International Journal of Molecular Sciences

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13 pages, 4205 KiB

Open AccessArticle

Human Intravenous Immunoglobulin Alleviates Neuropathic Symptoms in a Rat Model of Paclitaxel-Induced Peripheral Neurotoxicity

by Cristina Meregalli, Laura Monza, Alessia Chiorazzi, Carla Scali, Chiara Guarnieri, Giulia Fumagalli, Paola Alberti, Eleonora Pozzi, Annalisa Canta, Elisa Ballarini, Virginia Rodriguez-Menendez, Norberto Oggioni, Guido Cavaletti and Paola Marmiroli

Int. J. Mol. Sci. 2021, 22(3), 1058; https://doi.org/10.3390/ijms22031058 - 21 Jan 2021

Cited by 14 | Viewed by 3716

Abstract

The onset of chemotherapy-induced peripheral neurotoxicity (CIPN) is a leading cause of the dose reduction or discontinuation of cancer treatment due to sensory symptoms. Paclitaxel (PTX) can cause painful peripheral neuropathy, with a negative impact on cancer survivors’ quality of life. While recent [...] Read more.

The onset of chemotherapy-induced peripheral neurotoxicity (CIPN) is a leading cause of the dose reduction or discontinuation of cancer treatment due to sensory symptoms. Paclitaxel (PTX) can cause painful peripheral neuropathy, with a negative impact on cancer survivors’ quality of life. While recent studies have shown that neuroinflammation is involved in PTX-induced peripheral neurotoxicity (PIPN), the pathophysiology of this disabling side effect remains largely unclear and no effective therapies are available. Therefore, here we investigated the effects of human intravenous immunoglobulin (IVIg) on a PIPN rat model. PTX-treated rats showed mechanical allodynia and neurophysiological alterations consistent with a severe sensory axonal polyneuropathy. In addition, morphological evaluation showed a reduction of intra-epidermal nerve fiber (IENF) density and evidenced axonopathy with macrophage infiltration, which was more prominent in the distal segment of caudal nerves. Three weeks after the last PTX injection, mechanical allodynia was still present in PTX-treated rats, while the full recovery in the group of animals co-treated with IVIg was observed. At the pathological level, this behavioral result was paralleled by prevention of the reduction in IENF density induced by PTX in IVIg co-treated rats. These results suggest that the immunomodulating effect of IVIg co-treatment can alleviate PIPN neurotoxic manifestations, probably through a partial reduction of neuroinflammation. Full article

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

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14 pages, 2407 KiB

Open AccessArticle

In Vitro Induction of Trained Innate Immunity by bIgG and Whey Protein Extracts

by Anneke H. Hellinga, Theodoros Tsallis, Talitha Eshuis, Vassilis Triantis, Laurien H. Ulfman and R. J. Joost van Neerven

Int. J. Mol. Sci. 2020, 21(23), 9077; https://doi.org/10.3390/ijms21239077 - 28 Nov 2020

Cited by 11 | Viewed by 2819

Abstract

Bovine immunoglobulin G (bIgG) was previously shown to enhance innate immune responses to toll-like receptor (TLR) stimulation, via induction of trained immunity. In this study, we investigated whether minimally processed dairy streams with high levels of whey proteins as potential infant nutrition ingredients [...] Read more.

Bovine immunoglobulin G (bIgG) was previously shown to enhance innate immune responses to toll-like receptor (TLR) stimulation, via induction of trained immunity. In this study, we investigated whether minimally processed dairy streams with high levels of whey proteins as potential infant nutrition ingredients could also induce trained immunity, and to what extent this can be explained by the presence of bIgG. The minimally processed whey ingredients serum protein concentrate (SPC) and whey protein concentrate (WPC) were tested for their ability to induce trained immunity in human peripheral blood monocytes. Both ingredients induced trained immunity as evidenced by an increased production of TNF-α and, to a lesser extent, of IL-6 upon stimulation with TLR ligands. This was comparable to isolated bovine immunoglobulin G (bIgG) that served as positive control. Depletion of bIgG from both whey protein-containing ingredients did not significantly inhibit the induction of trained immunity, suggesting that the streams contain other components in addition to bIgG that are able to induce trained immunity. These results indicate that minimally processed whey ingredients may contribute to protection against infections through enhancing innate immune responsiveness to pathogens. Full article

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

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16 pages, 2929 KiB

Open AccessArticle

Dietary Supplementation with Spray-Dried Porcine Plasma Attenuates Colon Inflammation in a Genetic Mouse Model of Inflammatory Bowel Disease

by Lluïsa Miró, Concepció Amat, Cristina Rosell-Cardona, Joy M. Campbell, Javier Polo, Anna Pérez-Bosque and Miquel Moretó

Int. J. Mol. Sci. 2020, 21(18), 6760; https://doi.org/10.3390/ijms21186760 - 15 Sep 2020

Cited by 14 | Viewed by 2922

Abstract

Dietary supplementation with spray-dried porcine plasma (SDP) can modulate the immune response of gut-associated lymphoid tissue. SDP supplementation reduces acute mucosal inflammation, as well as chronic inflammation associated with aging. The aim of this study was to analyze if SDP supplementation could ameliorate [...] Read more.

