Elevated Inflammatory State Research Articles

Comparison of Glomerular Filtration Rate Equations in a Rural New Mexico Cohort: Results from the COMPASS Study.

The NKF-ASN Task Force recommends accurate kidney function estimation avoiding biases through racial adjustments. We explored the use of multiple kidney function biomarkers and hence estimated glomerular filtration rate (eGFR) equations to improve kidney function calculations in an ethnically diverse patient population. Prospective community cohort study. rural New Mexico clinic with patients > 18 yo. Markers of kidney function, IDMS-Creatinine (SCr), chemiluminescence Beta-2 Microglobulin (B2M), Nephelometry-calibrated ELISA Cystatin C (CysC), inflammation, glucose tolerance, demographics, BUN/UACR from the baseline visit of the COMPASS cohort, were analyzed by Kernel-based Virtual Machine learning methods. Among 205 participants, the mean age was 50.1, 62% were female, 54.1% Hispanic American and 30.2% Native American. Average kidney function biomarkers were: SCr 0.9 mg/dl, B2M 1.8 mg/L, and CysC 0.7 mg/dl. The highest agreement was observed between SCr and B2M-based eGFR equations [mean difference in eGFRs: (4.48 ml/min/1.73m2], and the lowest agreement between B2M and CysC-based eGFR equations (-24.75 ml/min/1.73m2). There was no pattern of association between the differences in eGFR measures and gender. In the continuous analyses, the absolute eGFR value (p<2 x 10-16) and serum albumin (p =6.4 x 10-5) predicted the difference between B2M- and SCr-based e-GFR. The absolute eGFR value (p<2 x 10-16) and age (p =7.6 x 10-5) predicted the difference between CysC- and SCr-based e-GFR. Relatively small sample size, elevated inflammatory state in majority of study participants and no inulin excretion rate measurements. B2M should be strongly considered as a kidney function biomarker fulfilling the criteria for the NKF-ASN. B2M's eGFR equation does not need adjustment for gender or race and showed the highest agreement with SCr-based eGFR equations.

#2697 Association between neutrophil-lymphocyte ratio and morbidity among patients on maintenance hemodialysis with ESRD from diabetic nephropathy

Abstract Background and Aims The prevalence of end-stage renal disease (ESRD) is on the rise in the Philippines, and the prognosis for ESRD worsens with the presence of diabetes mellitus. Although the neutrophil-to-lymphocyte ratio (NLR) is a dependable prognostic marker for mortality, its applicability as a prognostic biomarker in patients with diabetes and chronic kidney disease remains uncertain. This study seeks to establish the correlation between NLR and morbidity among Filipino patients with ESRD due to diabetic nephropathy undergoing maintenance hemodialysis. To determine the association between NLR and morbidity among Filipino patients on maintenance hemodialysis due to ESRD secondary to diabetic nephropathy. Method Among the 191 screened ESRD patients on maintenance hemodialysis, 71 were attributed to diabetic nephropathy, and only 63 met the inclusion criteria for the study. Clinicodemographic information, encompassing age, sex, height, weight, body mass index (BMI), medications, and comorbidities, was extracted from the medical records of these 63 eligible patients. Subsequently, the patients were categorized into two groups based on their baseline neutrophil-to-lymphocyte ratio (NLR) values, with a cutoff set at 3.5—forming the high NLR group (≥3.5) and the low NLR group (&amp;lt;3.5). This threshold was established considering data indicating that an NLR of ≥3.5 is associated with heightened inflammatory states, leading to increased morbidity. After a 6-month follow-up, data on the primary outcome measure, i.e., the occurrence of the disease, were collected. Results Out of the 63 patients assessed, the majority (n=39, 61.9%) had a baseline NLR value of &amp;lt;3.5, and only 2 individuals in this group developed a disease. The high NLR group comprised 24 (38.1%) patients, with 15 of them developing diseases. Among these cases, 4 (0.16%) had diabetic foot, 3 (0.125%) had pneumonia, 3 (0.125%) developed catheter-related bloodstream infections, and 2 (0.08%) had pulmonary edema. Additionally, 1 case each of coronary artery disease (0.04%), hypertensive emergency (0.04%), and calciphylaxis (0.04%) were observed. NLR demonstrated a significant association with clinical outcomes (p &amp;lt; 0.05). Conclusion In conclusion, there is a significant correlation between the neutrophil-to-lymphocyte ratio (NLR) and disease development in Filipino patients undergoing maintenance hemodialysis for ESRD attributed to diabetic nephropathy. Patients with a high baseline NLR exhibit an elevated inflammatory state and a greater susceptibility to developing disease conditions compared to those with an NLR&amp;lt;3.5. Therefore, a high baseline NLR can serve as a predictive indicator for prognosis within this specific population.

