C-reactive protein and natural IgM antibodies are activators of complement in a rat model of intestinal ischemia and reperfusion

Padilla, Niubel Diaz; Vliet, Arlène K. van; Schoots, Ivo G.; Serón, Mercedes Valls; Maas, Marjolein; Peltenburg, Esther E. Posno; Vries, Annebeth de; Niessen, Hans W.M.; Hack, C. Erik; Gulik, Thomas M. van

doi:10.1016/j.surg.2007.05.015

Cited by 25 publications

(30 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RAG1 Ϫ/Ϫ mice, which do not have any antibodies, are highly resistant to intestinal I/R-induced injury but become susceptible again after reconstitution with purified serum IgM from naïve WT mice or an IgM mAb alone (clone B4), which specifically recognizes annexin IV (15). In addition to annexin IV, natural IgM reactive to PC has also been implicated in the pathogenesis of intestinal I/R-induced injury (12,15,50). Consistent with these previous reports, we found that natural IgM specific for PC and annexin IV were significantly reduced in the blood of CD6 Ϫ/Ϫ mice compared with WT mice in association with decreased intestinal I/R-induced injury and that supplementing IgMs isolated from naïve WT mice into CD6 Ϫ/Ϫ mice increased titers of both PC-and annexin IV-specific IgMs, leading to exacerbated intestinal inflammation after I/R.…”

Section: Discussionmentioning

confidence: 99%

“…Because natural IgM is reported to be polyreactive and only the pathogenic natural IgMs, e.g. anti-phosphorylcholine (PC) IgM and anti-annexin IV IgM, are critical in initiating intestinal I/Rinduced injury (12,34), we specifically measured titers of these pathogenic IgMs in the WT and CD6 Ϫ/Ϫ mice that were used in the I/R studies and found a 1.2-and 1.4-fold reduction of annexin IV-and PC-specific IgM titers, respectively, in the sera of CD6 Ϫ/Ϫ mice (Fig. 2, C and D).…”

Section: Cd6mentioning

confidence: 99%

See 1 more Smart Citation

CD6 Receptor Regulates Intestinal Ischemia/Reperfusion-induced Injury by Modulating Natural IgM-producing B1a Cell Self-renewal

Enyindah-Asonye

Wei

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Luke O'NeillIntestinal ischemia/reperfusion (I/R) injury is a relatively common pathological condition that can lead to multi-organ failure and mortality. Regulatory mechanism for this disease is poorly understood, although it is established that circulating pathogenic natural IgM, which is primarily produced by B1a cells outside of the peritoneal cavity, are integrally involved. CD6 was originally identified as a marker for T cells and was later found to be present on some subsets of B cells in humans; however, whether CD6 plays any role in intestinal I/R-induced injury and, if so, the underlying mechanisms, remain unknown. Here we report that CD6؊/؊ mice were significantly protected from intestinal inflammation and mucosal damage compared with WT mice in a model of intestinal I/R-induced injury. Mechanistically, we found that CD6 was selectively expressed on B1 cells outside of the bone marrow and peritoneal cavity and that pathogenic natural IgM titers were reduced in the CD6 ؊/؊ mice in association with significantly decreased B1a cell population. Our results reveal an unexpected role of CD6 in the pathogenesis of intestinal IR-induced injury by regulating the self-renewal of B1a cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Cd6mentioning

confidence: 99%

CD6 Receptor Regulates Intestinal Ischemia/Reperfusion-induced Injury by Modulating Natural IgM-producing B1a Cell Self-renewal

Enyindah-Asonye

Wei

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…More interestingly, the scFv-QuVHVL or its derivative when fully humanized may become a useful therapeutic tool, especially when used together with exogenously supplied recombinant C1-inhibitor (Padilla et al, 2007;Széplaki et al, 2007) and C4b-and C3b-scavenging (nonspecific) intravenous immunoglobulin preparations (Boackle et al,. 2006;Arumugam et al 2007), designed to control complement-mediated assaults on host tissues in circumstances such as organ transplants, antibody-mediated autoimmune diseases, extended cardiac damage following myocardial infarctions and neuronal cell death following stroke.…”

Section: Discussionmentioning

confidence: 99%

Highly specific inhibition of C1q globular-head binding to human IgG: A novel approach to control and regulate the classical complement pathway using an engineered single chain antibody variable fragment

Duvall

Tomlinson

Boackle

2008

Molecular Immunology

View full text Add to dashboard Cite

We sought to specifically regulate the binding of human C1q, and thus the activation of the first complement component, via the construction of a single chain antibody variable binding region fragment (scFv) targeting the C1q globular heads. Here we describe details of the construction, expression and evaluation of this scFv, which was derived from a high affinity hybridoma (Qu) specific for the C1q globular heads. The scFv was comprised of the Qu variable-heavy chain domain (VH) linked to the Qu variable-light chain domain (VL) and was termed scFv-QuVHVL. When mixed with either purified C1q or with human serum as a source of C1, scFv-QuVHVL bound to C1q and competitively restricted the interaction of C1q or C1 with immobilized IgG or with IgG1 antibody-coated cells, and prevented the activation of native C1 in human serum as determined by analyses of C1-mediated C4 deposition and fluid phase C4 conversion. However scFv-QuVHVL could be manipulated to become a C1 activator when it was irreversibly immobilized onto microtiter ELISA plates, prior to contact with human serum complement. This functional dichotomy can be a useful tool in selectively elucidating, differentiating, inducing or inhibiting specific roles of human C1q and the classical complement pathway in complement-mediated physiological processes. We project that once fully humanized, fluid phase scFv-QuVHVL could become a useful therapeutic in limiting inadvertent host tissue damage elicited by the classical complement pathway.