Dietary supplementation with spray-dried porcine plasma (SDP) can modulate the immune response of gut-associated lymphoid tissue. SDP supplementation reduces acute mucosal inflammation, as well as chronic inflammation associated with aging. The aim of this study was to analyze if SDP supplementation could ameliorate colitis in a genetic mouse model of inflammatory bowel disease (IBD). Wild-type mice and Mdr1a knockout (KO) mice were administered a control diet or an SDP-supplemented diet from day 21 (weaning) until day 56. The histopathological index, epithelial barrier, and intestinal immune system were analyzed in the colonic mucosa. KO mice had higher epithelial permeability, increased Muc1 and Muc4 expression, and lower abundance of E-cadherin and Muc2 (all p < 0.001). SDP prevented these effects (all p < 0.05) and decreased the colonic inflammation observed in KO mice, reducing neutrophil and monocyte infiltration and activation and the percentage of activated T helper lymphocytes in the colonic mucosa (all p < 0.05). SDP also diminished proinflammatory cytokine expression and increased the anti-inflammatory IL-10 concentration in the colonic mucosa (all p < 0.05). In conclusion, dietary supplementation with SDP enhances colon barrier function and reduces mucosal inflammation in a mouse model of IBD. Full article

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

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14 pages, 2535 KiB

Open AccessArticle

Anti-PD-1 Therapy Does Not Influence Hearing Ability in the Most Sensitive Frequency Range, but Mitigates Outer Hair Cell Loss in the Basal Cochlear Region

by Judit Szepesy, Gabriella Miklós, János Farkas, Dániel Kucsera, Zoltán Giricz, Anita Gáborján, Gábor Polony, Ágnes Szirmai, László Tamás, László Köles, Zoltán V. Varga and Tibor Zelles

Int. J. Mol. Sci. 2020, 21(18), 6701; https://doi.org/10.3390/ijms21186701 - 13 Sep 2020

Cited by 4 | Viewed by 3124

Abstract

The administration of immune checkpoint inhibitors (ICIs) often leads to immune-related adverse events. However, their effect on auditory function is largely unexplored. Thorough preclinical studies have not been published yet, only sporadic cases and pharmacovigilance reports suggest their significance. Here we investigated the [...] Read more.

The administration of immune checkpoint inhibitors (ICIs) often leads to immune-related adverse events. However, their effect on auditory function is largely unexplored. Thorough preclinical studies have not been published yet, only sporadic cases and pharmacovigilance reports suggest their significance. Here we investigated the effect of anti-PD-1 antibody treatment (4 weeks, intraperitoneally, 200 μg/mouse, 3 times/week) on hearing function and cochlear morphology in C57BL/6J mice. ICI treatment did not influence the hearing thresholds in click or tone burst stimuli at 4–32 kHz frequencies measured by auditory brainstem response. The number and morphology of spiral ganglion neurons were unaltered in all cochlear turns. The apical-middle turns (<32 kHz) showed preservation of the inner and outer hair cells (OHCs), whilst ICI treatment mitigated the age-related loss of OHCs in the basal turn (>32 kHz). The number of Iba1-positive macrophages has also increased moderately in this high frequency region. We conclude that a 4-week long ICI treatment does not affect functional and morphological integrity of the inner ear in the most relevant hearing range (4–32 kHz; apical-middle turns), but a noticeable preservation of OHCs and an increase in macrophage activity appeared in the >32 kHz basal part of the cochlea. Full article

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

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22 pages, 2618 KiB

Open AccessArticle

Filling the Antibody Pipeline in Allergy: PIPE Cloning of IgE, IgG₁ and IgG₄ against the Major Birch Pollen Allergen Bet v 1

by Verena K. Köhler, Silvia Crescioli, Judit Fazekas-Singer, Heather J. Bax, Gerhard Hofer, Christina L. Pranger, Karin Hufnagl, Rodolfo Bianchini, Sabine Flicker, Walter Keller, Sophia N. Karagiannis and Erika Jensen-Jarolim

Int. J. Mol. Sci. 2020, 21(16), 5693; https://doi.org/10.3390/ijms21165693 - 8 Aug 2020

Cited by 3 | Viewed by 4415

Abstract

Birch pollen allergy is among the most prevalent pollen allergies in Northern and Central Europe. This IgE-mediated disease can be treated with allergen immunotherapy (AIT), which typically gives rise to IgG antibodies inducing tolerance. Although the main mechanisms of allergen immunotherapy (AIT) are [...] Read more.

