Analysis of Natural Antibodies during the Development of Phantom Pain Syndrome.

We determined natural antibodies (n-Abs) to the regulators of the main systems of biochemical homeostasis: ß-endorphin, serotonin, dopamine, histamine, orphanin, angiotensin, GABA, glutamate, bradykinin, vasopressin, thrombin, and α-2-macroglobulin in individuals with phantom pain syndrome (PPS), resulting from amputation after injury. It was established that each patient has an individual immunoprofile, but for all of them there was a significant increase in the level of antibodies to serotonin, histamine, and angiotensin, which reflect the chronicity of the pain syndrome and do not depend on the self-assessment of the severity of PPS. Determination of the role of regulators of biochemical homeostasis in the development of phantom pain showed that, at high, moderate, and weak severity of PPS, the biogenic amine and angiotensinergic systems are activated. A decrease in PPS intensity normalizes deviations in all immunological parameters. The levels of n-Abs for the pain (ß-endorphin) and analgesic (orphanin) systems are significant only at low PPS. Monitoring the individual profile of n-Abs to endogenous regulators allows us to obtain an objective picture of the pain status of the patient's body.

Immunopathogenesis of urticaria: a clinical perspective on histamine and cytokine involvement.

BACKGROUND: Urticaria is a clinical condition characterized by the appearance of wheals (hives), angioedema, or both. Over the last several decades, a better understanding of the mechanisms at play in the immunopathogenesis of urticaria has underscored the existence of numerous urticaria subtypes. Separating the different kinds of urticaria explicitly helps find the best detection method for the management of this skin disorder. Subtypes of urticaria also include both spontaneous and physical types. The conventional ones include spontaneous urticaria, constituting both acute and chronic urticaria. Therefore, a broad and effective therapy is essential for the diagnosis and treatment of urticaria. METHODS: To understand the immunopathogenesis of urticaria, various databases, including PubMed, Scopus, and Web of Science, were used to retrieve original articles and reviews related to urticaria. While information on several clinical trials were obtained from clinicaltrials.gov database. RESULTS: This article highlights the immunopathogenesis involved in the intricate interaction between cellular infiltration, immune reactions, coagulation cascades, and autoantibodies that underlie urticaria's pathophysiology. CONCLUSION: The recent progress in understanding urticaria can help to understand the intricate characteristics in the immunopathogenesis of urticaria and could play a beneficial role in the management of urticaria.

Extracellular Nucleotides and Histamine Suppress TLR3- and RIG-I-Mediated Release of Antiviral IFNs from Human Airway Epithelial Cells.

Respiratory viruses stimulate the release of antiviral IFNs from the airway epithelium. Previous studies have shown that asthmatic patients show diminished release of type I and type III IFNs from bronchial epithelia. However, the mechanism of this suppression is not understood. In this study, we report that extracellular nucleotides and histamine, which are elevated in asthmatic airways, strongly inhibit release of type I and type III IFNs from human bronchial airway epithelial cells (AECs). Specifically, ATP, UTP, and histamine all inhibited the release of type I and type III IFNs from AECs induced by activation of TLR3, retinoic acid-inducible gene I (RIG-I), or cyclic GMP-AMP synthase-STING. This inhibition was at least partly mediated by Gq signaling through purinergic P2Y2 and H1 receptors, but it did not involve store-operated calcium entry. Pharmacological blockade of protein kinase C partially reversed inhibition of IFN production. Conversely, direct activation of protein kinase C with phorbol esters strongly inhibited TLR3- and RIG-I-mediated IFN production. Inhibition of type I and type III IFNs by ATP, UTP, histamine, and the proteinase-activated receptor 2 (PAR2) receptor agonist SLIGKV also occurred in differentiated AECs grown at an air-liquid interface, indicating that the suppression is conserved following mucociliary differentiation. Importantly, histamine and, more strikingly, ATP inhibited type I IFN release from human airway cells infected with live influenza A virus or rhinovirus 1B. These results reveal an important role for extracellular nucleotides and histamine in attenuating the induction of type I and III IFNs from AECs and help explain the molecular basis of the suppression of IFN responses in asthmatic patients.

Mast cells and histamine are involved in the neuronal damage observed in a quinolinic acid-induced model of Huntington's disease.

