Proteomic Analysis of the Acid-Insoluble Fraction of Whole Saliva from Patients Affected by Different Forms of Non-histaminergic Angioedema

Abstract

We analyzed by bidimensional electrophoresis the acid-insoluble fraction of saliva from three classes of angioedema patients and a healthy control group, highlighting significant variations of several normalized spot volumes. Characterization of the corresponding proteins was performed by in-gel tryptic digestion of the spots, followed by high-resolution HPLC-ESI-MS/MS analysis of tryptic mixtures. By this strategy, 16 differentially-expressed proteins among two or more groups were identified. We found higher concentration of proteins involved in immune response (interleukin-1 receptor antagonist and annexin A1), and of moonlighting proteins acting as plasminogen receptors (glyceraldehyde-3-phosphate dehydrogenase, α-enolase, and annexin A2) in patients affected by the idiopathic non-histaminergic or hereditary angioedema with unknown origin with respect to healthy controls. These data provide new information on the molecular basis of these less characterized types of angioedema.

Graphical Abstract

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Abbreviations

AAE:

acquired angioedema

ACN:

acetonitrile

Abs:

antibodies

C1-INH:

complement component 1 esterase inhibitor

DTT:

Dithiotreitol

EAACI:

European Academy of Allergy and Clinical Immunology

E-FABP:

epidermal fatty acid-binding protein

ENOA:

α-enolase, FA, formic acid

FXII:

coagulation factor XII

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

HAWK:

Hereditary Angioedema International Working Group

HAE:

hereditary angioedema

HC:

healthy controls

HMWK:

prekallikrein-high-molecular-weight-kininogen

IAM:

iodoacetamide

IH:

idiopathic histaminergic

InH:

idiopathic non histaminergic

IL-1:

interleukin 1

IL-1Ra:

interleukin-1 receptor antagonist

IPG:

immobilized pH gradient

LC-MS:

liquid mass spectrometry

LEI:

leukocyte elastase inhibitor

MS/MS:

tandem mass spectrometry

MW:

molecular weight; pI, isoelectric point

PAGE:

polyacrylamide Gel Electrophoresis

pIgR:

polymeric immunoglobulin receptor

PIP:

prolactin inducible protein

PLG:

plasminogen

PTMs:

post-translational modifications

SC:

secretory component

SDS:

sodium dodecyl sulfate; #, spot

TA:

tranexamic acid

TFA:

trifluoroacetic acid

TCA:

trichloroacetic acid

U-HAE:

hereditary angioedema without an identified cause

2-DE:

2-dimensional electrophoresis

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Acknowledgements

This research was supported by an unrestricted grant to Dr. Firinu by C.S.L. Behring, Italy (64330-2018/MLOI, 2018) for research in primary immunodeficiency and HAE. The authors acknowledge also the financial support of Cagliari University (FIR 2016) and Catholic University. The authors wish to thank Prof. Enzo Tramontano for the use of the ChemiDoc imaging system.

Authorship Contributions

Study conception and design: MTS, TC, DF, SDG; Cared for patients, extracted the clinical and lab data DF, GC, MA, SDG; Acquisition of data: MA, MTS, FI, FV; Analysis and interpretation of data: TC, IM, MC, MTS, DF; Drafting of manuscript: MTS, MA, TC, DF, GC, SDG; Critical revision: MC, IM, TC, FV, FI. All authors read and worked on the manuscript.

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Firinu, D., Arba, M., Vincenzoni, F. et al. Proteomic Analysis of the Acid-Insoluble Fraction of Whole Saliva from Patients Affected by Different Forms of Non-histaminergic Angioedema. J Clin Immunol 40, 840–850 (2020). https://doi.org/10.1007/s10875-020-00802-w

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Keywords

  • 2-dimensional electrophoresis
  • Human saliva
  • Mass spectrometry
  • Angioedema
  • Tandem mass spectrometry