 cells. Identifying and studying subgroups of patients with shared defective gene expression could aid our understanding of the mechanisms underlying highly heterogeneous diseases such as CD.
doi:10.1111/imm.12338
PMCID: PMC4264909  PMID: 24943399
cytokine; gene expression; inflammatory bowel disease; immunodeficiency; inflammation
2.  Highlights of Historical Events Leading to National Surveillance of Vaccination Coverage in the United States 
Public Health Reports  2011;126(Suppl 2):3-12.
The articles published in this special supplement of Public Health Reports provide examples of only some of the current efforts in the United States for evaluating vaccination coverage. So, how did we get here? The history of vaccination and assessment of vaccination coverage in the U.S. has its roots in the pre-Revolutionary War era. In many cases, development of vaccines, and attention devoted to the assessment of vaccination coverage, has grown from the impact of infectious disease on major world events such as wars. The purpose of this commentary is to provide a brief overview of the key historical events in the U.S. that influenced the development of vaccines and the efforts to track vaccination coverage, which laid the foundation for contemporary vaccination assessment efforts.
PMCID: PMC3113425  PMID: 21815302
3.  Vaccination Coverage Among U.S. Children Aged 19–35 Months Entitled by the Vaccines for Children Program, 2009 
Public Health Reports  2011;126(Suppl 2):109-123.
Objectives
Following the measles outbreaks of the late 1980s and early 1990s, vaccination coverage was found to be low nationally, and there were pockets of underimmunized children primarily in inner cities. We described the percentage and demographics of children who were entitled to the Vaccines for Children (VFC) program in 2009 and evaluated whether Healthy People 2010 (HP 2010) vaccination coverage objectives of 90% were achieved among these children.
Methods
We analyzed data from 16,967 children aged 19–35 months sampled by the National Immunization Survey in 2009. VFC-entitled children included children who were (1) on Medicaid, (2) not covered by health insurance, (3) of American Indian/Alaska Native race/ethnicity, or (4) covered by private health insurance that did not pay all of the costs of vaccines, but who were vaccinated at a Federally Qualified Health Center or a Rural Health Center.
Results
An estimated 49.7% of all children aged 19–35 months were entitled to VFC vaccines. Compared with children who did not qualify for VFC, the VFC-entitled children were significantly more likely to be Hispanic or non-Hispanic black; to have a mother who was widowed, divorced, separated, or never married; and to live in a household with an annual income below the federal poverty level. Mothers of VFC-entitled children were significantly less likely to have some college experience or to be college graduates. Of nine vaccines analyzed, two vaccines—polio at 91.7% and hepatitis B at 92.2%—achieved the HP 2010 90% coverage objective for VFC-entitled children, and four others, including measles-mumps-rubella at 88.8%, achieved greater than 80% coverage.
Conclusions
Today, children with demographic characteristics like those of children who were at the epicenter of the measles outbreaks two decades ago are entitled to VFC vaccines at no cost, and have achieved high vaccination coverage levels.
PMCID: PMC3113436  PMID: 21812175
4.  Parental Delay or Refusal of Vaccine Doses, Childhood Vaccination Coverage at 24 Months of Age, and the Health Belief Model 
Public Health Reports  2011;126(Suppl 2):135-146.
Objective
We evaluated the association between parents' beliefs about vaccines, their decision to delay or refuse vaccines for their children, and vaccination coverage of children at aged 24 months.
Methods
We used data from 11,206 parents of children aged 24–35 months at the time of the 2009 National Immunization Survey interview and determined their vaccination status at aged 24 months. Data included parents' reports of delay and/or refusal of vaccine doses, psychosocial factors suggested by the Health Belief Model, and provider-reported up-to-date vaccination status.
