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Cited by 51Monoclonal and Polyclonal Antibodies ResearchFungal Infections and StudiesGlycosylation and Glycoproteins Research

A Monoclonal Antibody to Cryptococcus neoformans Glucuronoxylomannan Manifests Hydrolytic Activity for Both Peptides and Polysaccharides

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Bowen, Anthony, Wear, Maggie P., Cordero, Radames J.B., Oscarson, Stefan, Casadevall, Arturo·2017·Journal of Biological Chemistry
DOI 10.1074/jbc.m116.767582PMC PMC5241721
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Abstract

Studies in the 1980s first showed that some natural antibodies were "catalytic" and able to hydrolyze peptide or phosphodiester bonds in antigens.Many naturally occurring catalytic antibodies have since been isolated from human sera and associated with positive and negative outcomes in autoimmune disease and infection.The function and prevalence of these antibodies, however, remain unclear.A previous study suggested that the 18B7 monoclonal antibody against glucuronoxylomannan (GXM), the major component of the Cryptococcus neoformans polysaccharide capsule, hydrolyzed a peptide antigen mimetic.Using mass spectrometry and Fo ¨rster resonance energy transfer techniques, we confirm and characterize the hydrolytic activity of 18B7 against peptide mimetics and show that 18B7 is able to hydrolyze an oligosaccharide substrate, providing the first example of a naturally occurring catalytic antibody for polysaccharides.Additionally, we show that the catalytic 18B7 antibody increases release of capsular polysaccharide from fungal cells.A serine protease inhibitor blocked peptide and oligosaccharide hydrolysis by 18B7, and a putative serine protease-like active site was identified in the light chain variable region of the antibody.An algorithm was developed to detect similar sites present in unique antibody structures in the Protein Data Bank.The putative site was found in 14 of 63 (22.2%) catalytic antibody structures and 119 of 1602 (7.4%) antibodies with no annotation of catalytic activity.The ability of many antibodies to cleave antigen, albeit slowly, supports the notion that this activity is an important immunoglobulin function in host defense.The discovery of GXM hydrolytic activity suggests new therapeutic possibilities for polysaccharide-binding antibodies.A central tenet in immunology is that immunoglobulin (Ig) variable (V) 2 regions bind antigen (Ag) and that the molecule's constant regions activate complement components or cellular receptors, triggering downstream immune pathways such as phagocytosis, granule release, cell-mediated cytotoxicity, and complement-mediated cytotoxicity.Research has also shown that antibodies possess important direct effects on Ag, such as neutralization of toxins or virions, bacterial agglutination, and precipitation of soluble Ag.Although it has long been accepted that each of these Ig functions are mediated by the binding of an antibody paratope to an Ag epitope, research in 1975 first showed that antibodies could be generated that not only bound Ag but also catalyzed a chemical reaction in the Ag substrate (1).Over the next 2 decades, many catalytic antibodies were generated against haptenic transition state analogues to catalyze a wide array of chemical reactions, a strategy first proposed by enzymologist W. Jencks in 1969 (2).This strategy has since been used to generate antibody catalysts for many distinct chemical reactions, albeit with reaction rates usually much slower than natural enzymes.The first indication that some naturally occurring antibodies (generated without an artificial Ag) possessed innate catalytic activity appeared in a 1989 study by Paul et al. (3) describing autoantibodies isolated from human sera that hydrolyzed vasoactive intestinal peptide.This work was soon followed by numerous descriptions of antibodies isolated from patients with autoimmune pathologies that were found to cleave peptide or phosphodiester bonds and were thought to contribute to disease (4 -12).Although these early reports often linked the presence of catalytic antibodies to pathogenic roles, more recent studies have suggested that at least some catalytic Igs play positive roles in homeostasis, autoimmunity, and microbial defense (13-21).Although some glycosidase antibodies have been generated using the transition state analogue immunization approach,

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Authors
Bowen, A., Wear, M. P., Cordero, R. J. B., Oscarson, S., & Casadevall, A.
Affiliations
  • Albert Einstein College of Medicine (US)
  • Johns Hopkins University (US)
  • University College Dublin (IE)
Corresponding author
Casadevall, Arturo
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2017-01
Volume
292
Issue
2
Pages
417-434
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m116.767582
PMC
PMC5241721
OpenAlex
W2555523852
Cited by
51
References
81
Citations by year
2026: 4 · 2025: 3 · 2024: 10 · 2023: 6 · 2022: 6 · 2021: 4 · 2020: 9 · 2019: 2 · 2018: 3 · 2017: 4
FWCI
2.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (R37-AI033142, T32-GM007288)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
Keywords
catalytic antibodies, Cryptococcus neoformans, glucuronoxylomannan, polysaccharide capsule, peptide hydrolysis, oligosaccharide hydrolysis, host defense
MeSH terms
Algorithms, Antibodies, Bacterial, Antibodies, Monoclonal, Cryptococcus neoformans, Humans, Hydrolysis, Peptides, Polysaccharides, Bacterial, Antibodies, Catalytic, Catalytic Domain

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