帕金森和多发性硬化

Research letterParkinson disease and multiple sclerosis are not associated with autoantibodies against structural proteins of the dermal –epidermal junctionDOI:10.1111/bjd.14538D EARE DITOR ,Bullous pemphigoid (BP),the most frequent autoimmune blistering disease,is associated with autoantibod-ies against two proteins of the dermal –epidermal junction (DEJ),BP180(type XVII collagen)and BP230[BP antigen 1(BPAG1)].1Two peculiar clinical features of BP are the advanced age of patients,with a mean age of between 75and 80years at disease onset,and its association with neurological disease.1Neurological diseases can be diagnosed in 30–50%of patients with BP,including cognitive impairment,stroke,epilepsy,Parkinson disease (PD)and multiple sclerosis (MS),with odds ratios (ORs)of 2Á2,1Á8–3Á3,1Á7–4Á0,2Á16–3Á50and 10Á7,respectively.2–7In addition,patients with MS are more likely to develop BP (OR 6Á7).8These findings are par-ticularly intriguing as the cutaneous target antigens of BP –BP180and BP230–are also expressed in the central nervous system (CNS).BP180expression was found in the cerebellum of rats and in autopsy samples of various neuroanatomical regions of human brain.9,10Mice with mutations in the dys-tonin gene encoding for various isoforms of BPAG1,includingthe epithelial isoform BP230,develop severe dystonia and sensory nerve degeneration.11While PD is thought to be a primary neurodegenerative disorder,inflammatory responses seem to be secondary.12,13MS is believed to be initially induced via a peripheral immune response,and further driven by immune reactions within the CNS with secondary neurode-generation.14During the process of neurodegeneration the two BP autoantigens in the CNS may have been exposed to the immune system,leading to the break of tolerance and,subsequently,to the generation of anti-BP180and anti-BP230antibodies,and,finally,to BP.9,15In the present study,according to this hypothesis,we expected to detect serum autoantibodies against BP180and BP230more frequently in patients with PD and MS compared with age-and sex-matched controls.Alternatively,or addition-ally,environmental factors that increase susceptibility to the development of neurological disorders might similarly change the risk of autoimmune blistering dermatoses.8We compared three age-and sex-matched groups of patients with PD (n =75,cohort A1),other neurological diseases [n =75,cohort A2;detailed information is given in Table S1(see Supporting Information)]and healthy controls (n =75,cohort A3)(Table 1).All sera from cohort A were prospec-tively collected and matched for age and sex.Furthermore,prospectively collected sera from consecutive patients with PD at another academic site (L €u beck;n =50,cohort C),a cohortTable 1Overview of serological results©2016British Association of Dermatologists British Journal of Dermatology (2016)1of patients with MS(n=50,cohort D)and patients with non-inflammatory skin diseases and older than75years(n=65, cohort B;Table1)were analysed.Cohort B was included to mirror the age group of patients with BP.To determine the sample sizes necessary to compare the frequency of reactive sera in patients and controls,a power calculation based on Fisher’s exact test was performed.To be clinically relevant,weassumed that the odds of detecting serumautoantibodies inpatients with PD and MS would be increased at leastfive times compared with controls,and that anti-BP180/BP230antibod-ies would be detected in1–2%of controls.16–18Based on these assumptions,the power(p)for detecting significantly different amounts of BP180/BP230-reactive sera between patients with PD/MS(n=175)and controls(n=215)was0Á51–0Á86.To detect reactivity against BP180and BP230,all sera were subjected to a panel of diagnostic assays,including(i)indirect immunofluorescence(IIF)microscopy on a BIOCHIPâmosaic (monkey oesophagus,split human skin,recombinant BP180 NC16A,HEK293expressing the BP180ectodomain,the BP230globular domain and full-length BP230;Euroimmun, L€u beck,Germany);(ii)BP180NC16A-based enzyme-linked immunosorbent assay(ELISA);(iii)BP230-based ELISA(both from