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Riordan, SM; Cj, McIver; Wakefield, Denis; Pc, Andreopoulos; Vm, Duncombe; Td, Bolin; Mc, Thomas

doi:10.1023/a:1018821200354

Cited by 12 publications

(2 citation statements)

References 18 publications

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“…In another report that measured complement in lumen samples, higher C3 and C4 levels were found in jejunal secretions from Crohn’s disease patients compared to healthy participants ( 58 ). Complement proteins were also detected in lumen samples collected from the small intestine of patients experiencing bacterial overgrowth ( 59 ). Noteworthy, and at odds with complement in the lumen, these authors failed to find MAC proteins, suggesting the MAC is not present (active) in the lumen.…”

Section: Complement and The Intestinementioning

confidence: 99%

Do Antimicrobial Peptides and Complement Collaborate in the Intestinal Mucosa?

et al. 2015

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It is well understood that multiple antimicrobial peptides (AMPs) are constitutively deployed by the epithelium to bolster the innate defenses along the entire length of the intestines. In addition to this constitutive/homeostatic production, AMPs may be inducible and levels changed during disease. In contrast to this level of knowledge on AMP sources and roles in the intestines, our understanding of the complement cascade in the healthy and diseased intestines is rudimentary. Epithelial cells make many complement proteins and there is compelling evidence that complement becomes activated in the lumen. With the common goal of defending the host against microbes, the opportunities for cross-talk between these two processes is great, both in terms of actions on the target microbes but also on regulating the synthesis and secretion of the alternate family of molecules. This possibility is beginning to become apparent with the finding that colonic epithelial cells possess anaphylatoxin receptors. There still remains much to be learned about the possible points of collaboration between AMPs and complement, for example, whether there is reciprocal control over expression in the intestinal mucosa in homeostasis and restoring the balance following infection and inflammation.

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Section: Complement and The Intestinementioning

confidence: 99%

Do Antimicrobial Peptides and Complement Collaborate in the Intestinal Mucosa?

et al. 2015

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“…Early serum depletion studies have suggested that vibriocidal titers are primarily derived from LPS O-antigen-specific IgM and, to a lesser extent, IgG1 and IgG3 antibodies (7,23). Despite this, complement-mediated protection is unlikely to be a critical component of mucosal immunity to a noninvasive bacterial pathogen given the small amount of complement in the intestinal tract (24,25). Moreover, vibriocidal titers decline to baseline levels before protective immunity wanes (26).…”

mentioning

confidence: 99%

Impact of Immunoglobulin Isotype and Epitope on the Functional Properties ofVibrio choleraeO-Specific Polysaccharide-Specific Monoclonal Antibodies

Kauffman

Adekunle

et al. 2021

mBio

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Vibrio cholerae causes the severe diarrheal disease cholera. Clinical disease and current oral cholera vaccines generate antibody responses associated with protection. Immunity is thought to be largely mediated by lipopolysaccharide (LPS)-specific antibodies, primarily targeting the O-antigen. However, the properties and protective mechanism of functionally relevant antibodies have not been well defined. We previously reported on the early B cell response to cholera in a cohort of Bangladeshi patients, from which we characterized a panel of human monoclonal antibodies (MAbs) isolated from acutely induced plasmablasts. All antibodies in that previous study were expressed in an IgG1 backbone irrespective of their original isotype. To clearly determine the impact of affinity, immunoglobulin isotype and subclass on the functional properties of these MAbs, we re-engineered a subset of low- and high-affinity antibodies in different isotype and subclass immunoglobulin backbones and characterized the impact of these changes on binding, vibriocidal, agglutination, and motility inhibition activity. While the high-affinity antibodies bound similarly to O-antigen, irrespective of isotype, the low-affinity antibodies displayed significant avidity differences. Interestingly, despite exhibiting lower binding properties, variants derived from the low-affinity MAbs had comparable agglutination and motility inhibition properties to the potently binding antibodies, suggesting that how the MAb binds to the O-antigen may be critical to function. In addition, not only pentameric IgM and dimeric IgA, but also monomeric IgA, was remarkably more potent than their IgG counterparts at inhibiting motility. Finally, analyzing highly purified F(ab) versions of these antibodies, we show that LPS cross-linking is essential for motility inhibition. IMPORTANCE Immunity to the severe diarrheal disease cholera is largely mediated by lipopolysaccharide (LPS)-specific antibodies. However, the properties and protective mechanisms of functionally relevant antibodies have not been well defined. Here, we have engineered low and high-affinity LPS-specific antibodies in different immunoglobulin backbones in order to assess the impact of affinity, immunoglobulin isotype, and subclass on binding, vibriocidal, agglutination, and motility inhibition functional properties. Importantly, we found that affinity did not directly dictate functional potency since variants derived from the low-affinity MAbs had comparable agglutination and motility inhibition properties to the potently binding antibodies. This suggests that how the antibody binds sterically may be critical to function. In addition, not only pentameric IgM and dimeric IgA, but also monomeric IgA, was remarkably more potent than their IgG counterparts at inhibiting motility. Finally, analyzing highly purified F(ab) versions of these antibodies, we show that LPS cross-linking is essential for motility inhibition.

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