Proteomic Analysis of Cerebrospinal Fluid: A Search for Biomarkers of Neuropsychiatric Systemic Lupus Erythematosus

Author(s): Johanna Pedroza-Díaz*, Tania Paola Luján Chavarria, Carlos Horacio Muñoz Vahos, Diego Francisco Hernández Ramírez, Elizabeth Olivares-Martínez, Gloria Vásquez, Luis Llorente, Hilda Fragoso-Loyo, Sarah Röthlisberger, Blanca Lucía Ortiz Reyes.

Journal Name: Current Proteomics

Volume 16 , Issue 2 , 2019

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Abstract:

Background: Neuropsychiatric systemic lupus erythematosus or NPSLE, as its name suggests, refers to the neurological and psychiatric manifestations of Systemic Lupus Erythematosus (SLE). In clinical practice, it is often difficult to reach an accurate diagnosis, as this disease presents differently in different patients, and the available diagnostic tests are often not specific enough.

Objectives: The aim of this study was to search for proteomic biomarkers in cerebrospinal fluid that could be proposed as diagnostic aids for this disease.

Methods: The proteomic profile of cerebrospinal fluid samples of 19 patients with NPSLE, 12 patients with SLE and no neuropsychiatric manifestation (SLEnoNP), 6 patients with neuropsychiatric symptoms but no SLE (NPnoSLE), 5 with Other Autoimmune Disorders without neuropsychiatric manifestations (OADs), and 4 Healthy Controls (HC), were obtained by two-dimensional gel electrophoresis and compared using ImageMaster Platinum 7.0 software.

Results: The comparative analysis of the different study groups revealed three proteins of interest that were consistently over-expressed in NPSLE patients. These were identified by mass spectrometry as albumin (spot 16), haptoglobin (spot 160), and beta-2 microglobulin (spot 161).

Conclusion: This work is one of the few proteomic studies of NPSLE that uses cerebrospinal fluid as the biological sample. Albumin has previously been proposed as a potential biomarker of rheumatoid arthritis and SLE, which is coherent with these results; but this is the first report of haptoglobin and beta-2 microglobulin in NPSLE, although haptoglobin has been associated with increased antibody production and beta-2 microglobulin with lupus nephritis.

Keywords: Biomarkers, cerebrospinal fluid, mass spectrometry, neuropsychiatric systemic lupus erythematosus, proteomics, two-dimensional gel electrophoresis.

