Top

Published in:

01-01-2021 | Multiple Sclerosis | Original Paper

Archeological neuroimmunology: resurrection of a pathogenic immune response from a historical case sheds light on human autoimmune encephalomyelitis and multiple sclerosis

Authors: Eduardo Beltrán, Manuela Paunovic, David Gebert, Emine Cesur, Markus Jeitler, Romana Höftberger, Joachim Malotka, Simone Mader, Naoto Kawakami, Edgar Meinl, Monika Bradl, Klaus Dornmair, Hans Lassmann

Published in: Acta Neuropathologica | Issue 1/2021

Abstract

Aim of our study was to identify the target auto-antigen in the central nervous system recognized by the immune system of a unique patient, who died more than 60 years ago from a disease with pathological changes closely resembling multiple sclerosis (MS), following a misguided immunization with lyophilized calf brain tissue. Total mRNA was isolated from formaldehyde fixed and paraffin embedded archival brain tissue containing chronic active inflammatory demyelinating lesions with inflammatory infiltrates rich in B-lymphocytes and plasma cells. Analysis of the transcriptome by next generation sequencing and reconstruction of the dominant antibody by bioinformatic tools revealed the presence of one strongly expanded B-cell clone, producing an autoantibody against a conformational epitope of myelin oligodendrocytes glycoprotein (MOG), similar to that recognized by the well characterized monoclonal anti-MOG antibody 8-18C5. The reconstructed antibody induced demyelination after systemic or intrathecal injection into animals with T-cell mediated encephalomyelitis. Our study suggests that immunization with bovine brain tissue in humans may—in a small subset of patients—induce a disease with an intermediate clinical and pathological presentation between MS and MOG-antibody associated inflammatory demyelinating disease (MOGAD).

Available only for authorised users

Alvord EC (1970) Acute disseminated encephalomyelitis and “allergic” neuroencephalopathies. In: Vinken PY, Bruyn GW (eds) Handbook of Clinical Neurology, 9th edn. Elsevier, New York, pp 500–571

Balaguer DDG (1888) Un caso de paralitica. Gazeta Medica Catalana 11:45–57

Bauer J, Lassmann H (2016) Neuropathological techniques to investigate central nervous system sections in multiple sclerosis. Methods Mol Biol 1304:211–229. https://doi.org/10.1007/7651_2014_151CrossRefPubMed

Berger T, Reindl M (2015) Antibody biomarkers in CNS demyelinating diseases—a long and winding road. Eur J Neurol 22:1162–1168. https://doi.org/10.1111/ene.12759CrossRefPubMed

Brändle SM, Obermeier B, Senel M et al (2016) Distinct oligoclonal band antibodies in multiple sclerosis recognize ubiquitous self-proteins. Proc Natl Acad Sci USA 113:7864–7869. https://doi.org/10.1073/pnas.1522730113CrossRefPubMedPubMedCentral

Breithaupt C, Schäfer B, Pellkofer H, Huber R, Linington C, Jacob U (2008) Demyelinating myelin oligodendrocyte glycoprotein-specific autoantibody response is focused on one dominant conformational epitope region in rodents. J Immunol 181:1255–1263. https://doi.org/10.4049/jimmunol.181.2.1255CrossRefPubMed

Breithaupt C, Schubart A, Zander H, Skerra A, Huber R, Linington C, Jacob U (2003) Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein. Proc Natl Acad Sci USA 100:9446–9451. https://doi.org/10.1073/pnas.1133443100CrossRefPubMedPubMedCentral

Dal-Bianco A, Grabner G, Kronnerwetter C et al (2017) Slow expansion of multiple sclerosis iron rim lesions: pathology and 7 T magnetic resonance imaging. Acta Neuropathol 133:25–42. https://doi.org/10.1007/s00401-016-1636-zCrossRefPubMed

Dawson JW (1916) The histology of disseminated sclerosis. Trans R Soc 50:517–540

10.

