Rearch letter
Parkinson dia and multiple sclerosis are not associated with autoantibodies against structural proteins of the dermal –epidermal junction
DOI:10.1111/bjd.14538
D EAR
E DITOR ,Bullous pemphigoid (BP),the most frequent autoimmune blistering dia,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 dia ont,and its association with neurological dia.1Neurological dias can be diagnod in 30–50%of patients with BP,including cognitive impairment,stroke,epilepsy,Parkinson dia (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).8The findings are par-ticularly intriguing as the cutaneous target antigens of BP –BP180and BP230–are also expresd in the central nervous system (CNS).BP180expression was found in the cerebellum of rats and in autopsy samples of various neuroa
natomical regions of human brain.9,10Mice with mutations in the dys-tonin gene encoding for various isoforms of BPAG1,including
发布房源the epithelial isoform BP230,develop vere dystonia and nsory nerve degeneration.11While PD is thought to be a primary neurodegenerative disorder,inflammatory respons em to be condary.12,13MS is believed to be initially induced via a peripheral immune respon,and further driven by immune reactions within the CNS with condary neurode-
generation.14During the process of neurodegeneration the two BP autoantigens in the CNS may have been expod to the immune system,leading to the break of tolerance and,subquently,to the generation of anti-BP180and anti-BP230antibodies,and,finally,to BP.9,15
In the prent study,according to this hypothesis,we expected to detect rum autoantibodies against BP180and BP230more frequently in patients with PD and MS compared with age-and x-matched controls.Alternatively,or addition-ally,environmental factors that increa susceptibility to the development of neurological disorders might similarly change the risk of autoimmune blistering dermatos.8
We compared three age-and x-matched groups of patients with PD (n =75,cohort A1),other neurol
ogical dias [n =75,cohort A2;detailed information is given in Table S1(e Supporting Information)]and healthy controls (n =75,cohort A3)(Table 1).All ra from cohort A were prospec-tively collected and matched for age and x.Furthermore,prospectively collected ra from concutive patients with PD at another academic site (L €u beck;n =50,cohort C),a cohort
Table 1Overview of rological results
©2016British Association of Dermatologists British Journal of Dermatology (2016)1
of patients with MS(n=50,cohort D)and patients with non-inflammatory skin dias and older than75years(n=65, cohort B;Table1)were analyd.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 ra in patients and controls,a power calculation bad on Fisher’s exact test was performed.To be clinically relevant,we
assumed that the odds of detecting rum
autoantibodies in
patients with PD and MS would be incread at leastfive times compared with controls,and that anti-BP180/BP230antibod-ies would be detected in1–2%of controls.16–18Bad on the assumptions,the power(p)for detecting significantly different amounts of BP180/BP230-reactive ra between patients with PD/MS(n=175)and controls(n=215)was0Á51–0Á86.
To detect reactivity against BP180and BP230,all ra 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-bad enzyme-linked immunosorbent assay(ELISA);(iii)BP230-bad 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-hou tests).16,18–20No signif-icant differences in the frequency of detecting rum 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(ven of the total390samples)than the corresponding BIOCHIP mosaic substrate(one of the total390samples).Altogether,antibodies against the DEJ were obrved in four of175PD/MS ra[2Á3%;95%confidence interval (CI)0Á9–5Á7]and16of215control ra(7Á4%;95%CI 4Á6–11Á7),which is in line with the known specificities of 98–99%of the employed test systems.16,18–20
Our results indicate that patients with PD and MS do not show a clinically relevant incread incidence of autoreactivity against BP180,BP230and laminin332.If there is a higher risk of patients with the neurological disorders developing BP,this is not reflected by our rologicalfindings.This notion indicates that rum 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,the additional risk factors remain disputed.19,21,22It is feasible that as-yet-uncovered environmental factors orchestrat
e the initiation of the neuro-logical disorders,the ont 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-ea may be regarded as a casualty of the organism in its efforts to prerve the brain.
Acknowledgments
We 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 E1,2
A.O E I1
F.H€U B N E R2
K.F E C H N E R3
J.G R A F4
J.H A G E N A H4大笑的英文
C.M A Y5养胃食物食谱大全
D.W O I T A L L A6
A.S A L M E N7
D.Z I L L I K E N S2
R.G O L D8
W.S C H L U M B E R G E R3
E.S C H M I D T1 1L€u beck Institute of Experimental
Dermatology(LIED),and Departments of
2Dermatology and4Neurology,University of
L€u beck,L€u beck,Germany
3Institute of Experimental Immunology,
Euroimmun Inc.,L€u beck,Germany
5Medizinisches Proteom-Center,Ruhr-
Universit€a t Bochum,Bochum,Germany
6Department of Neurology,Katholische
Kliniken Ruhrhalbinl GmbH,Esn,
Germany
7Department of Neurology,Inlspital,Bern
University Hospital,Bern,Switzerland
8Department of Neurology,St.Jof
Hospital,Ruhr-University Bochum,Germany
Correspondence:Enno Schmidt.
E-mail:enno.schmidt@uksh.de
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©2016British Association of Dermatologists British Journal of Dermatology(2016)
2Rearch letter
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表格背景
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Supporting Information
Additional Supporting Information may be found in the online version of this article at the publisher’s website:
Appendix S1.Supplemental methods.
酸菜炖五花肉
Table S1.Group of patients with‘other neurologic dias’(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)and
P.U.R.E.(Protein Unit for Rearch 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 with
Euroimmun.
©2016British Association of Dermatologists British Journal of Dermatology(2016)
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