Huntington´s disease (HD) is a pathological condition that can be studied in mice by the administration of quinolinic acid (QUIN), an agonist of the N-methyl-d-aspartate receptor (NMDAR) that induces NMDAR-mediated cytotoxicity and neuroinflammation. Mast cells (MCs) participate in numerous inflammatory processes through the release of important amounts of histamine (HA). In this study, we aimed to characterize the participation of MCs and HA in the establishment of neural and oxidative damage in the QUIN-induced model of HD. C57BL6/J mice (WT), MC-deficient c-KitW-sh/W-sh (Wsh) mice and Wsh mice reconstituted by intracerebroventricular (i.c.v.) injection of 5 × 105 bone marrow-derived mast cells (BMMCs), or i.c.v. administered with HA (5 µg) were used. All groups of animals were intrastriatally injected with 1 µL QUIN (30 nmol/µL) and 3 days later, apomorphine-induced circling behavior, striatal GABA levels and the number of Fluoro-Jade positive cells, as indicators of neuronal damage, were determined. Also, lipid peroxidation (LP) and reactive oxygen species production (ROS), as markers of oxidative damage, were analyzed. Wsh mice showed less QUIN-induced neuronal and oxidative damage than WT and Wsh-MC reconstituted animals. Histamine administration restored the QUIN-induced neuronal and oxidative damage in the non-reconstituted Wsh mice to levels equivalent or superior to those observed in WT mice. Our results demonstrate that MCs and HA participate in the neuronal and oxidative damages observed in mice subjected to the QUIN -induced model of Huntington's disease.

Histamine Increases Th2 Cytokine-Induced CCL18 Expression in Human M2 Macrophages.

The chemokine CCL18 is produced in cells of the myelomonocytic lineage and represents one of the most highly expressed chemokines in lesional skin and serum of atopic dermatitis patients. We investigated the role of histamine in CCL18 production in human monocyte-derived M2 macrophages differentiated in the presence of M-CSF and activated with IL-4, IL-13 or with IL-10. Since expression and regulation of histamine H1 receptor (H1R), H2R and H4R by IL-4 and IL-13 on human M2 macrophages were described, we analyzed expression of the histamine receptors in response to IL-10 stimulation by quantitative RT-PCR. IL-10 upregulated H2R and downregulated H4R mRNA expression by trend in M2 macrophages. IL-10, but in a more pronounced manner, IL-4 and IL-13, also upregulated CCL18. Histamine increased the cytokine-induced upregulation of CCL18 mRNA expression by stimulating the H2R. This effect was stronger in IL-10-stimulated M2 macrophages where the upregulation of CCL18 was confirmed at the protein level by ELISA using selective histamine receptor agonist and antagonists. The histamine-induced CCL18 upregulation in IL-10-activated M2 macrophages was almost similar in cells obtained from atopic dermatitis patients compared to cells from healthy control persons. In summary, our data stress a new function of histamine showing upregulation of the Th2 cells attracting chemokine CCL18 in human, activated M2 macrophages. This may have an impact on the course of atopic dermatitis and for the development of new therapeutic interventions.

Connections between Immune-Derived Mediators and Sensory Nerves for Itch Sensation.

Although histamine is a well-known itch mediator, histamine H1-receptor blockers often lack efficacy in chronic itch. Recent molecular and cellular based studies have shown that non-histaminergic mediators, such as proteases, neuropeptides and cytokines, along with their cognate receptors, are involved in evocation and modulation of itch sensation. Many of these molecules are produced and secreted by immune cells, which act on sensory nerve fibers distributed in the skin to cause itching and sensitization. This understanding of the connections between immune cell-derived mediators and sensory nerve fibers has led to the development of new treatments for itch. This review summarizes current knowledge of immune cell-derived itch mediators and neuronal response mechanisms, and discusses therapeutic agents that target these systems.

The Complex Interplay between Immunonutrition, Mast Cells, and Histamine Signaling in COVID-19.