Fransen NL, Hsiao CC, van der Poel M, Engelenburg HJ, Verdaasdonk K, Vincenten MCJ, Remmerswaal EBM, Kuhlmann T, Mason MRJ, Hamann J, Smolders J, Huitinga I (2020) Tissue-resident memory T-cells invade the brain parenchyma in multiple sclerosis white matter lesions. Brain 143:1714–1730. https://doi.org/10.1093/brain/awaa117CrossRefPubMed

11.

Gold R, Linington C, Lassmann H (2006) Understanding pathogenesis and therapy of multiple sclerosis vial animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129:1953–1971. https://doi.org/10.1093/brain/awl075CrossRefPubMed

12.

Haider L, Zrzavy T, Hametner S et al (2016) The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain. Brain 139:807–815. https://doi.org/10.1093/brain/awv398CrossRefPubMedPubMedCentral

13.

Höftberger R, Leisser M, Bauer J, Lassmann H (2015) Autoimmune encephalitis in humans: how closely does it reflect multiple sclerosis? Acta Neuropathol Commun 3:80. https://doi.org/10.1186/s40478-015-0260-9CrossRefPubMedPubMedCentral

14.

Höftberger R, Guo Y, Flanagan EP et al (2020) The pathology of central nervous system inflammatory demyelinating disease accompanying myelin oligodendrocyte glycoprotein autoantibody. Acta Neuropathol 139:875–892. https://doi.org/10.1007/s00401-020-02132-yCrossRefPubMedPubMedCentral

15.

Hohlfeld R, Dornmair K, Meinl E, Wekerle H (2016a) The search for the target antigens of multiple sclerosis, part 1: autoreactive CD4+ T lymphocytes as pathogenic effectors and therapeutic targets. Lancet Neurol 15:198–209. https://doi.org/10.1016/S1474-4422(15)00334-8CrossRefPubMed

16.

Hohlfeld R, Dornmair K, Meinl E, Wekerle H (2016b) The search for the target antigens of multiple sclerosis, part 2: CD8+ T cells, B cells, and antibodies in the focus of reverse-translational research. Lancet Neurol 15:317–331. https://doi.org/10.1016/S1474-4422(15)00313-0CrossRefPubMed

17.

Jarius S, Ruprecht K, Kleiter I et al (2016a) MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin. J Neuroinflamm 13:279. https://doi.org/10.1186/s12974-016-0717-1CrossRef

18.

Jarius S, Ruprecht K, Kleiter I et al (2016b) MOG-IgG in NMO and related disorders: a multicenter study of 50 patients Part 2: epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome. J Neuroinflamm 13:280. https://doi.org/10.1186/s12974-016-0718-0CrossRef

19.

Jellinger K, Seitelberger F (1958) Akute tödliche Entmarkungs-Encephalitis nach wiederholten Hirntrockenzellen-Injektionen [Acute fatal demyelinizing encephalitis after repeated injections of dry brain cells]. Klin Wochenschr 36:437–441. https://doi.org/10.1007/BF01478731CrossRefPubMed

20.

Kitley J, Woodhall M, Waters P et al (2012) Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology 79:1273–1277. https://doi.org/10.1212/WNL.0b013e31826aac4eCrossRefPubMed

21.

Koritschoner R, Schweinburg F (1927) Klinische und experimentelle Beobachtungen über Lähmungen nach Wutschutzimpfung. Z Immunitäts Forsch 42:217–283

22.

Kutzelnigg A, Lucchinetti CF, Stadelmann C et al (2005) Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128:2705–2712. https://doi.org/10.1093/brain/awh641CrossRefPubMed

23.

Lachance DH, Lennon VA, Pittock SJ et al (2010) An outbreak of neurological autoimmunity with polyradiculoneuropathy in workers exposed to aerosolised porcine neural tissue: a descriptive study. Lancet Neurol 9:55–66. https://doi.org/10.1016/S1474-4422(09)70296-0CrossRefPubMed

24.

Lassmann H (1983) Comparative neuropathology of chronic experimental allergic encephalomyelitis and multiple sclerosis, neurology series, 25th edn. Springer, BerlinCrossRef

25.

