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08.01.2020 | Original Article

RP-HPLC-ESI-IT Mass Spectrometry Reveals Significant Variations of the Human Salivary Protein Profile Associated with Predominantly Antibody Deficiencies

verfasst von: Cristina Contini, Davide Firinu, Simone Serrao, Barbara Manconi, Alessandra Olianas, Francesco Cinetto, Fausto Cossu, Massimo Castagnola, Irene Messana, Stefano Del Giacco, Tiziana Cabras

Erschienen in: Journal of Clinical Immunology | Ausgabe 2/2020

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Abstract

Purpose

Present study is designed to discover potential salivary biomarkers associated with predominantly antibody deficiencies, which include a large spectrum of disorders sharing failure of antibody production, and B cell defects resulting in recurrent infections, autoimmune and inflammatory manifestations, and tumor susceptibility. Understanding and clinical classification of these syndromes is still challenging.

Methods

We carried out a study of human saliva based on liquid chromatography-mass spectrometry measurements of intact protein mass values. Salivary protein profiles of patients (n = 23) and healthy controls (n = 30) were compared.

Results

Patients exhibited lower abundance of α-defensins 1-4, cystatins S1 and S2, and higher abundance of glutathionylated cystatin B and cystatin SN than controls. Patients could be clustered in two groups on the basis of different levels of cystatin SN, S1 and S2, suggesting that these proteins may play different roles in the disease.

Conclusions

Quantitative variations of these pro-inflammatory and antimicrobial peptides/proteins may be related to immunodeficiency and infectious condition of the patients. The high incidence of tumors in the group with the highest level of cystatin SN, which is recognized as tumoral marker, appeared an intriguing result deserving of future investigations. Data are available via ProteomeXchange with identifier PXD012688.

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Bousfiha A, Jeddane L, Picard C, Ailal F, Bobby Gaspar H, Al-Herz W, et al. The 2017 IUIS phenotypic classification for primary immunodeficiencies. J Clin Immunol. 2018;38:129–43.PubMed

Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, de la Morena MT, et al. International consensus document (ICON): common variable immunodeficiency disorders. J Allergy Clin Immunol Pract. 2016;4:38–59.PubMed

Kienzler AK, Hargreaves CE, Patel SY. The role of genomics in common variable immunodeficiency disorders. Clin Exp Immunol. 2017;188:326–32.PubMed

Chapel H, Lucas M, Lee M, Bjorkander J, Webster D, Grimbacher B, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008;112:277–86.PubMed

Patuzzo G, Barbieri A, Tinazzi E, Veneri D, Argentino G, Moretta F, et al. Autoimmunity and infection in common variable immunodeficiency (CVID). Autoimm Rev. 2016;15:877–82.

Cunningham-Rundles C. The many faces of common variable immunodeficiency. Hematology Am Soc Hematol Educ Program. 2012;2012:301–5.PubMed

Knight AK, Cunningham-Rundles C. Inflammatory and autoimmune complications of common variable immune deficiency. Autoimmun Rev. 2006;5:156–9.PubMed

Boldovin S, Montin D, Martino S, Sciascia S, Menegatti E, Roccatello D. Common variable immunodeficiency: crossroads between infections, inflammation and autoimmunity. Autoimmun Rev. 2013;12:796–801.

Mortaz E, Tabarsi P, Mansouri D, Khosravi A, Garssen J, Velayati A, et al. Cancers related to immunodeficiencies: update and perspectives. Front Immunol. 2016;7:365.PubMedPubMedCentral

10.

Bateman EA, Ayers L, Sadler R, Lucas M, Roberts C, Woods A, et al. T cell phenotypes in patients, with common variable immunodeficiency disorders: associations with clinical phenotypes in comparison with other groups with recurrent infections. Clin Exp Immunol. 2012;170:202–11.PubMedPubMedCentral

11.

Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Galicier L, Lepelletier Y, Webster D, et al. Common variable immunodeficiency is associated with defective functions of dendritic cells. Blood. 2004;104:2441–3.PubMed

12.

