DOCSLIB.ORG

Autoimmunity Against Cardiac Myosin Congenital Heart Disease Linked To

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Autoimmunity Against Cardiac Myosin Congenital Heart Disease Linked To Congenital Heart Disease Linked to Maternal Autoimmunity against Cardiac Myosin Charles R. Cole, Katherine E. Yutzey, Anoop K. Brar, Lisa S. Goessling, Sarah J. VanVickle-Chavez, Madeleine W. This information is current as Cunningham and Pirooz Eghtesady of September 29, 2021. J Immunol 2014; 192:4074-4082; Prepublished online 26 March 2014; doi: 10.4049/jimmunol.1301264 http://www.jimmunol.org/content/192/9/4074 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2014/03/26/jimmunol.130126 Material 4.DCSupplemental http://www.jimmunol.org/ References This article cites 47 articles, 14 of which you can access for free at: http://www.jimmunol.org/content/192/9/4074.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 29, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Congenital Heart Disease Linked to Maternal Autoimmunity against Cardiac Myosin Charles R. Cole,* Katherine E. Yutzey,* Anoop K. Brar,† Lisa S. Goessling,† Sarah J. VanVickle-Chavez,† Madeleine W. Cunningham,‡,1 and Pirooz Eghtesady†,1 Structural congenital heart disease (CHD) has not previously been linked to autoimmunity. In our study, we developed an auto- immune model of structural CHD that resembles hypoplastic left heart syndrome (HLHS), a life-threatening CHD primarily af- fecting the left ventricle. Because cardiac myosin (CM) is a dominant autoantigen in autoimmune heart disease, we hypothesized that immunization with CM might lead to transplacental passage of maternal autoantibodies and a prenatal HLHS phenotype in exposed fetuses. Elevated anti-CM autoantibodies in maternal and fetal sera, as well as IgG reactivity in fetal myocardium, were correlated with structural CHD that included diminished left ventricular cavity dimensions in the affected progeny. Further, fetuses that developed a marked HLHS phenotype had elevated serum titers of anti–b-adrenergic receptor Abs, as well as increased Downloaded from protein kinase A activity, suggesting a potential mechanism for the observed pathological changes. Our maternal–fetal model presents a new concept linking autoimmunity against CM and cardiomyocyte proliferation with cardinal features of HLHS. To our knowledge, this report shows the first evidence in support of a novel immune-mediated mechanism for pathogenesis of structural CHD that may have implications in its future diagnosis and treatment. The Journal of Immunology, 2014, 192: 4074–4082. ongenital heart disease (CHD) is the most common cause heart block, maternal autoantibodies in patients with systemic http://www.jimmunol.org/ of infant death resulting from birth defects (1). Hypo- lupus erythematosus cause injury to the conduction system of the C plastic left heart syndrome (HLHS), a severe and dev- fetal heart (14–16). We had previously hypothesized that auto- astating congenital heart malformation, accounts for nearly 25% immunity might play a role in a maternal–fetal model of of all neonatal deaths from CHD (1–3). HLHS is uniformly fatal structural left-sided CHD (12). Our hypothesis has been sup- without intervention, and despite aggressive medical and surgical ported by the observation of high titers of anti–human cardiac palliation, many affected children experience a significant devel- myosin (CM) IgG autoantibodies in sera from mothers of babies opmental delay and decreased quality of life (4, 5). Although with HLHS, but not other CHD or healthy controls, in an on- etiological mechanisms leading to HLHS are largely unknown, going clinical study (Clinicaltrial.gov 201102410). Anti-CM both genetic and environmental insults are potential contributors autoantibodies are linked to several autoimmune diseases of the by guest on September 29, 2021 (6–10). About one fourth of HLHS cases occur in the context of heart, including autoimmune myocarditis (17–22) and rheumatic recognized genetic disorders or syndromes; studies involving carditis, the most serious manifestation of group A streptococcus– nonsyndromic family members suggest that heritability is com- induced rheumatic fever (23–25). In this study we determined plex (9, 11) and environmental influences such as infection and whether maternal immunization with CM, a major autoantigen in autoimmunity might contribute to the phenotypic expression of human heart (22), could produce an HLHS-like phenotype in certain subsets of HLHS (3, 6, 12, 13). susceptible offspring following transplacental passage of anti- In some cases of CHD, transplacental passage of maternal IgG heart Abs. Experiments conducted