Birch pollen allergy is among the most prevalent pollen allergies in Northern and Central Europe. This IgE-mediated disease can be treated with allergen immunotherapy (AIT), which typically gives rise to IgG antibodies inducing tolerance. Although the main mechanisms of allergen immunotherapy (AIT) are known, questions regarding possible Fc-mediated effects of IgG antibodies remain unanswered. This can mainly be attributed to the unavailability of appropriate tools, i.e., well-characterised recombinant antibodies (rAbs). We hereby aimed at providing human rAbs of several classes for mechanistic studies and as possible candidates for passive immunotherapy. We engineered IgE, IgG₁, and IgG₄ sharing the same variable region against the major birch pollen allergen Bet v 1 using Polymerase Incomplete Primer Extension (PIPE) cloning. We tested IgE functionality and IgG blocking capabilities using appropriate model cell lines. In vitro studies showed IgE engagement with FcεRI and CD23 and Bet v 1-dependent degranulation. Overall, we hereby present fully functional, human IgE, IgG₁, and IgG₄ sharing the same variable region against Bet v 1 and showcase possible applications in first mechanistic studies. Furthermore, our IgG antibodies might be useful candidates for passive immunotherapy of birch pollen allergy. Full article

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

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16 pages, 2533 KiB

Open AccessArticle

Consequences of Vitamin A Deficiency: Immunoglobulin Dysregulation, Squamous Cell Metaplasia, Infectious Disease, and Death

by Sherri L. Surman, Rhiannon R. Penkert, Robert E. Sealy, Bart G. Jones, Tony N. Marion, Peter Vogel and Julia L. Hurwitz

Int. J. Mol. Sci. 2020, 21(15), 5570; https://doi.org/10.3390/ijms21155570 - 4 Aug 2020

Cited by 32 | Viewed by 6563

Abstract

Vitamin A is an important regulator of immune protection, but it is often overlooked in studies of infectious disease. Vitamin A binds an array of nuclear receptors (e.g., retinoic acid receptor, peroxisome proliferator-activated receptor, retinoid X receptor) and influences the barrier and immune [...] Read more.

Vitamin A is an important regulator of immune protection, but it is often overlooked in studies of infectious disease. Vitamin A binds an array of nuclear receptors (e.g., retinoic acid receptor, peroxisome proliferator-activated receptor, retinoid X receptor) and influences the barrier and immune cells responsible for pathogen control. Children and adults in developed and developing countries are often vitamin A-deficient or insufficient, characteristics associated with poor health outcomes. To gain a better understanding of the protective mechanisms influenced by vitamin A, we examined immune factors and epithelial barriers in vitamin A deficient (VAD) mice, vitamin D deficient (VDD) mice, double deficient (VAD+VDD) mice, and mice on a vitamin-replete diet (controls). Some mice received insults, including intraperitoneal injections with complete and incomplete Freund’s adjuvant (emulsified with PBS alone or with DNA + Fus-1 peptide) or intranasal inoculations with Sendai virus (SeV). Both before and after insults, the VAD and VAD+VDD mice exhibited abnormal serum immunoglobulin isotypes (e.g., elevated IgG2b levels, particularly in males) and cytokine/chemokine patterns (e.g., elevated eotaxin). Even without insult, when the VAD and VAD+VDD mice reached 3–6 months of age, they frequently exhibited opportunistic ascending bacterial urinary tract infections. There were high frequencies of nephropathy (squamous cell hyperplasia of the renal urothelium, renal scarring, and ascending pyelonephritis) and death in the VAD and VAD+VDD mice. When younger VAD mice were infected with SeV, the predominant lesion was squamous cell metaplasia of respiratory epithelium in lungs and bronchioles. Results highlight a critical role for vitamin A in the maintenance of healthy immune responses, epithelial cell integrity, and pathogen control. Full article

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

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13 pages, 2433 KiB

Open AccessArticle

Functional Block of Interleukin-6 Reduces a Bone Pain Marker But Not Bone Loss in Hindlimb-Unloaded Mice

by Hiroki Wakabayashi, Gaku Miyamura, Nobuto Nagao, Sho Kato, Yohei Naito and Akihiro Sudo

Int. J. Mol. Sci. 2020, 21(10), 3521; https://doi.org/10.3390/ijms21103521 - 15 May 2020

Cited by 8 | Viewed by 2345

Abstract

Interleukin-6 (IL-6) is widely accepted to stimulate osteoclasts. Our aim in this study was to examine whether the inhibitory effect of IL-6 on bone loss and skeletal pain associated with osteoporosis in hindlimb-unloaded (HU) mice in comparison with bisphosphonate. Eight-week-old male ddY mice [...] Read more.

Interleukin-6 (IL-6) is widely accepted to stimulate osteoclasts. Our aim in this study was to examine whether the inhibitory effect of IL-6 on bone loss and skeletal pain associated with osteoporosis in hindlimb-unloaded (HU) mice in comparison with bisphosphonate. Eight-week-old male ddY mice were tail suspended for 2 weeks. Starting immediately after reload, vehicle (HU group), alendronate (HU-ALN group), or anti-IL-6 receptor antibody (HU-IL-6i group) was injected subcutaneously. After a 2-week treatment, pain-related behavior was examined using von Frey filaments. The bilateral distal femoral and proximal tibial metaphyses were analyzed three-dimensionally with micro-computed tomography. Calcitonin gene-related peptide (CGRP) expressions in dorsal root ganglion (DRG) neurons innervating the hindlimbs were examined using immunohistochemistry. HU mice with tail suspension developed bone loss. The HU mice showed mechanical hyperalgesia in the hindlimbs and increased CGRP immunoreactive neurons in the L3-5 DRG. Treatment with IL-6i and ALN prevented HU-induced mechanical hyperalgesia and upregulation of CGRP expressions in DRG neurons. Furthermore, ALN but not IL-6i prevented HU-induced bone loss. In summary, treatment with IL-6i prevented mechanical hyperalgesia in hindlimbs and suppressed CGRP expressions in DRG neurons of osteoporotic models. The novelty of this research suggests that IL-6 is one of the causes of immobility-induced osteoporotic pain regardless improvement of bone loss. Full article

