title: Progressive multiple sclerosis cerebrospinal fluid induces inflammatory demyelination, axonal loss, and astrogliosis in mice.
abstract: Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelination and neurodegeneration throughout the CNS, which lead over time to a condition of irreversible functional decline known as progressive MS. Currently, there are no satisfactory treatments for this condition because the mechanisms that underlie disease progression are not well understood. This is partly due to the lack of a specific animal model that represents progressive MS. We investigated the effects of intracerebroventricular injections of cerebrospinal fluid (CSF) derived from untreated primary progressive (PPMS), secondary progressive (SPMS), and relapsing/remitting (RRMS) MS patients into mice. We found discrete inflammatory demyelinating lesions containing macrophages, B cell and T cell infiltrates in the brains of animals injected with CSF from patients with progressive MS. These lesions were rarely found in animals injected with RRMS-CSF and never in those treated with control-CSF. Animals that developed brain lesions also presented extensive inflammation in their spinal cord. However, discrete spinal cord lesions were rare and only seen in animals injected with PPMS-CSF. Axonal loss and astrogliosis were seen within the lesions following the initial demyelination. In addition, Th17 cell activity was enhanced in the CNS and in lymph nodes of progressive MS-CSF injected animals compared to controls. Furthermore, CSF derived from MS patients who were clinically stable following therapy had greatly diminished capacity to induce CNS lesions in mice. Finally, we provided evidence suggesting that differential expression of pro-inflammatory cytokines present in the progressive MS CSF might be involved in the observed mouse pathology. Our data suggests that the agent(s) responsible for the demyelination and neurodegeneration characteristic of progressive MS is present in patient CSF and is amenable to further characterization in experimental models of the disease.
authors.affiliation: Tisch MS Research Center of New York, New York, NY 10019, USA.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cristofanilli
authors.affiliation: Tisch MS Research Center of New York, New York, NY 10019, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Rosenthal
authors.affiliation: Tisch MS Research Center of New York, New York, NY 10019, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cymring
authors.affiliation: Tisch MS Research Center of New York, New York, NY 10019, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gratch
authors.affiliation: Tisch MS Research Center of New York, New York, NY 10019, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Pagano
authors.affiliation: Tisch MS Research Center of New York, New York, NY 10019, USA.
authors.forename: Boxun
authors.initials: B
authors.lastname: Xie
authors.affiliation: Tisch MS Research Center of New York, New York, NY 10019, USA. Electronic address: ssadiq@tischms.org.
authors.forename: Saud A
authors.initials: SA
authors.lastname: Sadiq
mesh_terms: D000328:Adult; D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology; D002555:Cerebrospinal Fluid / Q000737:chemistry / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D020278:Demyelinating Autoimmune Diseases, CNS / Q000209:etiology* / Q000276:immunology / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005911:Gliosis / Q000209:etiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009043:Motor Activity / Q000502:physiology; D020528:Multiple Sclerosis, Chronic Progressive / Q000134:cerebrospinal fluid*; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D016207:Cytokines
keywords: Cerebrospinal fluid; Demyelination lesion pathology; Inflammatory cytokines; Intracerebroventricular injection; Progressive multiple sclerosis