Aberrant 3'UTR Processing Regulates Leukemogenesis and Therapy Resistance

A block in cellular differentiation is a hallmark of acute myeloid leukemia (AML) that promote clonal expansion and influence therapy response 1,2. It has become evidently clear that non-genetic mechanisms are critical to prevent malignant cells to resume its lineage maturation trajectory 3,4. However, there is still an incomplete understanding of gene regulatory pathways that induce differentiation arrest of leukemia cells. Here, we applied an immunophenotypic readout and positive selection CRISPR/Cas9 screens to identify suppressors of leukemia differentiation. These screens converged on ZBTB7A, a zinc finger transcription factor whose loss-of-function restricted AML maturation in the prescence of differentiation-inducing agents. Mechanstically, ZBTB7A ablation led to an elevated inflammatory state to stimulate leukemia proliferation. In addition, we found that genetic deletion of ZBTB7A and its paralog, ZBTB7B cooperatively suppresses myeloid differentiation and promotes resistance to several clinical compounds. Lastly, we identify that leukemic cells hijack multiple upstream 3'UTR processes, such as alternative polyadenylation and mRNA decay to downregulate ZBTB7A and ZBTB7B expression. Together, these data provide fundamental insight into non-genetic mechanisms that impede myeloid differentiation and mediate drug resistance.

S2784 A Case of Delayed Cervical Cancer Diagnosis in a Patient With Crohn’s Disease

Introduction: Increased cancer risk in inflammatory bowel disease (IBD) is thought to be due to immunosuppression from biologic therapy and/or inflammation. Women with IBD have an increased risk of melanoma and adenocarcinoma of the small bowel and colon, and those that are on an immunosuppressive regimen that includes azathioprine have an additional increased risk of lymphoma and squamous cell carcinoma of the skin and cervix. Here we present a case of a patient with an atypical and rare malignancy, whose diagnosis was delayed due to overlap in the symptoms of the malignancy and her known IBD diagnosis. Case Description/Methods: A woman in her mid 40s with a 28-year history of colonic Crohn’s disease maintained on ustekinumab injection. She was previously taking azathioprine for 7 years and initially responded to adalimumab, but after a flare, was switched to ustekinumab with symptomatic and endoscopic response. She then presented to her gynecologist in November 2020 with complaints of bloating and large amounts of clear vaginal discharge. A cervical exam and routine pap smear of the ectocervix showed normal cytology. Eight months later, the patient presented to her gastroenterologist with worsening bloating, hematochezia, left lower quadrant pain, and persistent vaginal discharge. The patient was concerned for an IBD flare, but noted that the abdominal bloating and vaginal discharge were different than her usual flare. After CT abdomen/pelvis revealed 2 large pelvic complex cystic lesions, her biologic was stopped and she underwent a hysterectomy with bilateral salpingo-oophorectomy. Pathology revealed non-HPV associated invasive moderately differentiated gastric-type endocervical adenocarcinoma. She completed treatment with an anti-VEGF antibody, but a restaging PET scan six months later showed uptake consistent with peritoneal carcinomatosis. Discussion: This immunosuppressed patient had an advanced and aggressive non-HPV endocervical cancer which was missed on ectocervical pap smear. Pap smears that include inadequate endocervical samples are considered suboptimal, but are usually not grounds for further testing in the average patient. However, Crohn’s disease patients have increased risk of low- and high-grade squamous epithelial cervical lesions and cervical cancer compared to women without IBD, likely due to a combination of elevated inflammatory state and immunosuppressive medications. Cervical cancer screening in immunosuppressed patients with IBD should include adequate endocervical sampling.