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

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17 pages, 1400 KiB

Open AccessArticle

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

by Alexander N. Orekhov, Vasily N. Sukhorukov, Nikita G. Nikiforov, Marina V. Kubekina, Igor A. Sobenin, Kathy K. Foxx, Sergey Pintus, Philip Stegmaier, Daria Stelmashenko, Alexander Kel, Anastasia V. Poznyak, Wei-Kai Wu, Artem S. Kasianov, Vsevolod Y. Makeev, Ichiro Manabe and Yumiko Oishi

Int. J. Mol. Sci. 2020, 21(8), 2716; https://doi.org/10.3390/ijms21082716 - 14 Apr 2020

Cited by 19 | Viewed by 5348

Abstract

Accumulation of lipid-laden (foam) cells in the arterial wall is known to be the earliest step in the pathogenesis of atherosclerosis. There is almost no doubt that atherogenic modified low-density lipoproteins (LDL) are the main sources of accumulating lipids in foam cells. Atherogenic [...] Read more.

Accumulation of lipid-laden (foam) cells in the arterial wall is known to be the earliest step in the pathogenesis of atherosclerosis. There is almost no doubt that atherogenic modified low-density lipoproteins (LDL) are the main sources of accumulating lipids in foam cells. Atherogenic modified LDL are taken up by arterial cells, such as macrophages, pericytes, and smooth muscle cells in an unregulated manner bypassing the LDL receptor. The present study was conducted to reveal possible common mechanisms in the interaction of macrophages with associates of modified LDL and non-lipid latex particles of a similar size. To determine regulatory pathways that are potentially responsible for cholesterol accumulation in human macrophages after the exposure to naturally occurring atherogenic or artificially modified LDL, we used transcriptome analysis. Previous studies of our group demonstrated that any type of LDL modification facilitates the self-association of lipoprotein particles. The size of such self-associates hinders their interaction with a specific LDL receptor. As a result, self-associates are taken up by nonspecific phagocytosis bypassing the LDL receptor. That is why we used latex beads as a stimulator of macrophage phagocytotic activity. We revealed at least 12 signaling pathways that were regulated by the interaction of macrophages with the multiple-modified atherogenic naturally occurring LDL and with latex beads in a similar manner. Therefore, modified LDL was shown to stimulate phagocytosis through the upregulation of certain genes. We have identified at least three genes (F2RL1, EIF2AK3, and IL15) encoding inflammatory molecules and associated with signaling pathways that were upregulated in response to the interaction of modified LDL with macrophages. Knockdown of two of these genes, EIF2AK3 and IL15, completely suppressed cholesterol accumulation in macrophages. Correspondingly, the upregulation of EIF2AK3 and IL15 promoted cholesterol accumulation. These data confirmed our hypothesis of the following chain of events in atherosclerosis: LDL particles undergo atherogenic modification; this is accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. This chain of events may explain the relationship between cholesterol accumulation and inflammation. The primary sequence of events in this chain is related to inflammatory response rather than cholesterol accumulation. Full article

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

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Review

Jump to: Research

21 pages, 712 KiB

Open AccessReview

Monoclonal Antibodies and Airway Diseases

by Annina Lyly, Anu Laulajainen-Hongisto, Philippe Gevaert, Paula Kauppi and Sanna Toppila-Salmi

Int. J. Mol. Sci. 2020, 21(24), 9477; https://doi.org/10.3390/ijms21249477 - 13 Dec 2020

Cited by 11 | Viewed by 4421

Abstract

Monoclonal antibodies, biologics, are a relatively new treatment option for severe chronic airway diseases, asthma, allergic rhinitis, and chronic rhinosinusitis (CRS). In this review, we focus on the physiological and pathomechanisms of monoclonal antibodies, and we present recent study results regarding their use [...] Read more.

