Integrative analysis reveals the autoantibodyome neuroimmune signature of neurodegeneration

Júlia Nakanishi Usuda; Adriel Leal Nóbile; Fernando Yuri Nery do Vale; Yohan Lucas G. Corrêa; Anny Silva Adri; Roseane Galdioli Nava; Débora Gomes de Albuquerque Freitas; Ronaldy Santana Santos; Lena F. Schimke; Dennyson Leandro M. Fonseca; Gustavo Cabral-Miranda; Taj Ali Khan; Niels Olsen Câmara; Guido Moll; Alexandre H.C. Marques; Rodrigo J.S. Dalmolin; Helder I. Nakaya; Gabriela Riemekasten; Igor Salerno Filgueiras; Haroldo Dutra Dias; Otavio Cabral-Marques

doi:10.1016/j.isci.2026.114781

Integrative analysis reveals the autoantibodyome neuroimmune signature of neurodegeneration

Júlia Nakanishi Usuda^*, Adriel Leal Nóbile, Fernando Yuri Nery do Vale, Yohan Lucas G. Corrêa, Anny Silva Adri, Roseane Galdioli Nava, Débora Gomes de Albuquerque Freitas, Ronaldy Santana Santos, Lena F. Schimke, Dennyson Leandro M. Fonseca, Gustavo Cabral-Miranda, Taj Ali Khan, Niels Olsen Câmara, Guido Moll, Alexandre H.C. Marques, Rodrigo J.S. Dalmolin, Helder I. Nakaya, Gabriela Riemekasten, Igor Salerno Filgueiras, Haroldo Dutra DiasOtavio Cabral-Marques^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Abstract

Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), are complex conditions driven by systemic dysregulation that transcends the central nervous system. An integrative systems immunology framework was applied to characterize the neuroimmune “autoantibodyome” across neurodegeneration through an individual participant data meta-analysis of five protein microarray datasets, comprising 596 samples from patients with AD, PD, or MS and healthy controls. We mapped differentially reactive autoantibodies stratified by their targets, unveiling shared features among diseases, such as blood-brain barrier impairment and amplified pro-inflammatory activation, alongside disease-specific perturbations in neuroimmune processes, including short-term memory (AD), skeletal muscle contraction (PD), and pain perception (MS). We identified convergent dysregulation of various autoantibodies targeting diverse synaptic transmission pathways, including gamma-aminobutyric acid (GABA)ergic and glutamatergic signaling. These results indicate the potential of the autoantibodyome to interact with and report on central alterations, suggesting that neurodegeneration may be better understood as a systemic dyshomeostasis.

Originalsprache	Englisch
Aufsatznummer	114781
Zeitschrift	iScience
Jahrgang	29
Ausgabenummer	2
ISSN	2589-0042
DOIs	https://doi.org/10.1016/j.isci.2026.114781
Publikationsstatus	Veröffentlicht - 20.02.2026

Fördermittel

We thank the São Paulo Research Foundation (grants 2023/14417-2 to J.N.U., 2024/08016-8 to A.L.N., 2025/07090-2 to F.Y.N.d.V., 2024/22162-7 to R.G.N., 2025/02768-0 to D.G.d.A.F., 2023/13356-0 to D.L.M.F., 2019/14526-0 and 2020/04667-3 to G.C.-M., 2018/149332 to H.I.N., 2020/16246-2 to I.S.F., and 2018/18886-9 to O.C.-M.) for financial support. We also thank the National Council for Scientific and Technological Development (CNPq) (grants 140013/2025-3 to A.S.A., 130027/2023-5 to Y.L.G.C., 102430/2022-5 to L.F.S., and 309482/2022-4 to O.C.-M.) and the Coordination for the Improvement of Higher Education Personnel (CAPES) (CAPES/PROEX grants 88887.917898/2023-00 to J.N.U., 88887.801068/2023-00 to A.L.N., 88887.699840/2022-00 to F.Y.N.d.V., 88887.082794/2024-00 to R.S.S., and 88887.196113/2025-00 to I.S.F.) for financial support. J.N.U. was further supported by Charité, the Medizinische Hochschule Brandenburg Theodor Fontane , and the German Academic Exchange Service (DAAD; Ref. No. 91898528 ). G.M. was supported by grants from the German Federal Ministry of Education and Research (BMBF) and the German Research Foundation (DFG: EXPAND-PD project #CA2816/1 ) and through the BIH Center for Regenerative Therapies (BCRT) and the Berlin-Brandenburg School for Regenerative Therapies (BSRT: GSC203 ), respectively, and in part by the European Union’s Horizon 2020 Research and Innovation Program and the grant agreements no. 733006 (PACE), 779293 (HIPGEN), 754995 (EU-TRAIN), and 101095635 (PROTO). We thank DeMarshall and Nagele et al. for the rich data made publicly available, which was utilized in this study.