Cellular Mechanisms of Inflammaging and Periodontal Disease.

Increased age is associated with an increased prevalence of chronic inflammatory diseases and conditions. The term inflammaging has been used to describe the age-related changes to the immune response that results in a chronic and elevated inflammatory state that contributes, in part, to the increased prevalence of disease in older adults. Periodontal disease is a chronic inflammatory condition that affects the periodontium and increases in prevalence with age. To better understand the mechanisms that drive inflammaging, a broad body of research has focused on the pathological age-related changes to key cellular regulators of the immune response. This review will focus on our current understanding of how certain immune cells (neutrophils, macrophages, T cells) change with age and how such changes contribute to inflammaging and more specifically to periodontal disease.

Preimmunization correlates of protection shared across malaria vaccine trials in adults

Identifying preimmunization biological characteristics that promote an effective vaccine response offers opportunities for illuminating the critical immunological mechanisms that confer vaccine-induced protection, for developing adjuvant strategies, and for tailoring vaccination regimens to individuals or groups. In the context of malaria vaccine research, studying preimmunization correlates of protection can help address the need for a widely effective malaria vaccine, which remains elusive. In this study, common preimmunization correlates of protection were identified using transcriptomic data from four independent, heterogeneous malaria vaccine trials in adults. Systems-based analyses showed that a moderately elevated inflammatory state prior to immunization was associated with protection against malaria challenge. Functional profiling of protection-associated genes revealed the importance of several inflammatory pathways, including TLR signaling. These findings, which echo previous studies that associated enhanced preimmunization inflammation with protection, illuminate common baseline characteristics that set the stage for an effective vaccine response across diverse malaria vaccine strategies in adults.

Posttraumatic Stress, Inflammation, and Somatic Symptoms: Unifying Psychiatry and Physiology of Traumatic Stress in a Longitudinal Study of Syrian Refugees

Somatic symptoms are commonly reported in individuals with posttraumatic stress disorder (PTSD), and may contribute to worsened objective and perceived health. Elevated inflammatory state has also been associated with PTSD symptoms and may be a mediating link between psychological and somatic symptoms. The goal of the present study was to determine relations between perceptions, PTSD, and somatic symptoms, and the mediating role of inflammation. This model was expanded with a path analysis integrating perceived adversity proximal to trauma and perceived health distal to trauma in adult refugees.

Does vascular endothelial dysfunction play a role in physical frailty and sarcopenia? A systematic review.

Frailty is strongly associated with adverse cardiovascular outcomes; however, the underlying pathophysiological processes are largely unknown. Vascular endothelial dysfunction (VED) is the earliest stage of cardiovascular disease (CVD) progression and predicts long-term CVD outcomes. Both these conditions share an elevated inflammatory state as a common pathological factor. Systematic literature review was conducted to examine the evidence supporting an association between VED and physical frailty and/or sarcopenia, in electronic databases including Scopus, Ovid Medline, CINAHL, ScienceDirect, ProQuest Health & Medicine and Embase from January 1980 to August 2019. A total of 18 studies met the inclusion criteria. VED is independently associated with increased frailty phenotypes and measures of sarcopenia. Several markers of VED, including higher levels of asymmetric dimethylarginine, abnormal ankle brachial index, pulse wave velocity, pulse pressure and lower levels of flow-mediated dilatation, peripheral blood flow and endothelial progenitor cell counts, have been associated with frailty/sarcopenia measurements. Some studies demonstrated the effect of inflammation on the association. Recent studies, although limited, showed that VED could be one of the underlying mechanisms of frailty. It is entirely possible that inflammation-related pathological changes in the vascular endothelium are involved in the early causative mechanisms in physical frailty. The exact mechanism(s) underlying this association are still unclear and will need to be evaluated. The outcomes of these future research studies could potentially inform early preventative strategies for physical frailty and sarcopenia.

