Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study
Gillian I. Rice1, Gabriella Forte1, Marcin Szynkiewicz1, Diana Chase1, Alec Aeby2, Mohamed S Abdel-Hamid, Sam Ackroyd3, Rebecca L. Allcock4, Kathryn Bailey5, Umberto Balottin6, Christine Barnerias7, Geneviève Bernard8, Christine Bodemer9, Maria P. Botella, Cristina Cereda, Kate Chandler10, Lyvia Dabydeen11, Russell C. Dale12, Corinne De Laet, Christian de Goede, Mireia Del Toro, Laila Effat, Noemi Nunez Enamorado, Elisa Fazzi13, Blanca Gener, Madli Haldre14, Jean-Pierre S-M Jp Lin15, John Jh Livingston16, Charles Marques Lourenço17, Wilson Marques17, Patrick J. Oades, Pärt Peterson14, Magnhild Rasmussen18, Agathe Roubertie19, Johanna L. Schmidt20, Stavit A. Shalev21, Rogelio Simon, Ronen Spiegel21, Kathryn Kj Swoboda22, Samia Sa Temtamy, Grace Vassallo23, Catheline Vilain2, Julie Vogt24, Vanessa Wermenbol2, William Wp Whitehouse25, Doriette Soler26, Ivana Olivieri, Simona Orcesi, Mona Ms Aglan, Maha S. Zaki, Ghada Gm Abdel-Salam, Adeline Vanderver20, Kai Kisand14, Flore Rozenberg9, Pierre Lebon9, Yanick J. Crow10, Yanick J. Crow1 •
University of Manchester1, Université libre de Bruxelles2, Blackpool Victoria Hospital3, Lancashire Teaching Hospitals NHS Foundation Trust4, Coventry Health Care5, University of Pavia6, Necker-Enfants Malades Hospital7, Montreal Children's Hospital8, Paris Descartes University9, Central Manchester University Hospitals NHS Foundation Trust10, University Hospitals of Leicester NHS Trust11, Children's Hospital at Westmead12, University of Brescia13, University of Tartu14, Guy's and St Thomas' NHS Foundation Trust15, Leeds General Infirmary16, University of São Paulo17, Oslo University Hospital18, French Institute of Health and Medical Research19, George Washington University20, Rappaport Faculty of Medicine21, University of Utah22, Boston Children's Hospital23, University of Birmingham24, Nottingham University Hospitals NHS Trust25, Mater Dei Hospital26
TL;DR: AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls, and neutralisation assays suggested that measurable antiviral activity was related toInterferon α production.
Abstract: Summary Background Aicardi-Goutieres syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes ( TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1 , and ADAR ). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. Methods In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. Findings 74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14–20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57–1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r =−0·604; serum, r =−0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. Interpretation AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials. Funding European Union's Seventh Framework Programme; European Research Council.
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Randall Jeffrey Platt1, Sidi Chen2, Yang Zhou1, Michael Yim, Lukasz Swiech, Hannah R. Kempton1, James E. Dahlman2, Oren Parnas3, Thomas Eisenhaure4, Marko Jovanovic3, Daniel B. Graham3, Siddharth Jhunjhunwala2, Matthias Heidenreich, Ramnik J. Xavier3, Robert Langer2, Daniel G. Anderson, Nir Hacohen4, Aviv Regev2, Guoping Feng1, Phillip A. Sharp2, Feng Zhang •
TL;DR: In this paper, a Cre-dependent Cas9 knockin mouse was used to study the dynamics of KRAS, p53, and LKB1, the top three significantly mutated genes in lung adenocarcinoma.
Abstract: CRISPR-Cas9 is a versatile genome editing technology for studying the functions of genetic elements. To broadly enable the application of Cas9 in vivo, we established a Cre-dependent Cas9 knockin mouse. We demonstrated in vivo as well as ex vivo genome editing using adeno-associated virus (AAV)-, lentivirus-, or particle-mediated delivery of guide RNA in neurons, immune cells, and endothelial cells. Using these mice, we simultaneously modeled the dynamics of KRAS, p53, and LKB1, the top three significantly mutated genes in lung adenocarcinoma. Delivery of a single AAV vector in the lung generated loss-of-function mutations in p53 and Lkb1, as well as homology-directed repair-mediated KrasG12D mutations, leading to macroscopic tumors of adenocarcinoma pathology. Together, these results suggest that Cas9 mice empower a wide range of biological and disease modeling applications.
1,216 citations
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TL;DR: The molecular and cellular basis of the interferonopathies, their categorization, future treatment strategies and the insights they provide into normal physiology are discussed.
Abstract: This Review describes the type I interferonopathies — a set of Mendelian disorders associated with the upregulation of type I interferon activity. The authors explain how defects in key components of innate immune signalling pathways can lead to these diseases and discuss the immunological insights that have resulted from their study.
