Cleavage of cystatin C in the cerebrospinal fluid of patients with multiple sclerosis.
OBJECTIVE
The diagnosis of multiple sclerosis (MS) can be challenging because of the lack of a specific diagnostic test. Recent advances in proteomics, however, offer new opportunities for biomarker discovery and the study of disease pathogenesis.


METHODS
We analyzed cerebrospinal fluid (CSF) samples from 29 patients with MS or clinically isolated syndromes (CIS), 27 patients with transverse myelitis (TM), 50 patients with human immunodeficiency virus (HIV) infection, and 27 patients with other neurological diseases (ONDs) by surface-enhanced laser desorption/ionization time-of-flight mass spectroscopy.


RESULTS
We found a unique protein of 12.5 kDa that was 100% specific for MS/CIS compared with TM or OND. Low levels of this protein were found in some patients with HIV infection. Tandem mass spectroscopy of a tryptic digest of this 12.5 kDa protein identified it as a cleavage product of full-length cystatin C (13.4 kDa), an important inhibitor of cysteine proteases including the cathepsins. Although total cystatin C levels in the MS patients was not different compared with controls, the patients with the highest 12.5/13.4 peak ratios also had the greatest cathepsin B inhibitory activity.


CONCLUSIONS
This suggests that cleavage of cystatin C may be an adaptive host response and may identify a subgroup of patients with MS.
Irani
David N
DN
Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
Anderson
Caroline
C
Gundry
Rebekah
R
Cotter
Robert
R
Moore
Stacy
S
Kerr
Douglas A
DA
McArthur
Justin C
JC
Sacktor
Ned
N
Pardo
Carlos A
CA
Jones
Melina
M
Calabresi
Peter A
PA
Nath
Avindra
A
D000293:Adolescent; D000328:Adult; D002403:Cathepsins / Q000134:cerebrospinal fluid / Q000145:classification; D055316:Cystatin C; D015891:Cystatins / Q000134:cerebrospinal fluid* / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D005260:Female; D015658:HIV Infections / Q000134:cerebrospinal fluid; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D008970:Molecular Weight; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid*; D009422:Nervous System Diseases / Q000134:cerebrospinal fluid; D040081:Protein Array Analysis / Q000379:methods; D013223:Statistics as Topic
C525030:CST3 protein, human; D055316:Cystatin C; D015891:Cystatins; D002403:Cathepsins