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Biological predictors shared by dementia and bullous pemphigoid patients point out a cross-antigenicity between BP180/BP230 brain and skin isoforms

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Abstract

Bullous pemphigoid (BP) following dementia diagnosis has been reported in the elderly. Skin and brain tissues express BP180 and BP230 isoforms. Dementia has been associated with rs6265 (Val66Met) polymorphism of the brain-derived neurotrophic factor (BDNF) gene and low serum BDNF. Here we investigated a possible cross-antigenicity between BP180/BP230 brain and skin isoforms. We assessed antibodies against BP180/BP230 and BDNF levels by ELISA and BDNF Val66Met SNP by PCR in three groups: 50 BP patients, 50 patients with dementia, and 50 elderly controls. Heatmap hierarchical clustering and data mining decision tree were used to analyze the patients’ demographic and laboratorial data as predictors of dementia-BP association. Sixteen percent of BP patients with the lowest serological BDNF presented dementia-BP clinical association. Anti-BP180/230 positivity was unexpected observed among dementia patients (10%, 10%) and controls (14%, 1%). Indirect immunofluorescence using healthy human skin showed a BP pattern in two of 10 samples containing antibodies against BP180/BP230 obtained from dementia group but not in the control samples. Neither allelic nor genotypic BDNF Val66Met SNP was associated with dementia or with BP (associated or not with clinical manifestation of dementia). Heatmap analysis was able to differentiate the three studied groups and confirmed the ELISA results. The comprehensive data mining analysis revealed that BP patients and dementia patients shared biological predictors that justified the dementia-BP association. Autoantibodies against the BP180/BP230 brain isoforms produced by dementia patients could cross-react with the BP180/BP230 skin isoforms, which could justify cases of dementia preceding the BP disease.

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Acknowledgements

The authors would like to thank Aline Turatti and Natalia Aparecida de Paula (Laboratory of Dermatology, University Hospital, Ribeirão Preto Medical School, University of Sao Paulo, Brazil) for their technical assistance during the serological analysis, and the clinical staff who assisted bullous pemphigoid and dementia outpatients at the University Hospital of the Ribeirão Preto Medical School, University of São Paulo, Brazil.

Funding

This study was partially supported by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo) (#2010/51729-2). TJ received a scholarship from FAPESP (#2016/09011-3), SV received a scholarship from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), JD received a scholarship PDJ from CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), and MCS received a scholarship from CAPES.

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Authors and Affiliations

  1. Division of Dermatology, Department of Medical Clinics, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, São Paulo, 14049-900, Brazil

    Tamiris A. Julio, Sebastian Vernal & Ana M. Roselino

  2. Division of Clinical Immunology, Department of Medical Clinics, Ribeirão Preto Medical School, University of São Paulo, Ribeirao Preto, Brazil

    Juliana D. Massaro, Matheus C. Silva & Eduardo A. Donadi

  3. Division of Gerontology, Department of Medical Clinics, Ribeirão Preto Medical School, University of São Paulo, Ribeirao Preto, Brazil

    Julio C. Moriguti

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  1. Tamiris A. Julio
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  2. Sebastian Vernal
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  3. Juliana D. Massaro
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  4. Matheus C. Silva
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  6. Julio C. Moriguti
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  7. Ana M. Roselino
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Contributions

Conceptualization, methodology: TJ, AMR, JDM. Formal analysis: TJ, AMR, JDM, MCS. Funding acquisition: TJ, SV, AMR. Investigation, resources: TJ, SV, JDM, MCS, EAD, JCM, AMR. Supervision: AMR, JCM, EAD. Writing and reviewing manuscript: TJ, JDM, MCS, AMR.

Corresponding author

Correspondence to Ana M. Roselino.

Ethics declarations

The local Research Ethics Committee approved this study (CAAE: 45779715.5.0000.5440—June/2017). All the participants provided the informed consent.

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the research committee University Hospital of the Ribeirão Preto Medical School of the University of São Paulo and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Julio, T.A., Vernal, S., Massaro, J.D. et al. Biological predictors shared by dementia and bullous pemphigoid patients point out a cross-antigenicity between BP180/BP230 brain and skin isoforms. Immunol Res 66, 567–576 (2018). https://doi.org/10.1007/s12026-018-9028-1

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