Euroimmun);(iv)Western blotting with extracellular matrix of cultured human keratinocytes(for the detection of laminin332and full-length cell-derived BP180);(v)IIF microscopy on monkey oesophagus;and(vi)1mol LÀ1 NaCl-split human skin(both in-house tests).16,18–20No signif-icant differences in the frequency of detecting serum autoanti-bodies against proteins of the DEJ were found in patients with PD and MS compared with controls(Tables1and2).Reactiv-ities in all cohorts are detailed in Table1.In none of the sam-ples could reactivity against BP180or BP230be demonstrated by all test methods;however,the BP180NC16A ELISA was more often positive(seven of the total390samples)than the corresponding BIOCHIP mosaic substrate(one of the total390samples).Altogether,antibodies against the DEJ were observed in four of175PD/MS sera[2Á3%;95%confidence interval (CI)0Á9–5Á7]and16of215control sera(7Á4%;95%CI 4Á6–11Á7),which is in line with the known specificities of 98–99%of the employed test systems.16,18–20Our results indicate that patients with PD and MS do not show a clinically relevant increased incidence of autoreactivity against BP180,BP230and laminin332.If there is a higher risk of patients with these neurological disorders developing BP,this is not reflected by our serologicalfindings.This notion indicates that serum autoreactivity against proteins of the DEJ does not precede the clinical manifestation of BP in patients with PD/MS.Two other risk factors for developing antibodies to BP180and BP230–old age and chronic pruritus –have been described;however,these additional risk factors remain disputed.19,21,22It is feasible that as-yet-uncovered environmental factors orchestrate the initiation of the neuro-logical disorders,the onset of pruritus,and the loss of toler-ance against BP180and BP230in the elderly.One might speculate that such a factor could be a viral infection that affects both skin and CNS,such as varicella zoster virus.23It has been hypothesized that the development of autoimmunity against CNS antigens may be associated with repairing mecha-nisms of the CNS.24In this context,the autoimmune skin dis-ease may be regarded as a casualty of the organism in its efforts to preserve the brain.AcknowledgmentsWe thank Vanessa Krull for her assistance with the autoim-mune diagnostic procedures.This study was approved by the ethics committee of the University of L€u beck(10-229).A.R E C K E1,2A.O E I1F.H€U B N E R2K.F E C H N E R3J.G R A F4J.H A G E N A H4C.M A Y5D.W O I T A L L A6A.S A L M E N7D.Z I L L I K E N S2R.G O L D8W.S C H L U M B E R G E R3E.S C H M I D T1 1L€u beck Institute of ExperimentalDermatology(LIED),and Departments of2Dermatology and4Neurology,University ofL€u beck,L€u beck,Germany3Institute of Experimental Immunology,Euroimmun Inc.,L€u beck,Germany5Medizinisches Proteom-Center,Ruhr-Universit€a t Bochum,Bochum,Germany6Department of Neurology,KatholischeKliniken Ruhrhalbinsel GmbH,Essen,Germany7Department of Neurology,Inselspital,BernUniversity Hospital,Bern,Switzerland8Department of Neurology,St.JosefHospital,Ruhr-University Bochum,GermanyCorrespondence:Enno Schmidt.E-mail:enno.schmidt@uksh.deReferences1Schmidt E,Zillikens D.Pemphigoid ncet2013;381:320–32.Table2Association of positive serologicalfindings with neurologicaldiseases©2016British Association of Dermatologists British Journal of Dermatology(2016)2Research letter2Taghipour K,Chi C-C,Vincent A et al.The association of bullous pemphigoid with cerebrovascular disease and dementia:a case-control study.Arch Dermatol2010;146:1251–4.3Chen YJ,Wu CY,Lin MW et orbidity profiles among patients with bullous pemphigoid:a nationwide population-based study.Br J Dermatol2011;165:593–9.4Langan SM,Groves RW,West J.The relationship between neuro-logical disease and bullous pemphigoid:a population-based case–control study.J Invest Dermatol2011;131:631–6.5Bastuji-Garin S,Joly P,Lemordant P et al.Risk factors for bullous pemphigoid in the elderly:a prospective case–control study.J Invest Dermatol2011;131:637–43.6Brick KE,Weaver CH,Savica R et al.A population-based study of the association between bullous pemphigoid and neurologic disor-ders.J Am Acad Dermatol2014;71:1191–7.7Cordel N,Chosidow O,Hellot M-F et al.Neurological disorders in patients with bullous pemphigoid.Dermatology2007;215:187–91. 