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

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.

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IL-10 regulates plasmacytoid dendritic cell response to CpG-containing immunostimulatory sequences

Blood ◽

10.1182/blood-2003-07-2465 ◽

2003 ◽

Vol 102 (13) ◽

pp. 4487-4492 ◽

Cited By ~ 104

Author(s):

Omar Duramad ◽

Karen L. Fearon ◽

Jean H. Chan ◽

Holger Kanzler ◽

Jason D. Marshall ◽

...

Keyword(s):

T Cell ◽

Dendritic Cell ◽

Plasmacytoid Dendritic Cell ◽

Innate Immune ◽

Innate Immune Responses ◽

Cpg Dinucleotides ◽

Disease States ◽

T Cell Priming ◽

Anti Inflammatory Cytokine ◽

Unmethylated Cytosine

AbstractImmunostimulatory sequences (ISS) are short oligonucleotides containing unmethylated cytosine-phosphate-guanine (CpG) dinucleotides that stimulate innate immune responses through Toll-like receptor-9 on B cells and plasmacytoid dendritic cell (PDC) precursors. The anti-inflammatory cytokine interleukin (IL)-10 is predicted to be a potent inhibitor of many of the activities described for ISS, and this may impact the use of ISS in disease states characterized by elevated IL-10. As the activities of ISS on PDCs are central to many clinical applications of ISS, we have studied the effects of IL-10 on PDC stimulation by 3 distinct classes of ISS. IL-10 inhibited cytokine production and survival of ISS-activated PDCs; however, IL-12 induction was much more sensitive to inhibition than interferon (IFN)-α induction. Within the PDC population are cells that respond to ISS by producing either IL-12 or IFN-α but not both cytokines. IL-12-producing PDCs require costimulation through CD40 and appear more mature than IFN-α-producing PDCs. The 3 distinct classes of ISS differed with respect to induction of PDC maturation and T-cell priming capacity. IL-10 regulated PDC activation but did not inhibit the subsequent T-cell-priming ability of PDCs already activated by ISS. (Blood. 2003;102:4487-4492)

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Prostaglandin and the Suppression of Phagocyte Innate Immune Responses in Different Organs

Mediators of Inflammation ◽

10.1155/2012/327568 ◽

2012 ◽

Vol 2012 ◽

pp. 1-13 ◽

Cited By ~ 47

Author(s):

Alexandra Medeiros ◽

Camila Peres-Buzalaf ◽

Felipe Fortino Verdan ◽

C. Henrique Serezani

Keyword(s):

Immune Responses ◽

Inflammatory Responses ◽

Innate Immune ◽

Prostaglandin E ◽

Innate Immune Responses ◽

Disease States ◽

Relative Contribution ◽

Guanine Nucleotide Binding ◽

Nucleotide Binding Proteins ◽

Guanine Nucleotide Binding Proteins

The local and systemic production of prostaglandin E2(PGE2) and its actions in phagocytes lead to immunosuppressive conditions. PGE2is produced at high levels during inflammation, and its suppressive effects are caused by the ligation of the E prostanoid receptors EP2and EP4, which results in the production of cyclic AMP. However, PGE2also exhibits immunostimulatory properties due to binding to EP3, which results in decreased cAMP levels. The various guanine nucleotide-binding proteins (G proteins) that are coupled to the different EP receptors account for the pleiotropic roles of PGE2in different disease states. Here, we discuss the production of PGE2and the actions of this prostanoid in phagocytes from different tissues, the relative contribution of PGE2to the modulation of innate immune responses, and the novel therapeutic opportunities that can be used to control inflammatory responses.

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Mitochondrial antiviral signalling protein is crucial for the development of pulmonary fibrosis

European Respiratory Journal ◽

10.1183/13993003.00652-2020 ◽

2020 ◽

pp. 2000652

Author(s):

Sang-Hun Kim ◽

Jung Yeon Lee ◽

Chang Min Yoon ◽

Hyeon Jun Shin ◽

Sei Won Lee ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Therapeutic Strategy ◽

