REVIEW ARTICLEAutoimmunity in dengue pathogenesisShu-Wen Wan a,b, Chiou-Feng Lin a,b,c,d, Trai-Ming Yeh b,c,e,Ching-Chuan Liu b,f, Hsiao-Sheng Liu a,b,c, Shuying Wang a,b,c, Pin Ling a,b,c,Robert Anderson a,b,g,h,i, Huan-Yao Lei a,b,c,j, Yee-Shin Lin a,b,c,*aDepartment of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, TaiwanbCenter of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, TaiwancInstitute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, TaiwandInstitute of Clinical Medicine, National Cheng Kung University Medical College, Tainan, TaiwaneDepartment of Medical Laboratory Science and Biotechnology, National Cheng Kung University Medical College, Tainan,TaiwanfDepartment of Pediatrics, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, TaiwangDepartment of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, CanadahDepartment of Pediatrics, Dalhousie University, Halifax, Nova Scotia, CanadaiCanadian Center for Vaccinology, Dalhousie University, Halifax, Nova Scotia, CanadaReceived 20 October 2012; accepted 9 November 2012KEYWORDSautoimmunity;dengue;immunopathogenesisDengue is one of the most important vector-borne viral diseases. With climate change and theconvenience of travel, dengue is spreading beyond its usual tropical and subtropical bound-aries. Infection with dengue virus (DENV) causes diseases ranging widely in severity, fromself-limited dengue fever to life-threatening dengue hemorrhagic fever and dengue shocksyndrome. Vascular leakage, thrombocytopenia, and hemorrhage are the major clinical mani-festations associated with severe DENV infection, yet the mechanisms remain unclear. Besidesthe direct effects of the virus, immunopathogenesis is also involved in the development ofdengue disease. Antibody-dependent enhancement increases the efciency of virus infectionand may suppress type I interferon-mediated antiviral responses. Aberrant activation of T cellsand overproduction of soluble factors cause an increase in vascular permeability. DENV-induced autoantibodies against endothelial cells, platelets, and coagulatory molecules leadto their abnormal activation or dysfunction. Molecular mimicry between DENV proteins andhost proteins may explain the cross-reactivity of DENV-induced autoantibodies. Although no* Corresponding author. Department of Microbiology and Immunology, National Cheng Kung University Medical College, 1 University Road,Tainan 701, Taiwan.E-mail address: yslin1@mail.ncku.edu.tw (Y.-S. Lin).jDr Huan-Yao Lei passed away during the preparation of this manuscript. This review article is dedicated to Dr Lei.0929-6646/$ - see front matter Copyright 2012, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved.http://dx.doi.org/10.1016/j.jfma.2012.11.006Available online at www.sciencedirect.comjournal homepage: www.jfma-online.comJournal of the Formosan Medical Association (2013) 112, 3e11

licensed dengue vaccine is yet available, several vaccine candidates are under development.For the development of a safe and effective dengue vaccine, the immunopathogenic compli-cations of dengue disease need to be considered.Copyright 2012, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved.IntroductionDengue virus (DENV) belongs to the genus Flavivirus of thefamily Flaviviriade. Based on neutralization assay data,four serotypes (DENV-1, DENV-2, DENV-3, and DENV-4) canbe distinguished. DENV is transmitted to humans mainly byAedes aegypti and Aedes albopictus.1About 50 milliondengue infection cases, with around 500,000 cases per yearof severe dengue, have mainly been reported in the Asia-Pacic region, the Americas, and Africa. All four DENVserotypes are now circulating in these areas.2The trans-mission efciency and disease expression between theserotypes are still uncertain, but DENV-2 and DENV-3 mightcontribute the most to disease severity and mortality.3There have been several major outbreaks of dengue inTaiwan, particularly in 1981, 1987e1988, 2001e2002, and2007. Dengue outbreaks involve various combinations ofdengue serotypes, with certain serotypes predominating,such as DENV-2 in the year 2002.4,5Recent reports haveclaried the usual pattern in Taiwan outbreaks: starting byimport from abroad in early summer, spreading out locally,and ending in the winter. Dengue is primarily an adultdisease in Taiwan. Most cases of dengue fever (DF) havebeen reported in individuals in the 50e54-year age rangeand most cases of dengue hemorrhagic fever (DHF) in the60e64-year range.4However, dengue usually occurs inchildren in hyperendemic Southeast Asia. Secondaryinfection of DENV-2 was prevalent in the year 2002, butprimary infection of DENV-1 or DENV-3 in 2004e2007. Inaddition, adults or the elderly have a greater risk ofdeveloping the severe dengue disease.4DENV is a lipid-enveloped, single-positive-RNA virus,with a genome of about 10.7 kb. RNA of the virus is trans-lated to three structural proteins, namely capsid protein(C), precursor membrane protein (prM), and envelopeprotein (E). Besides the structural proteins, there are sevennonstructural proteins (NS), which are involved in variousfunctions affecting viral replication and disease pathogen-esis.6,7The replication cycle of DENV begins when thevirions attach to the surface of host cells and subsequentlyenter the cells by receptor-mediated endocytosis. Acidi-cation of the endosomal vesicle triggers conformationalchanges in the virion, which results in the fusion of the viraland cell membranes. After the fusion has occurred, thenucleocapsid is released into the cytoplasm. The positive-sense RNA is translated into a single polyprotein that isprocessed cotranslationally and post-translationally by viraland host proteases. Genome replication occurs on intra-cellular membranes. Virus assembly occurs on the surfaceof the endoplasmic reticulum (ER) when the structuralproteins and the newly synthesized RNA bud into the lumenof ER. The virion is maturated in the Golgi compartmentand exits by the secretory pathway. Two processes areinvolved in virus maturation. First, the prM protein iscleaved by host furin and forms the M protein in the trans-Golgi network. Second, the E protein undergoes a majorconformational rearrangement during the maturation ofvirus particles during exocytosis.7,8Infection with DENV causes diseases ranging from mildDF to severe DHF and dengue shock syndrome (DSS). DHF/DSS usually occurs in patients who are secondarily infectedwith heterotypic DENV, but it also occurs in case of primaryinfection.9DF presents with an onset of fever accompaniedby severe headache, retro-orbital pain, myalgia, arthralgia,abdominal pain, rash, and minor hemorrhage in the form ofpetechiae, epistaxis, or gingival bleeding. Leukopenia isa common nding in laboratory tests, whereas thrombocy-topenia may occasionally be observed in DF patients.10Inaddition to all the symptoms of DF, DHF is characterized bysevere hemorrhage (positive tourniquet test or spontaneousbleeding), thrombocytopenia (platelet counts