Association of common mitochondrial DNA variants with multiple sclerosis and systemic lupus erythematosus

Vyshkina, Tamara; Sylvester, Andrew; Sadiq, Saud; Bonilla, Eduardo; Canter, Jeff A.; Perl, András; Kálmán, Bernadette

doi:10.1016/j.clim.2008.07.011

Cited by 83 publications

(62 citation statements)

References 27 publications

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“…Recently, potential immunogenicity of peroxy-nitrite modified mitochondrial DNA (mtDNA) has been shown in SLE [9]. Additionally, increased serum level of mtDNA was detected in patients diagnosed with various neurodegenerative disorders, such as autism, Parkinson disease and multiple sclerosis [10,11,12]. Several authors have suggested that mtDNA can act as trigger points for the development of autoimmune disorders as well [10,13].…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, increased serum level of mtDNA was detected in patients diagnosed with various neurodegenerative disorders, such as autism, Parkinson disease and multiple sclerosis [10,11,12]. Several authors have suggested that mtDNA can act as trigger points for the development of autoimmune disorders as well [10,13]. Although immune reactivity towards nucleic acids is well established, it remains to determine which type of nucleic acids are more immunogenic in SLE.…”

Section: Introductionmentioning

confidence: 99%

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Differential Immuno-Reactivity to Genomic DNA, RNA and Mitochondrial DNA is Associated with Auto-Immunity

Ivanova

Khaiboullina

Черенкова

et al. 2014

Cell Physiol Biochem

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Background: Circulating auto-reactive antibodies are hallmark features of auto-immune diseases, however little is known with respect to the specificity of such bio-markers. In the present study, we investigated the specificity of anti-nucleic acid antibodies in the blood of subjects with systemic lupus erythematosus (SLE) and healthy controls. Methods: Sera from 12 SLE cases and 8 controls were evaluated for immuno-reactivity to purified RNA, DNA and mitochondrial DNA (mtDNA) by enzyme-linked immuno-sorbent assay (ELISA). Results: As expected, immuno-reactivity to total nucleic acids was significantly higher in subjects with SLE when compared to healthy controls, however a clear distinction was observed among the various nucleic acid sub-types, with sera from SLE subjects displaying the greatest immuno-reactivity to RNA followed by mtDNA and then total DNA. Conclusion: The identification of auto-reactive antibodies can serve as highly sensitive biomarkers, although their specificity may not always allow diagnostic certainty. The knowledge that auto-antibodies in subjects with SLE display differential immuno-reactivity may help to improve existing diagnostics and may lead to a better understanding of the pathogenesis of auto-immune disorders.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differential Immuno-Reactivity to Genomic DNA, RNA and Mitochondrial DNA is Associated with Auto-Immunity

Ivanova

Khaiboullina

Черенкова

et al. 2014

Cell Physiol Biochem

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“…5 The association of the K haplogroup with adult MS risk has recently been replicated. 6 Other mtDNA variants, such as 13966G or 14798C, have been published in rare case reports of patients with MS. 7 A restriction endonuclease splice variant in the 15927/15928 region of the mitochondrial tRNA (thr) gene was reportedly more frequent in patients with MS with severe optic neuropathy compared to controls, although the specific mutation responsible for this association was not identified. 8 An increased frequency of MS also has been reported in pedigrees of patients with Leber hereditary optic neuropathy (LHON), 9 which is caused by mutations in mtDNA, and optic nerve involvement is common in both conditions.…”

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confidence: 99%

Mitochondrial DNA haplogroups and mutations in children with acquired central demyelination

Venkateswaran

Zheng²,

Sacchetti³

et al. 2011

Neurology

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Objective: We investigated mitochondrial DNA (mtDNA) variants in children with a first episode of acquired demyelinating syndromes (PD-ADS) of the CNS and their relationship to disease phenotype, including subsequent diagnosis of multiple sclerosis (MS).Methods: This exploratory analysis included the initial 213 children with PD-ADS in the prospective Canadian Pediatric Demyelinating Study and 166 matched healthy sibling controls from the Canadian Autism Genome Project. A total of 31 single nucleotide polymorphisms (SNPs) were analyzed, including haplogroup-defining SNPs and mtDNA variants previously reported to be associated with MS. Results: Primary Leber hereditary optic neuropathy (LHON) mutations and other known patho-genic mtDNA mutations were absent in both patients with pediatric acquired demyelinating syndromes and controls. The 13708A haplogroup J-associated variant, previously linked to adult MS, was more frequent among subjects with PD-ADS (13.0%) compared to controls (6.2%; odds ratio [OR] 2.27; 95% confidence interval [CI] 1.06 to 4.83) and haplogroup M was associated with an earlier age at onset of PD-ADS (Ϫ1.74 years; 95% CI Ϫ3.33 to Ϫ0.07). In contrast, the haplogroup cluster UKJT, as well as 3 other SNPs, were each associated with a lower risk of PD-ADS. A total of 33 subjects with PD-ADS were diagnosed with MS during a mean follow-up period of 3.11 Ϯ 1.14 (SD) years. No single SNP was associated with the risk of subsequent diagnosis of MS. However, haplogroup H was associated with an increased risk of MS (OR 2.60; 95% CI 1.21 to 5.55). Conclusion:These data suggest an association between mtDNA variants and the risk of PD-ADS and of a subsequent MS diagnosis. Replication of these findings in an independent population of subjects with PD-ADS is required. Neurology ® 2011;76:774-780 GLOSSARY ADEM ϭ acute disseminated encephalomyelitis; ADS ϭ acquired demyelinating syndrome; CI ϭ confidence interval; LHON ϭ Leber hereditary optic neuropathy; MS ϭ multiple sclerosis; mtDNA ϭ mitochondrial DNA; OR ϭ odds ratio; PD-ADS ϭ first episode of acquired demyelinating syndrome; SNP ϭ single nucleotide polymorphism.

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“…To a large degree it is secondary to the chronic inflammation that occurs during the course of disease progression and/or during active disease. It may originate from many non-NADPH oxidase sources such as dysfunctional mitochondria in lupus T-lymphocytes linked to enhanced mitochondrial oxygen consumption (42) or polymorphisms in mitochondrial DNA complex I (43).…”

Section: Discussionmentioning

confidence: 99%

Systemic Lupus Erythematosus-associated Neutrophil Cytosolic Factor 2 Mutation Affects the Structure of NADPH Oxidase Complex

Armstrong

Eisenstein

Zidovetzki

et al. 2015

Journal of Biological Chemistry

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Background: Mutations in NCF2 predispose individuals to lupus. Results: NCF2 Arg-395 3 Trp is associated with lupus; Arg-395 stabilizes the C terminus of NCF4 and NCF2 loop 395-402. Conclusion: Trp-395 disrupts the NADPH oxidase complex. Significance: The results support a nuanced rather than strictly proinflammatory role for this pathway in immune regulation with important consequences for autoimmunity.

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Association of common mitochondrial DNA variants with multiple sclerosis and systemic lupus erythematosus

Cited by 83 publications

References 27 publications

Differential Immuno-Reactivity to Genomic DNA, RNA and Mitochondrial DNA is Associated with Auto-Immunity

Differential Immuno-Reactivity to Genomic DNA, RNA and Mitochondrial DNA is Associated with Auto-Immunity

Mitochondrial DNA haplogroups and mutations in children with acquired central demyelination

Systemic Lupus Erythematosus-associated Neutrophil Cytosolic Factor 2 Mutation Affects the Structure of NADPH Oxidase Complex

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