in the Lewis rat, an estab- has been reported to affect the fetus. For instance, in congenital lished model of CM-induced autoimmune heart disease (19, 20), led to an HLHS-like phenotype seen in human infants. Autoim- munity against the heart is a new concept in the pathogenesis of *Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Med- HLHS. ical Center, Cincinnati, OH 45229; †Division of Cardiothoracic Surgery, Washington University Medical Center, St. Louis, MO 63110; and ‡Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Materials and Methods OK 73104 Ag preparation 1M.W.C. and P.E. are cosenior authors. Rat CM was purified from rat heart tissue according to previously described Received for publication May 22, 2013. Accepted for publication February 18, 2014. techniques, with slight modifications (25, 26). Heart tissue was homoge- This work was supported in part by National Institutes of Health Grants R21- nized in a low-salt buffer [40 mM KCl, 20 mM imidazole, 5 mM ethylene HL104391 (to P.E.), F32-HL103054 (to C.R.C.), R01-HL56267 (to M.W.C.), and glycol-bis(b-aminoethyl ester)-N,N,N’,N’-tetraacetic acid, 5 mM DTT, 0.5 R37-HL35280 (to M.W.C.) and funds from the Saving Tiny Hearts Society. M.W.C. mM PMSF, 1 mg leupeptin per milliliter] for 15 s on ice. The washed is the recipient of a National Heart, Lung, and Blood Institute Method to Extend myofibrils were collected by centrifugation at 16,000 3 g for 10 min. The Research in Time Award. pellets were then resuspended in high-salt buffer [0.3 M KCl, 0.15 M Address correspondence and reprint requests to Dr. Pirooz Eghtesady, Pediatric Car- K2HPO4, 1 mM ethylene glycol-bis(b-aminoethyl ester)-N,N,N’,N’-tetra- diothoracic Surgery, Washington University School of Medicine, Campus Box 8234, acetic acid, 5 mM DTT, 0.5 mM PMSF, 1 mg leupeptin per milliliter] and St. Louis, MO 63110. E-mail address: [email protected] homogenized for three 30-s bursts on ice. The homogenized tissue was The online version of this article contains supplemental material. further incubated on ice, with stirring for 30 min to facilitate actomyosin Abbreviations used in this article: b-AR, b-adrenergic receptor; CHD, congenital extraction. After clarification by centrifugation, actomyosin was precipi- heart disease; CM, cardiac myosin; HLHS, hypoplastic left heart syndrome; LV, left tated by the addition of 10 volumes of cold water, followed by a pH ad- ventricle (ventricular); PKA, protein kinase A; RV, right ventricle (ventricular). justment to 6.5. DTT was added to 5 mM, and the precipitation was allowed to proceed for 30 min. The actomyosin was then pelleted by Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 centrifugation at 16,000 3 g. The actomyosin pellet was then resuspended www.jimmunol.org/cgi/doi/10.4049/jimmunol.1301264 The Journal of Immunology 4075 in high-salt buffer, ammonium sulfate was increased to 33%, and the KCl ventricular (RV) lateral and apical free walls, three measurements were concentration was increased to 0.5 M. After the actomyosin pellet and salts taken in 100-mm intervals. Three area measurements of the LV and RV were dissolved, ATP was added to 10 mM and MgCl2 was added to 5 mM, were also obtained using comparable apical four-chambered sections. and then the solution was centrifuged at 20,000 3 g for 15 min to remove Measurements were then averaged from each location for statistical actin filaments. The supernatant was removed and stored at 4˚C in the analysis. Owing to some cardiac damage during harvest that altered heart presence of the following inhibitors: 0.5 mM PMSF, 5 mg/ml N-tosyl-L- chamber dimensions, two affected and two unaffected fetal hearts were lysine chloromethyl ketone, and 1 mg leupeptin per milliliter. The presence excluded from LV/RV lumen area measurements. Maternal hearts were of CM was verified and quantitated by ELISA and Western immunoblot processed as previously described (20). A veterinary pathologist evaluated using mAb specific for CM protein. maternal heart sections for the presence of myocarditis and valvulitis. Immunization protocol Western blot analysis Specific pathogen–free female Lewis rats (LEW-RT1l)(∼8 wk old) were Binding of maternal and fetal serum to lysates (10 mg total protein) of adult purchased from Charles River Laboratories (Raleigh, NC) and were rat heart, liver, lung, and spleen was determined by Western blot analysis, maintained in a pathogen-free environment at Cincinnati Children’s Hos- as previously described (22). Sera from CM-injected maternal rats and pital animal facility. Rats were acclimated for 7 d prior to entering the affected fetal offspring, along with sera from control maternal rats and immunization protocol.
