Constitutive Production of Catalytic Antibodies to a Staphylococcus aureus Virulence Factor and Effect of Infection

Brown, Eric L.; Nishiyama, Yasuhiro; Dunkle, Jesse W.; Aggarwal, Shreya; Planque, Stephanie; Watanabe, Kenji; Csencsits-Smith, Keri; Bowden, M. Gabriela; Kaplan, Sheldon L.; Paul, Sudhir

doi:10.1074/jbc.m111.330043

Cited by 19 publications

(18 citation statements)

References 75 publications

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“…The apparent 5.11 × 10 3 (M −1 min −1 ) k cat /K M is similar in enzyme efficiency to previously reported catalytic antibodies with reactivity against different substrates. 19 , 37 , 38 Presence of the serine protease inhibitors, AEBSF and leupeptin (also a cysteine and threonine protease inhibitor), reduced IgM-mediated hydrolysis of Tc24 compared with no inhibition observed for the metalloprotease inhibitor EDTA. The diminished inhibitory effect of leupeptin relative to that of AEBSF was not surprising as leupeptin has been shown be a less effective serine protease inhibitor, and in one study failed completely to inhibit serum IgA-mediated hydrolysis.…”

Section: Resultsmentioning

confidence: 99%

“…IgM- or IgG-mediated hydrolysis of Tc24 (and control proteins) was determined by incubating 15 μL of respective purified immunoglobulin preparations with 5 μL of 10.4 μM Tc24 in PBS with 4 mM 3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate and 268 μg/mL gelatin at 37°C with shaking. 14 , 19 Reactions were stopped at various time points by adding 4× nonreducing SDS-PAGE loading buffer (Bio-Rad, Hercules, CA). Hydrolysis of target antigens was conducted using antibody concentrations ranging between 14 and 135 μg/mL (diluted in PBS).…”

Section: Methodsmentioning

confidence: 99%

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Identification and Characterization of the Trypanosoma cruzi B-cell Superantigen Tc24

Gunter¹,

Jones²,

Zhan³

et al. 2016

The American Society of Tropical Medicine and Hygiene

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Trypanosoma cruzi causes life-long disease after infection and leads to cardiac disease in 30% of infected individuals. After infection, the parasites are readily detectable in the blood during the first few days before disseminating to infect numerous cell types. Preliminary data suggested that the Tc24 protein that localizes to the T. cruzi membrane during all life stages possesses B-cell superantigenic properties. These antigens facilitate immune escape by interfering with antibody-mediated responses, particularly the avoidance of catalytic antibodies. These antibodies are an innate host defense mechanism present in the naive repertoire, and catalytic antibody–antigen binding results in hydrolysis of the target. We tested the B-cell superantigenic properties of Tc24 by comparing the degree of Tc24 hydrolysis by IgM purified from either Tc24 unexposed or exposed mice and humans. Respective samples were subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis, silver stained, and the degree of hydrolysis was measured. Data presented in this report suggest that the T. cruzi Tc24 is a B-cell superantigen based on the observations that 1) Tc24 was hydrolyzed by IgM present in serum of unexposed mice and humans and 2) exposure to Tc24 eliminated catalytic activity as early as 4 days after T. cruzi infection.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Identification and Characterization of the Trypanosoma cruzi B-cell Superantigen Tc24

Gunter¹,

Jones²,

Zhan³

et al. 2016

The American Society of Tropical Medicine and Hygiene

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“…In comparison, a maximum of 2 mol of antigen is bound per mol of stoichiometric IgGs with noncovalent binding activity. We described antibodies and antibody fragments to HIV gp120 (34), the Staphylococcus aureus virulence factor Efb (20) and the autoantigen amyloid ␤ (47) with neutralizing activity attributable to the catalytic function. The group of Uda and Hifumi has described catalytic antibody fragments to bacterial and viral target antigens that reduce infection in experimental animal models (48,49).…”

Section: Discussionmentioning

confidence: 99%

Constant Domain-regulated Antibody Catalysis

Sapparapu¹,

Planque

Mitsuda

et al. 2012

Journal of Biological Chemistry

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Background: Some antibody variable domains express nucleophilic catalytic sites. Results: The same variable domains displayed superior catalysis when expressed in the IgM compared with the IgG constant domain scaffold; all monoclonal IgMs were catalytic, and polyclonal IgM was more catalytic than IgG. Conclusion:The constant domains regulate variable domain catalysis. Significance: Catalysis may be a first line immune function expressed prior to adaptive antibody induction.

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“…Catalytic antibodies to DNA, RNA, and protease-activated receptor-2 (PAR-2) are found in the breast milk of healthy human mothers, possibly affording protection against infection (36,39,40). Polyclonal IgG preparations cause cleavage of the Staphylococcus aureus-secreted virulence factor extracellular fibrinogen-binding protein (Efb) (26). Secretion of urease by Helicobacter pylori is essential for colonization of the gut and results in neutralization of stomach acidity.…”

Section: Catalytic Antibodies To Microbesmentioning

confidence: 99%

Antibody-Mediated Catalysis in Infection and Immunity

2017

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The existence of catalytic antibodies has been known for decades. Natural antibodies capable of cleaving nucleic acid, protein, and polysaccharide substrates have been described. Although the discovery of catalytic antibodies initially aroused great interest because of their promise for the development of new catalysts, their enzymatic performance has been disappointing due to low reaction rates. However, in the areas of infection and immunity, where processes often occur over much longer times and involve high antibody concentrations, even low catalytic rates have the potential to influence biological outcomes. In this regard, the presence of catalytic antibodies recognizing host antigens has been associated with several autoimmune diseases. Furthermore, naturally occurring catalytic antibodies to microbial determinants have been correlated with resistance to infection. Recently, there has been substantial interest in harnessing the power of antibody-mediated catalysis against microbial antigens for host defense. Additional work is needed, however, to better understand the prevalence, function, and structural basis of catalytic activity in antibodies. Here we review the available information and suggest that antibody-mediated catalysis is a fertile area for study with broad applications in infection and immunity.

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Constitutive Production of Catalytic Antibodies to a Staphylococcus aureus Virulence Factor and Effect of Infection

Cited by 19 publications

References 75 publications

Identification and Characterization of the Trypanosoma cruzi B-cell Superantigen Tc24

Identification and Characterization of the Trypanosoma cruzi B-cell Superantigen Tc24

Constant Domain-regulated Antibody Catalysis

Antibody-Mediated Catalysis in Infection and Immunity

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