Monoclonal antibodies, biologics, are a relatively new treatment option for severe chronic airway diseases, asthma, allergic rhinitis, and chronic rhinosinusitis (CRS). In this review, we focus on the physiological and pathomechanisms of monoclonal antibodies, and we present recent study results regarding their use as a therapeutic option against severe airway diseases. Airway mucosa acts as a relative barrier, modulating antigenic stimulation and responding to environmental pathogen exposure with a specific, self-limited response. In severe asthma and/or CRS, genome–environmental interactions lead to dysbiosis, aggravated inflammation, and disease. In healthy conditions, single or combined type 1, 2, and 3 immunological response pathways are invoked, generating cytokine, chemokine, innate cellular and T helper (Th) responses to eliminate viruses, helminths, and extracellular bacteria/fungi, correspondingly. Although the pathomechanisms are not fully known, the majority of severe airway diseases are related to type 2 high inflammation. Type 2 cytokines interleukins (IL) 4, 5, and 13, are orchestrated by innate lymphoid cell (ILC) and Th subsets leading to eosinophilia, immunoglobulin E (IgE) responses, and permanently impaired airway damage. Monoclonal antibodies can bind or block key parts of these inflammatory pathways, resulting in less inflammation and improved disease control. Full article

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

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17 pages, 1230 KiB

Open AccessReview

Use of Intravenous Immunoglobulins in Sepsis Therapy—A Clinical View

by Dominik Jarczak, Stefan Kluge and Axel Nierhaus

Int. J. Mol. Sci. 2020, 21(15), 5543; https://doi.org/10.3390/ijms21155543 - 3 Aug 2020

Cited by 35 | Viewed by 7106

Abstract

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 [...] Read more.

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. Full article

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

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31 pages, 1469 KiB

Open AccessReview

Targeting of CD163⁺ Macrophages in Inflammatory and Malignant Diseases

by Maria K. Skytthe, Jonas Heilskov Graversen and Søren K. Moestrup

Int. J. Mol. Sci. 2020, 21(15), 5497; https://doi.org/10.3390/ijms21155497 - 31 Jul 2020

Cited by 141 | Viewed by 15320

Abstract

The macrophage is a key cell in the pro- and anti-inflammatory response including that of the inflammatory microenvironment of malignant tumors. Much current drug development in chronic inflammatory diseases and cancer therefore focuses on the macrophage as a target for immunotherapy. However, this [...] Read more.

The macrophage is a key cell in the pro- and anti-inflammatory response including that of the inflammatory microenvironment of malignant tumors. Much current drug development in chronic inflammatory diseases and cancer therefore focuses on the macrophage as a target for immunotherapy. However, this strategy is complicated by the pleiotropic phenotype of the macrophage that is highly responsive to its microenvironment. The plasticity leads to numerous types of macrophages with rather different and, to some extent, opposing functionalities, as evident by the existence of macrophages with either stimulating or down-regulating effect on inflammation and tumor growth. The phenotypes are characterized by different surface markers and the present review describes recent progress in drug-targeting of the surface marker CD163 expressed in a subpopulation of macrophages. CD163 is an abundant endocytic receptor for multiple ligands, quantitatively important being the haptoglobin-hemoglobin complex. The microenvironment of inflammation and tumorigenesis is particular rich in CD163⁺ macrophages. The use of antibodies for directing anti-inflammatory (e.g., glucocorticoids) or tumoricidal (e.g., doxorubicin) drugs to CD163⁺ macrophages in animal models of inflammation and cancer has demonstrated a high efficacy of the conjugate drugs. This macrophage-targeting approach has a low toxicity profile that may highly improve the therapeutic window of many current drugs and drug candidates. Full article

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

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17 pages, 557 KiB

Open AccessReview

Sialylated Immunoglobulins for the Treatment of Immuno-Inflammatory Diseases

by Yuliya V. Markina, Elena V. Gerasimova, Alexander M. Markin, Victor Y. Glanz, Wei-Kai Wu, Igor A. Sobenin and Alexander N. Orekhov

Int. J. Mol. Sci. 2020, 21(15), 5472; https://doi.org/10.3390/ijms21155472 - 31 Jul 2020

Cited by 21 | Viewed by 4475

Abstract

Immunoglobulins are the potent effector proteins of the humoral immune response. In the course of evolution, immunoglobulins have formed extremely diverse types of molecular structures with antigen-recognizing, antigen-binding, and effector functions embedded in a single molecule. Polysaccharide moiety of immunoglobulins plays the essential [...] Read more.

Immunoglobulins are the potent effector proteins of the humoral immune response. In the course of evolution, immunoglobulins have formed extremely diverse types of molecular structures with antigen-recognizing, antigen-binding, and effector functions embedded in a single molecule. Polysaccharide moiety of immunoglobulins plays the essential role in immunoglobulin functioning. There is growing evidence that the carbohydrate composition of immunoglobulin-linked glycans, and especially their terminal sialic acid residues, provide a key effect on the effector functions of immunoglobulins. Possibly, sialylation of Fc glycan is a common mechanism of IgG anti-inflammatory action in vivo. Thus, the post-translational modification (glycosylation) of immunoglobulins opens up significant possibilities in the diagnosis of both immunological and inflammatory disorders and in their therapies. This review is focused on the analysis of glycosylation of immunoglobulins, which can be a promising addition to improve existing strategies for the diagnosis and treatment of various immuno-inflammatory diseases. Full article

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

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34 pages, 874 KiB

Open AccessReview

Immunoglobulins with Non-Canonical Functions in Inflammatory and Autoimmune Disease States

by Evgeny A. Ermakov, Georgy A. Nevinsky and Valentina N. Buneva

Int. J. Mol. Sci. 2020, 21(15), 5392; https://doi.org/10.3390/ijms21155392 - 29 Jul 2020

Cited by 23 | Viewed by 5987

Abstract

Immunoglobulins are known to combine various effector mechanisms of the adaptive and the innate immune system. Classical immunoglobulin functions are associated with antigen recognition and the initiation of innate immune responses. However, in addition to classical functions, antibodies exhibit a variety of non-canonical [...] Read more.