There is an ongoing need for new therapeutic modalities against SARS-CoV-2 infection. Mast cell histamine has been implicated in the pathophysiology of COVID-19 as a regulator of proinflammatory, fibrotic, and thrombogenic processes. Consequently, mast cell histamine and its receptors represent promising pharmacological targets. At the same time, nutritional modulation of immune system function has been proposed and is being investigated for the prevention of COVID-19 or as an adjunctive strategy combined with conventional therapy. Several studies indicate that several immunonutrients can regulate mast cell activity to reduce the de novo synthesis and/or release of histamine and other mediators that are considered to mediate, at least in part, the complex pathophysiology present in COVID-19. This review summarizes the effects on mast cell histamine of common immunonutrients that have been investigated for use in COVID-19.

Histamine in cancer immunology and immunotherapy. Current status and new perspectives.

Cancer is the second leading cause of death globally and its incidence and mortality are rapidly increasing worldwide. The dynamic interaction of immune cells and tumor cells determines the clinical outcome of cancer. Immunotherapy comes to the forefront of cancer treatments, resulting in impressive and durable responses but only in a fraction of patients. Thus, understanding the characteristics and profiles of immune cells in the tumor microenvironment (TME) is a necessary step to move forward in the design of new immunomodulatory strategies that can boost the immune system to fight cancer. Histamine produces a complex and fine-tuned regulation of the phenotype and functions of the different immune cells, participating in multiple regulatory responses of the innate and adaptive immunity. Considering the important actions of histamine-producing immune cells in the TME, in this review we first address the most important immunomodulatory roles of histamine and histamine receptors in the context of cancer development and progression. In addition, this review highlights the current progress and foundational developments in the field of cancer immunotherapy in combination with histamine and pharmacological compounds targeting histamine receptors.

Conditional Deletions of Hdc Confirm Roles of Histamine in Anaphylaxis and Circadian Activity but Not in Autoimmune Encephalomyelitis.

Histamine is best known for its role in allergies, but it could also be involved in autoimmune diseases such as multiple sclerosis. However, studies using experimental autoimmune encephalomyelitis (EAE), the most widely used animal model for multiple sclerosis, have reported conflicting observations and suggest the implication of a nonclassical source of histamine. In this study, we demonstrate that neutrophils are the main producers of histamine in the spinal cord of EAE mice. To assess the role of histamine by taking into account its different cellular sources, we used CRISPR-Cas9 to generate conditional knockout mice for the histamine-synthesizing enzyme histidine decarboxylase. We found that ubiquitous and cell-specific deletions do not affect the course of EAE. However, neutrophil-specific deletion attenuates hypothermia caused by IgE-mediated anaphylaxis, whereas neuron-specific deletion reduces circadian activity. In summary, this study refutes the role of histamine in EAE, unveils a role for neutrophil-derived histamine in IgE-mediated anaphylaxis, and establishes a new mouse model to re-explore the inflammatory and neurologic roles of histamine.

Th2 cell-derived histamine is involved in nasal Th2 infiltration in mice.

OBJECTIVE: Histamine derived from mast cells and basophils plays important roles in inducing allergic symptoms. Although T cells also produce histamine, the involvement of the histamine produced from T cells has remained enigmatic. We sought to reveal the roles of T helper 2 (Th2) cell-derived histamine in nasal allergic disorders. METHODS: The histamine production from Th2 cells was measured by EIA. The mRNA expression of histidine decarboxylase (HDC) was measured by real-time PCR. To investigate the roles of Th2 cell-derived histamine in vivo, we analyzed an antigen-specific Th2 cell transfer mouse model. RESULTS: Th2 cells produced histamine by T cell receptor stimulation, and these properties were specific for Th2 cells, but not Th1 cells and naïve CD4 T cells. The histamine produced from Th2 cells was involved in the infiltrations of Th2 cells in response to antigen exposure. CONCLUSION: These results suggest that Th2 cell-derived histamine play important roles in nasal allergic disorders.

Histamine triggers the formation of neutrophil extracellular traps via NADPH oxidase, ERK and p38 pathways.

