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9 pages, 808 KiB

Open AccessArticle

The Impact of Onset Age on Eosinophils in Kawasaki Disease

by Yu-Jhen Chen, Mindy Ming-Huey Guo, Ling-Sai Chang and Ho-Chang Kuo

Biomedicines 2022, 10(4), 835; https://doi.org/10.3390/biomedicines10040835 - 1 Apr 2022

Cited by 6 | Viewed by 1885

Abstract

(1) Background: Kawasaki disease (KD) mainly affects children under the age of 5 years and eosinophilia in KD patients might be associated with the development of allergic diseases. We compared the age-adjusted Z-score (Z) of eosinophils and aimed to evaluate the impact of [...] Read more.

(1) Background: Kawasaki disease (KD) mainly affects children under the age of 5 years and eosinophilia in KD patients might be associated with the development of allergic diseases. We compared the age-adjusted Z-score (Z) of eosinophils and aimed to evaluate the impact of onset age on eosinophils in KD patients. (2) Methods: We divided 398 KD patients into seven age subgroups. Laboratory data and the age-adjusted Z-score of eosinophils during the phases of Kawasaki disease were analyzed. (3) Results: The absolute eosinophil count among all age groups showed significant differences in the post-intravenous immunoglobulin (IVIG) phase and throughout the course of KD with Z-score adjusted for age. Further analysis showed persistent elevation of the age-adjusted Z-score of eosinophils (Z-eosinophil) especially in the under six-month-old age subgroup. In addition, we divided the Z-eosinophil into two groups to find the relationship with coronary artery lesions (CALs). Patients with a higher eosinophil count than average age values had a higher risk of developing CALs, while those with a lower eosinophil count than average age values had a lower risk of having CALs. (4) Conclusions: These findings may provide information to clinicians to pay attention to allergic diseases during the follow-up of KD, especially for children who are younger than 6 months old at the onset of KD, and eosinophil count could be a crucial focus in KD. Full article

(This article belongs to the Special Issue Immunoglobulins in Inflammation 2.0)

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21 pages, 2412 KiB

Open AccessArticle

The Functional Role of IgA in the IgM/IgA-Enriched Immunoglobulin Preparation Trimodulin

by Fabian Bohländer, Sabrina Weißmüller, Dennis Riehl, Marcus Gutscher, Jörg Schüttrumpf and Stefanie Faust

Biomedicines 2021, 9(12), 1828; https://doi.org/10.3390/biomedicines9121828 - 3 Dec 2021

Cited by 6 | Viewed by 2259

Abstract

In comparison to human immunoglobulin (Ig) G, antibodies of IgA class are not well investigated. In line with this, the functional role of the IgA component in IgM/IgA-enriched immunoglobulin preparations is also largely unknown. In recent years, powerful anti-pathogenic and immunomodulatory properties of [...] Read more.

In comparison to human immunoglobulin (Ig) G, antibodies of IgA class are not well investigated. In line with this, the functional role of the IgA component in IgM/IgA-enriched immunoglobulin preparations is also largely unknown. In recent years, powerful anti-pathogenic and immunomodulatory properties of human serum IgA especially on neutrophil function were unraveled. Therefore, the aim of our work is to investigate functional aspects of the trimodulin IgA component, a new plasma-derived polyvalent immunoglobulin preparation containing ~56% IgG, ~23% IgM and ~21% IgA. The functional role of IgA was investigated by analyzing the interaction of IgA with FcαRI, comparing trimodulin with standard intravenous IgG (IVIG) preparation and investigating Fc receptor (FcR)-dependent functions by excluding IgM-mediated effects. Trimodulin demonstrated potent immunomodulatory, as well as anti-pathogenic effects in our neutrophil model (neutrophil-like HL-60 cells). The IgA component of trimodulin was shown to induce a strong FcαRI-dependent inhibitory immunoreceptor tyrosine-based activation motif (ITAMi) signaling, counteract lipopolysaccharide-induced inflammation and mediate phagocytosis of Staphylococcus aureus. The fine-tuned balance between immunomodulatory and anti-pathogenic effects of trimodulin were shown to be dose-dependent. Summarized, our data demonstrate the functional role of IgA in trimodulin, highlighting the importance of this immunoglobulin class in immunoglobulin therapy. Full article

(This article belongs to the Special Issue Immunoglobulins in Inflammation 2.0)

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15 pages, 4342 KiB

Open AccessArticle

Bispecific T-Cell Engagers Targeting Membrane-Bound IgE

by Aleksandra Rodak, Gerhard Stadlmayr, Katharina Stadlbauer, Dominic Lichtscheidl, Madhusudhan Reddy Bobbili, Florian Rüker and Gordana Wozniak-Knopp

Biomedicines 2021, 9(11), 1568; https://doi.org/10.3390/biomedicines9111568 - 29 Oct 2021

Cited by 1 | Viewed by 2380

Abstract

The increased incidence of allergies and asthma has sparked interest in IgE, the central player in the allergic response. Interaction with its high-affinity receptor FcεRI leads to sensitization and allergen presentation, extracellular membrane-proximal domain in membrane IgE can act as an antigen receptor [...] Read more.