653 citations
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TL;DR: The latest advances uncovering how cGAS and STING control inflammatory responses and are themselves regulated are reviewed, suggesting a major clinical impact in areas of cancer immunotherapy and vaccine development.
Abstract: DNA is highly immunogenic. It represents a key pathogen-associated molecular pattern (PAMP) during infection. Host DNA can, however, also act as a danger-associated molecular pattern (DAMP) and elicit strong inflammatory responses. The cGAS-STING pathway has emerged as a major pathway that detects intracellular DNA. Here, we highlight recent advances on how cGAS and STING mediate inflammatory responses and how these are regulated, allowing cells to readily respond to infections and noxious agents while avoiding the inappropriate sensing of self-DNA. A particular focus is placed on the role of cGAS in the context of sterile inflammatory conditions. Manipulating cGAS or STING may open the door for new therapeutic strategies for the treatment of acute and chronic inflammation relevant to many human diseases.
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Gillian I. Rice1, Yoandris del Toro Duany2, Yoandris del Toro Duany3, Emma M. Jenkinson1, Gabriella M A Forte1, Beverley Anderson1, Giada Ariaudo4, Brigitte Bader-Meunier5, Eileen Baildam, Roberta Battini, Michael W. Beresford6, Manuela Casarano, Mondher Chouchane, Rolando Cimaz7, Abigail Collins8, Nuno Cordeiro9, Russell C. Dale10, Joyce Davidson11, Liesbeth De Waele12, Isabelle Desguerre5, Laurence Faivre13, Elisa Fazzi14, Bertrand Isidor15, Lieven Lagae12, Andrew Latchman16, Pierre Lebon17, Chumei Li16, John H. Livingston18, Charles Marques Lourenço19, Maria Margherita Mancardi, Alice Masurel-Paulet13, Iain B. McInnes20, Manoj P. Menezes10, Cyril Mignot, James O'Sullivan1, Simona Orcesi, Paolo Picco, Enrica Riva21, Robert Robinson22, Diana Rodriguez15, Diana Rodriguez23, Elisabetta Salvatici21, Christiaan Scott24, Marta Szybowska16, John Tolmie25, Adeline Vanderver26, Catherine Vanhulle, José Pedro Vieira, Kate Webb24, Robyn Whitney16, Simon G. Williams1, Lynne A. Wolfe, Sameer M. Zuberi20, Sameer M. Zuberi11, Sun Hur2, Sun Hur3, Yanick J. Crow1 •
Manchester Academic Health Science Centre1, Boston Children's Hospital2, Harvard University3, University of Pavia4, Necker-Enfants Malades Hospital5, University of Liverpool6, University of Florence7, University of Colorado Denver8, NHS Ayrshire and Arran9, Children's Hospital at Westmead10, Royal Hospital for Sick Children11, Katholieke Universiteit Leuven12, University of Burgundy13, University of Brescia14, French Institute of Health and Medical Research15, McMaster Children's Hospital16, Paris Descartes University17, Leeds Teaching Hospitals NHS Trust18, University of São Paulo19, University of Glasgow20, University of Milan21, Great Ormond Street Hospital22, Pierre-and-Marie-Curie University23, University of Cape Town24, Southern General Hospital25, Children's National Medical Center26
TL;DR: It is demonstrated that aberrant sensing of nucleic acids can cause immune upregulation and heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state.
Abstract: The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutieres syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.