Casulli S, Coignard-Biehler H, Amazzough K, Shoai-Tehrani M, Bayry J, Mahlaoui N, et al. Defective functions of polymorphonuclear neutrophils in patients with common variable immunodeficiency. Immunol Res. 2014;60:69–76.PubMed

13.

Carvalho KI, Melo KM, Bruno FR, Snyder-Cappione JE, Nixon DF, Costa-Carvalho BT, et al. Skewed distribution of circulating activated natural killer T (NKT) cells in patients with common variable immunodeficiency disorders (CVID). PLoS One. 2010;5:e1652.

14.

Maggadottir SM, Li J, Glessner JT, Li YR, Wei Z, Chang X, et al. Rare variants at 16p11.2 are associated with common variable immunodeficiency. J. Allergy Clin. Immunol. 2015;135:1569–77.PubMedPubMedCentral

15.

Rodríguez-Cortez VC, Del Pino-Molina L, Rodríguez-Ubreva J, Ciudad L, Gómez-Cabrero D, Company C, et al. Monozygotic twins for common variable immunodeficiency reveal impaired DNA demethylation during naïve-to-memory B-cell transition. Nat Commun. 2015;6:7335.PubMed

16.

Tabak LA. A revolution in biomedical assessment: the development of salivary diagnostics. J Dent Educ. 2001;65:1335–9.PubMed

17.

Yoshizawa JM, Schafer CA, Schafer JJ, Farrell JJ, Paster BJ, Wong DT. Salivary biomarkers: toward future clinical and diagnostic utilities. Clin Microbiol Rev. 2013;26:781–91.PubMedPubMedCentral

18.

Pfaffe T, Cooper-White J, Beyerlein P, Kostner K, Punyadeera C. Diagnostic potential of saliva: current state and future applications. Clin Chem. 2011;57:675–87.PubMed

19.

Cabras T, Iavarone F, Manconi B, Olianas A, Sanna MT, Castagnola M, et al. Top-down analytical platforms for the characterization of the human salivary proteome. Bioanalysis. 2014;6:563–81.PubMed

20.

Bandhakavi S, Stone MD, Onsongo G, Van Riper SK, Griffin TJ. A dynamic range compression and three-dimensional peptide fractionation analysis platform expands proteome coverage and the diagnostic potential of whole saliva. J Proteome Res. 2009;8:5590–600.PubMedPubMedCentral

21.

Castagnola M, Cabras T, Iavarone F, Fanali C, Nemolato S, Peluso G, et al. The human salivary proteome: a critical overview of the results obtained by different proteomic platforms. Expert Rev Proteomics. 2012;9:33–46.PubMed

22.

Oh SS, Park S, Lee KW, Madhi H, Park SG, Lee HG, et al. Extracellular cystatin SN and cathepsin B prevent cellular senescence by inhibiting abnormal glycogen accumulation. Cell Death Dis. 2017;8:e2729.PubMedPubMedCentral

23.

Yoneda K, Iida H, Endo H, Hosono K, Akiyama T, Takahashi H, et al. Identification of Cystatin SN as a novel tumor marker for colorectal cancer. Int J Oncol. 2009;35:33–40.PubMed

24.

Zhang Z, Marshall AG. An universal algorithm for fast and automated charge state deconvolution of electrospray mass-to-charge ratio spectra. J Am Soc Mass Spectrom. 1998;9:225–33.PubMed

25.

Castagnola M, Cabras T, Iavarone F, Vincenzoni F, Vitali A, Pisano E, et al. Top-down platform for deciphering the human salivary proteome. J Matern Fetal Neonatal Med. 2012;25:27–43.PubMed

26.

Manconi B, Liori B, Cabras T, Vincenzoni F, Iavarone F, Lorefice L, et al. Top-down proteomic profiling of human saliva in multiple sclerosis patients. J Proteome. 2018;187:212–22.

27.

Messana I, Cabras T, Pisano E, Sanna MT, Olianas A, Manconi B, et al. Trafficking and postsecretory events responsible for the formation of secreted human salivary peptide: a proteomics approach. Mol Cell Proteomics. 2008;7:911–26.PubMed

28.