Lassmann H, Bradl M (2017) Multiple sclerosis: experimental models and reality. Acta Neuropathol 133:223–244. https://doi.org/10.1007/s00401-016-1631-4CrossRefPubMed

26.

Linington C, Bradl M, Lassmann H, Brunner C, Vass K (1988) Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein. Am J Pathol 130:443–454PubMedPubMedCentral

27.

Linnington C, Webb M, Woodhams PL (1984) A novel myelin-associated glycoprotein defined by a mouse monoclonal antibody. J Neuroimmunol 6:387–396. https://doi.org/10.1016/0165-5728(84)90064-xCrossRefPubMed

28.

Linington C, Lassmann H (1987) Antibody responses in chronic relapsing experimental allergic encephalomyelitis: correlation of serum demyelinating activity with antibody titre to the myelin/oligodendrocyte glycoprotein (MOG). J Neuroimmunol 17:61–69. https://doi.org/10.1016/0165-5728(87)90031-2CrossRefPubMed

29.

Machado-Santos J, Saji E, Tröscher AR et al (2018) The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells. Brain 141:2066–2082. https://doi.org/10.1093/brain/awy151CrossRefPubMedPubMedCentral

30.

Magliozzi R, Howell O, Vora A et al (2007) Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130:1089–1104. https://doi.org/10.1093/brain/awm038CrossRefPubMed

31.

Marburg O (1906) Die sogenannte “akute Multiple Sklerose.” Jahrb Psychiatrie 27:211–312

32.

Mayer MC, Breithaupt C, Reindl M et al (2013) Distinction and temporal stability of conformational epitopes on myelin oligodendrocyte glycoprotein recognized by patients with different inflammatory central nervous system diseases. J Immunol 191:3594–3604. https://doi.org/10.4049/jimmunol.1301296CrossRefPubMed

33.

Namimatsu S, Ghazizadeh M, Sugisaki Y (2005) Reversing the effects of formalin fixation with citraconic anhydride and heat: a universal antigen retrieval method. J Histochem Cytochem 53:3–11. https://doi.org/10.1177/002215540505300102CrossRefPubMed

34.

O’Connor KC, McLaughlin KA, De Jager PL et al (2007) Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat Med 13:211–217. https://doi.org/10.1038/nm1488CrossRefPubMedPubMedCentral

35.

Peschl P, Schanda K, Zeka B et al (2017) Human antibodies against the myelin oligodendrocyte glycoprotein can cause complement-dependent demyelination. J Neuroinflamm 14:208. https://doi.org/10.1186/s12974-017-0984-5CrossRef

36.

Piddlesden SJ, Lassmann H, Zimprich F, Morgan BP, Linington C (1993) The demyelinating potential of antibodies to myelin oligodendrocyte glycoprotein is related to their ability to fix complement. Am J Pathol 143:555–564PubMedPubMedCentral

37.

Reindl M, Schanda K, Woodhall M et al (2020) International multicenter examination of MOG antibody assays. Neurol Neuroimmunol Neuroinflamm 7:e674. https://doi.org/10.1212/NXI.0000000000000674CrossRefPubMedPubMedCentral

38.

Reindl M, Waters P (2019) Myelin oligodendrocyte glycoprotein antibodies in neurological disease. Nat Rev Neurol 15:89–102. https://doi.org/10.1038/s41582-018-0112-xCrossRefPubMed

39.

Rivers TM, Sprunt DH, Berry GP (1933) Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J Exp Med 58:39–53. https://doi.org/10.1084/jem.58.1.39CrossRefPubMedPubMedCentral

40.

Seitelberger F, Jellinger K, Tschabitscher H (1958) Zur Genese der akuten Entmarkungsencephalitis. Wien Klin Wschr 70:453–459PubMed

41.

Shugay M, Britanova OV, Merzlyak EM et al (2014) Towards error-free profiling of immune repertoires. Nat Methods 11:653–655. https://doi.org/10.1038/nmeth.2960CrossRefPubMed

42.