The Effect of Plant Derived Bioactive Compounds on Inflammation: A Systematic Review and Meta‐Analysis

A growing number of people worldwide are changing their lifestyle leading to an increasing number of overweight and obese individuals with metabolic syndrome (MetS). With obesity and MetS come an elevated inflammatory state resulting in increased risk of Type 2 diabetes, cardiovascular disease, among other lifestyle diseases. Fruits and vegetables (FV) contain phytochemicals with health beneficial effects including anti-oxidative and anti-inflammatory properties. This systematic review and meta-analysis aims to investigate the effects of diets high in FV, and plant-based products on C-reactive protein (CRP). A systematic search in PUBMED and EMBASE gave rise to 883 articles, 16 of which are included in the meta-analysis. The effects of plant-based products and diets are investigated in subgroups including overweight, obese, and diabetes; as wells as the effect of plant-oils and anthocyanin on CRP. The analysis shows an overall significant reduction in CRP for all articles (p = 0.0006). A significant decrease in diabetic (p = 0.01), overweight (p = 0.005), and obese patients (p = 0.05) is observed, including significant effects of anthocyanins (p = 0.001) and plant-oils (p <0.00001) on CRP. These findings strongly support the recommendation for diets high in FV and plant-oils to help attenuate elevated CRP.

Age-related chromatin landscapes in mouse macrophages

Abstract Aging is associated with changes in gene expression. Age-related changes in chromatin structure may contribute to alterations in gene expression and to aging phenotypes in human. Macrophages play essential roles in tissue homeostasis and repair. Macrophage activation by bacterial LPS leads to induction of a complex inflammatory gene program dependent on numerous transcription factor (TF) families. We previously showed that chromatin accessibility of macrophages is massively increased after LPS treatment. Similar programs may also contribute to the chronically elevated inflammatory state in aging. Therefore, it is important to understand how macrophages are epigenetically and functionally altered during aging. To address the age-associated differences in the transcriptome and chromatin landscape of macrophages, we have performed RNA-seq and ATAC-seq of tissue-resident macrophages in the presence or absence of LPS. Our results revealed that age effect in macrophages seems cell type-specific with the strongest effect in microglia. The majority of age-dependent TF footprints in macrophages showed reduced TF occupancy, but with either reduced or increased chromatin accessibility. We are investigating the functional relevance of the candidate TFs identified in our analysis. Our data highlight the tissue-specificity of aging features that occur in resident macrophages in vivo.

Macrophage subsets determine sex differences between male and female immune responses to Francisella tularensis

Abstract Francisella tularensisis the causative agent of the human disease tularemia. F. tularensisinfects a variety of cells, including macrophages, in order to cause pathogenicity. As few as 10 inhaled microorganisms cause a lethal infection by over-activating the host’s own inflammatory response. Differences in the intensity of the inflammatory response exist between the sexes which leads to differences in sensitivity to autoimmune and infectious disease. Males tend to be more susceptible to infectious diseases whereas females tend to be more susceptible to autoimmune diseases. However, our preliminary data unexpectedly demonstrated that female mice were more susceptible to F. tularensis-mediated disease than male mice. We hypothesize that the elevated inflammatory state of females may make them more susceptible to F. tularensis disease and that the M1 and M2 macrophage subsets may determine this differential inflammatory response. Naïve M1 and M2 macrophages will be purified from male and female mice and infected in vitro to directly compare cellular responses between male and female mice. In parallel, M0 macrophages will be differentiated in vitro prior to infection for similar comparison.

