News Article | January 21, 2017
A new study shares that tracking immune cells could potentially be able to assist in the identification of inflammatory arthritis. According to the study conducted by the researchers of the Massachusetts General Hospital (MGH) Center for Immunology and Inflammatory Diseases (CIID), there appears to be a connection between immune cells and inflammatory arthritis. Senior author of the study, Andrew Luster noted that Inflammatory arthritis is the direct effect of immune cells that are "recruited from blood into the joint" by means of a highly controlled procedure that is monitored by adhesion receptors and chemoattractants. However, when the ailment becomes symptomatic, it becomes tough to ascertain what could have been the catalyst in the process of the immune cell recruitment in the joint, as well as what is the exact role of the various types of chemoattractants. The latest study is intended to gain a thorough understanding of this process notes Luster. By understating the process, scientists would be able to develop an effective treatment for inflammatory arthritis. For the unfamiliar, arthritis is a disease where one or more joints get inflamed, which leads to swelling, stiffness or soreness. The most common types of arthritis are Inflammatory and non-inflammatory. This disease is more frequently prevalent in women than men. Prior to the latest study, many experts opined that inflammatory arthritis may involve genetic or hormonal factors as well. Rheumatoid or inflammatory arthritis can also occur in children alongside adults. Apart from joints it can take a toll on other organs of a human body, such as eyes and lungs. Living with inflammatory arthritis is a big challenge, even if the condition is treatable and there is no cure. The researchers have zoned in on the importance of the complement C5a molecule for immune cells dubbed neutrophils. This molecule gets the neutrophils to obey joint surfaces and travel to the joint. This process is the one that sets off the inflammatory cascade. "The control of immune cell entry into the joint represents a major point at which new therapies could be developed to reduce the symptoms of inflammatory arthritis," says Luster. The scientist also shared that the addition of imaging of the joints may aid in the understanding of the process of how a drug can have therapeutic effect. If it reveals that the joints have been affected by multiple chemoattractants, then the mechanism's understanding will enable the "rational design of combination therapies to completely shut down critical steps in the process." The study has been published in the journal Science Immunology. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.
Lochhead R.B.,University of Utah |
Zachary J.F.,University of Illinois at Urbana - Champaign |
Rosa L.D.,Federal University of Santa Maria |
Ma Y.,University of Utah |
And 4 more authors.
PLoS ONE | Year: 2015
MicroRNA-155 has been shown to play a role in immune activation and inflammation, and is suppressed by IL-10, an important anti-inflammatory cytokine. The established involvement of IL-10 in the murine model of Borrelia burgdorferi-induced Lyme arthritis and carditis allowed us to assess the interplay between IL-10 and miR-155 in vivo. As reported previously, Mir155 was highly upregulated in joints from infected severely arthritic B6 Il10-/-mice, but not in mildly arthritic B6 mice. In infected hearts, Mir155 was upregulated in both strains, suggesting a role of miR-155 in Lyme carditis. Using B. burgdorferi-infected B6, Mir155-/-, Il10-/-, and Mir155-/-Il10-/-double-knockout (DKO) mice, we found that anti-inflammatory IL-10 and pro-inflammatory miR-155 have opposite and somewhat compensatory effects on myeloid cell activity, cytokine production, and antibody response. Both IL-10 and miR-155 were required for suppression of Lyme carditis. Infected Mir155-/-mice developed moderate/ severe carditis, had higher B. burgdorferi numbers, and had reduced Th1 cytokine expression in hearts. In contrast, while Il10-/-And DKO mice also developed severe carditis, hearts had reduced bacterial numbers and elevated Th1 and innate cytokine expression. Surprisingly, miR-155 had little effect on Lyme arthritis. These results show that antagonistic interplay between IL-10 and miR-155 is required to balance host defense and immune activation in vivo, and this balance is particularly important for suppression of Lyme carditis. These results also highlight tissue-specific differences in Lyme arthritis and carditis pathogenesis, and reveal the importance of IL-10-mediated regulation of miR-155 in maintaining healthy immunity. Copyright: © 2015 Lochhead et al.
Malhotra R.,Cardiovascular Research Center |
Burke M.F.,Cardiovascular Research Center |
Martyn T.,Massachusetts General Hospital |
Shakartzi H.R.,Massachusetts General Hospital |
And 17 more authors.