Träger	Trägernummer
Bundesministerium für Forschung, Technologie und Raumfahrt
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Medizinische Hochschule Brandenburg Theodor Fontane
Conselho Nacional de Desenvolvimento Científico e Tecnológico	102430/2022-5, 309482/2022-4, 140013/2025-3, 130027/2023-5
Deutscher Akademischer Austauschdienst	91898528
Horizon 2020 Framework Programme	754995, 101095635, 733006, 779293
Fundação de Amparo à Pesquisa do Estado de São Paulo	2023/13356-0, 2018/149332, 2018/18886-9, 2025/07090-2, 2024/08016-8, 2019/14526-0, 2024/22162-7, 2020/04667-3, 2025/02768-0, 2020/16246-2, 2023/14417-2
PROEX	88887.801068/2023-00, 88887.917898/2023-00, 88887.082794/2024-00, 88887.196113/2025-00, 88887.699840/2022-00
Berlin-Brandenburg School for Regenerative Therapies	GSC203

UN SDGs

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)

DFG-Fachsystematik

2.21-05 Immunologie
2.22-18 Rheumatologie
2.23-05 Experimentelle Modelle zum Verständnis von Erkrankungen des Nervensystems

Dokumente

10.1016/j.isci.2026.114781

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Nakanishi Usuda, J., Nóbile, A. L., Nery do Vale, F. Y., Corrêa, Y. L. G., Adri, A. S., Nava, R. G., de Albuquerque Freitas, D. G., Santos, R. S., Schimke, L. F., Fonseca, D. L. M., Cabral-Miranda, G., Khan, T. A., Câmara, N. O., Moll, G., Marques, A. H. C., Dalmolin, R. J. S., Nakaya, H. I., Riemekasten, G., Filgueiras, I. S., ... Cabral-Marques, O. (2026). Integrative analysis reveals the autoantibodyome neuroimmune signature of neurodegeneration. iScience, 29(2), Artikel 114781. https://doi.org/10.1016/j.isci.2026.114781

@article{2a5b9f9ffc034a3ea76a93e8bd9409c6,

title = "Integrative analysis reveals the autoantibodyome neuroimmune signature of neurodegeneration",

abstract = "Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), are complex conditions driven by systemic dysregulation that transcends the central nervous system. An integrative systems immunology framework was applied to characterize the neuroimmune “autoantibodyome” across neurodegeneration through an individual participant data meta-analysis of five protein microarray datasets, comprising 596 samples from patients with AD, PD, or MS and healthy controls. We mapped differentially reactive autoantibodies stratified by their targets, unveiling shared features among diseases, such as blood-brain barrier impairment and amplified pro-inflammatory activation, alongside disease-specific perturbations in neuroimmune processes, including short-term memory (AD), skeletal muscle contraction (PD), and pain perception (MS). We identified convergent dysregulation of various autoantibodies targeting diverse synaptic transmission pathways, including gamma-aminobutyric acid (GABA)ergic and glutamatergic signaling. These results indicate the potential of the autoantibodyome to interact with and report on central alterations, suggesting that neurodegeneration may be better understood as a systemic dyshomeostasis.",

author = "\{Nakanishi Usuda\}, J{\'u}lia and N{\'o}bile, \{Adriel Leal\} and \{Nery do Vale\}, \{Fernando Yuri\} and Corr{\^e}a, \{Yohan Lucas G.\} and Adri, \{Anny Silva\} and Nava, \{Roseane Galdioli\} and \{de Albuquerque Freitas\}, \{D{\'e}bora Gomes\} and Santos, \{Ronaldy Santana\} and Schimke, \{Lena F.\} and Fonseca, \{Dennyson Leandro M.\} and Gustavo Cabral-Miranda and Khan, \{Taj Ali\} and C{\^a}mara, \{Niels Olsen\} and Guido Moll and Marques, \{Alexandre H.C.\} and Dalmolin, \{Rodrigo J.S.\} and Nakaya, \{Helder I.\} and Gabriela Riemekasten and Filgueiras, \{Igor Salerno\} and Dias, \{Haroldo Dutra\} and Otavio Cabral-Marques",

note = "Publisher Copyright: {\textcopyright} 2026 The Authors",

year = "2026",

month = feb,

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doi = "10.1016/j.isci.2026.114781",