Placental inflammation by HMGB1 activation of TLR4 at the syncytium

IntroductionNormal pregnancy is characterized by an elevated inflammatory state involving the placenta. The placental inflammation is further increased in preeclampsia, resulting in release of harmful danger signals to the maternal circulation. Activation of toll-like receptors (TLR)2 and TLR4 by endogenous danger signals plays a role in inflammatory diseases. Placental TLR2 and TLR4 expression has been reported, and high mobility group box 1 (HMGB1) is a likely endogenous activator of these receptors. We aimed to examine HMGB1 activation of TLR2 and TLR4 as mechanisms of placental inflammation in normal and preeclamptic pregnancies, by combined analysis of expression and function of the ligand HMGB1, the receptors TLR2 and TLR4, and the cytokine responder interleukin (IL)-8. MethodsProtein expression was analyzed in placental tissue from normal and preeclamptic pregnancies, and cytokine responses to two distinct HMGB1 isoforms were examined in placental explants and trophoblasts. Inflammatory and anti-angiogenic markers were measured in maternal serum. ResultsWe demonstrated strong co-localized expression of HMGB1, TLR4 and IL-8 in the syncytium layer of the placenta. Syncytium TLR4 expression and maternal serum levels of IL-8 were significantly increased in preeclamptic compared to normal pregnancies. Functionality was confirmed by TLR4-dependent release of IL-8 from placental explants and trophoblasts in response to the inflammatory isoform of HMGB1. DiscussionThis demonstrates a role for the HMGB1-TLR4 pathway at the syncytium layer and suggests involvement in placental inflammation and preeclampsia.

Leukocyte Phenotype Is Altered in Peripheral Arterial Disease

Peripheral arterial disease (PAD) is characterized by low-grade systemic inflammation. Monocytes and monocyte-derived macrophages (MDMs) play a central role in vascular inflammation and its resolution. We hypothesize that impaired resolution in PAD contributes to adverse clinical outcomes. In a cross-sectional study, we profiled serum cytokines, phagocytic activity of leukocytes, monocyte cell surface markers, and gene expression of MDM from healthy individuals (n ≥ 10) and patients with stable claudication (n ≥ 10). Leukocyte phagocytosis of fluorescently labeled Escherichia coli and monocyte surface markers were determined by flow cytometry. MDMs were cultured from peripheral blood monocytes isolated by density gradient centrifugation. MDM cytokine production and gene expression, before and after stimulation with lipopolysaccharide, were determined by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively. Patients with PAD had elevated serum high-sensitivity C-reactive protein (3.7 vs 0.6 mg/L; P = .004) and interleukin (IL) 6 (5.1 vs 1.1 pg/mL; P = .01) and trended toward higher levels of monocyte chemoattractant protein 1 and lower adiponectin compared with healthy individuals. Circulating monocytes and polymorphonuclear cells (PMNs) from PAD patients had reduced phagocytic activity for E. coli (monocytes, >30% [P < .001]; PMNs, >25% [P < .01]). Flow cytometry demonstrated a higher proportion of the proinflammatory intermediate monocyte subset (CD14++16+, 1.8-fold; P = .04) in PAD subjects. MDMs from PAD patients retain their intrinsic inflammatory program, producing more IL-6 (>4-fold; P = .03) and IL-1β (>10-fold; P = .04) and demonstrating increased expression of M1 genes (tumor necrosis factor α, monocyte chemoattractant protein 1, CXCL10) and decreased expression of M2 genes (CCL17, MRC1) vs healthy individuals (Table). Clinically stable PAD patients have elevated serum inflammatory markers compared with healthy individuals. Circulating monocytes and PMNs in patients with PAD have reduced phagocytic activity and a greater proportion of the proinflammatory intermediate monocyte subset. MDMs from PAD patients preserve their elevated inflammatory state in culture. These data demonstrate a heightened inflammatory and impaired resolution phenotype in PAD that has potential implications for disease progression and response to interventions.TableMonocyte-derived macrophage (MDM) gene expression of the peripheral arterial disease (PAD) cohort vs healthy individualsGeneMl or M2PAD patients relative to healthy individualsExpression fold changeP valueTNF-α (veh)Ml2.71.02aTNF-α (LPS)0.81.33MCP-1 (veh)Ml1.92.05aMCP-1 (LPS)1.91.01aiNOS (veh)Ml1.34.26iNOS (LPS)1.04.94CXCL10 (veh)Ml7.87.04aCXCL10 (LPS)1.8129IL-10 (veh)M21.50.19IL-10 (LPS)2.72.009aCCL17 (veh)M20.48.09CCL17 (LPS)022.14MRC1 (veh)M20.52.09MRC1 (LPS)0.30.01aCCL17, Chemokine (C-C motif) ligand 17; CXCL10, C-X-C motif chemokine 10; IL-10, interleukin 10; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide; MCP-1, monocyte chemoattractant protein 1; MRC1, mannose receptor C type 1; TNF-α, tumor necrosis factor α; veh, vehicle.Expression fold change was calculated as 2ˆ(–ΔΔCT) and represents the fold change in the average expression of the target gene within the PAD cohort (n = 10) vs the average expression of the target gene within the cohort of healthy individuals (n = 10), normalized to the housekeeping gene (HPRT). MDMs were stimulated with lipopolysaccharide to mimic the occurrence of an acute inflammatory event or vehicle for 24 hours before assessment of gene expression.aP < .05 by unpaired Student t-test. Open table in a new tab