PLoS ONE | Year: 2015
Objective: Matrix Gla protein (MGP) is reported to inhibit bone morphogenetic protein (BMP) signal transduction. MGP deficiency is associated with medial calcification of the arterial wall, in a process that involves both osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) and mesenchymal transition of endothelial cells (EndMT). In this study, we investigated the contribution of BMP signal transduction to the medial calcification that develops in MGP-deficient mice. Approach and Results: MGP-deficient mice (MGP-/-) were treated with one of two BMP signaling inhibitors, LDN-193189 or ALK3-Fc, beginning one day after birth. Aortic calcification was assessed in 28-day-old mice by measuring the uptake of a fluorescent bisphosphonate probe and by staining tissue sections with Alizarin red. Aortic calcification was 80% less in MGP-/- mice treated with LDN-193189 or ALK3-Fc compared with vehicle-treated control animals (P<0.001 for both). LDN-193189-treated MGP-/- mice survived longer than vehicle-treated MGP-/- mice. Levels of phosphorylated Smad1/5 and Id1 mRNA (markers of BMP signaling) did not differ in the aortas from MGP-/- and wild-type mice. Markers of EndMT and osteogenesis were increased in MGP-/- aortas, an effect that was prevented by LDN-193189. Calcification of isolated VSMCs was also inhibited by LDN-193189. Conclusions: Inhibition of BMP signaling leads to reduced vascular calcification and improved survival in MGP-/- mice. The EndMT and osteogenic transdifferentiation associated with MGP deficiency is dependent upon BMP signaling. These results suggest that BMP signal transduction has critical roles in the development of vascular calcification in MGP-deficient mice. © 2015 Malhotra et al.
Seung E.,Center for Immunology and Inflammatory Diseases
The Journal of infectious diseases | Year: 2013
Humanized mice historically have not been good models of human humoral immunity induced by either infection or immunization. However, newer versions of humanized mice generated in severely immunodeficient mice with a targeted disruption of the IL2Rγc gene have recently been reported to produce antigen-specific class-switched human antibodies, with some demonstrating neutralizing activities. Here we review the growing ability of humanized mice to support the study of human humoral immune responses, discussing the current and future potential of these models as well as their current limitations.
Chen H.-H.,Harvard Stem Cell Institute |
Welling M.,University Utrecht |
Bloch D.B.,Center for Immunology and Inflammatory Diseases |
Munoz J.,University Utrecht |
And 11 more authors.
Stem Cell Reports | Year: 2014
The scarcity of primordial germ cells (PGCs) in the developing mammalian embryo hampers robust biochemical analysis of the processes that underlie early germ cell formation. Here, we demonstrate that DAZL, a germ cell-specific RNA binding protein, is a robust PGC marker during in vitro germ cell development. Using Dazl-GFP reporter ESCs, we demonstrate that DAZL plays a central role in a large mRNA/protein interactive network that blocks the translation of core pluripotency factors, including Sox2 and Sall4, as well as of Suz12, a polycomb family member required for differentiation of pluripotent cells. Thus, DAZL limits both pluripotency and somatic differentiation in nascent PGCs. In addition, we observed that DAZL associates with mRNAs of key Caspases and similarly inhibits their translation. This elegant fail-safe mechanism ensures that, whereas loss of DAZL results in prolonged expression of pluripotency factors, teratoma formation is avoided due to the concomitant activation of the apoptotic cascade. © 2014 The Authors.
Rhee E.P.,Massachusetts General Hospital |
Rhee E.P.,Cambridge Broad Institute |
Cheng S.,Boston University |
Cheng S.,Brigham and Women's Hospital |
And 30 more authors.
Journal of Clinical Investigation | Year: 2011
Dyslipidemia is an independent risk factor for type 2 diabetes, although exactly which of the many plasma lipids contribute to this remains unclear. We therefore investigated whether lipid profiling can inform diabetes prediction by performing liquid chromatography/mass spectrometry - based lipid profiling in 189 individuals who developed type 2 diabetes and 189 matched disease-free individuals, with over 12 years of follow up in the Framingham Heart Study. We found that lipids of lower carbon number and double bond content were associated with an increased risk of diabetes, whereas lipids of higher carbon number and double bond content were associated with decreased risk. This pattern was strongest for triacylglycerols (TAGs) and persisted after multivariable adjustment for age, sex, BMI, fasting glucose, fasting insulin, total triglycerides, and HDL cholesterol. A combination of 2 TAGs further improved diabetes prediction. To explore potential mechanisms that modulate the distribution of plasma lipids, we performed lipid profiling during oral glucose tolerance testing, pharmacologic interventions, and acute exercise testing. Levels of TAGs associated with increased risk for diabetes decreased in response to insulin action and were elevated in the setting of insulin resistance. Conversely, levels of TAGs associated with decreased diabetes risk rose in response to insulin and were poorly correlated with insulin resistance. These studies identify a relationship between lipid acyl chain content and diabetes risk and demonstrate how lipid profiling could aid in clinical risk assessment. Copyright © 2011, The American Society for Clinical Investigation.
Arvikar S.L.,Harvard University |
Arvikar S.L.,Center for Immunology and Inflammatory Diseases |
Collier D.S.,Harvard University |
Fisher M.C.,Harvard University |
And 6 more authors.