Results
In 2009, approximately 60.2% of parents with children aged 24–35 months neither delayed nor refused vaccines, 25.8% only delayed, 8.2% only refused, and 5.8% both delayed and refused vaccines. Compared with parents who neither delayed nor refused vaccines, parents who delayed and refused vaccines were significantly less likely to believe that vaccines are necessary to protect the health of children (70.1% vs. 96.2%), that their child might get a disease if they aren't vaccinated (71.0% vs. 90.0%), and that vaccines are safe (50.4% vs. 84.9%). Children of parents who delayed and refused also had significantly lower vaccination coverage for nine of the 10 recommended childhood vaccines including diphtheria-tetanus-acellular pertussis (65.3% vs. 85.2%), polio (76.9% vs. 93.8%), and measles-mumps-rubella (68.4% vs. 92.5%). After adjusting for sociodemographic differences, we found that parents who were less likely to agree that vaccines are necessary to protect the health of children, to believe that their child might get a disease if they aren't vaccinated, or to believe that vaccines are safe had significantly lower coverage for all 10 childhood vaccines.
Conclusions
Parents who delayed and refused vaccine doses were more likely to have vaccine safety concerns and perceive fewer benefits associated with vaccines. Guidelines published by the American Academy of Pediatrics may assist providers in responding to parents who may delay or refuse vaccines.
PMCID: PMC3113438  PMID: 21812176
5.  The Association Between Intentional Delay of Vaccine Administration and Timely Childhood Vaccination Coverage 
Public Health Reports  2010;125(4):534-541.
SYNOPSIS
Objectives
We evaluated the association between intentional delay of vaccine administration and timely vaccination coverage.
Methods
We used data from 2,921 parents of 19- to 35-month-old children that included parents' reports of intentional delay of vaccine administration. Timely vaccination was defined as administration with ≥4 doses of diphtheria, tetanus, and pertussis; ≥3 doses of polio vaccine; ≥1 dose of measles, mumps, and rubella vaccine; ≥3 doses of Haemophilus influenzae type b vaccine; ≥3 doses of hepatitis B vaccine; and ≥1 dose of varicella vaccine by 19 months of age, as reported by vaccination providers.
Results
In all, 21.8% of parents reported intentionally delaying vaccinations for their children. Among parents who intentionally delayed, 44.8% did so because of concerns about vaccine safety or efficacy and 36.1% delayed because of an ill child. Children whose parents intentionally delayed were significantly less likely to receive all vaccines by 19 months of age than children whose parents did not delay (35.4% vs. 60.1%, p<0.05). Parents who intentionally delayed were significantly more likely to have heard or read unfavorable information about vaccines than parents who did not intentionally delay (87.6% vs. 71.9%, p<0.05). Compared with parents who intentionally delayed only because their child was ill, parents who intentionally delayed only because of vaccine safety or efficacy concerns were significantly more likely to seek additional information about their decision from the Internet (11.4% vs. 1.1%, p<0.05), and significantly less likely to seek information from a doctor (73.9% vs. 93.9%, p<0.05).
Conclusions
Intentionally delayed vaccine doses are not uncommon. Children whose parents delay vaccinations may be at increased risk of not receiving all recommended vaccine doses by 19 months of age and are more vulnerable to vaccine-preventable diseases. Providers should consider strategies such as educational materials that address parents' vaccine safety and efficacy concerns to encourage timely vaccination.
PMCID: PMC2882604  PMID: 20597453
6.  A co-crystal of 1,10-phenanthroline with boric acid: a novel aza-aromatic complex 
The title compound, C12H8N2·2B(OH)3, is best described as a host–guest complex in which the B(OH)3 mol­ecules form a hydrogen-bonded cyclic network of layers parallel to the ab plane into which the 1,10-phenanthroline mol­ecules are bound. An extensive network of hydrogen bonds are responsible for the crystal stability. No π-stacking inter­actions occur between the 1,10-phenanthroline mol­ecules.
doi:10.1107/S1600536813015134
PMCID: PMC3952236  PMID: 24627684
7.  Vaccination Coverage Estimates for Selected Counties: Achievement of Healthy People 2010 Goals and Association with Indices of Access to Care, Economic Conditions, and Demographic Composition 
Public Health Reports  2008;123(2):155-172.