Immunoglobulins are known to combine various effector mechanisms of the adaptive and the innate immune system. Classical immunoglobulin functions are associated with antigen recognition and the initiation of innate immune responses. However, in addition to classical functions, antibodies exhibit a variety of non-canonical functions related to the destruction of various pathogens due to catalytic activity and cofactor effects, the action of antibodies as agonists/antagonists of various receptors, the control of bacterial diversity of the intestine, etc. Canonical and non-canonical functions reflect the extreme human antibody repertoire and the variety of antibody types generated in the organism: antigen-specific, natural, polyreactive, broadly neutralizing, homophilic, bispecific and catalytic. The therapeutic effects of intravenous immunoglobulins (IVIg) are associated with both the canonical and non-canonical functions of antibodies. In this review, catalytic antibodies will be considered in more detail, since their formation is associated with inflammatory and autoimmune diseases. We will systematically summarize the diversity of catalytic antibodies in normal and pathological conditions. Translational perspectives of knowledge about natural antibodies for IVIg therapy will be also discussed. Full article

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

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19 pages, 705 KiB

Open AccessReview

The Functional Roles and Applications of Immunoglobulins in Neurodegenerative Disease

by Kyu-Young Sim, Kyeong Chan Im and Sung-Gyoo Park

Int. J. Mol. Sci. 2020, 21(15), 5295; https://doi.org/10.3390/ijms21155295 - 26 Jul 2020

Cited by 20 | Viewed by 5271

Abstract

Natural autoantibodies, immunoglobulins (Igs) that target self-proteins, are common in the plasma of healthy individuals; some of the autoantibodies play pathogenic roles in systemic or tissue-specific autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Recently, the field of autoantibody-associated diseases has [...] Read more.

Natural autoantibodies, immunoglobulins (Igs) that target self-proteins, are common in the plasma of healthy individuals; some of the autoantibodies play pathogenic roles in systemic or tissue-specific autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Recently, the field of autoantibody-associated diseases has expanded to encompass neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), with related studies examining the functions of Igs in the central nervous system (CNS). Recent evidence suggests that Igs have various effects in the CNS; these effects are associated with the prevention of neurodegeneration, as well as induction. Here, we summarize the functional roles of Igs with respect to neurodegenerative disease (AD and PD), focusing on the target antigens and effector cell types. In addition, we review the current knowledge about the roles of these antibodies as diagnostic markers and immunotherapies. Full article

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

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42 pages, 3323 KiB

Open AccessReview

Primary Humoral Immune Deficiencies: Overlooked Mimickers of Chronic Immune-Mediated Gastrointestinal Diseases in Adults

by Ida Judyta Malesza, Michał Malesza, Iwona Krela-Kaźmierczak, Aleksandra Zielińska, Eliana B. Souto, Agnieszka Dobrowolska and Piotr Eder

Int. J. Mol. Sci. 2020, 21(15), 5223; https://doi.org/10.3390/ijms21155223 - 23 Jul 2020

Cited by 11 | Viewed by 10313

Abstract

In recent years, the incidence of immune-mediated gastrointestinal disorders, including celiac disease (CeD) and inflammatory bowel disease (IBD), is increasingly growing worldwide. This generates a need to elucidate the conditions that may compromise the diagnosis and treatment of such gastrointestinal disorders. It is [...] Read more.

In recent years, the incidence of immune-mediated gastrointestinal disorders, including celiac disease (CeD) and inflammatory bowel disease (IBD), is increasingly growing worldwide. This generates a need to elucidate the conditions that may compromise the diagnosis and treatment of such gastrointestinal disorders. It is well established that primary immunodeficiencies (PIDs) exhibit gastrointestinal manifestations and mimic other diseases, including CeD and IBD. PIDs are often considered pediatric ailments, whereas between 25 and 45% of PIDs are diagnosed in adults. The most common PIDs in adults are the selective immunoglobulin A deficiency (SIgAD) and the common variable immunodeficiency (CVID). A trend to autoimmunity occurs, while gastrointestinal disorders are common in both diseases. Besides, the occurrence of CeD and IBD in SIgAD/CVID patients is significantly higher than in the general population. However, some differences concerning diagnostics and management between enteropathy/colitis in PIDs, as compared to idiopathic forms of CeD/IBD, have been described. There is an ongoing discussion whether CeD and IBD in CVID patients should be considered a true CeD and IBD or just CeD-like and IBD-like diseases. This review addresses the current state of the art of the most common primary immunodeficiencies in adults and co-occurring CeD and IBD. Full article