[1]
Kammer, G.M. Lupus, Molecular and Celular Pathogenesis, 1st ed; Humana Press Inc: New Jersey, USA, 1999, pp. 1-709.
[2]
Cervera, R.; Khamashta, M.A.; Font, J.; Sebastiani, G.D.; Gil, A.; Lavilla, P.; Mejia, J.C.; Aydintug, A.O.; Chwalinska-Sadowska, H.; de Ramon, E.; Fernandez-Nebro, A.; Galeazzi, M.; Valen, M.; Mathieu, A.; Houssiau, F.; Caro, N.; Alba, P.; Ramos-Casals, M.; Ingelmo, M.; Hughes, G.R. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: A comparison of early and late manifestations in a cohort of 1,000 patients. Medicine , 2003, 82, 299-308.
[3]
Bertsias, G.K.; Boumpas, D.T. Pathogenesis, diagnosis and management of neuropsychiatric SLE manifestations. Nat. Rev. Rheumatol., 2010, 6, 358-367.
[4]
Arriens, C.; Mohan, C. Systemic lupus erythematosus diagnostics in the “omics” era. Int. J. Clin. Rheumatol., 2013, 8, 671-687.
[5]
Wright, B.L.; Lai, J.T.; Sinclair, A.J. Cerebrospinal fluid and lumbar puncture: A practical review. J. Neurol., 2012, 259(8), 1530-1545.
[6]
Colasanti, T.; Delunardo, F.; Margutti, P.; Vacirca, D.; Piro, E.; Siracusano, A.; Ortona, E. Autoantibodies involved in neuropsychiatric manifestations associated with systemic lupus erythematosus. J. Neuroimmunol., 2009, 212, 3-9.
[7]
Zandman-Goddard, G.; Chapman, J.; Shoenfeld, Y. Autoantibodies involved in neuropsychiatric SLE and antiphospholipid syndrome. Semin. Arthritis Rheum., 2007, 36, 297-315.
[8]
Tin, S.K.; Xu, Q.; Thumboo, J.; Lee, L.Y.; Tse, C.; Fong, K.Y. Novel brain reactive autoantibodies: Prevalence in systemic lupus erythematosus and association with psychoses and seizures. J. Neuroimmunol., 2005, 169, 153-160.
[9]
Fragoso-Loyo, H.; Cabiedes, J.; Orozco-Narvaez, A.; Davila-Maldonado, L.; Atisha-Fregoso, Y.; Diamond, B.; Llorente, L.; Sanchez-Guerrero, J. Serum and cerebrospinal fluid autoantibodies in patients with neuropsychiatric lupus erythematosus. Implications for diagnosis and pathogenesis. PLoS One, 2008, 3, e3347.
[10]
Labrador-Horrillo, M.; Martinez-Valle, F.; Gallardo, E.; Rojas-Garcia, R.; Ordi-Ros, J.; Vilardell, M. Anti-ganglioside antibodies in patients with systemic lupus erythematosus and neurological manifestations. Lupus, 2012, 21, 611-615.
[11]
Williams, R.C.; Sugiura, K.; Tan, E.M. Antibodies to microtubule-associated protein 2 in patients with neuropsychiatric systemic lupus erythematosus. Arthritis Rheum., 2004, 50, 1239-1247.
[12]
Tsuchiya, H.; Haga, S.; Takahashi, Y.; Kano, T.; Ishizaka, Y.; Mimori, A. Identification of novel autoantibodies to GABA(B) receptors in patients with neuropsychiatric systemic lupus erythematosus. Rheumatology, 2014, 53, 1219-1228.
[13]
Santer, D.M.; Yoshio, T.; Minota, S.; Moller, T.; Elkon, K.B. Potent induction of IFN-alpha and chemokines by autoantibodies in the cerebrospinal fluid of patients with neuropsychiatric lupus. J. Immunol., 2009, 182, 1192-1201.
[14]
Sato, T.; Fujii, T.; Yokoyama, T.; Fujita, Y.; Imura, Y.; Yukawa, N.; Kawabata, D.; Nojima, T.; Ohmura, K.; Usui, T.; Mimori, T. Anti-U1 RNP antibodies in cerebrospinal fluid are associated with central neuropsychiatric manifestations in systemic lupus erythematosus and mixed connective tissue disease. Arthritis Rheum., 2010, 62, 3730-3740.
[15]
Sherer, Y.; Gorstein, A.; Fritzler, M.J.; Shoenfeld, Y. Autoantibody explosion in systemic lupus erythematosus: More than 100 different antibodies found in SLE patients. Semin. Arthritis Rheum., 2004, 34, 501-537.
[16]
Okamoto, H.; Kobayashi, A.; Yamanaka, H. Cytokines and chemokines in neuropsychiatric syndromes of systemic lupus erythematosus. J. Biomed. Biotechnol., 2010, 2010, 268436.
[17]
Sun, L.; Chen, H.; Hu, C.; Wang, P.; Li, Y.; Xie, J.; Tang, F.; Ba, D.; Zhang, X.; He, W. Identify biomarkers of neuropsychiatric systemic lupus erythematosus by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry combined with weak cation magnetic beads. J. Rheumatol., 2011, 38, 454-461.