show abstract

“…Results were expressed as a percentage of rat CRP in a control pool (Sanquin). Levels of rat IgM were measured in plasma as described previously [20]. Briefly, goat anti-rat IgM (Bethyl Laboratories) was used as catching Abs.…”

Section: Methodsmentioning

confidence: 99%

“…Myocardial and gastrointestinal models in MBL knockout mice have shown both IgM and MBL to be essential for generation of tissue damage [17,18]. Studies in rat intestinal I/R and in patients with myocardial infarcts have also suggested a role for CRP in local complement activation [19,20]. The administration of human CRP has been shown to exacerbate cardiac tissue damage in a complement-dependent fashion in a rat model of myocardial infarction [21,22].…”

Section: Introductionmentioning

confidence: 99%

Immunoglobulin M, C-Reactive Protein and Complement Activation in Rat Hepatic Ischemia-Reperfusion Injury

Diepenhorst

Graaf²,

Niessen³

et al. 2014

Eur Surg Res

Self Cite

View full text Add to dashboard Cite

Background: Ischemia-reperfusion (I/R) models have shown that C-reactive protein (CRP) and immunoglobulin M (IgM) are involved in complement activation. Binding of CRP and IgM to damaged cell membranes initiates complement activation and aggravates I/R injury in various organs. However, the time course of CRP- and IgM-mediated complement activation and the relation to hepatocellular injury and inflammation in liver I/R are unknown. Aim: To evaluate the time course of IgM- and CRP-related complement activation and the relation to hepatocellular injury and inflammation in a hepatic I/R rat model. Methods: Male Wistar rats were allocated to (1) five groups of animals exposed to 60 min of partial ischemia (70%) induced via clamping of the left segmental portal triad, followed by 0, 3, 6, 12 or 24 h of reperfusion (n = 6 in each group); (2) five groups of sham-operated animals with corresponding reperfusion times (n = 5), and (3) a control group sacrificed before ischemia (n = 5). Hepatocellular injury, inflammatory response, rat plasma CRP and IgM levels and immunohistochemical depositions of CRP, IgM and C3 were assessed for each group. Results: Histopathological injury scores of hematoxylin and eosin sections of ischemic liver lobes demonstrated increasing values throughout the reperfusion time with a peak at 12 h. Plasma aminotransferases (alanine aminotransferase and aspartate aminotransferase) significantly increased after 3 h of reperfusion, peaking at 6 h (3,100 ± 800 U/l; p < 0.05). Hepatic neutrophil influx significantly increased from 3 to 6 h of reperfusion (p < 0.05) and demonstrated the highest value at 12 h (1.1 ± 0.2 U/mg of protein). Plasma IL-6 levels in the ischemia groups showed peak values after 6 h of reperfusion, decreasing significantly thereafter (p < 0.05). Plasma CRP values reached highest levels after 3 h of reperfusion (mean 91 ± 5% of control pool), decreasing significantly thereafter. Rat IgM concentrations in plasma did not significantly change throughout the reperfusion time. Immunohistochemical depositions of IgM, CRP and C3 in ischemic lobes demonstrated a similar pattern in time, reaching maximum values at 12 h of reperfusion. The percentages of depositions of CRP and IgM were significantly correlated [r(S) = 0.569; p < 0.001; Spearman test]. The time course of C3 and CRP depositions throughout reperfusion and C3 and IgM staining were significantly similar [r(S) = 0.797 and r(S) = 0.656, respectively; p < 0.0001; ANOVA]. Conclusions: CRP and IgM depositions demonstrate a parallel time course throughout the reperfusion to hepatocellular damage, inflammatory response and activated complement deposition in this rat hepatic I/R model. Furthermore, the time course of CRP and IgM depositions was significantly similar to that of activated complement depositions.

show abstract

C-reactive protein and natural IgM antibodies are activators of complement in a rat model of intestinal ischemia and reperfusion

Cited by 25 publications

References 43 publications

CD6 Receptor Regulates Intestinal Ischemia/Reperfusion-induced Injury by Modulating Natural IgM-producing B1a Cell Self-renewal

CD6 Receptor Regulates Intestinal Ischemia/Reperfusion-induced Injury by Modulating Natural IgM-producing B1a Cell Self-renewal

Highly specific inhibition of C1q globular-head binding to human IgG: A novel approach to control and regulate the classical complement pathway using an engineered single chain antibody variable fragment

Immunoglobulin M, C-Reactive Protein and Complement Activation in Rat Hepatic Ischemia-Reperfusion Injury

Contact Info

Product

Resources

About