SYNOPSIS
Objective
We provided vaccination coverage estimates for 181 counties; evaluated the extent to which Healthy People 2010 (HP 2010) vaccination coverage objectives were achieved; and examined how variations in those estimates depend on access to care and economic conditions.
Methods
We analyzed data for 24,031 children aged 19 to 35 months sampled from the 2004 and 2005 National Immunization Survey.
Results
Children living in the 181 counties represented 49% of all the 19- to 35-month-old children living in the U.S. None of the 181 counties had coverage for the polio, measles-mumps-rubella, Haemophilus influenzae type B, and hepatitis B vaccines that was significantly lower than the HP 2010 objective of 90% coverage. However, as many as 30.4% of the counties did not achieve the HP 2010 objective for diphtheria, tetanus toxoids, and acellular pertussis or diphtheria and tetanus toxoids and pertussis (DtaP/DTP), and as many as 6.6% did not achieve the goal for varicella (VAR). If children who received three doses of DTaP/DTP had received a final fourth dose, and if all children had received one dose of VAR, all of the 181 counties would have achieved the HP 2010 vaccination coverage target of 80% for the entire 4:3:1:3:3:1 vaccination series. Factors found to be associated with low county-level vaccination coverage rates were correlates of poverty, and factors found to be associated with high county-level vaccination coverage rates were correlates of access to pediatric services.
Conclusions
HP 2010 vaccination coverage goals for all 181 counties can be achieved by improving vaccination coverage for only two vaccines. Those goals may be achieved most efficiently by targeting interventions in counties where indices of poverty are high or where access to pediatric services is low.
PMCID: PMC2239325  PMID: 18457068
8.  Trends in the Risk of U.S. Polio Outbreaks and Poliovirus Vaccine Availability for Response 
Public Health Reports  2012;127(1):23-37.
SYNOPSIS
Objectives
The United States eliminated indigenous wild polioviruses (WPVs) in 1979 and switched to inactivated poliovirus vaccine in 2000, which quickly ended all indigenous live poliovirus transmission. Continued WPV circulation and use of oral poliovirus vaccine globally allow for the possibility of reintroduction of these viruses. We evaluated the risk of a U.S. polio outbreak and explored potential vaccine needs for outbreak response.
Methods
We synthesized information available on vaccine coverage, exemptor populations, and population immunity. We used an infection transmission model to explore the potential dynamics of a U.S. polio outbreak and potential vaccine needs for outbreak response, and assessed the impacts of heterogeneity in population immunity for two different subpopulations with potentially low coverage.
Results
Although the risk of poliovirus introduction remains real, widespread transmission of polioviruses appears unlikely in the U.S., given high routine coverage. However, clusters of un- or underimmunized children might create pockets of susceptibility that could potentially lead to one or more paralytic polio cases. We found that the shift toward combination vaccine utilization, with limited age indications for use, and other current trends (e.g., decreasing proportion of the population with immunity induced by live polioviruses and aging of vaccine exemptor populations) might increase the vulnerability to poliovirus reintroduction at the same time that the ability to respond may decrease.
Conclusions
The U.S. poliovirus vaccine stockpile remains an important resource that may potentially be needed in the future to respond to an outbreak if a live poliovirus gets imported into a subpopulation with low vaccination coverage.