[18]
Chung, S.A.; Criswell, L.A. PTPN22: Its role in SLE and autoimmunity. Autoimmunity, 2007, 40, 582-590.
[19]
Bombardier, C.; Gladman, D.D.; Urowitz, M.B.; Caron, D.; Chang, C.H. Derivation of the SLEDAI. A disease activity index for lupus patients. The committee on prognosis studies in SLE. Arthritis Rheum., 1992, 35, 630-640.
[20]
Griffiths, B.; Mosca, M.; Gordon, C. Assessment of patients with systemic lupus erythematosus and the use of lupus disease activity indices. Best Pract. Res. Clin. Rheumatol., 2005, 19, 685-708.
[21]
Petri, M.; Orbai, A-M.; Alarcón, G.S.; Gordon, C.; Merrill, J.T.; Fortin, P.R.; Bruce, I.N.; Isenberg, D.; Wallace, D.J.; Nived, O.; Sturfelt, G.; Ramsey-Goldman, R.; Bae, S-C.; Hanly, J.G.; Sánchez-Guerrero, J.; Clarke, A.; Aranow, C.; Manzi, S.; Urowitz, M.; Gladman, D.; Kalunian, K.; Costner, M.; Werth, V.P.; Zoma, A.; Bernatsky, S.; Ruiz-Irastorza, G.; Khamashta, M.A.; Jacobsen, S.; Buyon, J.P.; Maddison, P.; Dooley, M.A.; van Vollenhoven, R.F.; Ginzler, E.; Stoll, T.; Peschken, C.; Jorizzo, J.L.; Callen, J.P.; Lim, S.S.; Fessler, B.J.; Inanc, M.; Kamen, D.L.; Rahman, A.; Steinsson, K.; Franks, A.G.; Sigler, L.; Hameed, S.; Fang, H.; Pham, N.; Brey, R.; Weisman, M.H.; McGwin, G.; Magder, L.S. Jr.; Magder, L.S. Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum., 2012, 64, 2677-2686.
[22]
Bai, S.; Liu, S.; Guo, X.; Qin, Z.; Wang, B.; Li, X.; Qin, Y.; Liu, Y.H. Proteome analysis of biomarkers in the cerebrospinal fluid of neuromyelitis optica patients. Mol. Vis., 2009, 15, 1638-1648.
[23]
Mosca, M.; Bombardieri, S. Assessing remission in systemic lupus erythematosus. Clin. Exp. Rheumatol., 2006, 24, S-99-S-104.
[24]
Ahmed, R.M.; Paterson, R.W.; Warren, J.D.; Zetterberg, H.; O’Brien, J.T.; Fox, N.C.; Halliday, G.M.; Schott, J.M. Biomarkers in dementia: Clinical utility and new directions. J. Neurol. Neurosurg. Psychiatry, 2014, 85, 1426-1434.
[25]
Blennow, K.; Hampel, H. CSF markers for incipient alzheimer’s disease. Lancet Neurol., 2003, 2, 605-613.
[26]
Schutzer, S.E.; Angel, T.E.; Liu, T.; Schepmoes, A.A.; Clauss, T.R.; Adkins, J.N.; Camp, D.G.; Holland, B.K.; Bergquist, J.; Coyle, P.K.; Smith, R.D.; Fallon, B.A.; Natelson, B.H. Distinct cerebrospinal fluid proteomes differentiate post-treatment lyme disease from chronic fatigue syndrome. PLoS One, 2011, 6, e17287.
[27]
Blennow, K.; Dubois, B.; Fagan, A.M.; Lewczuk, P.; de Leon, M.J.; Hampel, H. Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early alzheimer’s disease. Alzheimers Dement., 2015, 11, 58-69.
[28]
Petrak, J.; Ivanek, R.; Toman, O.; Cmejla, R.; Cmejlova, J.; Vyoral, D.; Zivny, J.; Vulpe, C.D. Deja vu in proteomics. A hit parade of repeatedly identified differentially expressed proteins. Proteomics, 2008, 8, 1744-1749.
[29]
Fanali, G.; di Masi, A.; Trezza, V.; Marino, M.; Fasano, M.; Ascenzi, P. Human serum albumin: From bench to bedside. Mol. Aspects Med., 2012, 33, 209-290.
[30]
Kazemipour, N.; Qazizadeh, H.; Sepehrimanesh, M.; Salimi, S. Biomarkers identified from serum proteomic analysis for the differential diagnosis of systemic lupus erythematosus. Lupus, 2015, 24, 582-587.
[31]
Yip, J.; Aghdassi, E.; Su, J.; Lou, W.; Reich, H.; Bargman, J.; Scholey, J.; Gladman, D.D.; Urowitz, M.B.; Fortin, P.R. Serum albumin as a marker for disease activity in patients with systemic lupus erythematosus. J. Rheumatol., 2010, 37, 1667-1672.
[32]
Galicia, J.G.; Ceuppens, J.L. Haptoglobin function and regulation in autoimmune diseases; Acute Phase Proteins-Regulat. Funct. Acute Phase Proteins, 2011, pp. 229-240.
[33]