Matrix degradation in osteoarthritis primes the superficial region of cartilage for mechanical damage

Osteoarthritis (OA) is a degenerative disease that affects 25% of the world’s population over fifty years of age. It is a chronic disease of the synovial joints, primarily the hip and knee. The main pathologies are degradation of the articular cartilage and changes to the subchondral bone, as a result of both mechanical wear and a locally elevated inflammatory state. This study compares the viscoelastic properties of cartilage that represents the biochemical changes in OA and age-matched healthy tissue. Further, the mechanical damage induced by this compressive loading cycle was characterised and the mechanism for it was investigated. The storage modulus of OA cartilage was shown to be significantly lower than that of healthy cartilage whilst having a higher capacity to hold water. Following mechanical testing, there was a significant increase in the surface roughness of OA cartilage. This change in surface structure occurred following a reduction in sulphated glycosaminoglycan content of the superficial region in OA, as seen by alcian blue staining and quantified by micro X-ray fluorescence. These findings are important in understanding how the chemical changes to cartilage matrix in OA influence its dynamic mechanical properties and structural integrity. Statement of significanceCartilage has a very specialised tissue structure which acts to resist compressive loading. In osteoarthritis (OA), there is both mechanically- and chemically-induced damage to cartilage, resulting in severe degradation of the tissue. In this study we have undertaken a detailed mechanical and chemical analysis of macroscopically undamaged OA and healthy cartilage tissue. We have demonstrated, for the first time in human tissue, that the mechanical degradation of the tissue is attributed to a chemical change across the structure. In macroscopically undamaged OA tissue, there is a reduction in the elastic response of cartilage tissue and an associated destabilisation of the matrix that leaves it susceptible to damage. Understanding this allows us to better understand the progression of OA to design better therapeutic interventions.

Abstract 20: Resolution Phenotype of Monocytes and Macrophages is Altered in Peripheral Arterial Disease

Introduction: Peripheral arterial disease (PAD) is a chronic disease characterized by systemic inflammation. Monocytes (Mo) and macrophages play a central role in vascular inflammation and its resolution. We hypothesize that impaired resolution in PAD results in poor clinical outcomes. Methods: Resolution phenotype was assessed by phagocytic activity of leukocytes, Mo cell surface markers, and cytokine profiling of Mo-derived macrophages (MDM). Phagocytosis and cell-surface markers were determined by flow cytometry. MDMs were generated from peripheral blood mononuclear cells via density gradient centrifugation. Cytokines were measured by ELISA following MDM differentiation and subsequent stimulation with LPS. Results: Circulating Mo and neutrophils (PMN) isolated from PAD patients (n=9) demonstrated significantly lower phagocytic activity (Mo: &gt;30%, p&lt;.001; PMN: &gt;25%, p&lt;.01, Fig. 1) as compared to healthy subjects (HS) (n=14). Cell-surface marker analysis demonstrated a higher proportion of the pro-inflammatory intermediate Mo subset (CD14 ++ 16 + , 1.8-fold, p=.04) in PAD compared to HS. MDM from PAD subjects retain their intrinsic inflammatory program by producing more IL-6 (PAD 3138±2676 ng/mL, HS 731±854 ng/mL p=.03) and IL-1β (PAD 244±236 ng/mL, HS 24.1±23.8 ng/mL p=.04) than those from HS. Upon stimulation with LPS, MDM from PAD subjects secrete more IL-6 (PAD 23353±22483 ng/mL, HS 5097±5836 ng/mL p=.05) than those from HS. Conclusions: Circulating Mo and PMN in patients with PAD have substantially lower phagocytic activity as well as a greater proportion of the pro-inflammatory intermediate Mo subset compared to HS. MDM preserve their elevated inflammatory state throughout culture and retain a heightened response upon latter stimulatory cues. Collectively these data demonstrate a heightened inflammatory and impaired resolution phenotype in PAD that has potential implications for disease progression and response to interventions.