470 citations
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Yanick J. Crow1, Diana Chase1, Johanna Lowenstein Schmidt2, Marcin Szynkiewicz1, Gabriella Forte1, Hannah Gornall1, Anthony Oojageer1, Beverley Anderson1, Amy Pizzino2, Guy Helman2, Mohamed S. Abdel-Hamid, Ghada M H Abdel-Salam, Sam Ackroyd3, Alec Aeby4, Guillermo Agosta5, Catherine Albin6, Stavit Allon-Shalev7, Montse Arellano8, Giada Ariaudo9, Vijay Aswani10, Riyana Babul-Hirji11, Eileen Baildam, Nadia Bahi-Buisson12, Kathryn Bailey13, Christine Barnerias12, Magalie Barth14, Roberta Battini15, Michael W. Beresford16, Geneviève Bernard17, Marika Bianchi, Thierry Billette de Villemeur18, Edward Blair19, Miriam Bloom2, Alberto B. Burlina, Maria Luisa Carpanelli, Daniel R. Carvalho, Manuel Castro-Gago20, Anna Cavallini, Cristina Cereda, Kate Chandler21, David Chitayat11, Abigail Collins22, Concepcion Sierra Corcoles, Nuno Cordeiro23, Giovanni Crichiutti24, Lyvia Dabydeen25, Russell C. Dale26, Stefano D'Arrigo, Christian de Goede, Corinne De Laet, Liesbeth De Waele, Inés Denzler5, Isabelle Desguerre12, Koenraad Devriendt27, Maja Di Rocco28, Michael C Fahey29, Elisa Fazzi30, Colin D. Ferrie31, António Figueiredo, Blanca Gener, Cyril Goizet, Nirmala Rani Gowrinathan6, Kalpana Gowrishankar, Donncha Hanrahan32, Bertrand Isidor33, Bülent Kara34, Nasaim Khan21, Mary D. King35, Edwin P. Kirk36, Ram L. Kumar, Lieven Lagae27, Pierre Landrieu37, Heinz Lauffer38, Vincent Laugel, Roberta La Piana17, Ming K. Lim39, Jean-Pierre Lin40, Tarja Linnankivi41, Mark T Mackay42, Daphna Marom, Charles Marques Lourenço43, Shane McKee32, Isabella Moroni, Jenny Morton, Marie Laure Moutard44, Kevin J. Murray45, Rima Nabbout12, Sheela Nampoothiri46, Noemi Nunez-Enamorado, Patrick J. Oades, Ivana Olivieri, John R. Østergaard47, Belén Pérez-Dueñas8, Julie S. Prendiville48, Venkateswaran Ramesh36, Magnhild Rasmussen49, Luc Régal27, Federica Ricci, Marlène Rio12, Diana Rodriguez18, Agathe Roubertie, Elisabetta Salvatici50, Karin Segers51, Gyanranjan P. Sinha, Doriette Soler52, Ronen Spiegel7, Tommy Stödberg53, Rachel Straussberg54, Kathryn J. Swoboda55, Mohnish Suri56, Uta Tacke57, Tiong Yang Tan58, Johann te Water Naude59, Keng Wee Teik, Maya Thomas60, Marianne Till, Davide Tonduti, Enza Maria Valente61, Rudy Van Coster62, Marjo S. van der Knaap63, Grace Vassallo36, Raymon Vijzelaar, Julie Vogt, Geoffrey Wallace36, Evangeline Wassmer36, Hannah J. Webb64, William P Whitehouse65, Robyn Whitney66, Maha S. Zaki, Sameer M. Zuberi67, John H. Livingston31, Flore Rozenberg12, Pierre Lebon12, Adeline Vanderver2, Simona Orcesi, Gillian I. Rice1 •
University of Manchester1, George Washington University2, Bradford Royal Infirmary3, Université libre de Bruxelles4, Hospital Italiano de Buenos Aires5, Kaiser Permanente6, Technion – Israel Institute of Technology7, University of Barcelona8, University of Pavia9, Marshfield Clinic10, University of Toronto11, University of Paris12, University Hospitals Coventry and Warwickshire NHS Trust13, University of Angers14, University of Pisa15, University of Liverpool16, McGill University17, French Institute of Health and Medical Research18, University of Oxford19, University of Santiago de Compostela20, St Mary's Hospital21, University of Colorado Boulder22, NHS Ayrshire and Arran23, University of Udine24, University Hospitals of Leicester NHS Trust25, University of Sydney26, Katholieke Universiteit Leuven27, Istituto Giannina Gaslini28, Monash University29, University of Brescia30, Leeds General Infirmary31, Belfast Health and Social Care Trust32, University of Nantes33, Kocaeli University34, Temple University35, Boston Children's Hospital36, University of Paris-Sud37, University of Greifswald38, HealthPartners39, Guy's and St Thomas' NHS Foundation Trust40, University of Helsinki41, Royal Children's Hospital42, University of São Paulo43, Pierre-and-Marie-Curie University44, Princess Margaret Hospital for Children45, Amrita Vishwa Vidyapeetham46, Aarhus University47, University of British Columbia48, Rikshospitalet–Radiumhospitalet49, University of Milan50, University of Liège51, Mater Dei Hospital52, Karolinska Institutet53, Tel Aviv University54, University of Utah55, Nottingham University Hospitals NHS Trust56, University of Basel57, University of Melbourne58, University Hospital of Wales59, Christian Medical College & Hospital60, Casa Sollievo della Sofferenza61, Ghent University62, VU University Amsterdam63, Mount Sinai St. Luke's and Mount Sinai Roosevelt64, University of Nottingham65, McMaster University66, University of Glasgow67
TL;DR: A robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferOn‐stimulated gene transcripts in peripheral blood is observed.
Abstract: Aicardi-Goutieres syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutieres syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.
437 citations
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TL;DR: During a study of the interference produced by heat-inactivated influenza virus with the growth of live virus in fragments of chick chorio-allantoic membrane it was found that following incubation of heated virus with membrane a new factor was released.