PMCID: PMC3234395  PMID: 22298920
9.  Lipidomic profiling in Crohn's disease: Abnormalities in phosphatidylinositols, with preservation of ceramide, phosphatidylcholine and phosphatidylserine composition 
Crohn's disease is a chronic inflammatory condition largely affecting the terminal ileum and large bowel. A contributing cause is the failure of an adequate acute inflammatory response as a result of impaired secretion of pro-inflammatory cytokines by macrophages. This defective secretion arises from aberrant vesicle trafficking, misdirecting the cytokines to lysosomal degradation. Aberrant intestinal permeability is also well-established in Crohn's disease. Both the disordered vesicle trafficking and increased bowel permeability could result from abnormal lipid composition. We thus measured the sphingo- and phospholipid composition of macrophages, using mass spectrometry and stable isotope labelling approaches. Stimulation of macrophages with heat-killed Escherichia coli resulted in three main changes; a significant reduction in the amount of individual ceramide species, an altered composition of phosphatidylcholine, and an increased rate of phosphatidylcholine synthesis in macrophages. These changes were observed in macrophages from both healthy control individuals and patients with Crohn's disease. The only difference detected between control and Crohn's disease macrophages was a reduced proportion of newly-synthesised phosphatidylinositol 16:0/18:1 over a defined time period. Shotgun lipidomics analysis of macroscopically non-inflamed ileal biopsies showed a significant decrease in this same lipid species with overall preservation of sphingolipid, phospholipid and cholesterol composition.
doi:10.1016/j.biocel.2012.06.016
PMCID: PMC3778899  PMID: 22728312
CCT, Phosphocholine cytidylyltransferase; CD, Crohn's disease; GWAS, Genome-wide association study; HC, Healthycontrol; HkEc, Heat-killed Escherichia coli; PA, Phosphatidic acid; PC, Phosphatidylcholine; PI, Phosphatidylinositol; PS, Phosphatidylserine; TNF, Tumor necrosis factor; Crohn's disease; Macrophage; Lipids; Ceramide; Sphingolipid; Phospholipid
10.  Cellular entry of nanoparticles via serum sensitive clathrin-mediated endocytosis, and plasma membrane permeabilization 
Increasing production and application of nanomaterials raises significant questions regarding the potential for cellular entry and toxicity of nanoparticles. It was observed that the presence of serum reduces the cellular association of 20 nm carboxylate-modified fluorescent polystyrene beads up to 20-fold, relative to cells incubated in serum-free media. Analysis by confocal microscopy demonstrated that the presence of serum greatly reduces the cell surface association of nanoparticles, as well as the potential for internalization. However, both in the presence and absence of serum, nanoparticle entry depends upon clathrin-mediated endocytosis. Finally, experiments performed with cells cooled to 4°C suggest that a proportion of the accumulation of nanoparticles in cells was likely due to direct permeabilization of the plasma membrane.
doi:10.2147/IJN.S29334
PMCID: PMC3356167  PMID: 22619541
nanoparticles; polystyrene beads; serum; endocytosis; dynamin; clathrin; permeabilization
12.  Vaccination Coverage Among U.S. Adolescents Aged 13–17 Years Eligible for the Vaccines for Children Program, 2009 
Public Health Reports  2011;126(Suppl 2):124-134.
Objectives
We compared (1) characteristics of adolescents who are and are not entitled to receive free vaccines from the Vaccines for Children (VFC) program and (2) vaccination coverage with meningococcal conjugate (MCV4), quadrivalent human papillomavirus (HPV4), and tetanus-diphtheria-acellular pertussis (Tdap) vaccines among VFC-eligible and non-VFC-eligible adolescents.
Methods
We analyzed data from the 2009 National Immunization Survey-Teen, a nationally representative, random-digit-dialed survey of households with adolescents aged 13–17 years (n=20,066). Differences in sociodemographic characteristics and provider-reported vaccination coverage were evaluated using t-tests.