8Langer-Gould A,Albers KB,Van Den Eeden SK,Nelson LM.Autoimmune diseases prior to the diagnosis of multiple sclerosis:a population-based case–control study.Mult Scler2010;16:855–61. 9Sepp€a nen A,Miettinen R,Alafuzoff I.Neuronal collagen XVII is localized to lipofuscin granules.NeuroReport2010;21:1090–4.10Claudepierre T,Manglapus MK,Marengi N et al.Collagen XVII and BPAG1expression in the retina:evidence for an anchoring complex in the central nervous system.J Comp Neurol2005;487:190–203.11Guo L,Degenstein L,Dowling J et al.Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration in strati-fied epithelia and neurologic degeneration.Cell1995;81:233–43. 12Sanchez-Guajardo V,Barnum CJ,Tansey MG,Romero-Ramos M.Neuroimmunological processes in Parkinson’s disease and their relation to a-synuclein:microglia as the referee between neuronal processes and peripheral immunity.ASN Neuro2013;5:113–39.13Pradhan S,Andreasson mentary:progressive inflammation as a contributing factor to early development of Parkinson’s dis-ease.Exp Neurol2013;241:148–55.14Hemmer B,Kerschensteiner M,Korn T.Role of the innate and adaptive immune responses in the course of multiple n-cet Neurol2015;14:406–19.15Taghipour K,Chi C-C,Bhogal B et al.Immunopathological charac-teristics of patients with bullous pemphigoid and neurological dis-ease.J Eur Acad Dermatol Venereol2014;28:569–73.16Bl€o cker IM,D€a hnrich C,Probst C et al.Epitope mapping of BP230 leading to a novel enzyme-linked immunosorbent assay for autoantibodies in bullous pemphigoid.Br J Dermatol2012;166:964–70.17Tampoia M,Giavarina D,Di Giorgio C,Bizzaro N.Diagnostic accuracy of enzyme-linked immunosorbent assays(ELISA)to detect anti-skin autoantibodies in autoimmune blistering skindiseases:a systematic review and meta-analysis.Autoimmun Rev 2012;12:121–6.18Pr€ußmann J,Pr€ußmann W,Recke A et al.Co-occurrence of autoan-tibodies in healthy blood donors.Exp Dermatol2014;23:519–21. 19van Beek N,Dohse A,Riechert F et al.Serum autoantibodies against the dermal-epidermal junction in patients with chronic pruritic disorders,elderly individuals and blood donors prospec-tively recruited.Br J Dermatol2014;170:943–7.20van Beek N,Rentzsch K,Probst C et al.Serological diagnosis of autoimmune bullous skin diseases:prospective comparison of the BIOCHIP mosaic-based indirect immunofluorescence technique with the conventional multi-step single test strategy.Orphanet J Rare Dis2012;7:49.21Schmidt T,Sitaru C,Amber K,Hertl M.BP180-and BP230-specific IgG autoantibodies in pruritic disorders of the elderly:a preclinical stage of bullous pemphigoid?Br J Dermatol2014;171:212–19.22Meijer JM,Lamberts A,Pas HH,Jonkman MF.Significantly higher prevalence of circulating bullous pemphigoid(BP)-specific IgG autoantibodies in elderly patients with a nonbullous skin disorder.Br J Dermatol2015;173:1274–6.23Kamiya K,Aoyama Y,Suzuki T et al.Possible enhancement of BP180autoantibody production by herpes zoster.J Dermatol2016;43:197–9.24Schwartz M,Baruch K.Breaking peripheral immune tolerance to CNS antigens in neurodegenerative diseases:boosting autoimmu-nity tofight-off chronic neuroinflammation.J Autoimmun2014;54:8–14.Supporting InformationAdditional Supporting Information may be found in the online version of this article at the publisher’s website:Appendix S1.Supplemental methods.Table S1.Group of patients with‘other neurologic diseases’(subcohort A2).Funding sources:This work was supported by Deutsche Forschungsge-meinschaft KFO303/1,and received infrastructural support from Excellence Cluster Inflammation at Interfaces(EXC306/2)andP.U.R.E.(Protein Unit for Research in Europe),a project of the federal German state Nordrhein-Westfalen.Conflicts of interest:A.R.,D.Z.and E.S.have received a scientific award from Euroimmun.D.Z.and E.S.have a scientific cooperation withEuroimmun.©2016British Association of Dermatologists British Journal of Dermatology(2016)Research letter3。