Abstract: During a study of the interference produced by heat-inactivated influenza virus with the growth of live virus in fragments of chick chorio-allantoic membrane it was found that following incubation of heated virus with membrane a new factor was released. This factor, recognized by its ability to induce interference in fresh pieces of chorio-allantoic membrane, was called interferon. Following a lag phase interferon was first detected in the membranes after 3 h incubation and thereafter it was released into the surrounding fluid.
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TL;DR: Global gene expression profiling of peripheral blood mononuclear cells is used to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.
Abstract: Systemic lupus erythematosus (SLE) is a complex, inflammatory autoimmune disease that affects multiple organ systems. We used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls. Strikingly, about half of the patients studied showed dysregulated expression of genes in the IFN pathway. Furthermore, this IFN gene expression “signature” served as a marker for more severe disease involving the kidneys, hematopoetic cells, and/or the central nervous system. These results provide insights into the genetic pathways underlying SLE, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.
2,075 citations
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TL;DR: It is shown that different viruses are targeted by unique sets of ISGs, and that each viral species is susceptible to multiple antiviral genes, which together encompass a range of inhibitory activities.
Abstract: The type I interferon response protects cells against invading viral pathogens. The cellular factors that mediate this defence are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified since their discovery more than 25 years ago, only a few have been characterized with respect to antiviral activity. For most ISG products, little is known about their antiviral potential, their target specificity and their mechanisms of action. Using an overexpression screening approach, here we show that different viruses are targeted by unique sets of ISGs. We find that each viral species is susceptible to multiple antiviral genes, which together encompass a range of inhibitory activities. To conduct the screen, more than 380 human ISGs were tested for their ability to inhibit the replication of several important human and animal viruses, including hepatitis C virus, yellow fever virus, West Nile virus, chikungunya virus, Venezuelan equine encephalitis virus and human immunodeficiency virus type-1. Broadly acting effectors included IRF1, C6orf150 (also known as MB21D1), HPSE, RIG-I (also known as DDX58), MDA5 (also known as IFIH1) and IFITM3, whereas more targeted antiviral specificity was observed with DDX60, IFI44L, IFI6, IFITM2, MAP3K14, MOV10, NAMPT (also known as PBEF1), OASL, RTP4, TREX1 and UNC84B (also known as SUN2). Combined expression of pairs of ISGs showed additive antiviral effects similar to those of moderate type I interferon doses. Mechanistic studies uncovered a common theme of translational inhibition for numerous effectors. Several ISGs, including ADAR, FAM46C, LY6E and MCOLN2, enhanced the replication of certain viruses, highlighting another layer of complexity in the highly pleiotropic type I interferon system.
1,926 citations
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TL;DR: Microarray analysis of blood cells reveals that immature granulocytes may be involved in SLE pathogenesis, and the IFN signature confirms the central role of this cytokine in Sle, using oligonucleotide microarrays.
Abstract: Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease characterized by flares of high morbidity. Using oligonucleotide microarrays, we now show that active SLE can be distinguished by a remarkably homogeneous gene expression pattern with overexpression of granulopoiesis-related and interferon (IFN)-induced genes. Using the most stringent statistical analysis (Bonferroni correction), 15 genes were found highly up-regulated in SLE patients, 14 of which are targets of IFN and one, defensin DEFA-3, a major product of immature granulocytes. A more liberal correction (Benjamini and Hochberg correction) yielded 18 additional genes, 12 of which are IFN-regulated and 4 granulocyte-specific. Indeed immature neutrophils were identified in a large fraction of SLE patients white blood cells. High dose glucocorticoids, a standard treatment of disease flares, shuts down the interferon signature, further supporting the role of this cytokine in SLE. The expression of 10 genes correlated with disease activity according to the SLEDAI. The most striking correlation (P < 0.001, r = 0.55) was found with the formyl peptide receptor-like 1 protein that mediates chemotactic activities of defensins. Therefore, while the IFN signature confirms the central role of this cytokine in SLE, microarray analysis of blood cells reveals that immature granulocytes may be involved in SLE pathogenesis.
1,873 citations
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TL;DR: It is possible that the production of interferon may contribute to immunologic aberrations in auto-immune diseases and also protect the already compromised host from viral infections.
Abstract: The observation that type II, or immune, interferon could be produced by peripheral-blood leukocytes in vitro on an immune-specific basis suggested that it also might be produced in vivo in various autoimmune disorders. We found immune interferon in the serums of patients with systemic lupus erythematosus, rheumatoid arthritis, scleroderma and Sjogren's syndrome. Among 28 patients with systemic lupus erythematosus, 71 per cent of those with active and 21 per cent of those with inactive disease showed interferon in their serums. Serial serum samples showed a good correlation between interferon titers and disease activity. Moreover, interferon titers correlated positively with antibodies to DNA and negatively with serum levels of the third component of complement. It is possible that the production of interferon may contribute to immunologic aberrations in auto-immune diseases and also protect the already compromised host from viral infections.
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