CD4+ T cell mitochondrial genotype in Multiple Sclerosis: a cross-sectional and longitudinal analysis

Abstract

Multiple Sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS), with a largely unknown etiology, where mitochondrial dysfunction significantly contributes to neuroaxonal loss and brain atrophy. Mirroring the CNS, peripheral immune cells from patients with MS, particularly CD4+ T cells, show inappropriate mitochondrial phenotypes and/or oxidative phosphorylation (OxPhos) insufficiency, with a still unknown contribution of mitochondrial DNA (mtDNA). We hypothesized that mitochondrial genotype in CD4+ T cells might influence MS disease activity and progression. Thus, we performed a retrospective cross-sectional and longitudinal study on patients with a recent diagnosis of either Clinically Isolated Syndrome (CIS) or Relapsing-Remitting MS (RRMS) at two timepoints: six months (VIS1) and 36 months (VIS2) after disease onset. Our primary outcomes were the differences in mtDNA extracted from CD4+ T cells between: (I) patients with CIS/RRMS (PwMS) at VIS1 and age- and sex-matched healthy controls (HC), in the cross-sectional analysis, and (II) different diagnostic evolutions in PwMS from VIS1 to VIS2, in the longitudinal analysis. We successfully performed mtDNA whole genome sequencing (WGS) (mean coverage: 2055.77 reads/base pair) in 183 samples (61 triplets). Nonetheless, mitochondrial genotype was not associated with a diagnostic of CIS/RRMS, nor with longitudinal diagnostic evolution.

Competing Interest Statement

F.C.F. reports no disclosures relevant to the manuscript. S.A. received speakers honoraria from Alexion, Bayer and Roche. C.C. received speaking honoraria from Bayer and research funding from Novartis, unrelated to the current study. H.G.Z. received speaking honoraria from Bayer and Novartis and research funding from Novartis, unrelated to the current study. K.R. received research support from Novartis Pharma, Merck Serono, German Ministry of Education and Research, European Union (821283-2), Stiftung Charite, Guthy Jackson Charitable Foundation and Arthur Arnstein Foundation; received travel grants from Guthy Jackson Charitable Foundation. K.R. is a participant in the BIH Clinical Fellow Program funded by Stiftung Charite. T.S.-H. reports no disclosures relevant to the manuscript. J.B.-S. received speaking honoraria and travel grants from Bayer Healthcare, and sanofi-aventis/Genzyme, in addition received compensation for serving on a scientific advisory board of Roche, unrelated to the presented work. F.P. serves as an Associate Editor for Neurology: Neuroimmunology & Neuroinflammation and PLoS ONE, reports speaker honoraria and/or travel grants from Bayer, Novartis, Biogen Idec, Teva, Sanofi-Aventis / Genzyme, Merck Serono, Alexion, Chugai, MedImmune, Shire, Roche, Actelion, and Celgene, research support from Bayer, Novartis, Biogen Idec, Teva, Sanofi-Aventis / Genzyme, Alexion, Merck Serono, German Research Council (DFG Exc 257), Werth Stiftung of the City of Cologne, German Ministry of Education and Research (BMBF Competence Network Multiple Sclerosis), Arthur Arnstein Stiftung Berlin, EU FP7 Framework Program (combims.eu), Arthur Arnstein Foundation Berlin, Guthy Jackson Charitable Foundation, and National Multiple Sclerosis Society of the USA, consultancies for Sanofi-Aventis / Genzyme, Biogen Idec, MedImmune, Shire, and Alexion, and is a member of the steering committee of the OCTIMS study (Novartis). V.A.M. reports no disclosures relevant to the manuscript.

Funding Statement

This research was funded by Merck Germany (restricted research grant), the National Multiple Sclerosis Society (NMSS), NMSS Pilot Research Grant (PP.1712.29466), and Fundacao para a Ciencia e Tecnologia (FCT) (FCT/PTDC/MEDNEU/7976/2020). F.C.F. stipend was supported by FCT (PD/BD/114122/2015) and by Merck Germany (restricted research grant). V.A.M. is an iFCT researcher (IF/01693/2014; IMM/CT/27/2020). The NeuroCure Clinical Research Center (NCRC) is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany Excellence Strategy/EXC/2049/390688087 (granted to F.P.). We would also like to acknowledge the Fundos Europeus Estruturais e de Investimento (FEEI) from Programa Operacional Regional de Lisboa 2020 and FCT, grants LISBOA/01/0145/FEDER/016394, LISBOA/01/0145/FEDER/016417, and POCI/01/0145/FEDER/022184, as well as PPBI/POCI/01/0145/FEDER/022122.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee/IRB of the Charite Universitatsmedizin Berlin (application number: EA1/182/10) gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

All data produced in the present study are available upon reasonable request to the authors.

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