Results
Overall, 32.1% (±1.2%) of adolescents were VFC-eligible. VFC-eligible adolescents were significantly less likely than non-VFC-eligible adolescents to be white and to live in suburban areas, and more likely to live in poverty and to have younger and less educated mothers. Nationally, coverage among non-VFC-eligible adolescents was 57.1% (±1.5%) for ≥1 dose of Tdap, 55.4% (±1.5%) for ≥1 dose of MCV4, and 43.2% (±2.2%) for ≥1 dose of HPV4. Coverage among VFC-eligible adolescents was 52.5% (±2.4%) for ≥1 dose of Tdap, 50.1% (±2.4%) for ≥1 dose of MCV4, and 46.6% (±3.5%) for ≥1 dose of HPV4. Only 27.5% (±1.8%) of non-VFC-eligible adolescents and 25.0% (±2.9%) of VFC-eligible adolescents received ≥3 doses of HPV4. Vaccination coverage was significantly higher among non-VFC-eligible adolescents for Tdap and MCV4, but not for one-dose or three-dose HPV4.
Conclusions
Coverage with some recommended vaccines is lower among VFC-eligible adolescents compared with non-VFC-eligible adolescents. Continued monitoring of adolescent vaccination rates, particularly among VFC-eligible populations, is needed to ensure that all adolescents receive all routinely recommended vaccines.
PMCID: PMC3113437  PMID: 21815303
13.  The San Diego Immunization Survey: A Model for Local Vaccination Coverage Assessment 
Public Health Reports  2008;123(1):39-44.
SYNOPSIS
Objective
Assessing vaccination coverage as part of a comprehensive intervention has been demonstrated to result in increased coverage rates. The National Immunization Survey provides coverage estimates at the national level and selected urban areas. However, it is important for other localities to understand vaccination coverage in their areas. The San Diego Immunization Branch conducts the San Diego Immunization Survey (SDIS) to gather vaccination coverage information in San Diego County. This article describes the methodology and results of the SDIS.
Methods
The SDIS is a two-phase immunization survey. The first phase is a random-digit-dialing survey in which vaccination information is obtained by phone. The second phase involves the verification of this information and/or obtaining vaccination information via the registry or the child's provider(s).
Results
In 2005, the sample size included 839 respondents. From 1995 to 2005, coverage for the following individual vaccines increased: diphtheria and tetanus toxoids, and acellular pertussis (92.0% to 96.5% for ≥3 doses, and 75.0% to 89.0% for ≥4 doses), polio (83.0% to 94.7%), measles-mumps-rubella (85.0% to 95.8%), Haemophilus influenzae type b (87.0% to 93.2%), and hepatitis B (67.0% to 93.6%).
Conclusion
The results of the SDIS demonstrate that San Diego County has exceeded the Healthy People 2010 goal to reach at least 80% coverage for the series of universally recommended vaccinations.
PMCID: PMC2099324  PMID: 18348478
14.  Sclerosing epithelioid fibrosarcoma as a rare cause of ascites in a young man: a case report 
Introduction
Sclerosing epithelioid fibrosarcoma is a rare but distinct variant of fibrosarcoma that not only presents as a deep-seated mass on the limbs and neck but can also occur adjacent to the fascia or peritoneum, as well as the trunk and spine. We report the case of an intra-abdominal sclerosing epithelioid fibrosarcoma, which to best of the authors' knowledge has not been described previously. The patient discussed here developed lung metastases but is still alive 1-year post-diagnosis.
Case presentation
A 29-year-old man presented with a 2-week history of progressive abdominal distension and pain and was found to have marked ascites. A full liver screen was unremarkable with abdominal and chest computed tomography scans only confirming ascites. After a diagnostic laparotomy, biopsies were taken from the greater omentum and peritoneal nodules. Histopathology revealed a malignant tumour composed of sheets and cords of small round cells set in collagenized stroma. After further molecular investigation at the Mayo Clinic, USA, the diagnosis of a high-grade sclerosing epithelioid fibrosarcoma was confirmed.