Load more

Recommended publications
  • Alternatively Activated Macrophages in Infection and Autoimmunity
    NIH Public Access Author Manuscript J Autoimmun. Author manuscript; available in PMC 2010 November 1. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: J Autoimmun. 2009 ; 33(3-4): 222±230. doi:10.1016/j.jaut.2009.09.012. Alternatively activated macrophages in infection and autoimmunity DeLisa Fairweathera,* and Daniela Cihakovab a Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland 21205, USA b Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA Abstract Macrophages are innate immune cells that play an important role in activation of the immune response and wound healing. Pathogens that require T helper-type 2 (Th2) responses for effective clearance, such as parasitic worms, are strong inducers of alternatively activated or M2 macrophages. However, infections such as bacteria and viruses that require Th1-type responses may induce M2 as a strategy to evade the immune system. M2 are particularly efficient at scavenging self tissues following injury through receptors like the mannose receptor and scavenger receptor-A. Thus, M2 may increase autoimmune disease by presenting self tissue to T cells. M2 may also exacerbate immune complex (IC)-mediated pathology and fibrosis, a hallmark of autoimmune disease in women, due to the release of profibrotic factors such as interleukin (IL)-1β, transforming growth factor-β, fibronectin and matrix metalloproteinases. We have found that M2 comprise anywhere from 30% to 70% of the infiltrate during acute viral or experimental autoimmune myocarditis, and shifts in M2 populations correlate with increased IC-deposition, fibrosis and chronic autoimmune pathology.
    [Show full text]
  • In Kawasaki Syndrome Anti-Human Cardiac Myosin Autoantibodies
    Anti-Human Cardiac Myosin Autoantibodies in Kawasaki Syndrome Madeleine W. Cunningham, H. Cody Meissner, Janet S. Heuser, Biagio A. Pietra, David K. Kurahara and Donald Y. This information is current as M. Leung2 of September 29, 2021. J Immunol 1999; 163:1060-1065; ; http://www.jimmunol.org/content/163/2/1060 Downloaded from References This article cites 34 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/163/2/1060.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 29, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1999 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Anti-Human Cardiac Myosin Autoantibodies in Kawasaki Syndrome1 Madeleine W. Cunningham,* H. Cody Meissner,† Janet S. Heuser, * Biagio A. Pietra,§ David K. Kurahara,‡ and Donald Y. M. Leung2¶ Kawasaki syndrome (KS) is the major cause of acquired heart disease in children. Although acute myocarditis is observed in most patients with KS, its pathogenesis is unknown.
    [Show full text]
  • Myocarditis in Humans and in Experimental Animal Models
    REVIEW published: 16 May 2019 doi: 10.3389/fcvm.2019.00064 Myocarditis in Humans and in Experimental Animal Models Przemysław Błyszczuk 1,2* 1 Department of Clinical Immunology, Jagiellonian University Medical College, Cracow, Poland, 2 Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland Myocarditis is defined as an inflammation of the cardiac muscle. In humans, various infectious and non-infectious triggers induce myocarditis with a broad spectrum of histological presentations and clinical symptoms of the disease. Myocarditis often resolves spontaneously, but some patients develop heart failure and require organ transplantation. The need to understand cellular and molecular mechanisms of inflammatory heart diseases led to the development of mouse models for experimental myocarditis. It has been shown that pathogenic agents inducing myocarditis in humans can often trigger the disease in mice. Due to multiple etiologies of inflammatory heart diseases in humans, a number of different experimental approaches have been developed to induce myocarditis in mice. Accordingly, experimental myocarditis in mice can be induced by infection with cardiotropic agents, such as coxsackievirus B3 and Edited by: protozoan parasite Trypanosoma cruzi or by activating autoimmune responses against JeanSébastien Silvestre, Institut National de la Santé et de la heart-specific antigens. In certain models, myocarditis is followed by the phenotype of Recherche Médicale dilated cardiomyopathy and the end stage of heart failure. This review describes the most (INSERM), France commonly used mouse models of experimental myocarditis with a focus on the role of Reviewed by: the innate and adaptive immune systems in induction and progression of the disease. Sophie Van Linthout, Charité Medical University of The review discusses also advantages and limitations of individual mouse models in the Berlin, Germany context of the clinical manifestation and the course of the disease in humans.
