IgM-Enriched Immunoglobulin Attenuates Systemic Endotoxin Activity in Early Severe Sepsis: A Before-After Cohort Study

Wand, Saskia; Klages, Matthias; Kirbach, Christin; Warszawska, Joanna; Meybohm, Patrick; Zacharowski, Kai; Koch, Alexander

doi:10.1371/journal.pone.0160907

Cited by 24 publications

(22 citation statements)

References 34 publications

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“…A beneficial effect of Pentoglobin in comparison to conventional intravenous IgGRT is its effective reduction of endotoxin [ 33 , 34 ]. Direct effects on bacterial killing are also observed.…”

Section: Discussionmentioning

confidence: 99%

IgM Augments Complement Bactericidal Activity with Serum from a Patient with a Novel CD79a Mutation

et al. 2018

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Antibody replacement therapy for patients with antibody deficiencies contains only IgG. As a result, concurrent IgM and IgA deficiency present in a large proportion of antibody deficient patients persists. Especially patients with IgM deficiency remain at risk for recurrent infections of the gastrointestinal and respiratory tract. The lack of IgM in the current IgG replacement therapy is likely to contribute to the persistence of these mucosal infections because this antibody class is especially important for complement activation on the mucosal surface. We evaluated whether supplementation with IgM increased serum bactericidal capacity in vitro. Serum was collected from a patient with agammaglobulinemia and supplemented with purified serum IgM to normal levels. Antibody and complement deposition on the bacterial surface was determined by multi-color flow cytometry. Bacterial survival in serum was determined by colony-forming unit counts. We present a patient previously diagnosed with agammaglobulinemia due to CD79A (Igα) deficiency revealing a novel pathogenic insertion variant in the CD79a gene (NM_001783.3:c.353_354insT). Despite IgG replacement therapy and antibiotic prophylaxis, this patient developed a Campylobacter jejuni spondylodiscitis of lumbar vertebrae L4–L5. We found that serum IgM significantly contributes to complement activation on the bacterial surface of C. jejuni. Furthermore, supplementation of serum IgM augmented serum bactericidal activity significantly. In conclusion, supplementation of intravenous IgG replacement therapy with IgM may potentially offer greater protection against bacterial infections, also in the context of increasing antibiotic resistance.

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Section: Discussionmentioning

confidence: 99%

IgM Augments Complement Bactericidal Activity with Serum from a Patient with a Novel CD79a Mutation

et al. 2018

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“…Human studies have focused on neonates and preterm infants, or on neutropenic patients [77][78][79]. Recently, a small controlled study in adult patients with sepsis and septic shock and elevated endotoxin levels demonstrated that IgGAM significantly attenuated LPS levels and had a beneficial effect on sepsis-related coagulopathy in terms of platelet count and fibrinogen concentrations [80].…”

Section: Considerations For the Therapeutic Use Of Immunoglobulinsmentioning

confidence: 99%

“…The precise mechanisms by which IgGAM brings about these effects in patients with sepsis or septic shock are not conclusively clarified until now. In addition to the opsonisation of pathogens and the neutralization of bacterial endotoxins and exotoxins, IgGAM modulates the immune response by attenuating an excessive inflammatory response [80][81][82][83]. The reduced production of IL-2 when IgGAM is used is considered to be one of the proven mechanisms of action [84].…”

Section: Considerations For the Therapeutic Use Of Immunoglobulinsmentioning

confidence: 99%

“…Nevertheless, due to their pleiotropic effects and the potential modulation of both pro-and anti-inflammatory processes, polyvalent intravenous immunoglobulins offer a promising strategy within the context of inflammation and immunity. Experimental studies have shown that polyvalent immunoglobulins can improve phagocytosis of pathogens via opsonisation, neutralize exo-and endotoxins and interact with complement factors, thereby preventing nonspecific activation [80,[82][83][84]. Nevertheless, the Surviving Sepsis Campaign (SSC) guidelines suggested against IVIg use in sepsis therapy 2016 due to lack of sufficient evidence of efficacy for preparations containing only IgG [90].…”