Conclusion
Sclerosing epithelioid fibrosarcoma is an extremely rare tumour, which is often difficult to diagnose and which few pathologists have encountered. This case is particularly unusual because of the intra-abdominal origin of the tumour. Owing to the rarity of sclerosing epithelioid fibrosarcoma, there is no clear evidence regarding the prognosis of such a tumour, although sclerosing epithelioid fibrosarcoma is able to metastasize many years post-presentation. It is important that physicians and pathologists are aware of this unusual tumour.
doi:10.1186/1752-1947-2-248
PMCID: PMC2503998  PMID: 18657268
15.  Distribution of SR protein exonic splicing enhancer motifs in human protein-coding genes 
Nucleic Acids Research  2005;33(16):5053-5062.
Exonic splicing enhancers (ESEs) are pre-mRNA cis-acting elements required for splice-site recognition. We previously developed a web-based program called ESEfinder that scores any sequence for the presence of ESE motifs recognized by the human SR proteins SF2/ASF, SRp40, SRp55 and SC35 (). Using ESEfinder, we have undertaken a large-scale analysis of ESE motif distribution in human protein-coding genes. Significantly higher frequencies of ESE motifs were observed in constitutive internal protein-coding exons, compared with both their flanking intronic regions and with pseudo exons. Statistical analysis of ESE motif frequency distributions revealed a complex relationship between splice-site strength and increased or decreased frequencies of particular SR protein motifs. Comparison of constitutively and alternatively spliced exons demonstrated slightly weaker splice-site scores, as well as significantly fewer ESE motifs, in the alternatively spliced group. Our results underline the importance of ESE-mediated SR protein function in the process of exon definition, in the context of both constitutive splicing and regulated alternative splicing.
doi:10.1093/nar/gki810
PMCID: PMC1201331  PMID: 16147989
16.  The first oral rotavirus vaccine, 1998-1999: estimates of uptake from the National Immunization Survey. 
Public Health Reports  2003;118(2):134-143.
OBJECTIVE: On August 31, 1998, the rhesus-human reassortant rotavirus vaccine (RRV-TV) was licensed for use in the U.S. During the next nine months, 15 cases of intussusception were reported among infants who received the vaccine. Case-control and cohort studies showed a significantly increased risk of developing intussusception within one week of receiving the vaccine; subsequent ecologic studies did not. In this study, the authors used data on RRV-TV vaccination rates from the National Immunization Survey (NIS) to estimate state and national RRV-TV uptake rates and factors associated with receiving RRV-TV. These estimates are a key component in evaluating published ecologic studies designed to investigate the relationship between receipt of the vaccine and intussusception. METHODS: The authors analyzed NIS data for children ages 19 to 35 months who were eligible to receive RRV-TV between September 1998 and July 1999. The authors estimated vaccine coverage and the number of doses administered by state, NIS sampling quarter, and birth cohort, and analyzed demographic and socioeconomic variables to evaluate their relationship with receiving RRV-TV. RESULTS: It was estimated that approximately 1 million doses of RRV-TV were administered to 504,585 (+/-61,854) children, 13.4% (+/-1.6%) of children who were eligible. The estimated number of doses administered and the vaccination coverage rate varied greatly from state to state. Children living in households with higher socioeconomic conditions were more likely to receive the vaccine. CONCLUSION: Ecologic studies had a limited ability to detect a significant increase in the population incidence rate of intussusception that could be attributed to RRV-TV because populations in these studies consisted primarily of children who did not receive the vaccine. The example from RRV-TV demonstrates some of the challenges of assessing the magnitude of the association between a vaccine and an uncommon or rare adverse event.
PMCID: PMC1497516  PMID: 12690067
18.  An Intelligent Tutoring System for Antibody Identification 
Empirical studies of medical technology students indicate that there is considerable need for additional skill development in performing tasks such as antibody identification. While this need is currently met by on-the-job training after employment, computer-based tutoring systems offer an alternative or supplemental problem-based learning environment that could be more cost effective.
We have developed a prototype for such a tutoring system as part of a project to develop educational tools for the field of transfusion medicine. This system provides a microworld in which students can explore and solve cases, receiving assistance and tutoring from the computer as needed.