Inzitari R, Cabras T, Pisano E, Fanali C, Manconi B, Scarano E, et al. HPLC-ESI-MS analysis of oral human fluids reveals that gingival crevicular fluid is the main source of oral thymosins beta(4) and beta(10). J Sep Sci. 2009;32:57–63.PubMed

29.

Cabras T, Manconi B, Iavarone F, Fanali C, Nemolato S, Fiorita A, et al. RP-HPLC-ESI-MS evidenced that salivary cystatin B is detectable in adult human whole saliva mostly as S-modified derivatives: S-Glutathionyl, S-cysteinyl and S-S 2-mer. J Proteome. 2012;75:908–13.

30.

Manconi B, Liori B, Cabras T, Vincenzoni F, Iavarone F, Castagnola M, et al. Salivary cystatins: exploring new post-translational modifications and polymorphisms by top-down high-resolution mass spectrometry. J Proteome Res. 2017;16:4196–07.PubMed

31.

Cabras T, Pisano E, Montaldo C, Giuca MR, Iavarone F, Zampino G, et al. Significant modifications of the salivary proteome potentially associated with complications of Down syndrome revealed by top-down proteomics. Mol Cell Proteomics. 2013;12:1844–52.PubMedPubMedCentral

32.

Cabras T, Pisano E, Mastinu A, Denotti G, Pusceddu PP, Inzitari R, et al. Alterations of the salivary secretory peptidome profile in children affected by type 1 diabetes. Mol Cell Proteomics. 2010;9:2099–108.PubMedPubMedCentral

33.

Cabras T, Sanna M, Manconi B, Fanni D, Demelia L, Sorbello O, et al. Proteomic investigation of whole saliva in Wilson's disease. J Proteome. 2015;128:154–63.

34.

Castagnola M, Inzitari R, Fanali C, Iavarone F, Vitali A, Desiderio C, et al. The surprising composition of the salivary proteome of preterm human newborn. Mol Cell Proteomics. 2011;10:M110.003467.PubMed

35.

Ong SE, Mann M. Mass spectrometry-based proteomics turns quantitative. Nat Chem Biol. 2005;1:252–62.PubMed

36.

Messana I, Inzitari R, Fanali C, Cabras T, Castagnola M. Facts and artifacts in proteomics of body fluids. What proteomics of saliva is telling us? J Sep Sci. 2008;31:1948–63.PubMed

37.

Vizcaíno JA, Csordas A, del-Toro N, Dianes JA, Griss J, Lavidas I, et al. 2016 update of the PRIDE database and its related tools. Nucleic Acids Res. 2016;44(D1):D447–56.PubMed

38.

Arba M, Iavarone F, Vincenzoni F, Manconi B, Vento G, Tirone C, et al. Proteomic characterization of the acid-insoluble fraction of whole saliva from preterm human newborns. J Proteome. 2016;2(146):48–57.

39.

Cabras T, Pisano E, Boi R, Olianas A, Manconi B, Inzitari R, et al. Age-dependent modifications of the human salivary secretory protein complex. J Proteome Res. 2009;8:4126–34.PubMed

40.

Cabras T, Melis M, Castagnola M, Padiglia A, Tepper BJ, Messana I, et al. Responsiveness to 6-n-propylthiouracil (PROP) is associated with salivary levels of two specific basic proline-rich proteins in humans. PLoS One. 2012;7:e30962.PubMedPubMedCentral

41.

Padiglia A, Orrù R, Boroumand M, Olianas A, Manconi B, Sanna MT, et al. Extensive characterization of the human salivary basic proline-rich protein family by top-down mass spectrometry. J Proteome Res. 2018;17:3292–07.PubMed

42.

Ganz T, Lehrer RI. Defensins. Curr Opin Immunol. 1994;6:584–9.PubMed

43.

Dale BA, Fredericks LP. Antimicrobial peptides in the oral environment: expression and function in health and disease. Curr Issues Mol Biol. 2005;7:119–33.PubMedPubMedCentral

44.

Pisano E, Cabras T, Montaldo C, Piras V, Inzitari R, Olmi C, et al. Peptides of human gingival crevicular fluid determinated by HPLC-ESI-IT-MS. Eur J Oral Sci. 2005;11:462–8.