The increased incidence of allergies and asthma has sparked interest in IgE, the central player in the allergic response. Interaction with its high-affinity receptor FcεRI leads to sensitization and allergen presentation, extracellular membrane-proximal domain in membrane IgE can act as an antigen receptor on B cells, and the interaction with low-affinity IgE receptor CD23 additionally influences its homeostatic range. Therapeutic anti-IgE antibodies act by the inhibition of IgE functions by interfering with its receptor binding or by the obliteration of IgE-B cells, causing a reduction of serum IgE levels. Fusion proteins of antibody fragments that can act as bispecific T-cell engagers have proven very potent in eliciting cytotoxic T-lymphocyte-mediated killing. We have tested five anti-IgE Fc antibodies, recognizing different epitopes on the membrane-expressed IgE, for the ability to elicit specific T-cell activation when expressed as single-chain Fv fragments fused with anti-CD3ε single-chain antibody. All candidates could specifically stain the cell line, expressing the membrane-bound IgE-Fc and bind to CD3-positive Jurkat cells, and the specific activation of engineered CD3-overexpressing Jurkat cells and non-stimulated CD8-positive cells was demonstrated for 8D6- and ligelizumab-based bispecific antibodies. Thus, such anti-IgE antibodies have the potential to be developed into agents that reduce the serum IgE concentration by lowering the numbers of IgE-secreting cells. Full article

(This article belongs to the Special Issue Immunoglobulins in Inflammation 2.0)

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17 pages, 3350 KiB

Open AccessArticle

The FcγRIII Engagement Augments PMA-Stimulated Neutrophil Extracellular Traps (NETs) Formation by Granulocytes Partially via Cross-Talk between Syk-ERK-NF-κB and PKC-ROS Signaling Pathways

by Cheng-Hsun Lu, Ko-Jen Li, Cheng-Han Wu, Chieh-Yu Shen, Yu-Min Kuo, Song-Chou Hsieh and Chia-Li Yu

Biomedicines 2021, 9(9), 1127; https://doi.org/10.3390/biomedicines9091127 - 1 Sep 2021

Cited by 5 | Viewed by 4746

Abstract

Polymorphonuclear neutrophils (PMNs) are the most abundant white blood cell in the circulation capable of neutrophil extracellular traps (NETs) formation after stimulation. Both NADPH oxidase-dependent and -independent pathways are involved in NET formation. The IgG is the most abundant immunoglobulin in human serum. [...] Read more.

Polymorphonuclear neutrophils (PMNs) are the most abundant white blood cell in the circulation capable of neutrophil extracellular traps (NETs) formation after stimulation. Both NADPH oxidase-dependent and -independent pathways are involved in NET formation. The IgG is the most abundant immunoglobulin in human serum. However, the impact of the circulating IgG on NET formation is totally unexplored. In this study, the all-trans retinoic acid (ATRA)-induced mature granulocytes (dHL-60) were pre-treated with monomeric human IgG, papain-digested Fab fragment, crystallizable IgG Fc portion, rituximab (a human IgG1), or IgG2. The NET formation of the dHL-60 in the presence/absence of phorbol 12-myristate 13-acetate (PMA) stimulation was then measured by the fluorescent area after SYTOX green nucleic acid stain. The intracellular reactive oxygen species (ROS) generation was measured by flow cytometry. Total and phosphorylated Syk, SHP-1, and ERK were detected by immunoblot. We found that human monomeric IgG and its subclasses IgG1 and IgG2 per se induced negligible NET formation of dHL-60, but the FcγRIII engagement by these IgG subclasses and Fc portion augment PMA-stimulated dHL-60 NET formation in a dose-dependent manner. Furthermore, we found that increased Syk and ERK phosphorylation, intracellular ROS generation, and pro-inflammatory cytokines, IL-8 and TNF-α, production could be induced after FcγRIII engagement. Blocking FcγRIII engagement by a specific antibody diminished the augmented NET formation. In conclusion, we discovered that cross-talk between FcγRIII engagement-induced Syk-ERK and PMA-induced PKC signaling pathways augment NET formation of dHL-60 via increased ROS generation and pro-inflammatory cytokines, IL-8 and TNF-α, production. Full article