Interrelationship Between Periapical Lesion and Systemic Metabolic Disorders.

Periapical periodontitis, also known as periapical lesion, is a common dental disease, along with periodontitis (gum disease). Periapical periodontitis is a chronic inflammatory disease, caused by endodontic infection, and its development is regulated by the host immune/inflammatory response. Metabolic disorders, which are largely dependent on life style such as eating habits, have been interpreted as a "metabolically-triggered" low-grade systemic inflammation and may interact with periapical periodontitis by triggering immune modulation. The host immune system is therefore considered the common fundamental mechanism of both disease conditions. We have reviewed >200 articles to discuss the interrelationship between periapical lesions and metabolic disorders including type 2 diabetes mellitus, hypertension, and non-alcoholic fatty liver diseases (NAFLD), and their common pathological background in immunology/osteoimmunology and cytokine biology. An elevated inflammatory state caused by metabolic disorders can impact the clinical outcome of periapical lesions and interfere with wound healing after endodontic treatment. Although additional well-designed clinical studies are needed, periapical lesions appear to affect insulin sensitivity and exacerbate non-alcoholic steatohepatitis. Immune regulatory cytokines produced by various cell types, including immune cells and adipose tissue, play an important role in this interrelationship.

Molecular signatures differentiate immune states in type 1 diabetic families.

Mechanisms associated with type 1 diabetes (T1D) development remain incompletely defined. Using a sensitive array-based bioassay where patient plasma is used to induce transcriptional responses in healthy leukocytes, we previously reported disease-specific, partially interleukin (IL)-1−dependent signatures associated with preonset and recent onset (RO) T1D relative to unrelated healthy control subjects (uHC). To better understand inherited susceptibility in T1D families, we conducted cross-sectional and longitudinal analyses of healthy autoantibody-negative (AA−) high HLA−risk siblings (HRS) (DR3 and/or DR4) and AA− low HLA−risk siblings (LRS) (non-DR3/non-DR4). Signatures, scored with a novel ontology-based algorithm, and confirmatory studies differentiated the RO T1D, uHC, HRS, and LRS plasma milieus. Relative to uHC, T1D family members exhibited an elevated inflammatory state, consistent with innate receptor ligation that was independent of HLA, AA, or disease status and included elevated plasma IL-1α, IL-12p40, CCL2, CCL3, and CCL4 levels. Longitudinally, signatures of T1D progressors exhibited increasing inflammatory bias. Conversely, HRS possessing decreasing AA titers revealed emergence of an IL-10/transforming growth factor-β−mediated regulatory state that paralleled temporal increases in peripheral activated CD4+/CD45RA−/FoxP3high regulatory T-cell frequencies. In AA− HRS, the familial innate inflammatory state also was temporally supplanted by immunoregulatory processes, suggesting a mechanism underlying the decline in T1D susceptibility with age.

Primary antiphospholipid antibody syndrome—one further aspect of thrombophilia in overweight and obese patients with venous thromboembolism

