Viruses and Multiple Sclerosis

Multiple sclerosis (MS) is a chronic demyelinating disorder of unknown etiology, possibly caused by a virus or virus-triggered immunopathology. The virus might reactivate after years of latency and lyse oligodendrocytes, as in progressive multifocal leukoencephalopathy, or initiate immunopathological demyelination, as in animals infected with Theiler’s murine encephalomyelitis virus or coronaviruses. The argument for a viral cause of MS is supported by epidemiological analyses and studies of MS in identical twins, indicating that disease is acquired. However, the most important evidence is the presence of bands of oligoclonal IgG (OCBs) in MS brain and CSF that persist throughout the lifetime of the patient. OCBs are found almost exclusively in infectious CNS disorders, and antigenic targets of OCBs represent the agent that causes disease. Here, the authors review past attempts to identify an infectious agent in MS brain cells and discuss the promise of using recombinant antibodies generated from clonally expanded plasma cells in brain and CSF to identify disease-relevant antigens. They show how this strategy has been used successfully to analyze antigen specificity in subacute sclerosing panencephalitis, a chronic encephalitis caused by measles virus, and in neuromyelitis optica, a chronic autoimmune demyelinating disease produced by antibodies directed against the aquaporin-4 water channel.

Download Full-text

Old Dog Encephalitis and Demyelinating Diseases in Man

Veterinary Pathology ◽

10.1177/030098587501200307 ◽

1975 ◽

Vol 12 (3) ◽

pp. 220-226 ◽

Cited By ~ 17

Author(s):

J. M. Adams ◽

W. J. Brown ◽

H. D. Snow ◽

S. D. Lincoln ◽

A. W. Sears ◽

...

Keyword(s):

Multiple Sclerosis ◽

Neuromyelitis Optica ◽

Plasma Cells ◽

Demyelinating Disease ◽

Subacute Sclerosing Panencephalitis ◽

Fluorescent Antibody ◽

Optic Tract ◽

Demyelinating Diseases ◽

Relationship Of ◽

Perivascular Infiltration

Pathologic findings in mature dogs with old dog encephalitis were compared with the findings in multiple sclerosis, subacute sclerosing panencephalitis and neuromyelitis optica in man. Fluorescent antibody studies in animal and human tissues were compared. Optic neuritis in dogs with chronic distemper shows changes similar to those in the optic tract of human patients with severe demyelinating disease. The pathologic changes in multiple sclerosis, such as perivascular infiltration with lymphocytes, plasma cells and demyelination are similar to those seen in old dog encephalitis. Demyelination in old dog encephalitis is usually diffuse. The findings strongly support a possible relationship of old dog encephalitis to multiple sclerosis, subacute sclerosing panencephalitis, and neuromyelitis optica.

Download Full-text

Slow Infections of the Central Nervous System

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100120463 ◽

1977 ◽

Vol 4 (2) ◽

pp. 81-88

Author(s):

Laurence E. Becker

Keyword(s):

Multiple Sclerosis ◽

Nervous System ◽

Host Response ◽

Measles Virus ◽

Subacute Sclerosing Panencephalitis ◽

Infectious Agent ◽

Epidemiological Data ◽

Neurologic Diseases ◽

Jakob Disease ◽

The Central Nervous System

SummaryThis review describes the recent advances in slow infections of the nervous system emphasizing the pathogenetic aspects of these diseases. A theoretical model for the pathogenesis of subacute sclerosing panencephalitis (SSPE) is proposed, illustrating the factors that may affect host response to the measles virus and allow it to persist and produce the panencephalitis. The isolation of an oncogenic virus from progressive multifocal leukoencephalopathy (PML) has implications in the consideration of a viral etiology for some brain tumors. The agent responsible for the transmissibility of kuru and Creutzfeldt-Jakob disease (CJD) remains uncharacterized despite recent interest in viroids and abnormalities in replication of cell membranes. The epidemiological data on multiple sclerosis suggests an exposure to an infectious agent at an early age of life modified by the host response. No specific agent has been consistently associated with multiple sclerosis. Amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Mollare’s meningitis and Behcet’s disease are other examples where a virus is suspect but unproven. The ability of viruses to persist in the host for months to years has linked many chronic neurologic diseases to an infectious agent, enlarging the spectrum of disease caused by viruses.