(This article belongs to the Special Issue Immunoglobulins in Inflammation 2.0)

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12 pages, 1728 KiB

Open AccessArticle

CD40 Agonist Monoclonal Antibody-Mediated Hepatitis in TNF-Receptor 1 Gene Knockout Mice

by Oksana Raabe, Thomas Birchler, Hubert Rehrauer and Elisabeth Eppler

Biomedicines 2021, 9(8), 863; https://doi.org/10.3390/biomedicines9080863 - 22 Jul 2021

Viewed by 2834

Abstract

Tumor necrosis factor-alpha (TNF-α) plays an important role in liver inflammation. CD40-CD40 ligand (CD40-CD40L) is a key receptor–ligand signaling pair involved in the adaptive immune response and pathogenesis of autoimmune diseases. In mice, CD40 activation leads to sickness behavior syndrome (SBS) comprising weight [...] Read more.

Tumor necrosis factor-alpha (TNF-α) plays an important role in liver inflammation. CD40-CD40 ligand (CD40-CD40L) is a key receptor–ligand signaling pair involved in the adaptive immune response and pathogenesis of autoimmune diseases. In mice, CD40 activation leads to sickness behavior syndrome (SBS) comprising weight loss, sleep disruption and depression, which can be blocked by administration of the TNF-inhibitor etanercept. In the present study, we assessed the extent of hepatic inflammation in mice devoid of the TNF-receptor 1 (TNFR1)-mediated signaling pathway. The TNFR1-depleted (TNFR1−/−) adult mice and their wild type littermates were given a single intra-peritoneal injection of CD40 agonist monoclonal antibody (mAb) or rat IgG2a isotope control. As described previously, TNFR1−/− mice were protected from SBS upon CD40 mAb treatment. Cd40, tnf and tnfr1 mRNA and Tnf-α peptide were increased in the liver of CD40 mAb-stimulated wild type mice. Serum alanine aminotransferase was elevated in both CD40-activated wild type and TNFR1−/− mice. TNFR1−/− mice showed much less intra-parenchymal infiltrates, hepatocellular necrosis, and perivascular clusters upon CD40 mAb activation than their wild type littermates. A gene expression microarray detected increased activity of metabolic and detoxification pathways and decreased activity of inflammatory pathways. We conclude that immune activation and development of liver inflammation in CD40L interactions depend on TNFR1-mediated signaling pathways and are counteracted by alterations in metabolic pathways. Full article

(This article belongs to the Special Issue Immunoglobulins in Inflammation 2.0)

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22 pages, 1530 KiB

Open AccessArticle

The Dual Role of a Polyvalent IgM/IgA-Enriched Immunoglobulin Preparation in Activating and Inhibiting the Complement System

by Carolin Schmidt, Sabrina Weißmüller, Fabian Bohländer, Matthias Germer, Martin König, Alexander Staus, Andrea Wartenberg-Demand, Corina C. Heinz and Jörg Schüttrumpf

Biomedicines 2021, 9(7), 817; https://doi.org/10.3390/biomedicines9070817 - 14 Jul 2021

Cited by 8 | Viewed by 3021

Abstract

Activation of the complement system is important for efficient clearance of a wide variety of pathogens via opsonophagocytosis, or by direct lysis via complement-dependent cytotoxicity (CDC). However, in severe infections dysregulation of the complement system contributes to hyperinflammation. The influence of the novel [...] Read more.

Activation of the complement system is important for efficient clearance of a wide variety of pathogens via opsonophagocytosis, or by direct lysis via complement-dependent cytotoxicity (CDC). However, in severe infections dysregulation of the complement system contributes to hyperinflammation. The influence of the novel IgM/IgA-enriched immunoglobulin preparation trimodulin on the complement pathway was investigated in in vitro opsonophagocytosis, binding and CDC assays. Immunoglobulin levels before and after trimodulin treatment were placed in relation to complement assessments in humans. In vitro, trimodulin activates complement and induces opsonophagocytosis, but also interacts with opsonins C3b, C4b and anaphylatoxin C5a in a concentration-dependent manner. This was not observed for standard intravenous IgG preparation (IVIg). Accordingly, trimodulin, but not IVIg, inhibited the downstream CDC pathway and target cell lysis. If applied at a similar concentration range in healthy subjects, trimodulin treatment resulted in C3 and C4 consumption in a concentration-dependent manner, which was extended in patients with severe community-acquired pneumonia. Complement consumption is found to be dependent on underlying immunoglobulin levels, particularly IgM, pinpointing their regulative function in humans. IgM/IgA provide a balancing effect on the complement system. Trimodulin may enhance phagocytosis and opsonophagocytosis in patients with severe infections and prevent excessive pathogen lysis and release of harmful anaphylatoxins. Full article

