Sage Journals: Discover world-class research

Abstract

Background:

Recent studies have revealed that the disruption of the blood–brain barrier (BBB) might contribute to the induction of neurodegeneration in the progressive stage of multiple sclerosis (MS).

Objective:

We investigated a potential target for the serum auto-antibodies responsible for the BBB impairment in patients with secondary progressive MS (SPMS).

Methods:

We identified undetermined target antigens in human brain microvascular endothelial cells (BMECs) that reacted with auto-antibodies in sera from SPMS patients using a proteomic approach. In addition, we examined how the identified auto-antibodies compromise the BBB integrity.

Results:

We found that 10 of 11 SPMS sera had auto-antibodies against galectin-3, although the patients with other neurological diseases did not have these antibodies. Downregulation of galectin-3 led to elevated intercellular adhesion molecule-1 (ICAM-1) and phospho-nuclear factor-kappa (NFκ) B p65 expression in the BMECs. Exposure to SPMS patients’ sera also increased the protein levels of ICAM-1 and phospho-NFκB p65 in BMECs, but these effects induced by anti-galectin-3 immunoreactivity were canceled by the downregulation of galectin-3.

Conclusion:

Galectin-3 is a possible immunological target molecule of the pathogenic auto-antibodies and contributes to the persistent BBB breakdown in patients with SPMS. These antibodies may also serve as a novel biomarker for SPMS.

Keywords

Galectin-3 blood–brain barrier secondary progressive multiple sclerosis

Get full access to this article

View all access options for this article.

References

Bradl

Lassmann

Progressive multiple sclerosis. Semin Immunopathol 2009; 31: 455–465.

Mahad

Trapp

Lassmann

Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol 2015; 14: 183–193.

Ontaneda

Fox

Chataway

Clinical trials in progressive multiple sclerosis: Lessons learned and future perspectives. Lancet Neurol 2015; 14: 208–223.

Dutta

Trapp

BD.

Relapsing and progressive forms of multiple sclerosis: Insights from pathology. Curr Opin Neurol 2014; 27: 271–278.

Alvarez

Cayrol

Prat

Disruption of central nervous system barriers in multiple sclerosis. Biochim Biophys Acta 2011; 1812: 252–264.

Kermode

Thompson

Tofts

. Breakdown of the blood-brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis. Pathogenetic and clinical implications. Brain 1990; 113: 1477–1489.

Claudio

Raine

Brosnan

CF.

Evidence of persistent blood-brain barrier abnormalities in chronic-progressive multiple sclerosis. Acta Neuropathol 1995; 90: 228–238.

Plumb

McQuaid

Mirakhur

. Abnormal endothelial tight junctions in active lesions and normal-appearing white matter in multiple sclerosis. Brain Pathol 2002; 12: 154–169.

Kirk

Plumb

Mirakhur

. Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood-brain barrier leakage and active demyelination. J Pathol 2003; 201: 319–327.

10.

Leech

Kirk

Plumb

. Persistent endothelial abnormalities and blood-brain barrier leak in primary and secondary progressive multiple sclerosis. Neuropathol Appl Neurobiol. 2007; 33: 86–98.

11.

Shimizu

Tasaki

Sano

. Sera from remitting and secondary progressive multiple sclerosis patients disrupt the blood-brain barrier. PLoS ONE 2014; 9: e92872.

12.

Nishihara

Shimizu

Sano

. Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis. PLoS ONE 2015; 10: e0121488.

13.

Polman

Reingold

Banwell

. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69: 292–302.

14.

Wingerchuk

Lennon

Pittock

. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006; 66: 1485–1489.

15.

Brooks

BR.

El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial “Clinical limits of amyotrophic lateral sclerosis” workshop contributors. J Neurol Sci 1994; 124: 96–107.

16.

Bohan

Peter

Bowman

. Computer-assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine 1977; 56: 255–286.

17.

Sano

Shimizu

Abe

. Establishment of a new conditionally immortalized human brain microvascular endothelial cell line retaining an in vivo blood-brain barrier function. J Cell Physiol 2010; 225: 519–528.

18.

Maeda

Sano

Abe

. Establishment and characterization of spinal cord microvascular endothelial cell lines. Clin Exp Neuroimmunol 2013; 4: 326–338.

19.

