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Ann Neurol 1998 Jul;44(1):87-98

Neuronal molecular mimicry in immune-mediated neurologic disease.

Levin MC, Krichavsky M, Berk J, Foley S, Rosenfeld M, Dalmau J, Chang G,
Posner JB, Jacobson S


Viral Immunology Section, Neuroimmunology Branch, National Institute of
Neurological Diseases and Stroke, National Institutes of Health, Bethesda,
MD, USA.


Molecular mimicry is implicated in the pathogenesis of autoimmune diseases
such as diabetes mellitus, rheumatoid arthritis, and multiple sclerosis
(MS). Cellular and antibody-mediated immune responses to shared viral-host
antigens have been associated with the development of disease in these
patients. Patients infected with human T-lymphotropic virus type I (HTLV-I)
develop HTLV-I-associated myelopathy/tropical spastic paraparesis
(HAM/TSP), an immune-mediated disorder of the central nervous system (CNS)
that resembles some forms of MS. Damage to neuronal processes in the CNS of
HAM/TSP patients is associated with an activated cellular and
antibody-mediated immune response. In this study, IgG isolated from HAM/TSP
patients was immunoreactive with uninfected neurons and this reactivity was
HTLV-I specific. HAM/TSP IgG stained uninfected neurons in human CNS and
cell lines but not nonneuronal cells. Neuronal western blots showed IgG
reactivity with a single 33-kd band in all HAM/TSP patients tested. By
contrast, no neuron-specific IgG reactivity could be demonstrated from
HTLV-I seronegative controls and, more important, from HTLV-I seropositive,
neurologically asymptomatic individuals. Both immunocytochemical staining
and western blot reactivity were abolished by preincubating HAM/TSP IgG
with HTLV-I protein lysate but not by control proteins. Staining of CNS
tissue by a monoclonal antibody to HTLV-I tax (an immunodominant HTLV-I
antigen) mimicked HAM/TSP IgG immunoreactivity. There was no staining by
control antibodies. Absorption of HAM/TSP IgG with recombinant HTLV-I tax
protein or preincubation of CNS tissue with the monoclonal antibody to
HTLV-I tax abrogated the immunocytochemical and western blot reactivity of
HAM/TSP IgG. Furthermore, in situ human IgG localized to neurons in HAM/TSP
brain but not in normal brain. These data indicate that HAM/TSP patients
develop an antibody response that targets uninfected neurons, yet
reactivity is blocked by HTLV-I, suggesting viral-specific autoimmune
reactivity to the CNS, the damaged target organ in HAM/TSP.


PMID: 9667596, UI: 98330170

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J Immunol 1998 Jul 1;161(1):504-512

Experimental autoimmune encephalomyelitis induced with a combination of
myelin basic protein and myelin oligodendrocyte glycoprotein is ameliorated
by administration of a single myelin basic protein peptide.


Leadbetter EA, Bourque CR, Devaux B, Olson CD, Sunshine GH, Hirani S,
Wallner BP, Smilek DE, Happ MP

ImmuLogic Pharmaceutical Corporation, Waltham, MA 02154, USA.

Multiple sclerosis is an autoimmune disease of the central nervous system
in which T cell reactivity to several myelin proteins, including myelin
basic protein (MBP), proteolipid protein, and myelin oligodendrocyte
glycoprotein (MOG), has been implicated in the perpetuation of the disease
state. Experimental autoimmune encephalomyelitis (EAE) is used commonly as
a model in which potential therapies for multiple sclerosis are evaluated.
The ability of T cell epitope-containing peptides to down-regulate the
disease course is well documented for both MBP- and proteolipid
protein-induced EAE, and recently has been shown for MOG-induced EAE. In
this study, we describe a novel EAE model, in which development of severe
disease symptoms in (PL/J x SJL)F1 mice is dependent on reactivity to two
different immunizing Ags, MBP and MOG. The disease is often fatal, with a
relapsing/progressive course in survivors, and is more severe than would be
predicted by immunization with either Ag alone. The MOG plus MBP disease
can be treated postinduction with a combination of the MOG 41-60 peptide
(identified as the major therapeutic MOG epitope for this strain) and the
MBP Ac1-11[4Y] peptide. A significant treatment effect can also be obtained
by administration of the MBP peptide alone, but this effect is strictly
dose dependent. This MBP peptide does not treat the disease induced only
with MOG. These results suggest that peptide immunotherapy can provide an
effective means of mitigating disease in this model, even when the
treatment is targeted to only one component epitope or one component
protein Ag of a diverse autoimmune response.


PMID: 9647262, UI: 98309477

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Mult Scler 1998 Feb;4(1):31-36

Identification of peptides binding to IgG in the CSF of multiple sclerosis
patients.

Cortese I, Capone S, Tafi R, Grimaldi LM, Nicosia A, Cortese R


Clinica Neurologica, Universita di Roma TorVergata, Italy.


Phage displayed random peptide libraries were screened in order to identify
phagotopes reacting with the IgG present in the cerebrospinal fluid (CSF)
of multiple sclerosis (MS) patients. Six families of phagotopes each
composed of different isolates were identified. These phagotopes were used
as reagents, to characterise IgG present in the CSF of MS patients. The
following results were obtained: (a) CSF antibodies from different patients
display different specificities; (b) anti-phagotope antibodies are also
present in the serum of MS patients; (c) Anti-phagotope antibodies are
equally frequent in the serum of MS patients and of healthy individuals;
(d) some of the anti-phagotope antibodies are enriched in the CSF of MS
patients. These data show that the natural antigen(s) recognised by CSF
antibodies is rather common in the general population. By using the
selected phagotopes as immunogens in rabbits, we have derived large
quantities of anti-phagotope antisera which can provide for useful tools
toward the identification of the natural antigen(s) recognised by MS CSF
antibodies.


PMID: 9532590, UI: 98193769

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