(This article belongs to the Special Issue Immunoglobulins in Inflammation 2.0)

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Review

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21 pages, 3202 KiB

Open AccessReview

Recent Advances in Monoclonal Antibody-Based Approaches in the Management of Bacterial Sepsis

by Kusum Kharga, Lokender Kumar and Sanjay Kumar Singh Patel

Biomedicines 2023, 11(3), 765; https://doi.org/10.3390/biomedicines11030765 - 2 Mar 2023

Cited by 12 | Viewed by 5120

Abstract

Sepsis is a life-threatening condition characterized by an uncontrolled inflammatory response to an infectious agent and its antigens. Immune cell activation against the antigens causes severe distress that mediates a strong inflammatory response in vital organs. Sepsis is responsible for a high rate [...] Read more.

Sepsis is a life-threatening condition characterized by an uncontrolled inflammatory response to an infectious agent and its antigens. Immune cell activation against the antigens causes severe distress that mediates a strong inflammatory response in vital organs. Sepsis is responsible for a high rate of morbidity and mortality in immunosuppressed patients. Monoclonal antibody (mAb)-based therapeutic strategies are now being explored as a viable therapy option for severe sepsis and septic shock. Monoclonal antibodies may provide benefits through two major strategies: (a) monoclonal antibodies targeting the pathogen and its components, and (b) mAbs targeting inflammatory signaling may directly suppress the production of inflammatory mediators. The major focus of mAb therapies has been bacterial endotoxin (lipopolysaccharide), although other surface antigens are also being investigated for mAb therapy. Several promising candidates for mAbs are undergoing clinical trials at present. Despite several failures and the investigation of novel targets, mAb therapy provides a glimmer of hope for the treatment of severe bacterial sepsis and septic shock. In this review, mAb candidates, their efficacy against controlling infection, with special emphasis on potential roadblocks, and prospects are discussed. Full article

(This article belongs to the Special Issue Immunoglobulins in Inflammation 2.0)

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Other

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19 pages, 2121 KiB

Open AccessSystematic Review

The Clinical Utility of Soluble Serum Biomarkers in Autoimmune Pancreatitis: A Systematic Review

by Ana Dugic, Cristina Verdejo Gil, Claudia Mellenthin, Miroslav Vujasinovic, J.-Matthias Löhr and Steffen Mühldorfer

Biomedicines 2022, 10(7), 1511; https://doi.org/10.3390/biomedicines10071511 - 26 Jun 2022

Cited by 5 | Viewed by 2956

Abstract

Autoimmune pancreatitis (AIP) is a rare etiological type of chronic pancreatitis. The clinical and radiological presentation of AIP often resembles that of pancreatic cancer. Identifying non-invasive markers for their early distinction is of utmost importance to avoid unnecessary surgery or a delay in [...] Read more.

Autoimmune pancreatitis (AIP) is a rare etiological type of chronic pancreatitis. The clinical and radiological presentation of AIP often resembles that of pancreatic cancer. Identifying non-invasive markers for their early distinction is of utmost importance to avoid unnecessary surgery or a delay in steroid therapy. Thus, this systematic review was conducted to revisit all current evidence on the clinical utility of different serum biomarkers in diagnosing AIP, distinguishing AIP from pancreatic cancer, and predicting disease course, steroid therapy response, and relapse. A systematic review was performed for articles published up to August 2021 by searching electronic databases such as MEDLINE, Web of Science, and EMBASE. Among 5123 identified records, 92 studies were included in the qualitative synthesis. Apart from immunoglobulin (Ig) G4, which was by far the most studied biomarker, we identified autoantibodies against the following: lactoferrin, carboanhydrase II, plasminogen-binding protein, amylase-α2A, cationic (PRSS1) and anionic (PRSS2) trypsinogens, pancreatic secretory trypsin inhibitor (PSTI/SPINK1), and type IV collagen. The identified novel autoantigens were laminin 511, annexin A11, HSP-10, and prohibitin. Other biomarkers included cytokines, decreased complement levels, circulating immune complexes, N-glycan profile changes, aberrant miRNAs expression, decreased IgA and IgM levels, increased IgE levels and/or peripheral eosinophil count, and changes in apolipoprotein isoforms levels. To our knowledge, this is the first systematic review that addresses biomarkers in AIP. Evolving research has recognized numerous biomarkers that could help elucidate the pathophysiological mechanisms of AIP, bringing us closer to AIP diagnosis and its preoperative distinction from pancreatic cancer. Full article

(This article belongs to the Special Issue Immunoglobulins in Inflammation 2.0)

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