Pavon, E.J.; Munoz, P.; Lario, A.; Longobardo, V.; Carrascal, M.; Abian, J.; Martin, A.B.; Arias, S.A.; Callejas-Rubio, J.L.; Sola, R.; Navarro-Pelayo, F.; Raya-Alvarez, E.; Ortego-Centeno, N.; Zubiaur, M.; Sancho, J. Proteomic analysis of plasma from patients with systemic lupus erythematosus: Increased presence of haptoglobin alpha2 polypeptide chains over the alpha1 isoforms. Proteomics, 2006, 6(Suppl. 1), S282-S292.
[34]
Haas, B.; Serchi, T.; Wagner, D.R.; Gilson, G.; Planchon, S.; Renaut, J.; Hoffmann, L.; Bohn, T.; Devaux, Y. Proteomic analysis of plasma samples from patients with acute myocardial infarction identifies haptoglobin as a potential prognostic biomarker. J. Proteomics, 2011, 75, 229-236.
[35]
Van Vlierberghe, H.; Langlois, M.; Delanghe, J. Haptoglobin polymorphisms and iron homeostasis in health and in disease. Clin. Chim. Acta, 2004, 345, 35-42.
[36]
Hanasaki, K.; Powell, L.D.; Varki, A. Binding of human plasma sialoglycoproteins by the B cell-specific lectin CD22. Selective recognition of immunoglobulin M and haptoglobin. J. Biol. Chem., 1995, 270, 7543-7550.
[37]
Zhao, X.; Song, S.; Sun, G.; Strong, R.; Zhang, J.; Grotta, J.C.; Aronowski, J. Neuroprotective role of haptoglobin after intracerebral hemorrhage. J. Neurosci., 2009, 29, 15819-15827.
[38]
Chang, K.H.; Tseng, M.Y.; Ro, L.S.; Lyu, R.K.; Tai, Y.H.; Chang, H.S.; Wu, Y.R.; Huang, C.C.; Hsu, W.C.; Kuo, H.C.; Chu, C.C.; Chen, C.M. Analyses of haptoglobin level in the cerebrospinal fluid and serum of patients with neuromyelitis optica and multiple sclerosis. Clin. Chim. Acta, 2013, 417, 26-30.
[39]
Elovaara, I.; Icen, A.; Palo, J.; Erkinjuntti, T. CSF in alzheimer’s disease. Studies on blood-brain barrier function and intrathecal protein synthesis. J. Neurol. Sci., 1985, 70, 73-80.
[40]
Fragoso-Loyo, H.; Richaud-Patin, Y.; Orozco-Narvaez, A.; Davila-Maldonado, L.; Atisha-Fregoso, Y.; Llorente, L.; Sanchez-Guerrero, J. Interleukin-6 and chemokines in the neuropsychiatric manifestations of systemic lupus erythematosus. Arthritis Rheum., 2007, 56, 1242-1250.
[41]
Hirohata, S.; Kanai, Y.; Mitsuo, A.; Tokano, Y.; Hashimoto, H. Accuracy of cerebrospinal fluid IL-6 testing for diagnosis of lupus psychosis. A multicenter retrospective study. Clin. Rheumatol., 2009, 28, 1319-1323.
[42]
Bruschi, M.; Santucci, L.; Candiano, G.; Ghiggeri, G.M. Albumin heterogeneity in low-abundance fluids. The case of urine and cerebro-spinal fluid. Biochim. Biophys. Acta, Gen. Subj., 2013, 1830, 5503-5508.
[43]
Domenicali, M.; Baldassarre, M.; Giannone, F.A.; Naldi, M.; Mastroroberto, M.; Biselli, M.; Laggetta, M.; Patrono, D.; Bertucci, C.; Bernardi, M.; Caraceni, P. Posttranscriptional changes of serum albumin: Clinical and prognostic significance in hospitalized patients with cirrhosis. Hepatology, 2014, 60, 1851-1860.
[44]
Shah, A.; Singh, H.; Sachdev, V.; Lee, J.; Yotsukura, S.; Salgia, R.; Bharti, A. Differential serum level of specific haptoglobin isoforms in small cell lung cancer. Curr. Proteomics, 2010, 7, 49-65.
[45]
Kim, H.A.; Jeon, J.Y.; Yoon, J.M.; Suh, C.H. Beta 2-microglobulin can be a disease activity marker in systemic lupus erythematosus. Am. J. Med. Sci., 2010, 339, 337-340.
[46]
Madureira-Silva, M.V.; Moscoso-Solorzano, G.T.; Nishida, S.K.; Mastroianni-Kirsztajn, G. Serum beta 2-microglobulin/cystatin C index: A useful biomarker in lupus nephritis? Nephron Extra, 2012, 2, 169-176.
[47]
Calderon, C.; Zucht, H.D.; Kuhn, A.; Wozniacka, A.; Szepietowski, J.C.; Nyberg, F.; Weichenthal, M.; Piantone, A.; Budde, P. A multicenter photoprovocation study to identify potential biomarkers by global peptide profiling in cutaneous lupus erythematosus. Lupus, 2015, 24, 1406-1420.


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Article Details

VOLUME: 16
ISSUE: 2
Year: 2019
Page: [110 - 118]
Pages: 9
DOI: 10.2174/1570164615666180911125252
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