    [Show full text]
  • Role of Autoimmunity in Dilated Cardiomyopathy Br Heart J: First Published As 10.1136/Hrt.72.6 Suppl.S30 on 1 December 1994
    S 30 BrHeartJ 1994;72 (Supplement):S 30-S 34 Role of autoimmunity in dilated cardiomyopathy Br Heart J: first published as 10.1136/hrt.72.6_Suppl.S30 on 1 December 1994. Downloaded from A L P Caforio Persistent viral infection of the myocardium disposition and environmental influences. and autoimmunity are two of the main patho- The genetic predisposition accounts for both genic hypotheses for dilated cardiomyopathy the fact that different autoimmune conditions (DCM). A unifying hypothesis also suggests may be associated in patients or in their family that an initial viral insult may trigger or pre- members and the common finding that single cipitate autoimmunity. Is it becoming clearer autoimmune diseases often run in families. whether DCM is a chronic viral disease, a The inheritance of susceptibility is usually post-infectious autoimmune process, or polygenic. Organ-specific autoimmune dis- genetically determined organ-specific auto- eases are commonly associated with specific immune disease? HLA class II antigens,' but it is not known When tolerance to "self' antigens is lost how the HLA system determines the pre- autoimmune disease results. It is charac- disposition to a specific disease. terised by the presence of circulating autoanti- Most organ-specific autoimmune diseases bodies, which are not necessarily pathogenic are chronic and apparently idiopathic. Organ but represent markers of continuing tissue and disease specific antibodies are found in damage.' In autoimmune disease that is not the affected patients. These antibodies are organ specific there are autoantibodies against also detected in family members, sometimes ubiquitous autoantigens and tissue damage is years before the disease develops, and they generalised.
    [Show full text]
  • Women and Autoimmune Diseases Delisa Fairweather* and Noel R
    Women and Autoimmune Diseases DeLisa Fairweather* and Noel R. Rose* Autoimmune diseases affect approximately 8% of the eases tend to cluster in families and in individuals (a per- population, 78% of whom are women. The reasons for the son with one autoimmune disease is more likely to get high prevalence in women are unknown, but circumstantial another), which indicates that common mechanisms are evidence links autoimmune diseases with preceding infec- involved in disease susceptibility. Studies of the preva- tions. Animal models of autoimmune diseases have shown lence of autoimmune disease in monozygotic twins show that infections can induce autoimmune disease. For exam- ple, coxsackievirus B3 (CB3) infection of susceptible mice that genetic as well as environmental factors (such as results in inflammation of the heart (myocarditis) that infection) are necessary for the disease to develop (6). resembles myocarditis in humans. The same disease can Genetic factors are important in the development of be induced by injecting mice with heart proteins mixed with autoimmune disease, since such diseases develop in cer- adjuvant(s), which indicates that an active infection is not tain strains of mice (e.g., systemic lupus erythematosus or necessary for the development of autoimmune disease. lupus in MRL mice) without any apparent infectious envi- We have found that CB3 triggers autoimmune disease in ronmental trigger. However, a body of circumstantial evi- susceptible mice by stimulating elevated levels of proin- dence links diabetes, multiple sclerosis, myocarditis, and flammatory cytokines from mast cells during the innate many other autoimmune diseases with preceding infec- immune response. Sex hormones may further amplify this hyperimmune response to infection in susceptible persons, tions (Table) (7,8).
