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For personal use. Only reproduce with permission from The Lancet Publishing Group. REVIEW Autoimmune diseases affect about 5% of individuals inAlthough the prevalence of mostincidence has greatly increased over the past few years, asgroups that are often selected as targets for vaccination http://image.thelancet.com/extras/02art9340web.pdfDepartment of Pathology and Microbiology, University of Bristol,Bristol, UK(Prof D C Wraith H™pital Erasme, Brussels, Belgium(Prof M Goldman ; and Human beings have a highly complex immune systemthat evolved from the fairly simple system found ininvertebrates. The so-called innate invertebrate immunesystem responds non-specifically to infection, does notinvolve lymphocytes, and hence does not displaydesigned to provide protection against almost allinfections. Furthermore, polymorphisms in genes thatcontrol the immune system ensure that the species as awhole can generate sufficient immunological diversity to Vaccination and autoimmune disease: what is the evidence? Review THELANCET As many as one in 20 people in Europe and North America have some form of autoimmune disease. These diseases implications for vaccination in human beings. We did a computer-aided search of PubMed and ISI Web ofScience, using the search terms: vaccine and autoimmuneprimary published work on the subject. We did not limit our For personal use. Only reproduce with permission from The Lancet Publishing Group. A popular explanation for how infectious agentsstimulate autoimmunity in an antigen-specific way is viaorganisms can thus be recognised by the host immunesystem as being similar to antigenic determinants of sugar structures is common and leads to numerousmanifestations of infection-associated and antibody-all cases of Guillain-BarrŽ syndrome are preceded bya lipopolysaccharide molecule that mimics variousgangliosides present in high concentrations in peripheral As a result, viral infections are often associated withvaccines ha

ve been linked with induction of themolecules. To serve as a molecular mimic for anan appropriate MHC molecule. Molecular mimicry provided compelling evidence,autoimmune disease induced by CD4 T cells elicited that T cells specific for a peptide derived from this virus THELANCET Frequently asked questions aboutautoimmunity and autoimmune diseasesA situation characterised by the development of one or severalWhat is an autoimmune disease?A disease that results from autoimmunity, when pathogenicautoantibodies or autoreactive T cells (cell-mediatedautoimmune disease) can reach corresponding targetsWhat diseases have been proven to have an autoimmunebasis?Are autoimmune diseases always clinically apparent?No. Clinical expression will be present only when tissueexample, the autoimmune process that leads to the destructionof pancreatic islets in type 1 diabetes can take months or yearsDoes the presence of autoantibodies or autoreactive T cellsalways indicate that disease is present or will occur inDisease will not always occur. To be pathogenic, autoantibodiesHow does atopy differ from autoimmunity? Atopy is a totally distinct immunological process associatedwith IgE antibody responses against foreign antigens*These questions were formulated by the WHO Advisory Committee onVaccine Safety. Responses to these questions were prepared by us. Panel 2: Frequently asked questions about possiblecauses of and factors in favour of autoimmuneAutoimmune responses usually result from the combinedeffects of antigen-specific stimuli on the immune system andRegulatory mechanisms limit the development of autoimmuneHow can infections induce autoimmune responses?First, there is a potential role of antigenic similarity betweenseem to play an essential part in enhancing theimmunogenicity of host antigens or of host-mimickingthat limit autoimmune responses Are all people equally susceptible to autoimmune diseases?There is a clear genetic predisposition for some autoi

mmunediseases, but environmental factors also play a crucial part At what age is autoimmune disease most likely to be seen?Specific age patterns are seen for most autoimmunediseases. For example, juvenile idiopathic arthritis or type 1diabetes have an early onset (age 1Ð16 years), whereasautoimmune diseases generally affect elderly individualsWhat is meant by the term trigger?Some events do not cause autoimmunity but can lead to theexacerbation (triggering) of an underlying silent autoimmuneprocess, and thus to the clinical expression of an autoimmunedisease. For example, acute respiratory infections by influenzahappened some time later*These questions were formulated by the WHO Advisory Committee on Vaccine Safety. Responses to these questions were prepared by us. For personal use. Only reproduce with permission from The Lancet Publishing Group. we consider the nature of T-cell-receptor recognition of Another mechanism whereby micro-organisms mightinstance, microbial infection causes the release ofinnate immune response, resulting in activation of self-antigen-expressing antigen presenting cells (figure 2).from studies in transgenic mice containing high numbersinfected organ. For example, infection of the CNS byantigen presenting cells. These cells display an innateT cells. Indeed, microbial products engage Toll-likereceptors on dendritic and other antigen presenting cells,resulting in up-regulation of the membrane expression ofwith self-antigens. Furthermore, there is increasingdisease is not more frequently induced by infection. Webelieve that the immune system has evolved to protect thehost from infection. However, fail-safe mechanisms haveThe immune system is controlled by homoeostatic REVIEW THELANCET (one in 30000 For personal use. Only reproduce with permission from The Lancet Publishing Group. an optimum predetermined level. There is overwhelmingIn ahomoeostatic proliferation, are released from peripheralThe immune system is equ