Overweight and obesity are established risk factors for venous thromboembolism (VTE). We examined the difference in the frequency of primary antiphospholipid antibody syndrome (PAPS) in VTE patients according to their BMI. We included 998 VTE patients treated at our institution between 2009 and 2011 in a retrospective data analysis. Thrombophilia screening including evaluation for APS (lupus anticoagulant, anti-cardiolipin, and anti-B2-glycoprotein-I IgG and IgM antibodies) was performed in all patients. PAPS was diagnosed in 6.8% (24/355) of normal weight (BMI < 24 kg/m2) VTE patients, in 11.1% (50/452) of overweight (BMI 25-30 kg/m2) VTE patients, and in 15.7% (30/191) of obese (BMI > 31 kg/m2) VTE patients. The difference of PAPS occurrence between these groups was statistically significant (P = 0.001). PAPS patients demonstrated higher fibrinogen levels as compared to non-PAPS patients (median 416.0 md/dl vs. 352.0 mg/dl, P = 0.001). Furthermore, fibrinogen levels increased significantly according to the body weight of patients (median normal weight patients 330.0 mg/dl vs. overweight patients 359.0 mg/dl vs. obese patients 415.0 mg/dl, P = 0.001). PAPS seems to be more frequent in overweight and obese patients. As PAPS patients showed significantly higher fibrinogen levels and as fibrinogen levels increased significantly according to the body weight of patients, an elevated inflammatory state in overweight and obese patients as a reason for the increased PAPS occurrence can be assumed.

The maternal autoimmune environment affects the social behavior of offspring

Autism spectrum disorders (ASD) are neurodevelopmental disorders with unknown etiology. BTBR-T+tf/J (BTBR) mice, a mouse strain with behaviors that resemble autism and with elevated levels of anti-brain antibodies (Abs), have enhanced activation of peripheral B cells and CD4+ T cells and an expanded percentage of CD4+ T cells expressing Vβ6 chains. The CD4+CD25+Vβ6+ and Vβ6-splenic cells of BTBR mice have elevated levels of IL-4, IFN-γ and IL-17, but there appears to be no preferential CD4+ T subset skewing/polarization. The high level of IgG production by BTBR B cells was dependent on T cells from BTBR mice. The CD4+ T cells of BTBR mice, especially those expressing Vβ6 become spontaneously activated and expanded in an autoimmune-like manner, which occurred in both BTBR and B6 hosts that received an equal number of BTBR and B6 bone marrow cells. BTBR mice also have an elevated percentage of peripheral blood neutrophils, which may represent their elevated inflammatory state. B6 offspring derived from B6 dams that were gestationally injected with purified IgG from sera of BTBR mice, but not IgG of B6 mice, developed significantly impaired social behavior. Additionally, B6 offspring that developed in BTBR dams had impaired social behavior, while BTBR offspring that developed in B6 dams had improved social behavior. All of the immunological and behavioral parameters of BTBR mice were compared with those of B6 mice, which have relatively normal behaviors. The results indicate maternal Abs and possibly other maternal influences affect the social behavior of offspring.

A Comparison of Mediterranean-Style and MyPyramid Diets on Weight Loss and Inflammatory Biomarkers in Postpartum Breastfeeding Women

Of postpartum women, 15%-20% retain ≥ 5 kg of their gestational weight gain, increasing risk for adult weight gain. Postpartum women are also in a persistent elevated inflammatory state. Both factors could increase the risk of obesity-related chronic disease. We hypothesized that breastfeeding women randomized to a Mediterranean-style (MED) diet for 4 months would demonstrate significantly greater reductions in body weight, body fat, and inflammation than women randomized to the U.S. Department of Agriculture's (USDA) MyPyramid diet for Pregnancy and Breastfeeding (comparison diet). A randomized, controlled dietary intervention trial was conducted in 129 overweight (body mass index [BMI] 27.2 ± 4.9 kg/m(2)), mostly exclusively breastfeeding (73.6%) women who were a mean 17.5 weeks postpartum. Dietary change was assessed using a validated Food Frequency Questionnaire (FFQ) before and after intervention as well as plasma fatty acid measures (gas chromatography/flame ionization detector [GC/FID]). Anthropometric measurements and biomarkers of inflammation, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), also were assessed at baseline and 4 months via enzyme-linked immunosorbent assay (ELISA). Participants in both diet groups demonstrated significant (p<0.001) reductions in body weight (-2.3 ± 3.4 kg and -3.1 ± 3.4 kg for the MED and comparison diets, respectively) and significant (p ≤ 0.002) reductions in all other anthropometric measurements; no significant between-group differences were shown as hypothesized. A significant decrease in TNF-α but not IL-6 was also demonstrated in both diet groups, with no significant between-group difference. Both diets support the promotion of postpartum weight loss and reduction in inflammation (TNF-α) in breastfeeding women.