Section: Immunoglobulins In Clinical Usementioning

confidence: 99%

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Use of Intravenous Immunoglobulins in Sepsis Therapy—A Clinical View

Jarczak

Kluge

Nierhaus

2020

IJMS

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Sepsis is a life-threatening organ dysfunction, defined by a dysregulated host immune response to infection. During sepsis, the finely tuned system of immunity, inflammation and anti-inflammation is disturbed in a variety of ways. Both pro-inflammatory and anti-inflammatory pathways are upregulated, activation of the coagulation cascade and complement and sepsis-induced lymphopenia occur. Due to the manifold interactions in this network, the use of IgM-enriched intravenous immunoglobulins seems to be a promising therapeutic approach. Unfortunately, there is still a lack of evidence-based data to answer the important questions of appropriate patient populations, optimal timing and dosage of intravenous immunoglobulins. With this review, we aim to provide an overview of the role of immunoglobulins, with emphasis on IgM-enriched formulations, in the therapy of adult patients with sepsis and septic shock.

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“…Pentaglobin is treated with ß-propiolactone, which decreases immunoglobulin aggregation, but also affects complement fixation and Fc-binding capacity [ 84 , 85 ]. A clear beneficial effect of Pentoglobin in comparison to conventional intravenous IgG is its effective reduction of endotoxin [ 86 , 87 ]. Direct effects on bacterial killing has also been observed by in vitro experiments.…”

Section: Possible Improvements; Iga- And/or Igm-enriched Immunoglobulmentioning

confidence: 99%

Limited Innovations After More Than 65 Years of Immunoglobulin Replacement Therapy: Potential of IgA- and IgM-Enriched Formulations to Prevent Bacterial Respiratory Tract Infections

2018

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Patients with primary immunoglobulin deficiency have lower immunoglobulin levels or decreased immunoglobulin function, which makes these patients more susceptible to bacterial infection. Most prevalent are the selective IgA deficiencies (~1:3,000), followed by common variable immune deficiency (~1:25,000). Agammaglobulinemia is less common (~1:400,000) and is characterized by very low or no immunoglobulin production resulting in a more severe disease phenotype. Therapy for patients with agammaglobulinemia mainly relies on prophylactic antibiotics and the use of IgG replacement therapy, which successfully reduces the frequency of invasive bacterial infections. Currently used immunoglobulin preparations contain only IgG. As a result, concurrent IgA and IgM deficiency persist in a large proportion of agammaglobulinemia patients. Especially patients with IgM deficiency remain at risk for recurrent infections at mucosal surfaces, which includes the respiratory tract. IgA and IgM have multiple functions in the protection against bacterial infections at the mucosal surface. Because of their multimeric structure, both IgA and IgM are able to agglutinate bacteria efficiently. Agglutination allows for entrapment of bacteria in mucus that increases clearance from the respiratory tract. IgA is also important for blocking bacterial adhesion by interfering with bacterial adhesion receptors. IgM in its place is very well capable of activating complement, therefore, it is thought to be important in complement-mediated protection at the mucosal surface. The purpose of this Mini Review is to highlight the latest advances regarding IgA- and IgM-enriched immunoglobulin replacement therapy. We describe the different IgA- and IgM-enriched IgG formulations, their possible modes of action and potential to protect against respiratory tract infections in patients with primary immunoglobulin deficiencies.

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IgM-Enriched Immunoglobulin Attenuates Systemic Endotoxin Activity in Early Severe Sepsis: A Before-After Cohort Study

Cited by 24 publications

References 34 publications

IgM Augments Complement Bactericidal Activity with Serum from a Patient with a Novel CD79a Mutation

IgM Augments Complement Bactericidal Activity with Serum from a Patient with a Novel CD79a Mutation

Use of Intravenous Immunoglobulins in Sepsis Therapy—A Clinical View

Limited Innovations After More Than 65 Years of Immunoglobulin Replacement Therapy: Potential of IgA- and IgM-Enriched Formulations to Prevent Bacterial Respiratory Tract Infections

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