45.

Lehrer RI. Primate defensins. Nat Rev Microbiol. 2004;2:727–38.PubMed

46.

Chalifour A, Jeannin P, Gauchat JF, Blaecke A, Malissard M, N’Guyen T, et al. Direct bacterial protein PAMP recognition by human NK cells involves TLRs and triggers alpha-defensin production. Blood. 2004;104:1778–83.PubMed

47.

Hazlett L, Wu M. Defensins in innate immunity. Cell Tissue Res. 2011;343:175–88.PubMed

48.

Agerberth B, Charo J, Werr J, Olsson B, Idali F, Lindbom L, et al. The human antimicrobial and chemotactic peptides LL-37 and alpha-defensins are expressed by specific lymphocyte and monocyte populations. Blood. 2000;96:3086–93.PubMed

49.

Vordenbäumen S, Schneider M. Defensins: potential effectors in autoimmune rheumatic disorders. Polymers. 2011;3:1268–81.

50.

Becker SC, Szyska M, Mensen A, Hellwig K, Otto R, Olfe L, et al. A comparative analysis of human bone marrow–resident and peripheral memory B cells. J allergy Clyn Immunol. 2018;141:1911–3.

51.

Agarwal S, Mayer L. Diagnosis and treatment of gastrointestinal disorders in patients with primary immunodeficiency. Clin Gastroenterol Hepatol. 2013;11:1050–63.PubMedPubMedCentral

52.

van de Ven AAJM, Janssen WJM, Schulz LS, van Loon AM, Voorkamp K, EAM S, et al. increased prevalence of gastrointestinal viruses and diminished secretory immunoglobulin a levels in antibody deficiencies. J Clin Immunol. 2014;34:962–70.PubMed

53.

Gounder AP, Myers ND, Treuting PM, Bromme BA, Wilson SS, Wiens ME, et al. Defensins potentiate a neutralizing antibody response to enteric viral infection. PLoS Pathog. 2016;12:e1005474.PubMedPubMedCentral

54.

Chaly YV, Paleolog EM, Kolesnikova TS, Tikhonov II, Petratchenko EV, Voitenok NN. Neutrophil alpha-defensin human neutrophil peptide modulates cytokine production in human monocytes and adhesion molecule expression in endothelial cells. Eur Cytokine Netw. 2000;11:257–66.PubMed

55.

Ryan CM, Souda P, Halgand F, Wong DT, Loo JA, Faull KF, et al. Confident assignment of intact mass tags to human salivary cystatins using top-down Fourier-transform ion cyclotron resonance mass spectrometry. J Am Soc Mass Spectrom. 2010;21:908–17.PubMedPubMedCentral

56.

Dickinson DP. Salivary (SD-type) cystatins: over one billion years in the making-but to what purpose? Crit Rev Oral Biol Med. 2002;13:485–08.PubMed

57.

Hopsu-Havu VK, Joronen IA, Järvinen M, Rinne A, Aalto M. Cysteine proteinase inhibitors produced by mononuclear phagocytes. Cell Tissue Res. 1984;236:161–4.PubMed

58.

Suzuki T, Hashimoto S, Toyoda N, Nagai S, Yamazaki N, Dong HY, et al. Comprehensive gene expression profile of LPS-stimulated human monocytes by SAGE. Blood. 2000;96:2584–91.PubMed

59.

Yang F, Tay KH, Dong L, Thorne RF, Jiang CC, Yang E, et al. Cystatin B inhibition of TRAIL-induced apoptosis is associated with the protection of FLIP(L) from degradation by the E3 ligase itch in human melanoma cells. Cell Death Differ. 2010;17:1354–67.PubMed

60.

Ceru S, Konjar S, Maher K, Repnik U, Krizaj I, Bencina M, et al. Stefin B interacts with histones and cathepsin L in the nucleus. J Biol Chem. 2010;285:10078–86.PubMedPubMedCentral

61.

Maher K, Jerič Kokelj B, Butinar M, Mikhaylov G, Manček-Keber M, Stoka V, et al. Role for Stefin B (Cystatin B) in inflammation and Endotoxemia. J Biol Chem. 2014;289:31736–50.PubMedPubMedCentral

62.