Histamine plays a central role in various allergic diseases, such as allergic asthma and allergic rhinitis. Neutrophil extracellular traps (NETs) formation is a novel effector mechanism of neutrophils to defend against various stimuli. In this present study, we aimed to investigate the role of histamine on bovine NET formation, and examined its preliminary molecular mechanisms. Cell Counting Kit-8 (CCK8) and Lactate dehydrogenase assays showed that histamine had no significant influence on PMNs (polymorphonuclear leukocytes) viability. Confocal microscopy analyses identified NET structures by co-localizing the main components of NETs, and NET quantification revealed that histamine-triggered NETs were released in a dose-dependent manner. Furthermore, we found reactive oxygen species (ROS) production, phosphorylated extracellular signal-regulated kinase (ERK) and p38 proteins were significantly elevated in histamine-challenged PMNs. By applying functional inhibitors of nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase), ERK and p38, histamine-triggered NETs were markedly reduced, indicating their importance in histamine-triggered NET formation. Our findings described histamine-triggered NET formation, and revealed its potential molecular mechanisms via NADPH oxidase, ERK and p38 pathways. This is the first study to depict histamine-triggered NET formation, which could provide a new insight into histamine-related diseases.

Th2 cells and macrophages cooperatively induce allergic inflammation through histamine signaling.

Histamine, which is mainly produced by mast cells and basophils, participates in various allergic symptoms, and some studies have reported that macrophages also produce histamine. Moreover, recent studies have revealed that macrophages, especially alternatively activated macrophages (M2) induced by T helper 2 (Th2) cytokines, such as interleukin (IL)-4 and IL-13, participate in the pathogenesis of allergic diseases. The major source of Th2 cytokines is antigen-specific Th2 cells. To elucidate the relationship between histamine, macrophages, and Th2 cells in allergic inflammation, we established a macrophage-Th2 cell co-culture model in vitro and an antigen-specific Th2 cell transfer mouse model of rhinitis. In vitro analyses indicated that macrophages produce histamine by interacting with antigen-specific Th2 cells through the antigen. Furthermore, Th2 cells and macrophages cooperatively elicited rhinitis in the mouse model. We determined that histamine induces Th2- and macrophage-elicited sneezing responses through H1 receptor signaling, whereas it induces nasal eosinophil infiltrations through H4 receptor signaling. Collectively, these results indicate a novel histamine production mechanism by macrophages, in which Th2 cells and macrophages cooperatively induce nasal allergic inflammation through histamine signaling.

Histamine detection in fish samples based on indirect competitive ELISA method using iron-cobalt co-doped carbon dots labeled histamine antibody.

Due to complex matrixes and specific reagent deficiency, the rapid detection of histamine is still a challenge to date. Based on the high peroxidase-like activity of iron-cobalt co-doped carbon dots, an indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) was established for histamine detection using the mimic enzyme labeled with histamine antibody (His-Ab). Through the competitive binding of the labeled His-Ab to solid-phase and sample antigens, histamine content was detected with a linear range of 2.5-150 µg mL-1. The detection limit based on 3σ/K was 0.50 mg kg-1, which was much lower than those of commercial His-kit and HPLC methods. The ic-ELISA method was applied to histamine detection in fish samples with the recovery of (103.4 ± 0.5)%, which was in accord with those of commercial His-kit and HPLC methods. The results indicated that the established ic-ELISA method was suitable for rapid detection of histamine in fish samples with high accuracy, sensitivity and stability.

Fatty acid chain length drives lysophosphatidylserine-dependent immunological outputs.

In humans, lysophosphatidylserines (lyso-PSs) are potent lipid regulators of important immunological processes. Given their structural diversity and commercial paucity, here we report the synthesis of methyl esters of lyso-PS (Me-lyso-PSs) containing medium- to very-long-chain (VLC) lipid tails. We show that Me-lyso-PSs are excellent substrates for the lyso-PS lipase ABHD12, and that these synthetic lipids are acted upon by cellular carboxylesterases to produce lyso-PSs. Next, in macrophages we demonstrate that VLC lyso-PSs orchestrate pro-inflammatory responses and in turn neuroinflammation via a Toll-like receptor 2 (TLR2)-dependent pathway. We also show that long-chain (LC) lyso-PSs robustly induce intracellular cyclic AMP production, cytosolic calcium influx, and phosphorylation of the nodal extracellular signal-regulated kinase to regulate macrophage activation via a TLR2-independent pathway. Finally, we report that LC lyso-PSs potently elicit histamine release during the mast cell degranulation process, and that ABHD12 is the major lyso-PS lipase in these immune cells.

The role of basophils in acquired protective immunity to tick infestation.