Download Full-text

Presence of antibody in virus-infected brain cells of SSPE ferrets

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100077591 ◽

1983 ◽

Vol 41 ◽

pp. 804-805

Author(s):

Hannah R. Brown ◽

Tammy L. Donato ◽

Halldor Thormar

Keyword(s):

Measles Virus ◽

Plasma Cells ◽

Subacute Sclerosing Panencephalitis ◽

Protein A ◽

Neutralizing Antibody ◽

Brain Cells ◽

Antibody Titers ◽

A Cell ◽

The Central Nervous System ◽

The Brain

Measles virus specific immunoglobulin G (IgG) has been found in the brains of patients with subacute sclerosing panencephalitis (SSPE), a slowly progressing disease of the central nervous system (CNS) in children. IgG/albumin ratios indicate that the antibodies are synthesized within the CNS. Using the ferret as an animal model to study the disease, we have been attempting to localize the Ig's in the brains of animals inoculated with a cell associated strain of SSPE. In an earlier report, preliminary results using Protein A conjugated to horseradish peroxidase (PrAPx) (Dynatech Diagnostics Inc., South Windham, ME.) to detect antibodies revealed the presence of immunoglobulin mainly in antibody-producing plasma cells in inflammatory lesions and not in infected brain cells.In the present experiment we studied the brain of an SSPE ferret with neutralizing antibody titers of 1:1024 in serum and 1:512 in CSF at time of sacrifice 7 months after i.c. inoculation with SSPE measles virus-infected cells. The animal was perfused with saline and portions of the brain and spinal cord were immersed in periodate-lysine-paraformaldehyde (P-L-P) fixative. The ferret was not perfused with fixative because parts of the brain were used for virus isolation.

Download Full-text

IgG1 Subclass Restriction of Oligoclonal Measles Virus-Specific IgG Antibodies in Patients with Subacute Sclerosing Panencephalitis and in a Patient with Multiple Sclerosis

Scandinavian Journal of Immunology ◽

10.1111/j.1365-3083.1977.tb02145.x ◽

1977 ◽

Vol 6 (6-7) ◽

pp. 651-657 ◽

Cited By ~ 27

Author(s):

B. VANDVIK ◽

J. B. NATVIG ◽

E. NORRBY

Keyword(s):

Multiple Sclerosis ◽

Measles Virus ◽

Subacute Sclerosing Panencephalitis ◽

Igg Antibodies ◽

Specific Igg ◽

Igg1 Subclass ◽

Specific Igg Antibodies

Download Full-text

Screening Random Peptide Libraries with Subacute Sclerosing PanencephalitisBrain-Derived Recombinant Antibodies Identifies Multiple Epitopes in the C-Terminal Region of the Measles Virus Nucleocapsid Protein

Journal of Virology ◽

10.1128/jvi.01704-06 ◽

2006 ◽

Vol 80 (24) ◽

pp. 12121-12130 ◽

Cited By ~ 12

Author(s):

Gregory P. Owens ◽

Andrew J. Shearer ◽

Xiaoli Yu ◽

Alanna M. Ritchie ◽

Kathryne M. Keays ◽

...

Keyword(s):

Nucleocapsid Protein ◽

Measles Virus ◽

Inflammatory Diseases ◽

Subacute Sclerosing Panencephalitis ◽

Recombinant Antibodies ◽

Oligoclonal Bands ◽

Unknown Etiology ◽

Enzyme Linked Immunosorbent Assay ◽

Protein Database ◽

Variable Regions

ABSTRACT Infectious and inflammatory diseases of the CNS are often characterized by a robust B-cell response that manifests as increased intrathecal immunoglobulin G (IgG) synthesis and the presence of oligoclonal bands. We previously used laser capture microdissection and single-cell PCR to analyze the IgG variable regions of plasma cells from the brain of a patient with subacute sclerosing panencephalitis (SSPE). Five of eight human IgG1 recombinant antibodies (rAbs) derived from SSPE brain plasma cell clones recognized the measles virus (MV) nucleocapsid protein, confirming that the antibody response in SSPE targets primarily the agent causing disease. In this study, as part of our work on antigen identification, we used four rAbs to probe a random phage-displayed peptide library to determine if epitopes within the MV nucleocapsid protein could be identified with SSPE brain rAbs. All four of the SSPE rAbs enriched phage-displayed peptide sequences that reacted specifically to their panning rAb by enzyme-linked immunosorbent assay. BLASTP searches of the NCBI protein database revealed clear homologies in three peptides and different amino acid stretches within the 65 C-terminal amino acids of the MV nucleocapsid protein. The specificities of SSPE rAbs to these regions of the MV nucleocapsid protein were confirmed by binding to synthetic peptides or to short cDNA expression products. These results indicate the feasibility of using peptide screening for antigen discovery in central nervous system inflammatory diseases of unknown etiology, such as multiple sclerosis, neurosarcoidosis, or Behcet's syndrome.