Arthritis Research and Therapy | Year: 2013
Introduction: Prior studies have demonstrated an increased frequency of antibodies to Porphyromonas gingivalis (Pg), a leading agent of periodontal disease, in rheumatoid arthritis (RA) patients. However, these patients generally had long-standing disease, and clinical associations with these antibodies were inconsistent. Our goal was to examine Pg antibody responses and their clinical associations in patients with early RA prior to and after disease-modifying antirheumatic drug (DMARD) therapy. Methods: Serum samples from 50 DMARD-naïve RA patients were tested using an enzyme-linked immunosorbent assay with whole-Pg sonicate. For comparison, serum samples were tested from patients with late RA, patients with other connective tissue diseases (CTDs), age-similar healthy hospital personnel and blood bank donors. Pg antibody responses in early RA patients were correlated with standard RA biomarkers, measures of disease activity and function. Results: At the time of enrollment, 17 (34%) of the 50 patients with early RA had positive immunoglobulin G (IgG) antibody responses to Pg, as did 13 (30%) of the 43 patients with late RA. RA patients had significantly higher Pg antibody responses than healthy hospital personnel and blood bank donors (P < 0.0001). Additionally, RA patients tended to have higher Pg antibody reactivity than patients with other CTDs (P = 0.1), and CTD patients tended to have higher Pg responses than healthy participants (P = 0.07). Compared with Pg antibody-negative patients, early RA patients with positive Pg responses more often had anti-cyclic citrullinated peptide (anti-CCP) antibody reactivity, their anti-CCP levels were significantly higher (P = 0.03) and the levels of anti-Pg antibodies correlated directly with anti-CCP levels (P < 0.01). Furthermore, at the time of study entry, the Pg-positive antibody group had greater rheumatoid factor values (P = 0.04) and higher inflammatory markers (erythrocyte sedimentation rate, or ESR) (P = 0.05), and they tended to have higher disease activity scores (Disease Activity Score based on 28-joint count (DAS28)-ESR and Clinical Disease Activity Index) and more functional impairment (Health Assessment Questionnaire). In Pg-positive patients, greater disease activity was still apparent after 12 months of DMARD therapy. Conclusions: A subset of early RA patients had positive Pg antibody responses. The responses correlated with anti-CCP antibody reactivity and to a lesser degree with ESR values. There was a trend toward greater disease activity in Pg-positive patients, and this trend remained after 12 months of DMARD therapy. These findings are consistent with a role for Pg in disease pathogenesis in a subset of RA patients. © 2013 Arvikar et al.; licensee BioMed Central Ltd.
Angin M.,Massachusetts Institute of Technology |
Sharma S.,Massachusetts Institute of Technology |
King M.,Massachusetts Institute of Technology |
Murooka T.T.,Center for Immunology and Inflammatory Diseases |
And 8 more authors.
Journal of Infectious Diseases | Year: 2014
The impact of CD4+ regulatory T cells (Tregs) on human immunodeficiency virus type 1 (HIV-1) pathogenesis remains incompletely understood. Although it has been shown that Tregs can be infected with HIV-1, the consequences of infection on a per-cell basis are still unknown. In vitro HIV-GFP infected and noninfected Tregs were isolated by flow-based cell-sorting to investigate Treg suppressive capacity and gene expression profiles. Our data show that HIV-1-infected Tregs were significantly less suppressive than noninfected Tregs and demonstrated down-regulation of genes critical to Treg function. This impaired function may have detrimental consequences for the control of generalized immune activation and accelerate HIV disease progression. © The Author 2014.
TH17 Cytokine Responses in Lyme Disease Correlate with Borreliaburgdorferi Antibodies During Early Infection in Patients with Erythema Migrans and with Autoantibodies Late in the Illness in Patients with Antibiotic-Refractory Lyme Arthritis
PubMed | Center for Immunology and Inflammatory Diseases and Harvard University
Type: | Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America | Year: 2017
Control of Lyme disease is attributed predominantly to innate and adaptive TLevels of 21 cytokines and chemokines, representative of innate, TCompared with healthy subjects, EM patients had significantly higher levels of innate, TPatients with Lyme disease often develop pronounced T
PubMed | University Utrecht, Dana-Farber Cancer Institute, Guangzhou Medical College, Erasmus Medical Center and 3 more.
Type: Journal Article | Journal: Stem cell reports | Year: 2014
The scarcity of primordial germ cells (PGCs) in the developing mammalian embryo hampers robust biochemical analysis of the processes that underlie early germ cell formation. Here, we demonstrate that DAZL, a germ cell-specific RNA binding protein, is a robust PGC marker during invitro germ cell development. Using Dazl-GFP reporter ESCs, we demonstrate that DAZL plays a central role in a large mRNA/protein interactive network that blocks the translation of core pluripotency factors, including Sox2 and Sall4, as well as of Suz12, a polycomb family member required for differentiation of pluripotent cells. Thus, DAZL limits both pluripotency and somatic differentiation in nascent PGCs. In addition, we observed that DAZL associates with mRNAs of key Caspases and similarly inhibits their translation. This elegant fail-safe mechanism ensures that, whereas loss of DAZL results in prolonged expression of pluripotency factors, teratoma formation is avoided due to the concomitant activation of the apoptotic cascade.