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

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24 pages, 944 KiB

Open AccessReview

The Cellular and Molecular Bases of Allergy, Inflammation and Tissue Fibrosis in Patients with IgG4-related Disease

by Song-Chou Hsieh, Chieh-Yu Shen, Hsien-Tzung Liao, Ming-Han Chen, Cheng-Han Wu, Ko-Jen Li, Cheng-Shiun Lu, Yu-Min Kuo, Hung-Cheng Tsai, Chang-Youh Tsai and Chia-Li Yu

Int. J. Mol. Sci. 2020, 21(14), 5082; https://doi.org/10.3390/ijms21145082 - 18 Jul 2020

Cited by 17 | Viewed by 4901

Abstract

IgG4-related disease (IgG4-RD) is a spectrum of complex fibroinflammatory disorder with protean manifestations mimicking malignant neoplasms, infectious or non-infectious inflammatory process. The histopathologic features of IgG4-RD include lymphoplasmacytic infiltration, storiform fibrosis and obliterative phlebitis together with increased in situ infiltration of IgG4 bearing-plasma [...] Read more.

IgG4-related disease (IgG4-RD) is a spectrum of complex fibroinflammatory disorder with protean manifestations mimicking malignant neoplasms, infectious or non-infectious inflammatory process. The histopathologic features of IgG4-RD include lymphoplasmacytic infiltration, storiform fibrosis and obliterative phlebitis together with increased in situ infiltration of IgG4 bearing-plasma cells which account for more than 40% of all IgG-producing B cells. IgG4-RD can also be diagnosed based on an elevated serum IgG4 level of more than 110 mg/dL (normal < 86.5 mg/mL in adult) in conjunction with protean clinical manifestations in various organs such as pancreato–hepatobiliary inflammation with/without salivary/lacrimal gland enlargement. In the present review, we briefly discuss the role of genetic predisposition, environmental factors and candidate autoantibodies in the pathogenesis of IgG4-RD. Then, we discuss in detail the immunological paradox of IgG4 antibody, the mechanism of modified Th2 response for IgG4 rather than IgE antibody production and the controversial issues in the allergic reactions of IgG4-RD. Finally, we extensively review the implications of different immune-related cells, cytokines/chemokines/growth factors and Toll-like as well as NOD-like receptors in the pathogenesis of tissue fibro-inflammatory reactions. Our proposals for the future investigations and prospective therapeutic strategies for IgG4-RD are shown in the last part. Full article

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

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15 pages, 1518 KiB

Open AccessReview

The Role of IgG4 in the Fine Tuning of Tolerance in IgE-Mediated Allergy and Cancer

by Rodolfo Bianchini, Sophia N. Karagiannis, Galateja Jordakieva and Erika Jensen-Jarolim

Int. J. Mol. Sci. 2020, 21(14), 5017; https://doi.org/10.3390/ijms21145017 - 16 Jul 2020

Cited by 44 | Viewed by 9400

Abstract

Among the four immunoglobulin G (IgG) subclasses, IgG4 is the least represented in serum of a healthy human and it is considered an “odd” antibody. The IgG4 antibody has unique structural features that affect its biological function. These include the ability to undergo [...] Read more.

Among the four immunoglobulin G (IgG) subclasses, IgG4 is the least represented in serum of a healthy human and it is considered an “odd” antibody. The IgG4 antibody has unique structural features that affect its biological function. These include the ability to undergo antigen-binding fragment (Fab)-arm exchange, to create fragment crystallizable (Fc) – Fc binding with other IgG4 and other IgG subclass antibodies, have a unique affinity profile for Fc gamma receptors (FcγRs) and no binding to complement component C1q. Altogether, these characteristics support anti-inflammatory roles of IgG4 leading to immune tolerance. Under conditions of chronic antigenic stimulation and Th2-type inflammation, both tissue and serum IgG4 levels are increased. This review seeks to highlight how in allergen immunotherapy IgG4 can confer a protective role as a “blocking” antibody and safeguard from subsequent allergen exposure, while IgG4 can confer immunomodulatory functions to support malignancy. While Th2 conditions drive polarization of macrophages to the M2a subtype, chronic antigen stimulation drives B cell class switching to IgG4 to further support phenotypical macrophage changes towards an M2b-like state. M2b-like macrophages can secrete chemokine (C-C motif) ligand 1 (CCL1) and interleukin-10 (IL-10) to support regulatory cell recruitment and to further shape a tolerogenic microenvironment. Thereby, IgG4 have a Janus-faced role, favorable in allergy but detrimental in cancer. Full article

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

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13 pages, 1108 KiB

Open AccessReview

Beyond Macrophages and T Cells: B Cells and Immunoglobulins Determine the Fate of the Atherosclerotic Plaque

by Harald Mangge, Florian Prüller, Wolfgang Schnedl, Wilfried Renner and Gunter Almer

Int. J. Mol. Sci. 2020, 21(11), 4082; https://doi.org/10.3390/ijms21114082 - 8 Jun 2020

Cited by 22 | Viewed by 5048

Abstract

Atherosclerosis (AS) leading to myocardial infarction and stroke remains worldwide the main cause for mortality. Vulnerable atherosclerotic plaques are responsible for these life-threatening clinical endpoints. Atherosclerosis is a chronic, complex, inflammatory disease with interactions between metabolic dysfunction, dyslipidemia, disturbed microbiome, infectious triggers, vascular, [...] Read more.