    [Show full text]
  • Immunopathological Basis of Virus-Induced Myocarditis
    CORE Metadata, citation and similar papers at core.ac.uk Provided by PubMed Central Clinical & Developmental Immunology, March 2004, Vol. 11 (1), pp. 1–5 Immunopathological Basis of Virus-induced Myocarditis REINHARD MAIER, PHILIPPE KREBS and BURKHARD LUDEWIG* Research Department, Kantonal Hospital St. Gallen, 9007 St. Gallen, Switzerland Heart diseases are an important cause of morbidity and mortality in industrialized countries. Dilated cardiomyopathy (DCM), one of the most common heart diseases, may be the consequence of infection- associated myocardits. Coxsackievirus B3 (CVB3) can be frequently detected in the inflamed heart muscle. CVB3-induced acute myocarditis is most likely the consequence of direct virus-induced myocyte damage, whereas chronic CVB3 infection-associated heart disease is dominated by its immunopathological sequelae. Bona fide autoimmunity, for example, directed against cardiac myosin, may favor chronic destructive immune damage in the heart muscle and thereby promote the development of DCM. The immunopathogenesis of myocarditis and subsequent DCM induced either by pathogens or autoantigens can be investigated in well-established animal models. In this article, we review recent studies on the role of viruses, with particular emphasis on CVB3, and different immunological effector mechanisms in initiation and progression of myocarditis. Keywords: Myocarditis; Dilated cardiomyopathy; Immunopathology; Bystander activation; Molecular mimicry Abbreviations: CVB3, Coxsackievirus B3; CMV, cytomegalovirus; DCM, dilated cardiomyopathy INTRODUCTION In the second phase of the biphasic myocarditis, infectious virus is usually no longer detectable and ongoing Infections with viruses, protozoan intracellular parasites inflammation leads to heart muscle fibrosis and ventricular or bacteria may be associated with myocarditis (Brown dilation. Mouse strains showing a biphasic disease and O’Connell, 1995; Bowles et al., 2003).
    [Show full text]
  • Systemic Autoimmunity Induced by the TLR7/8 Agonist Resiquimod Causes Myocarditis and Dilated Cardiomyopathy in a New Mouse Model of Autoimmune Heart Disease Muneer G
    © 2017. Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2017) 10, 259-270 doi:10.1242/dmm.027409 RESEARCH ARTICLE Systemic autoimmunity induced by the TLR7/8 agonist Resiquimod causes myocarditis and dilated cardiomyopathy in a new mouse model of autoimmune heart disease Muneer G. Hasham1, Nicoleta Baxan2, Daniel J. Stuckey3, Jane Branca1, Bryant Perkins1, Oliver Dent4, Ted Duffy1, Tolani S. Hameed4, Sarah E. Stella4, Mohammed Bellahcene4, Michael D. Schneider4, Sian E. Harding4, Nadia Rosenthal1,4 and Susanne Sattler4,* ABSTRACT disease results from direct target-specific tissue damage due to Systemic autoimmune diseases such as systemic lupus autoreactive effector cells and antibodies, as well as from indirect erythematosus (SLE) and rheumatoid arthritis (RA) show significant damage due to increased systemic levels of inflammatory cytokines heart involvement and cardiovascular morbidity, which can be due to (Abou-Raya and Abou-Raya, 2006; Abusamieh and Ash, 2004; systemically increased levels of inflammation or direct autoreactivity Knockaert, 2007). targeting cardiac tissue. Despite high clinical relevance, cardiac The most common cardiac complication of the prototype systemic damage secondary to systemic autoimmunity lacks inducible rodent autoimmune disease systemic lupus erythematosus (SLE) is models. Here, we characterise immune-mediated cardiac tissue pericarditis, followed by myocarditis or myocardial fibrosis due to damage in a new model of SLE induced by topical application of the infiltration of inflammatory cells (Jastrzebską et al., 2013). Toll-like receptor 7/8 (TLR7/8) agonist Resiquimod. We observe a Myocarditis may be idiopathic, infectious or autoimmune in origin. cardiac phenotype reminiscent of autoimmune-mediated dilated Inflammation may resolve or persist and lead to cardiac remodelling, cardiomyopathy, and identify auto-antibodies as major contributors ventricular dilation with normal or reduced left ventricular wall to cardiac tissue damage.