Shugay M, Bagaev DV, Turchaninova MA, Bolotin DA, Britanova OV, Putintseva EV, Pogorelyy MV, Nazarov VI, Zvyagin IV, Kirgizova VI, Kirgizov KI, Skorobogatova EV, Chudakov DM (2015) VDJtools: unifying post-analysis of T cell receptor repertoires. PLoS Comput Biol 11:e1004503. https://doi.org/10.1371/journal.pcbi.1004503CrossRefPubMedPubMedCentral

43.

Spadaro M, Winklmeier S, Beltrán E et al (2018) Pathogenicity of human antibodies against myelin oligodendrocyte glycoprotein. Ann Neurol 84:315–328. https://doi.org/10.1002/ana.25291CrossRefPubMed

44.

Stone SH, Lerner EM (1965) Chronic disseminated allergic encephalomyelitis in guinea pigs. Ann N Y Acad Sci 122:227–241. https://doi.org/10.1111/j.1749-6632.1965.tb20206.xCrossRefPubMed

45.

Stuart G, Krikorian KS (1928) The neuro-paralytic accidents of anti-rabies treatment. Ann Trop Med Parasitol 22:327–377CrossRef

46.

Takai Y, Misu T, Kaneko K et al (2020) Myelin oligodendrocyte glycoprotein antibody-associated disease: an immunopathological study. Brain 143:1431–1446. https://doi.org/10.1093/brain/awaa102CrossRefPubMed

47.

Tea F, Lopez JA, Ramanathan S et al (2019) Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination. Acta Neuropathol Commun 7:145. https://doi.org/10.1186/s40478-019-0786-3CrossRefPubMedPubMedCentral

48.

Uchimura I, Shiraki H (1957) A contribution to the classification and the pathogenesis of demyelinating encephalomyelitis. J Neuropathol Exp Neurol 16:139–203CrossRefPubMed

49.

van Nierop GP, van Luijn MM, Michels SS et al (2017) Phenotypic and functional characterization of T cells in white matter lesions of multiple sclerosis patients. Acta Neuropathol 134:383–401. https://doi.org/10.1007/s00401-017-1744-4CrossRefPubMedPubMedCentral

50.

Wucherpfennig KW, Allen PM, Celada F, Cohen IR, De Boer R, Garcia KC, Goldstein B, Greenspan R, Hafler D, Hodgkin P, Huseby ES, Krakauer DC, Nemazee D, Perelson AS, Pinilla C, Strong RK, Sercarz EE (2007) Polyspecificity of T cell and B cell receptor recognition. Semin Immunol 19:216–224. https://doi.org/10.1016/j.smim.2007.02.012CrossRefPubMedPubMedCentral

Title: Archeological neuroimmunology: resurrection of a pathogenic immune response from a historical case sheds light on human autoimmune encephalomyelitis and multiple sclerosis
Authors: Eduardo Beltrán
Manuela Paunovic
David Gebert
Emine Cesur
Markus Jeitler
Romana Höftberger
Joachim Malotka
Simone Mader
Naoto Kawakami
Edgar Meinl
Monika Bradl
Klaus Dornmair
Hans Lassmann
Publication date: 01-01-2021
Publisher: Springer Berlin Heidelberg
Keywords: Multiple Sclerosis
Autoimmune Encephalitis
Published in: Acta Neuropathologica / Issue 1/2021
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-020-02239-2

At a glance: The STEP trials

Springer Medicine

Archeological neuroimmunology: resurrection of a pathogenic immune response from a historical case sheds light on human autoimmune encephalomyelitis and multiple sclerosis

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2021

Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer’s disease models and human brains

Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis

Correction to: Antibody against TDP-43 phosphorylated at serine 369 suggests conformational differences of TDP-43 aggregates among FTLD-TDP subtypes

Brain arteriolosclerosis

Correction to: Epigenomic, genomic, and transcriptomic landscape of schwannomatosis

Lewy pathology of the esophagus correlates with the progression of Lewy body disease: a Japanese cohort study of autopsy cases