Enhanced Pro-apoptotic Effects of Fe(II)-Modified IVIG on Human Neutrophils.

Stefanie Graeter,Richard D Cummings,David F Smith,Tchavdar Vassilev,Jordan D Dimitrov,Stephan Von Gunten,Peter Villiger,Sandro Von Däniken,Hans-Uwe Simon,Frank Seibold,Christoph Schneider,Nikhil Yawalkar,Daniëlle Verschoor

doi:10.3389/fimmu.2020.00973

Abstract

Mild modification of intravenous immunoglobulin (IVIG) has been reported to result in enhanced polyspecificity and leveraged therapeutic effects in animal models of inflammation. Here, we observed that IVIG modification by ferrous ions, heme or low pH exposure, shifted the repertoires of specificities in different directions. Ferrous ions exposed Fe(II)-IVIG, but not heme or low pH exposed IVIG, showed increased pro-apoptotic effects on neutrophil granulocytes that relied on a FAS-dependent mechanism. These effects were also observed in human neutrophils primed by inflammatory mediators or rheumatoid arthritis joint fluid in vitro, or patient neutrophils ex vivo from acute Crohn's disease. These observations indicate that IVIG-mediated effects on cells can be enhanced by IVIG modification, yet specific modification conditions may be required to target specific molecular pathways and eventually to enhance the therapeutic potential.

Highlights

Intravenous immunoglobulin (IVIG) preparations consist of polyclonal plasma-derived IgG collected from thousands of donors
The mitochondrial potential was significantly lower upon culture of neutrophils in presence of Fe(II)-intravenous immunoglobulin (IVIG) (Figure 2C). These findings indicate that the increased neutrophil death-inducing capacity of IVIG upon ferrous ion exposure depends on apoptosis
Given that array technology allows for high-throughput profiling of antibody repertoires [1, 15, 30, 38,39,40], here we employed glycan array technology to compare immunoprofiles upon modification of IVIG by ferrous ions, heme or low pH exposure

Summary

Introduction

Intravenous immunoglobulin (IVIG) preparations consist of polyclonal plasma-derived IgG collected from thousands of donors. Its inherent polyspecificity may provide the basis of its pluripotent anti-inflammatory effects if used as a high-dose therapy [2], whereby a broad range of different mechanisms may act in concert, depending on the pathogenesis of the targeted disease [3,4,5]. IVIG is successfully used for the treatment of a broad range of heterogenous diseases, including neutrophil-associated disorders such as Kawasaki disease, an acute febrile vasculitis syndrome [6]. Modified IVIG Enhances Neutrophil Death cells, can cause significant tissue damage and they have been linked to the pathogenesis of a number of other inflammatory disorders, such as psoriasis [7], or Crohn’s disease [8]. In Kawasaki disease, apoptosis of circulating neutrophils is delayed, and high-dose IVIG treatment dramatically reduces blood neutrophil counts, which has been linked to IVIGmediated apoptosis [11, 12]. We and others previously reported that IVIG has the capacity to promote death in human neutrophils by the action of specific antibodies to Siglec-9, or the classical death receptor FAS [13,14,15,16]

Methods

Results

Conclusion