Download Full-text

Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis

Science ◽

10.1126/science.abj8222 ◽

2022 ◽

Author(s):

Kjetil Bjornevik ◽

Marianna Cortese ◽

Brian C. Healy ◽

Jens Kuhle ◽

Michael J. Mina ◽

...

Keyword(s):

Multiple Sclerosis ◽

Epstein Barr Virus ◽

Demyelinating Disease ◽

Serum Levels ◽

Unknown Etiology ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Barr Virus ◽

The Central Nervous System ◽

Epstein Barr

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system of unknown etiology. We tested the hypothesis that MS is caused by Epstein-Barr virus (EBV) in a cohort comprising more than 10 million young adults on active duty in the US military, 955 of whom were diagnosed with MS during their period of service. Risk of MS increased 32-fold after infection with EBV but was not increased after infection with other viruses, including the similarly transmitted cytomegalovirus. Serum levels of neurofilament light chain, a biomarker of neuroaxonal degeneration, increased only after EBV seroconversion. These findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.

Download Full-text

IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel

Journal of Experimental Medicine ◽

10.1084/jem.20050304 ◽

2005 ◽

Vol 202 (4) ◽

pp. 473-477 ◽

Cited By ~ 1353

Author(s):

Vanda A. Lennon ◽

Thomas J. Kryzer ◽

Sean J. Pittock ◽

A.S. Verkman ◽

Shannon R. Hinson

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Blood Brain Barrier ◽

Neuromyelitis Optica ◽

Immunoglobulin G ◽

Protein Complex ◽

Demyelinating Disease ◽

Water Channel ◽

Aquaporin 4 ◽

Specific Marker

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that selectively affects optic nerves and spinal cord. It is considered a severe variant of multiple sclerosis (MS), and frequently is misdiagnosed as MS, but prognosis and optimal treatments differ. A serum immunoglobulin G autoantibody (NMO-IgG) serves as a specific marker for NMO. Here we show that NMO-IgG binds selectively to the aquaporin-4 water channel, a component of the dystroglycan protein complex located in astrocytic foot processes at the blood-brain barrier. NMO may represent the first example of a novel class of autoimmune channelopathy.

Download Full-text

Pathogen Specificity and Autoimmunity Are Distinct Features of Antigen-Driven Immune Responses in Neuroborreliosis

Infection and Immunity ◽

10.1128/iai.00260-07 ◽

2007 ◽

Vol 75 (8) ◽

pp. 3842-3847 ◽

Cited By ~ 21

Author(s):

Sandra Kuenzle ◽

Hans-Christian von Büdingen ◽

Mirjam Meier ◽

Melanie D. Harrer ◽

Eduard Urich ◽

...

Keyword(s):

Immune Responses ◽

Plasma Cell ◽

Plasma Cells ◽

Molecular Mimicry ◽

Recombinant Expression ◽

Infectious Agent ◽

Cross Reactivity ◽

Antigen Specificity ◽

Humoral Immune ◽

Self Antigens

ABSTRACT Neuroborreliosis (NB) is a chronic infectious disease of the central nervous system (CNS) caused by a tick-borne spirochete, Borrelia burgdorferi. In addition to direct effects of the causative infectious agent, additional immunity-mediated mechanisms are thought to play a role in the CNS pathology of NB. In order to further understand the involvement of humoral immune mechanisms in NB, we dissected the intrathecal antibody responses down to the single-plasma-cell level. Starting with single-cell reverse transcription-PCR of fluorescence-activated cell sorter-sorted cerebrospinal fluid plasma cells from an NB patient, we identified expanded clones and resurrected the antigen specificity of their secreted antibodies through recombinant expression of the correctly paired immunoglobulin heavy- and light-chain genes as monoclonal antibodies (MAbs). As expected, we found specificity for the causative infectious agent, B. burgdorferi, among the clonally expanded plasma cell (cePC)-derived MAbs. However, from an independent cePC of the same patient, we could derive MAbs specific for human CNS myelin, without detectable cross-reactivity with B. burgdorferi antigens. While reactivity against B. burgdorferi is a known feature of humoral immune responses in NB, we show (i) that immune responses specific for self antigens may be a distinct feature of CNS infections independent of pathogen reactivity and (ii) that humoral autoimmunity in NB (since found in cePC) is the result of a truly antigen-driven immune response. Our findings indicate that in NB mechanisms may be at play that induce distinct immune responses specific for pathogen and self antigens independent from “molecular mimicry.”

Download Full-text