Molecular mimicry: cross-reactive antibodies from patients with immune-mediated neurologic disease inhibit neuronal firing.

Abstract:

:Recent data indicate that molecular mimicry may play a role in the pathogenesis of human-T-lymphotropic virus type-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), an immune-mediated disease of the central nervous system (CNS). Specifically, HAM/TSP patients developed antibodies that cross-react with heterogeneous nuclear ribonuclear protein A1 (hnRNP A1), an antigen highly expressed in neurons. Antibodies to HTLV-1-tax cross-reacted with hnRNP A1, suggesting molecular mimicry between the two proteins. In support of this hypothesis, HAM/TSP IgG and antibodies to hnRNP A1 and HTLV-1-tax inhibited neuronal firing, suggesting that these antibodies can be pathogenic. We extended these observations by carrying out studies on over 20 different neurons. We also tested IgG isolated from six different HAM/TSP patients and two HTLV-1 seronegative controls and added experiments that control for antibody isotype, antibody target, and neuron viability. In these studies, IgG was infused into the extracellular space during whole-cell current clamp recordings of neurons. Our results confirm that in contrast to normal IgG, IgG from all HAM/TSP patients completely inhibited neuronal firing. Affinity-purified antibodies specific for hnRNP A1 and a monoclonal antibody to HTLV-1-tax (which reacted with hnRNP A1 and whose epitope overlaps the human immunodominant epitope of tax) also inhibited neuronal firing. Monoclonal antibodies to neurofilament did not change neuronal firing. These data indicate that antibodies to neurons can be pathogenic, that biologic activity can be affected by a cross-reactive epitope between HTLV-1-tax and hnRNP A1, and that molecular mimicry may play a role in the pathogenesis of HAM/TSP.

journal_name

J Neurosci Res

authors

Kalume F,Lee SM,Morcos Y,Callaway JC,Levin MC

doi

10.1002/jnr.20137

keywords:

subject

Has Abstract

pub_date

2004-07-01 00:00:00

pages

82-9

issue

1

eissn

0360-4012

issn

1097-4547

journal_volume

77

pub_type

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