Ticks are blood-feeding ectoparasites that transmit a variety of pathogens to host animals and humans, causing severe infectious diseases such as Lyme disease. In a certain combination of animal and tick species, tick infestation elicits acquired immunity against ticks in the host, which can reduce the ability of ticks to feed on blood and to transmit pathogens in the following tick infestations. Therefore, our understanding of the cellular and molecular mechanisms of acquired tick resistance (ATR) can advance the development of anti-tick vaccines to prevent tick infestation and tick-borne diseases. Basophils are a minor population of white blood cells circulating in the bloodstream and are rarely observed in peripheral tissues under steady-state conditions. Basophils have been reported to accumulate at tick-feeding sites during re-infestation in cattle, rabbits, guinea pigs and mice. Selective ablation of basophils resulted in a loss of ATR in guinea pigs and mice, illuminating the essential role of basophils in the manifestation of ATR. In this review, we discuss the recent advance in the elucidation of the cellular and molecular mechanisms underlying basophil recruitment to the tick-feeding site and basophil-mediated ATR.

Historical Anecdotes and Breakthroughs of Histamine: From Discovery to Date.

AIM: Investigating about the history of allergies and discovery of the histamine's role in the immune response through historical references, starting with ancient anecdotes, analysing the first immunization attempts on animals to understand its importance as the anaphylaxis mediator. Moreover, we shortly resume the most recent discoveries on mast cell role in allergic diseases throughout the latest updates on its antibody-independent receptors. METHODS: Publications, including reviews, treatment guidelines, historical and medical books, on the topic of interest were found on Medline, PubMed, Web of Knowledge, Web of Science, Google Scholar, Elsevier's (EMBASE.comvarious internet museum archives. Texts from the National Library of Greece (Stavros Niarchos Foundation), from the School of Health Sciences of the National and Kapodistrian University of Athens (Greece). We selected key articles which could provide ahistorical and scientific insight into histamine molecule and its mechanism of action's discovery starting with Egyptian, Greek and Chinese antiquity to end with the more recent pharmacological and molecular discoveries. RESULTS: Allergic diseases were described by medicine since ancient times, without exactly understanding the physio-pathologic mechanisms of immuno-mediated reactions and of their most important biochemical mediator, histamine. Researches on histamine and allergic mechanisms started at the beginning of the 20th century with the first experimental observations on animals of anaphylactic reactions. Histamine was then identified as their major mediator of many allergic diseases and anaphylaxis, but also of several physiologic body's functions, and its four receptors were characterized. Modern researches focus their attention on the fundamental role of the antibody-independent receptors of mast cells in allergic mechanisms, such as MRGPRX2, ADGRE2 and IL-33 receptor. CONCLUSION: New research should investigate how to modulate immunity cells activity in order to better investigate possible multi-target therapies for host's benefits in preclinical and clinical studies on allergic diseases in which mast cells play a major role.

Therapeutic Potential of Antileukotriene Drug-Camellia sinensis Extract Co-Formulation on Histamine Induced Asthma in Guinea Pigs.

BACKGROUND/OBJECTIVE: To study the therapeutic potential of Antileukotriene drug- Camellia sinensis extract co-formulation on histamine induced asthma in guinea pigs. METHODS: SRSD of Montelukast sodium was prepared by the solvent evaporation method. Lyophilized aqueous extract of Camellia sinensis leaves and SRSD mixture was filled in capsule and the capsule shell was coated to achieve initial release lag time. In vitro and pharmacokinetic study of capsules was performed and compared with commercial tablets. A further role of green tea, as an antioxidant adjunct for asthma management, has been analyzed by lung histology, mast cell count and oxidative stress assay in the serum of control and experimental animals. RESULTS: The drug release from the commercial tablet was immediate and rapid, but capsule has shown an initial 3.5 hr lag time followed by sustained action up to 8 hr. Pharmacokinetic results show that studied formulations are bioequivalent with respect to Cmax and AUC, while rest parameters showed asignificant difference. Mast cells count in lung tissue were increased (p<0.001) in the experimental group along with glycoprotein deposition in asthmatic bronchioles. Levels of SOD and GPX were decreased (p<0.05) while CAT was increased (p<0.04) in the asthma group in comparison to control. CONCLUSION: In the experimental animal model, co-formulation was effective in modulating allergic inflammation and contributing to better control of the inflammatory response. Our findings suggest that Camellia sinensis leaves extract may be used as an adjunct for future improvements in asthma treatment and prevention.