PMCID: PMC2245473
19.  Defective tumor necrosis factor release from Crohn's disease macrophages in response to toll-like receptor activation: Relationship to phenotype and genome-wide association susceptibility loci 
Inflammatory Bowel Diseases  2012;18(11):2120-2127.
Abstract
Background:
Recent work provides evidence of a failure of acute inflammation in Crohn's disease (CD), and suggests that the primary defect operates at the level of the macrophage and cytokine release. Here we extend the characterization of the innate immune defect in CD by investigating the macrophage response to Toll-like receptor (TLR) agonists and assess potential links between genome-wide association study (GWAS) susceptibility loci, disease phenotype, and therapeutic regimens on tumor necrosis factor α (TNF) release.
Methods:
Peripheral blood-derived macrophages were cultured from control subjects and patients with CD, stimulated with TLR ligands, and the release of TNF measured. Genomic DNA was purified from blood and genotyped for 34 single nucleotide polymorphisms (SNPs) identified as being associated with CD by GWAS.
Results:
All stimuli resulted in a reduction (32%–48%) in TNF release from macrophages derived from CD patients (n = 28–101) compared to those from healthy control (HC) subjects. All phenotypes demonstrated impaired TNF release, with the greatest defect in patients with colonic disease. There was no detectable relationship between the level of TNF released and the presence of GWAS susceptibility loci in CD patients. Reduced TNF levels were not influenced by age, gender, or use of aminosalicylate (5-ASA) medication.
Conclusions:
This study supports the hypothesis of defective proinflammatory cytokine secretion and an innate immunodeficiency in CD. Abnormal TNF secretion is evident downstream of multiple TLRs, affects all disease phenotypes, and is unrelated to 34 polymorphisms associated with CD by GWAS. (Inflamm Bowel Dis 2012;)
doi:10.1002/ibd.22952
PMCID: PMC3532612  PMID: 22434667
IBD; inflammation; genetic polymorphisms; macrophages; Crohn's disease
20.  Disruption of macrophage pro-inflammatory cytokine release in Crohn's disease is associated with reduced optineurin expression in a subset of patients 
Immunology  2014;144(1):45-55.
Crohn's disease (CD) is a complex and highly heterogeneous chronic inflammatory disorder, primarily affecting the gastrointestinal tract. Genetic and functional studies have highlighted a key role for innate immunity in its pathogenesis. Profound systemic defects in innate immunity and acute inflammation are understood to result in markedly delayed clearance of bacteria from the tissues, leading to local chronic granulomatous inflammation and compensatory adaptive immunological changes. Macrophages, key orchestrators of acute inflammation, are likely to play an important role in the initial impaired innate immune response. Monocyte-derived macrophages from CD patients stimulated with Escherichia coli were shown to release attenuated levels of tumour necrosis factor and interferon-γ with normal secretion of interleukin-8 (IL-8), IL-10 and IL-6. In controls, the secretion of these cytokines was strongly positively correlated, which was not seen with CD macrophages. The transcriptomes of CD and control macrophages were examined in an attempt to understand the molecular basis of this defect. There were no differentially expressed genes identified between the two groups, consistent with genetic heterogeneity; however, a number of molecules were found to be under-expressed in subgroups of CD patients. The most common of these was optineurin (OPTN) which was under-expressed in approximately 10% of the CD patients. Reduced OPTN expression coincided with lower intracellular protein levels and diminished cytokine secretion after bacterial stimulation both in the patients and with small interfering RNA knockdown in THP-1 cells. Identifying and studying subgroups of patients with shared defective gene expression could aid our understanding of the mechanisms underlying highly heterogeneous diseases such as CD.
doi:10.1111/imm.12338
PMCID: PMC4264909  PMID: 24943399
cytokine; gene expression; inflammatory bowel disease; immunodeficiency; inflammation

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