Lehtinen MK, Tegelberg S, Schipper H, Su H, Zukor H, Manninen O, et al. Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1. J Neurosci. 2009;29:5910–5.PubMedPubMedCentral

63.

Kopitar-Jerala N. The role of Stefin B in Neuro-inflammation. Front Cell Neurosci. 2015;9:458.PubMedPubMedCentral

64.

Polajnar M, Ceru S, Kopitar-Jerala N, Zerovnik E. Human stefin B normal and patho-physiological role: molecular and cellular aspects of amyloid-type aggregation of certain EPM1 mutants. Frontiers Mol Neurosci. 2012;5:88.

65.

Aukrust P, Berge RK, Muller F, Ueland PM, Svardal AM, Froland SS. Elevated plasma levels of reduced homocysteine in common variable immunodeficiency - a marker of enhanced oxidative stress. Eur J Clin Investig. 1997;27:723–30.

66.

Fábián TK, Hermann P, Beck A, Fejérdy P, Fábián G. Salivary defense proteins: their network and role in innate and acquired oral immunity. Int J Mol Sci. 2012;13:4295–320.PubMedPubMedCentral

67.

Zavasnik-Bergant T. Cystatin protease inhibitor and immune function. Front Biosci. 2008;13:4625–37.PubMed

68.

Ruzindana-Umunyana A, Weber JM. Interactions of human lacrimal and salivary cystatins with adenovirus endopeptidase. Antivir Res. 2001;51:203–14.PubMed

69.

Magister S, Kos J. Cystatins in immune system. J Cancer. 2013;4:45–56.PubMed

70.

Lindh E, Brӓnnstrӧm J, Jones P, Wermeling F, Hӓssler S, Betterle C, et al. Autoimmunity and cystatin SA1 deficiency behind chronic mucocutaneous candidiasis in autoimmune polyendocrine syndrome type 1. J Autoimmun. 2013;42:1–6.PubMed

71.

Baron A, DeCarlo A, Featherstone J. Functional aspects of the human salivary cystatins in the oral environment. Oral Dis. 1999;5:234–40.PubMed

72.

Cao X, Li Y, Luo RZ, Zhang L, Zhang SL, Zeng J, et al. Expression of Cystatin SN significantly correlates with recurrence, metastasis, and survival duration in surgically resected non-small cell lung cancer patients. Scientifc Reports. 2015;5:8230.

73.

Dai DN, Li Y, Chen B, Du Y, Li SB, Lu SX, et al. Elevated expression of CST1 promotes breast cancer progression and predicts a poor prognosis. J. Mol. Med. 2017;95:873–86.PubMed

74.

Jiang J, Liu HL, Liu ZH, Tan SW, Wu B. Identification of cystatin SN as a novel biomarker for pancreatic cancer. Tumor Biol. 2015;36:3903–10.

75.

Mayor PC, Eng KH, Singel KL, Abrams SI, Odunsi K, Moysich KB, et al. Cancer in primary immunodeficiency diseases: cancer incidence in the United States immune deficiency network registry. J Allergy Clin Immunol. 2018;141:1028–35.PubMed

Titel: RP-HPLC-ESI-IT Mass Spectrometry Reveals Significant Variations of the Human Salivary Protein Profile Associated with Predominantly Antibody Deficiencies
verfasst von: Cristina Contini
Davide Firinu
Simone Serrao
Barbara Manconi
Alessandra Olianas
Francesco Cinetto
Fausto Cossu
Massimo Castagnola
Irene Messana
Stefano Del Giacco
Tiziana Cabras
Publikationsdatum: 08.01.2020
Verlag: Springer US
Erschienen in: Journal of Clinical Immunology / Ausgabe 2/2020
Print ISSN: 0271-9142
Elektronische ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-020-00743-4

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RP-HPLC-ESI-IT Mass Spectrometry Reveals Significant Variations of the Human Salivary Protein Profile Associated with Predominantly Antibody Deficiencies

Abstract

Purpose

Methods

Results

Conclusions

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Abstract

Purpose

Methods

Results

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