Monday, 23 January 2012

Research MSers react against myelin proteins

Epub ahead of print Quintana FJ, Farez MF, Izquierdo G, Lucas M, Cohen IR, Weiner HL. Antigen microarrays identify CNS-produced autoantibodies in RRMS.Neurology. 2012 Jan


OBJECTIVE:
Multiple sclerosis (MS) is characterized by the local production of antibodies in the CNS and the presence of oligoclonal bands in the CSF. Antigen arrays allow the study of antibody reactivity against a large number of antigens using small volumes of fluid with greater sensitivity than ELISA. We investigated whether there were unique autoantibodies in the CSF of patients with MS as measured by antigen arrays and whether these antibodies differed from those in serum.


METHODS: We used antigen arrays to analyze the reactivity of antibodies in matched serum and CSF samples of 20 patients with untreated relapsing-remitting MS (RRMS), 26 methylprednisolone-treated patients with RRMS, and 20 control patients with other noninflammatory neurologic conditions (ONDs) against 334 different antigens including heat shock proteins, lipids, and myelin antigens.


RESULTS: We found different antibody signatures in matched Cerebospinal fluid (CSF) and serum samples The targets of these antibodies included epitopes of the myelin antigens cyclic nucleotide phophodiesterase, myelin basic protein, myelin-associated oligodendrocyte basic protein, proteolipid protein (59%), Heat shock protein 60 KDa and heat shock protein 70 Kda (38%), and the 68-kDa neurofilament (3%).

The antibody response in patients with MS was heterogeneous; CSF antibodies in individual patients reacted with different autoantigens. These autoantibodies were locally synthesized in the CNS and were of the immunoglobulin G class. Finally, we found that treatment with steroids decreased autoantibody reactivity, epitope spreading (when the immune reaction changes from targeting the primary epitope to also targeting other epitopes. With time the number of targets expand) and intrathecal (within the space surrounding the brain and spinal cord) autoantibody synthesis.


CONCLUSIONS: These studies provide a new avenue to investigate the local antibody response in the CNS, which may serve as a biomarker to monitor both disease progression and response to therapy in MS.

Heterogeneous autoantibody reactivity in CSF antibodies from Relapsing remitting MS. Heatmap in which each column represents an RRMS patient, and each row shows the antibody reactivity to an antigen according to the colorimetric scale shown on the left.

The role of autoreactive antibodies in multiple sclerosis (MS) has received intense attention since the discovery of oligoclonal immunoglobulin (Ig) bands in the majority of patients with MS. However, many questions remain. It is still possible that the intrathecal production of antibody is an epiphenomenon of CNS autoimmunity, resulting from growth factor-driven expansion of long-lived B cells in the meningeal compartment. Alternatively antibody production from antigen-driven proliferation of B-cell clones could be a component of CNS immunopathology. Antibodies from oligoclonal bands is produced by B lineage cells within the CNS. These have been shown to recognizes epitopes of multiple neurotropic viruses and Epstein-Barr virus antigens. However, as this study shows anti-myelin antibodies also occur in the serum and CSF of patients with MS.

The array contained a large number of myelin protein epitopes that could be probed to see what antibodies were present in the blood and cerebrospinal fluid of MSers but these were largely linear peptide sequences of about 20 amino acids (proteins are often around 300-400 amino acids) and thus would fail to detect antibodies that detect conformational epitopes, which detect three-dimentional structures that have been found to be more important with regard to pathogenic-disease causing antibodies. There were some whole proteins and tissue extracts on this arrray.

As found previously in animal autoimmunity, there can be a wide diverisity of autoantibody (antibodies that react to the body) response and that this can broaden with time. There was alot of diversity seen between individuals and there was not one protein that everybody reacted to but it was evident that everyone with MS was reacting to at least one of the proteins. This occurred with relative high frequency for some of the epitopes such as over 60% of MSers vereses 0% in health individuals. However myelin is being damaged in MS and one wonders if this triggers an antibody response so it is secondary to the problem rather than being a primary problem.

If you get immunosuppression with your drug of interest, it may be hoped that the antibody responses would be reduced. This may be a new tool to detect this.



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