Characterization of systemic allergenicity of tropomyosin from shrimp (Macrobrachium nipponense) and anaphylactic reactions in digestive tract.

BACKGROUND: Tropomyosin (TM) is the major allergen of crustaceans. The allergenicity of TM from Macrobrachium nipponense (MnTM) and the anaphylactic reaction in the digestive tract are still unclear. The aim of this study was to evaluate the allergenicity of MnTM and the anaphylactic reaction in the digestive tract. RESULTS: Serum IgE and IgG1 binding ability in the TM group were significantly higher than those in the PBS and CT groups (P < 0.01) and CP group (P < 0.05), while serum IgG and IgG2a binding ability showed no obvious difference between the four groups (P > 0.05). The levels of cytokines IL-4, IL-5 and IL-13 in TM and CP groups were significantly higher than those in PBS and CT groups. Histamine and ß-hexosaminidase in the TM and CP groups from basophil cell models were significantly higher than those in the PBS group. The highest mRNA expression of IL-4 and IL-13 was in the jejunum from TM-sensitized mice. Histopathological analysis showed that more immune cells infiltrated into the jejunum than the duodenum and ileum from the TM-sensitized mice. CONCLUSIONS: MnTM could promote an allergic response in mice and lead to degranulation in basophil cells. The jejunum was more easily affected by MnTM than duodenum and ileum, and the jejunum may be the major site of allergic response in the digestive tract. © 2020 Society of Chemical Industry.

Impact of histamine H4 receptor deficiency on the modulation of T cells in a murine breast cancer model.

BACKGROUND: The histamine H4 receptor (H4R) is preferentially expressed in immune cells and is a potential therapeutic target for inflammatory and autoimmune diseases. This study aimed at further exploring the role of H4R in the immunobiology of breast cancer. METHODS: We used wild type (WT) and H4R deficient mice (KO) to evaluate whether H4R genotypes show a different distribution of T cell subsets in spleens, tumours and tumour draining lymph nodes (TDLN) in a syngeneic ErbB2-positive breast cancer model developed orthotopically with LM3 cells and its impact on tumour growth. RESULTS: The presence of tumours had a differential impact on the distribution of T cells in TDLN from KO mice compared to WT ones. At day 21 post-inoculation (p.i.) of cells, despite no significant changes in the tumour weight, TDLN from KO mice showed a significantly increased proportion of CD8+ T cells compared to WT mice. At day 38 p.i. of cells a reduced tumour weight was evident in KO mice. This was accompanied by a decreased proportion of CD4+CD25+FoxP3+ regulatory T cells in TDLN of KO compared to WT mice. Tumour-bearing KO mice showed a better survival compared to WT mice. CONCLUSIONS: H4R-mediated mechanisms may modulate the immune tumour microenvironment, promoting an immunosuppressive milieu. Results suggest that H4R could be explored as an immunotherapeutic target with potential benefit in combination with immunotherapy. Further preclinical and clinical studies are necessary to confirm this hypothesis.

Immunobiology of Acquired Resistance to Ticks.

Ticks are blood-sucking arthropods of great importance in the medical and veterinary fields worldwide. They are considered second only to mosquitos as vectors of pathogenic microorganisms that can cause serious infectious disorders, such as Lyme borreliosis and tick-borne encephalitis. Hard (Ixodid) ticks feed on host animals for several days and inject saliva together with pathogens to hosts during blood feeding. Some animal species can acquire resistance to blood-feeding by ticks after a single or repeated tick infestation, resulting in decreased weights and numbers of engorged ticks or the death of ticks in subsequent infestations. Importantly, this acquired tick resistance (ATR) can reduce the risk of pathogen transmission from pathogen-infected ticks to hosts. This is the basis for the development of tick antigen-targeted vaccines to forestall tick infestation and tick-borne diseases. Accumulation of basophils is detected in the tick re-infested skin lesion of animals showing ATR, and the ablation of basophils abolishes ATR in mice and guinea pigs, illustrating the critical role for basophils in the expression of ATR. In this review article, we provide a comprehensive overview of recent advances in our understanding of the cellular and molecular mechanisms responsible for the development and manifestation of ATR, with a particular focus on the role of basophils.