Akada

Okuda

Hiramoto

. Proteomic characterization of Helicobacter pylori CagA antigen recognized by child serum antibodies and its epitope mapping by peptide array. PLoS ONE 2014; 9: e104611.

20.

Wang

Kuramitsu

Ueno

. Glyoxalase I (GLO1) is up-regulated in pancreatic cancerous tissues compared with related non-cancerous tissues. Anticancer Res 2012; 32: 3219–3222.

21.

Han

Cui

. Cisplatin up-regulates ICAM-1 expression in endothelial cell via a NF-kappaB dependent pathway. Cancer Sci 2008; 99: 391–397.

22.

Guevremont

Martel-Pelletier

Boileau

. Galectin-3 surface expression on human adult chondrocytes: A potential substrate for collagenase-3. Ann Rheum Dis 2004; 63: 636–643.

23.

Cristofanilli

Rosenthal

Cymring

. Progressive multiple sclerosis cerebrospinal fluid induces inflammatory demyelination, axonal loss, and astrogliosis in mice. Exp Neurol 2014; 261: 620–632.

24.

Haines

Vidaurre

Zhang

. Multiple sclerosis patient-derived CSF induces transcriptional changes in proliferating oligodendrocyte progenitors. Mult Scler 2015; 21: 1655–1669.

25.

Gao

Functions of galectin-3 and its role in fibrotic diseases. J Pharmacol Exp Ther 2014; 351: 336–343.

26.

Tsai

Chen

. Galectin-3 suppresses mucosal inflammation and reduces disease severity in experimental colitis. J Mol Med 2016; 94: 545–556.

27.

Dumic

Dabelic

Flogel

Galectin-3: An open-ended story. Biochim Biophys Acta 2006; 1760: 616–635.

28.

Ott

Jacobs

Haucke

. Role of advanced glycation end products in cellular signaling. Redox Biology 2014; 2: 411–429.

29.

Ochieng

Leite-Browning

Warfield

Regulation of cellular adhesion to extracellular matrix proteins by galectin-3. Biochem Biophys Res Commun 1998; 246: 788–791.

30.

Shin

The pleiotropic effects of galectin-3 in neuroinflammation: A review. Acta Histochem 2013; 115: 407–411.

31.

Radosavljevic

Volarevic

Jovanovic

. The roles of galectin-3 in autoimmunity and tumor progression. Immunol Res 2012; 52: 100–110.

32.

James

Hillis

Adorjan

. Loss of galectin-3 decreases the number of immune cells in the subventricular zone and restores proliferation in a viral model of multiple sclerosis. Glia 2016; 64: 105–121.

33.

Jeon

Yoon

Chang

. Galectin-3 exerts cytokine-like regulatory actions through the JAK-STAT pathway. J Immunol 2010; 185: 7037–7046.

34.

Stancic

van Horssen

Thijssen

. Increased expression of distinct galectins in multiple sclerosis lesions. Neuropathol Appl Neurobiol. 2011; 37: 654–671.

35.

Zlokovic

BV.

The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 2008; 57: 178–201.

36.

Jensen-Jarolim

Neumann

Oberhuber

. Anti-Galectin-3 IgG autoantibodies in patients with Crohn’s disease characterized by means of phage display peptide libraries. J Clin Immunol 2001; 21: 348–356.

37.

Shi

Tan

Meng

. Association of anti-acidic ribosomal protein P0 and anti-galectin 3 antibodies with the development of skin lesions in systemic lupus erythematosus. Arthritis Rheumatol 2015; 67: 193–203.

38.

Fukushi

Makagiansar

Stallcup

WB.

NG2 proteoglycan promotes endothelial cell motility and angiogenesis via engagement of galectin-3 and alpha3beta1 integrin. Mol Biol Cell 2004; 15: 3580–3590.

39.

Shepro

Morel

NM.

Pericyte physiology. FASEB J 1993; 7: 1031–1038.

40.

Abbott

Mendonca

Dolman

DE.

The blood-brain barrier in systemic lupus erythematosus. Lupus 2003; 12: 908–915.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.10 MB

0.22 MB

Identification of galectin-3 as a possible antibody target for secondary progressive multiple sclerosis

Abstract

Background:

Objective:

Methods:

Results:

Conclusion:

Keywords

Get full access to this article

References

Supplementary Material