ipped with a wide range ofThis selection depends on several mechanisms, including:induced cell death results in the immune systemmechanisms limit the response of the immune system to a reactive for self-antigens, we believeimmune response to infection, and toimmune response to antigen is alsoThese CD4 cells arise in theselected by recognition of self-antigen.first described these cellsresulting in widespread autoimmunefrom naive lymphocytes in peripheralare similar to T-regulatory type 1cells,The physiological role of T-regulatorytype 1cells is probably to moderate the immune responseto infection and thereby limit the collateral damage thatindividual from developing autoimmune disease duringresponse to vaccination. Autoimmune responses shouldattenuated organism will be much lower than that induced REVIEW THELANCET MicrobeMicrobial antigen Naive T cellActivatedT cell ActivatedT cellActivatedT cellAPC APCActivatedB cellActivatedB cellDefenceagainstdiseaseDefenceagainstdisease Autoimmunity Autoimmunityor Host tissue Figure 1: Mechanisms of molecular mimicryAPC=antigen presenting cell. A: Microbe-reactive B lymphocytes are activated by direct recognition ofmicrobial antigen. Activated B cells then cross-react with antigens expressed by host tissues, For personal use. Only reproduce with permission from The Lancet Publishing Group. new vaccine should, therefore, be assessed on a case-by-public-health provision. An effective vaccine shouldconsequence of vaccination. Only in a few rare cases,1 million people vaccinated) is now judged substantiallyrelated complications. 30000 vaccinated children. However, it is noteworthyPatients with a history of highly publicised reports that claim a link betweento public concern over the risk of inducing autoimmunebetween 1991 and 1997, within 8 weeks of recombinantThe neurologicalcerebrospinal fluid and lesions were noted in the cerebralwhite matter on T2-weighted MR images. Clinicallyneurological manifestati

ons arose in individuals judged athigh risk of multiple sclerosisÑeg, a preponderance ofIn France, nearly 25 million people (40% of theduring this period, of whom 18 million were adults. Sincewas compared with that in the four previous 2-month643 patients who had a relapse, 2á3% had been vaccinatedprevious 2 months was 0á71 (95% CI 0á40Ð1á26). Therewas no increase in the specific short-term risk of relapseresearchers did a nested case-control study in two large REVIEW THELANCET Figure 2: Mechanisms of infection-induced autoimmunityAPC=antigen presenting cell. Microbial infection of host tissue leads totissue damage (1) and release of self-antigen (2). Microbial molecules For personal use. Only reproduce with permission from The Lancet Publishing Group. NursesÕ Health Study (which has followed up 121700women since 1976) and those who took part in theNursesÕ Health Study II (which has followed up 116671cancer were selected as controls. The analyses included(95% CI 0á5Ð1á6). The relative risk associated withthe disease was 0á7 (95% CI 0á3Ð1á8). These results wereepidemiological studies. Results of a case-control studyfollow-up study of more than 100000 Finnish children4, 6, and 14Ð18 months were compared with those who concerned. The association should, for instance, not arisethe results of carefully undertaken clinical trials forwhich a study design was ascertained a priorispecifically for testing the hypothesis of such anassociation. Such studies will normally be one of thefollowing, in descending order of probability ofcontrolled clinical trial, cohort study, case controlstudy, or controlled case-series analysis. Case reportscan form the basis on which a hypothesis can beformulated. However, even numerous case reportsautoimmune events seem to be attributable to avaccine, investigators should then ascertain whetherthey are studying a predisposed set of individuals (by age, population, or genetic, immunological,the results of more than one

clinical trial beingconsistent. The studies should all be carefully under-taken, by different investigators, in different populat-ions, but have consistent results, despite the use ofa non-random temporal association between admini-stration of vaccine and adverse event. There shouldbe a strict definition of the autoimmune adverse event in clinical, pathological, and biochemical terms, as far as is achievable. To be consideredadverse event in the immunised population should besubstantially different from that in the non- REVIEW THELANCET For personal use. Only reproduce with permission from The Lancet Publishing Group. produce strong, innate responses.to reduce the risk that a new vaccine will induceSecond, potential molecular and immunologicalbioinformatics and immunological studies. One shouldMolecular mimicry in itself is not sufficient to triggerexample, a new Lyme disease vaccine contains anBorrelia burgdorfericonsidered for inclusion in the monitoring protocol. Suchsystem has evolved sufficient fail-safe mechanisms to Conflict of interest statementM Goldman has served as a consultant for Aventis-Pasteur, BruCells,Glaxo SmithKline, and OM-Pharma. P-H Lambert has served as aconsultant for Aventis-Pasteur, Chiron, Glaxo SmithKline, and AcknowledgmentsWe thank the WHO Advisory Committee for Vaccine Safety Noni MacDonald and Claire-Anne Siegrist for their suggestions and review of this report. 1Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and2Onkamo P, Vaananen S, Karvonen M, Tuomilehto J. Worldwide3EURODIAB ACE Study Group. Variation and trends in incidence of4Wynn DR, Rodriguez M, OÕFallon WM, Kurland LT. A reappraisal5Stuart G, Krikorian KS. The neuro-paralytic accidents of anti-rabies6Todd JA, Wicker LS. Genetic protection from the inflammatory7Bach JF. The effect of infections on susceptibility to autoimmune and8Nemazee D. Receptor selection in B and T lymphocytes. 9Wucherpfennig KW. Mechanisms for the induction of autoimm

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