Atherosclerosis (AS) leading to myocardial infarction and stroke remains worldwide the main cause for mortality. Vulnerable atherosclerotic plaques are responsible for these life-threatening clinical endpoints. Atherosclerosis is a chronic, complex, inflammatory disease with interactions between metabolic dysfunction, dyslipidemia, disturbed microbiome, infectious triggers, vascular, and immune cells. Undoubtedly, the immune response is a most important piece of the pathological puzzle in AS. Although macrophages and T cells have been the focus of research in recent years, B cells producing antibodies and regulating T and natural killer (NKT) cell activation are more important than formerly thought. New results show that the B cells exert a prominent role with atherogenic and protective facets mediated by distinct B cell subsets and different immunoglobulin effects. These new insights come, amongst others, from observations of the effects of innovative B cell targeted therapies in autoimmune diseases like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). These diseases associate with AS, and the beneficial side effects of B cell subset depleting (modifying) therapies on atherosclerotic concomitant disease, have been observed. Moreover, the CANTOS study (NCT01327846) showed impressive results of immune-mediated inflammation as a new promising target of action for the fight against atherosclerotic endpoints. This review will reflect the putative role of B cells in AS in an attempt to connect observations from animal models with the small spectrum of the thus far available human data. We will also discuss the clinical therapeutic potency of B cell modulations on the process of AS. Full article

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

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23 pages, 1360 KiB

Open AccessReview

Anti-Citrullinated Protein Antibodies in Patients with Rheumatoid Arthritis: Biological Effects and Mechanisms of Immunopathogenesis

by Chao-Yi Wu, Huang-Yu Yang and Jenn-Haung Lai

Int. J. Mol. Sci. 2020, 21(11), 4015; https://doi.org/10.3390/ijms21114015 - 4 Jun 2020

Cited by 65 | Viewed by 10477

Abstract

Individuals with high anti-citrullinated protein antibody (ACPA) titers have an increased risk of developing rheumatoid arthritis (RA). Although our knowledge of the generation and production of ACPAs has continuously advanced during the past decade, our understanding on the pathogenic mechanisms of how ACPAs [...] Read more.

Individuals with high anti-citrullinated protein antibody (ACPA) titers have an increased risk of developing rheumatoid arthritis (RA). Although our knowledge of the generation and production of ACPAs has continuously advanced during the past decade, our understanding on the pathogenic mechanisms of how ACPAs interact with immune cells to trigger articular inflammation is relatively limited. Citrullination disorders drive the generation and maintenance of ACPAs, with profound clinical significance in patients with RA. The loss of tolerance to citrullinated proteins, however, is essential for ACPAs to exert their pathogenicity. N-linked glycosylation, cross-reactivity and the structural interactions of ACPAs with their citrullinated antigens further direct their biological functions. Although questions remain in the pathogenicity of ACPAs acting as agonists for a receptor-mediated response, immune complex (IC) formation, complement system activation, crystallizable fragment gamma receptor (FcγR) activation, cross-reactivity to joint cartilage and neutrophil extracellular trap (NET)-related mechanisms have all been suggested recently. This paper presents a critical review of the characteristics and possible biological effects and mechanisms of the immunopathogenesis of ACPAs in patients with RA. Full article

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

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13 pages, 299 KiB

Open AccessReview

SARS-CoV-2 Inflammatory Syndrome. Clinical Features and Rationale for Immunological Treatment

by Marcella Prete, Elvira Favoino, Giacomo Catacchio, Vito Racanelli and Federico Perosa

Int. J. Mol. Sci. 2020, 21(9), 3377; https://doi.org/10.3390/ijms21093377 - 10 May 2020

Cited by 58 | Viewed by 7520

Abstract

The current pandemic coronavirus, SARS-CoV-2, is a global health emergency because of its highly contagious nature, the great number of patients requiring intensive care therapy, and the high fatality rate. In the absence of specific antiviral drugs, passive prophylaxis, or a vaccine, the [...] Read more.

The current pandemic coronavirus, SARS-CoV-2, is a global health emergency because of its highly contagious nature, the great number of patients requiring intensive care therapy, and the high fatality rate. In the absence of specific antiviral drugs, passive prophylaxis, or a vaccine, the treatment aim in these patients is to prevent the potent virus-induced inflammatory stimuli from leading to the acute respiratory distress syndrome (ARDS), which has a severe prognosis. Here, the mechanism of action and the rationale for employing immunological strategies, which range from traditional chemically synthesized drugs, anti-cytokine antibodies, human immunoglobulin for intravenous use, to vaccines, are reviewed. Full article

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

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