    [Show full text]
  • Cardiac Myosin-Th17 Responses Promote Heart Failure in Human Myocarditis
    Cardiac myosin-Th17 responses promote heart failure in human myocarditis Jennifer M. Myers, … , Carol J. Cox, Madeleine W. Cunningham JCI Insight. 2016;1(9):e85851. https://doi.org/10.1172/jci.insight.85851. Research Article Immunology In human myocarditis and its sequela dilated cardiomyopathy (DCM), the mechanisms and immune phenotype governing disease and subsequent heart failure are not known. Here, we identified a Th17 cell immunophenotype of human myocarditis/DCM with elevated CD4+IL17+ T cells and Th17-promoting cytokines IL-6, TGF-β, and IL-23 as well as GM- CSF–secreting CD4+ T cells. The Th17 phenotype was linked with the effects of cardiac myosin on CD14+ monocytes, TLR2, and heart failure. Persistent heart failure was associated with high percentages of IL-17–producing T cells and IL- 17–promoting cytokines, and the myocarditis/DCM phenotype included significantly low percentages of FOXP3+ Tregs, which may contribute to disease severity. We demonstrate a potentially novel mechanism in human myocarditis/DCM in which TLR2 peptide ligands from human cardiac myosin stimulated exaggerated Th17-related cytokines including TGF-β, IL-6, and IL-23 from myocarditic CD14+ monocytes in vitro, and an anti-TLR2 antibody abrogated the cytokine response. Our translational study explains how an immune phenotype may be initiated by cardiac myosin TLR ligand stimulation of monocytes to generate Th17-promoting cytokines and development of pathogenic Th17 cells in human myocarditis and heart failure, and provides a rationale for targeting IL-17A as a therapeutic option. Find the latest version: https://jci.me/85851/pdf RESEARCH ARTICLE Cardiac myosin-Th17 responses promote heart failure in human myocarditis Jennifer M.
    [Show full text]
  • Cardiovascular Conclusions: Polysomy Occurs Commonly in Invasive Ductal Breast Carcinomas
    56A ANNUAL MEETING ABSTRACTS Results: The distribution of carcinomas by molecular classification and OncDX Conclusions: 1). Missed cancer rate is highest for non-image guided CNBX with non- recurrence score groups is listed in Table 1. For the 26 Luminal-A carcinomas, the specific benign diagnosis if there is also a mammographic and/or ultrasound mass. 2).The mean/ median OncotypeDX recurrence scores were 13.4/ 13.5 respectively (range, existing rad-path correlation protocols for image-guided CNBX effectively prevent 8 – 20). None of the Her2-V, Her2-C, or basal molecular groups had low recurrence delay in cancer diagnosis. 3). By using triple approach, pathologists and surgeons can risk OncotypeDX scores. Of the 40 high OncotypeDX recurrence score cases, 0 were recognize possible discordance between the pathologic findings and clinical/ radiologic luminal-A, 9 (22.5%) were Luminal-B, 8 (20.0%) were Her2-V, 14 (35.0%) were Her2- mass lesion, potentially leading to prompt re-biopsy and definitive diagnosis. C, and 9 (22.5%) were basal phenotype. All of the Her2-C and basal phenotype cases Nonsp- Nonsp- Nonsp-group; Nonsp-group; had very-low level positive ER values. CNBX I-CNBX N-CNBX group, group, pos imaging neg imaging, Conclusions: The Sorlie-based IHC molecular classification groups and OncotypeDX I-CNBX N-CNBX mass, N-CNBX N-CNBX Total 673 460 213 109 111 45 46 recurrence score overlapped to a substantial degree. Luminal A group carcinomas were Missed 13 4 9 3 9 7 0 highly correlated with low OncDX recurrence score. Although ER+, the high recurrence cancer (n) Missed risk OncDX score group was comprised of a mixture of neoplasms including Her2- 1.9% 0.8% 4.2% 2.7% 8.1% 15.6% 0 classic and basal phenotype neoplasms.
    [Show full text]
  • Programmed Death-Ligand 2 Deficiency Exacerbates
    International Journal of Molecular Sciences Article Programmed Death-Ligand 2 Deficiency Exacerbates Experimental Autoimmune Myocarditis in Mice Siqi Li 1, Kazuko Tajiri 1,* , Nobuyuki Murakoshi 1, DongZhu Xu 1, Saori Yonebayashi 1, Yuta Okabe 1, Zixun Yuan 1, Duo Feng 1, Keiko Inoue 1, Kazuhiro Aonuma 1, Yuzuno Shimoda 1, Zoughu Song 1, Haruka Mori 1, Honglan Huang 2, Kazutaka Aonuma 1 and Masaki Ieda 1 1 Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan; [email protected] (S.L.); [email protected] (N.M.); [email protected] (D.X.); [email protected] (S.Y.); [email protected] (Y.O.); [email protected] (Z.Y.); [email protected] (D.F.); [email protected] (K.I.); [email protected] (K.A.); [email protected] (Y.S.); [email protected] (Z.S.); [email protected] (H.M.); [email protected] (K.A.); [email protected] (M.I.) 2 Department of Pathogenobioligy, College of Basic Medical Sciences, Jilin University, Changchun 130012, China; [email protected] * Correspondence: [email protected]; Tel.: +81-29-853-3143 Abstract: Programmed death ligand 2 (PD-L2) is the second ligand of programmed death 1 (PD-1) protein. In autoimmune myocarditis, the protective roles of PD-1 and its first ligand programmed death ligand 1 (PD-L1) have been well documented; however, the role of PD-L2 remains unknown. In this study, we report that PD-L2 deficiency exacerbates myocardial inflammation in mice with experimental autoimmune myocarditis (EAM).