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Nakanishi Usuda, J, Nóbile, AL, Nery do Vale, FY, Corrêa, YLG, Adri, AS, Nava, RG, de Albuquerque Freitas, DG, Santos, RS, Schimke, LF, Fonseca, DLM, Cabral-Miranda, G, Khan, TA, Câmara, NO, Moll, G, Marques, AHC, Dalmolin, RJS, Nakaya, HI, Riemekasten, G, Filgueiras, IS, Dias, HD & Cabral-Marques, O 2026, 'Integrative analysis reveals the autoantibodyome neuroimmune signature of neurodegeneration', iScience, Jg. 29, Nr. 2, 114781. https://doi.org/10.1016/j.isci.2026.114781

TY - JOUR

T1 - Integrative analysis reveals the autoantibodyome neuroimmune signature of neurodegeneration

AU - Nakanishi Usuda, Júlia

AU - Nóbile, Adriel Leal

AU - Nery do Vale, Fernando Yuri

AU - Corrêa, Yohan Lucas G.

AU - Adri, Anny Silva

AU - Nava, Roseane Galdioli

AU - de Albuquerque Freitas, Débora Gomes

AU - Santos, Ronaldy Santana

AU - Schimke, Lena F.

AU - Fonseca, Dennyson Leandro M.

AU - Cabral-Miranda, Gustavo

AU - Khan, Taj Ali

AU - Câmara, Niels Olsen

AU - Moll, Guido

AU - Marques, Alexandre H.C.

AU - Dalmolin, Rodrigo J.S.

AU - Nakaya, Helder I.

AU - Riemekasten, Gabriela

AU - Filgueiras, Igor Salerno

AU - Dias, Haroldo Dutra

AU - Cabral-Marques, Otavio

PY - 2026/2/20

Y1 - 2026/2/20

N2 - Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), are complex conditions driven by systemic dysregulation that transcends the central nervous system. An integrative systems immunology framework was applied to characterize the neuroimmune “autoantibodyome” across neurodegeneration through an individual participant data meta-analysis of five protein microarray datasets, comprising 596 samples from patients with AD, PD, or MS and healthy controls. We mapped differentially reactive autoantibodies stratified by their targets, unveiling shared features among diseases, such as blood-brain barrier impairment and amplified pro-inflammatory activation, alongside disease-specific perturbations in neuroimmune processes, including short-term memory (AD), skeletal muscle contraction (PD), and pain perception (MS). We identified convergent dysregulation of various autoantibodies targeting diverse synaptic transmission pathways, including gamma-aminobutyric acid (GABA)ergic and glutamatergic signaling. These results indicate the potential of the autoantibodyome to interact with and report on central alterations, suggesting that neurodegeneration may be better understood as a systemic dyshomeostasis.

AB - Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), are complex conditions driven by systemic dysregulation that transcends the central nervous system. An integrative systems immunology framework was applied to characterize the neuroimmune “autoantibodyome” across neurodegeneration through an individual participant data meta-analysis of five protein microarray datasets, comprising 596 samples from patients with AD, PD, or MS and healthy controls. We mapped differentially reactive autoantibodies stratified by their targets, unveiling shared features among diseases, such as blood-brain barrier impairment and amplified pro-inflammatory activation, alongside disease-specific perturbations in neuroimmune processes, including short-term memory (AD), skeletal muscle contraction (PD), and pain perception (MS). We identified convergent dysregulation of various autoantibodies targeting diverse synaptic transmission pathways, including gamma-aminobutyric acid (GABA)ergic and glutamatergic signaling. These results indicate the potential of the autoantibodyome to interact with and report on central alterations, suggesting that neurodegeneration may be better understood as a systemic dyshomeostasis.

UR - https://www.scopus.com/pages/publications/105029093699

UR - https://www.mendeley.com/catalogue/7abb3b51-3f74-3086-bf26-0d5349bc0429/

U2 - 10.1016/j.isci.2026.114781

DO - 10.1016/j.isci.2026.114781

M3 - Journal articles

AN - SCOPUS:105029093699

SN - 2589-0042

VL - 29

JO - iScience

JF - iScience

IS - 2

M1 - 114781

ER -

Integrative analysis reveals the autoantibodyome neuroimmune signature of neurodegeneration

Abstract

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Strategische Forschungsbereiche und Zentren

DFG-Fachsystematik

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