Identification of galectin-3 as an autoantigen in patients with IgG 4 -related disease

Cory A. Perugino, Sultan B. AlSalem, Hamid Mattoo, Emanuel Della-Torre, Vinay Mahajan, Gayathri Ganesh, Hugues Allard-Chamard, Zachary Wallace, Sydney B. Montesi, Johannes Kreuzer, Wilhelm Haas, John H. Stone, Shiv Pillai

Research output: Contribution to journalArticle

Abstract

Background: The antigenic trigger that drives expansion of circulating plasmablasts and CD4 + cytotoxic T cells in patients with IgG 4 -related disease (IgG 4 -RD) is presently unknown. Objective: We sought to sequence immunoglobulin genes from single-cell clones of dominantly expanded plasmablasts and generate recombinant human mAbs to identify relevant antigens in patients with IgG 4 -RD by using mass spectrometry. Methods: Paired heavy and light chain cDNAs from dominant plasmablast clones were expressed as mAbs and used to purify antigens by using immunoaffinity chromatography. Affinity-purified antigens were identified by using mass spectrometry and validated by means of ELISA. Plasma levels of the antigen of interest were also determined by using ELISA. Results: mAbs expressed from the 2 dominant plasmablast clones of a patient with multiorgan IgG 4 -RD stained human pancreatic tissue sections. Galectin-3 was identified as the antigen specifically recognized by both mAbs. Anti–galectin-3 autoantibody responses were predominantly of the IgG 4 isotype (28% of the IgG 4 -RD cohort, P =.0001) and IgE isotype (11% of the IgG 4 -RD cohort, P =.009). No significant responses were seen from the IgG 1 , IgG 2 , or IgG 3 isotypes. IgG 4 anti–galectin-3 autoantibodies correlated with increased plasma galectin-3 levels (P =.001), lymphadenopathy (P =.04), total IgG level increase (P =.05), and IgG 4 level increase (P =.03). Conclusion: Affinity chromatography using patient-derived mAbs identifies relevant autoantigens in patients with IgG 4 -RD. IgG 4 galectin-3 autoantibodies are present in a subset of patients with IgG 4 -RD and correlate with galectin-3 plasma levels. The marked increases in levels of circulating IgG 4 and IgE observed clinically are, at least in part, caused by the development of IgG 4 - and IgE-specific autoantibody responses.

Original languageEnglish
Pages (from-to)736-745.e6
JournalJournal of Allergy and Clinical Immunology
Volume143
Issue number2
DOIs
Publication statusPublished - Feb 2019

Keywords

  • autoantibody
  • autoantigen
  • galectin-3
  • IgG -related disease
  • plasmablast

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Perugino, C. A., AlSalem, S. B., Mattoo, H., Della-Torre, E., Mahajan, V., Ganesh, G., Allard-Chamard, H., Wallace, Z., Montesi, S. B., Kreuzer, J., Haas, W., Stone, J. H., & Pillai, S. (2019). Identification of galectin-3 as an autoantigen in patients with IgG 4 -related disease. Journal of Allergy and Clinical Immunology, 143(2), 736-745.e6. https://doi.org/10.1016/j.jaci.2018.05.011