    [Show full text]
  • Fusidin Ameliorates Experimental Autoimmune Myocarditis in Rats by Inhibiting TNF-A Production
    ORIGINAL ARTICLES Department of Microbiology and Immunology, Faculty of Pharmacy, Belgrade, Serbia Fusidin ameliorates experimental autoimmune myocarditis in rats by inhibiting TNF-a production M. Milenkovic´, N. Arsenovic´-Ranin, D. Vucˇic´evic´, B. Bufan, Z. Stojic´-Vukanic´ Received October 20, 2006, accepted November 27, 2006 Marina Milenkovic´, M.D., Ph.D., Department of Microbiology and Immunology, Faculty of Pharmacy, 450 Vojvode Stepe, 11221 Belgrade (Kumodrazˇ), Serbia [email protected] Pharmazie 62: 445–448 (2007) doi: 10.1691/ph.2007.6.6739 Experimental autoimmune myocarditis (EAM) represents a model for human autoimmune myocarditis, a condition for which no optimal treatment is currently available. It has been reported that tumor necro- sis factor-a (TNF-a) plays a crucial role in pathogenesis of EAM. The immunomodulating antibiotic fusidic acid and its sodium salt (sodium fusidate-fusidin) were previously shown to reduce TNF-a pro- duction and its end-organ cytotoxicity, thus proving beneficial in several animal models of organ-speci- fic autoimmune diseases. To investigate the effects of fusidin on EAM the drug was given at dose 80 mg/kg i.m. to EAM rats. Fusidin was administered as an early, from day 0 to 10, or late treatment, from day 10 to 21, after induction of disease. Both early and late treatment with fusidin markedly ameliorated the clinical and histological signs of the disease. Fusidin-treated rats had significantly decreased blood levels of TNF-a compared with vehicle-treated animals. Similarly, TNF-a production by in vitro sensitized lymph node cells in both fusidin treated groups was significantly lower than that in EAM rats.
    [Show full text]
  • Unresolved Issues in Theories of Autoimmune Disease Using Myocarditis As a Framework
    Journal of Theoretical Biology 375 (2015) 101–123 Contents lists available at ScienceDirect Journal of Theoretical Biology journal homepage: www.elsevier.com/locate/yjtbi Unresolved issues in theories of autoimmune disease using myocarditis as a framework Robert Root-Bernstein a,1, DeLisa Fairweather b,n a Michigan State University, Department of Physiology, 2174 Biomedical and Physical Sciences Building, East Lansing, MI 48824, USA b Johns Hopkins Bloomberg School of Public Health, Department of Environmental Health Sciences, 615 N. Wolfe Street, Room E7628, Baltimore, MD 21205, USA HIGHLIGHTS Clinical and experimental evidence support some aspects of all theories. Critical comparative studies differentiating between theories and models needed. Theories monocausal but animal models suggest multi-factorial cause of disease. Theories do not adequately explain adjuvant, innate immunity or sex differences. New synthetic theory needed integrating anomalies, innate and adaptive immunity. article info abstract Article history: Many theories of autoimmune disease have been proposed since the discovery that the immune system Received 10 July 2014 can attack the body. These theories include the hidden or cryptic antigen theory, modified antigen Received in revised form theory, T cell bypass, T cell–B cell mismatch, epitope spread or drift, the bystander effect, molecular 10 November 2014 mimicry, anti-idiotype theory, antigenic complementarity, and dual-affinity T cell receptors. We critically Accepted 20 November 2014 review these theories and relevant mathematical models as they apply to autoimmune myocarditis. All Available online 4 December 2014 theories share the common assumption that autoimmune diseases are triggered by environmental Keywords: factors such as infections or chemical exposure. Most, but not all, theories and mathematical models are Autoimmune disease theories and modeling unifactorial assuming single-agent causation of disease.
    [Show full text]