Innate Immune ◽

Therapeutic Effects ◽

Innate Immune Responses ◽

Approved Drugs ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

Danger signals, or damage-associated molecular patterns (DAMPs), instigate mitochondrial innate immune responses wherein Mitochondrial Antiviral Signalling protein (MAVS) functions as a key platform molecule to mediate them. The role of MAVS in the pathogenesis of idiopathic pulmonary fibrosis (IPF), however, has not been identified yet. A possibility whether the MAVS signalling can be modulated by currently existing drugs has not been explored, either. Here, using an established model of pulmonary fibrosis, we demonstrate that MAVS plays as a critical mediator of multiple DAMPs signalling pathways and the consequent lung fibrosis after bleomycin-induced injury in vivo. After bleomycin injury, the expression of MAVS was mainly observed in macrophages. In addition, multimeric MAVS aggregation, a key event of MAVS signalling activation, was significantly increased and persisted in bleomycin-injured lungs. Interestingly, a proapoptotic BH3 mimetic ABT-263 attenuated the expression of MAVS and its signalling and, consequently, the development of experimental pulmonary fibrosis. In contrast, the therapeutic effects of Pirfenidone or Nintedanib, two approved drugs for IPF treatment, were not related to the modulation of MAVS or its signalling. Importantly, multimeric MAVS aggregation was significantly increased in lungs from the patients with IPF as well. In conclusion, MAVS may play an important role in the development of pulmonary fibrosis, and targeting MAVS with BH3 mimetics may provide a novel therapeutic strategy for IPF, a major unmet disorder.

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Inborn Errors in the LRR Domain of Nod2 and Their Potential Consequences on the Function of the Receptor

Cells ◽

10.3390/cells10082031 ◽

2021 ◽

Vol 10 (8) ◽

pp. 2031

Author(s):

Shamila D. Alipoor ◽

Mehdi Mirsaeidi

Keyword(s):

Critical Role ◽

Innate Immune ◽

Innate Immune Responses ◽

Inborn Errors ◽

Pathological Conditions ◽

Encoding Gene ◽

And Function ◽

Lrr Domain ◽

Recognition Receptor ◽

Oligomerization Domain

The innate immune system plays a critical role in the early detection of pathogens, primarily by relying on pattern-recognition receptor (PRR) signaling molecules. Nucleotide-binding oligomerization domain 2 (NOD2) is a cytoplasmic receptor that recognizes invading molecules and danger signals inside the cells. Recent studies highlight the importance of NOD2′s function in maintaining the homeostasis of human body microbiota and innate immune responses, including induction of proinflammatory cytokines, regulation of autophagy, modulation of endoplasmic reticulum (ER) stress, etc. In addition, there is extensive cross-talk between NOD2 and the Toll-like receptors that are so important in the induction and tuning of adaptive immunity. Polymorphisms of NOD2′s encoding gene are associated with several pathological conditions, highlighting NOD2′s functional importance. In this study, we summarize NOD2′s role in cellular signaling pathways and take a look at the possible consequences of common NOD2 polymorphisms on the structure and function of this receptor.

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Oral Immune Activation by Disgust and Disease-Related Pictures

Journal of Psychophysiology ◽

10.1027/0269-8803/a000143 ◽

2015 ◽

Vol 29 (3) ◽

pp. 119-129 ◽

Cited By ~ 4

Author(s):

Richard J. Stevenson ◽

Deborah Hodgson ◽

Megan J. Oaten ◽

Luba Sominsky ◽

Mehmet Mahmut ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Innate Immune Response ◽

Negative Control ◽

Innate Immune ◽

Innate Immune Responses ◽

Immune Markers ◽

Before And After ◽

Secondary Analyses ◽

Image Set

Abstract. Both disgust and disease-related images appear able to induce an innate immune response but it is unclear whether these effects are independent or rely upon a common shared factor (e.g., disgust or disease-related cognitions). In this study we directly compared these two inductions using specifically generated sets of images. One set was disease-related but evoked little disgust, while the other set was disgust evoking but with less disease-relatedness. These two image sets were then compared to a third set, a negative control condition. Using a wholly within-subject design, participants viewed one image set per week, and provided saliva samples, before and after each viewing occasion, which were later analyzed for innate immune markers. We found that both the disease related and disgust images, relative to the negative control images, were not able to generate an innate immune response. However, secondary analyses revealed innate immune responses in participants with greater propensity to feel disgust following exposure to disease-related and disgusting images. These findings suggest that disgust images relatively free of disease-related themes, and disease-related images relatively free of disgust may be suboptimal cues for generating an innate immune response. Not only may this explain why disgust propensity mediates these effects, it may also imply a common pathway.

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