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Controlling Mast Cell Activation and Homeostasis: Work Influenced by Bill Paul That Continues Today

Heather L. Caslin, Kasalina N. Kiwanuka ,Tamara T. Haque, Marcela T. Taruselli, H. Patrick MacKnight, Anuya Paranjape, and John J. Ryan

Mast cells are tissue resident, innate immune cells with heterogenous phenotypes tuned by cytokines and other microenvironmental stimuli. Playing a protective role in parasitic, bacterial, and viral infections, mast cells are also known for their role in the pathogenesis of allergy, asthma, and autoimmune diseases.

Here, we review factors controlling mast cell activation, with a focus on receptor signaling and potential therapies for allergic disease. Specifically, we will discuss our work with FcεRI and FγR signaling, IL-4, IL-10, and TGF-β1 treatment, and Stat5.

We conclude with potential therapeutics for allergic disease. Much of these efforts have been influenced by the work of Bill Paul.

With many mechanistic targets for mast cell activation and different classes of therapeutics being studied, there is reason to be hopeful for continued clinical progress in this area.

Activating and inhibitory signaling in mast cells: New opportunities for therapeutic intervention?

Vanessa L. Ott, PhD and John C. Cambier, PhD

DOI:https://doi.org/10.1067/mai.2000.109428

Abstract

Immune responses are tightly controlled by the activities of both activating and inhibitory signals. At the cellular level, these signals are generated through engagement of membrane-associated receptors and coreceptors.

The high-affinity IgE receptor FcϵRI is expressed on mast cells and basophils and, on cross-linking by multivalent antigen (allergen), stimulates the release of inflammatory mediators that induce acute allergic responses.

Activation signals mediated by a variety of immune receptors (eg, B-cell receptor, T-cell receptor, and FcϵRI) are subject to negative regulation by a growing family of structurally and functionally related inhibitory receptors.

Recent studies indicate that mast cells express multiple inhibitory receptors that may regulate FcϵRI-induced mast cell activation through similar mechanisms.

The ability of inhibitory receptors to attenuate IgE-mediated allergic responses implicates them as potential targets for therapeutic intervention in the treatment of atopic disease.

Indeed, coaggregation of activating and inhibitory receptors has been suggested as one possible mechanism to explain the beneficial effects of specific immunotherapy in the treatment of allergy.

In this review we summarize the current knowledge of inhibitory receptors expressed in mast cells and the mechanisms through which they regulate mast cell function. (J Allergy Clin Immunol 2000;106:429-40.)

Conclusions

Mast cells express multiple ITIM-containing inhibitory receptors that have the potential to regulate antigen-mediated FcϵRI signal transduction and cell activation.

The biologic significance of multiple inhibitory receptors is not well understood; however, identification of the li-gands for many of these receptors should provide insight into their role in the regulation of mast cell function.

Of the inhibitory receptors discussed above, only FcγRIIB is known to coaggregate with FcϵRI under physiologic conditions (ie, in the presence of allergen complexed with IgG) and may therefore be relevant to FcϵRI signaling in vivo. Coaggregation of FcγRIIB and FcϵRI suggests a possible mechanism to explain the beneficial effects of specific immunotherapy in the treatment of allergy.

As increasing doses of allergen are administered to allergic patients, an allergen-specific IgG response develops, leading to the formation of allergen-IgG complexes that are postulated to inhibit IgE-induced mast cell activation by coaggregating FcϵRI and FcγRIIB.

This mechanism of inhibition may have important implications in the treatment of atopic disease. For example, administering of allergen-IgG complexes to patients with allergic asthma significantly attenuated allergic symptoms.

Although the biologic function of many inhibitory receptors expressed in mast cells is not known, therapeutic strategies designed to coaggregate inhibitory receptors with FcϵRI may provide novel approaches for the treatment of atopic disease.

https://www.jacionline.org/article/S0091-6749(00)35305-2/fulltext

Of the seven coronaviruses that have been circulating among humans, three of them can kill you, however, four of them just give someone a cold.
Most people pick up at least one of these congestion-inducing viruses in their lifetime, and they’ve been bouncing between humans for a long time.

https://www.cdc.gov/coronavirus/general-information.html

Given this was for SARS CoV-1 and the receptor cups are different, but still…

Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

Martin J Vincent¹, Eric Bergeron², Stuart T Nichol, et.al

1Special Pathogens Brach, Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, Georgia, 30333, USA

2Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, 110 Pine Ave West, Montreal, QCH2W1R7, Canada

Virology Journal volume 2, Article number: 69 (2005)

Background

Severe acute respiratory syndrome (SARS) is caused by a newly discovered coronavirus (SARS-CoV). No effective prophylactic or post-exposure therapy is currently available.

Results

We report, however, that chloroquine has strong antiviral effects on SARS-CoV infection of primate cells. These inhibitory effects are observed when the cells are treated with the drug either before or after exposure to the virus, suggesting both prophylactic and therapeutic advantage. In addition to the well-known functions of chloroquine such as elevations of endosomal pH, the drug appears to interfere with terminal glycosylation of the cellular receptor, angiotensin-converting enzyme 2. This may negatively influence the virus-receptor binding and abrogate the infection, with further ramifications by the elevation of vesicular pH, resulting in the inhibition of infection and spread of SARS CoV at clinically admissible concentrations.

Conclusion

Chloroquine is effective in preventing the spread of SARS CoV in cell culture. Favorable inhibition of virus spread was observed when the cells were either treated with chloroquine prior to or after SARS CoV infection. In addition, the indirect immunofluorescence assay described herein represents a simple and rapid method for screening SARS-CoV antiviral compounds.

Read the science, not the sound bite

Breaking News

What Do We Know About COVID-19 Transmission?

Young, Kelly D. MD

If you read anything about SARS-CoV-2, the novel coronavirus that causes COVID-19, transmission is described as person-to-person via direct contact and respiratory droplets released by coughing, sneezing, or even talking, with fomites as a less common possibility.

But what everyone really wants to know is how you translate this information into practical recommendations. Is the advice for the widespread use of masks, frequent hand hygiene and disinfection of surfaces, and social distancing at six feet from others necessary? Is it enough?

Many emergency physicians and other high-risk health care workers have gone further, devising elaborate decontamination rituals, and some even electing to live apart from their families. Their concern is not unwarranted—20 percent of health care workers in Italy were reported to have become infected.

A new twist. When in deep flare ups I start to have Bradykinin cascade events instead of tryptase.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cea.13297

Well at lease changes from sleep PJs to “Gym Clothes” Daytime PJs

Very interesting theory and experiments on why infected cells don’t fight back and inflammation becomes overwhelming.

EDITORIAL| VOLUME 124, ISSUE 6, P523-525, JUNE 01, 2020

Drug allergy labeling and delabeling in the coronavirus disease 2019 era

What is important and what do we need to know
Mariana C. Castells, MD, PhD
DOI:https://doi.org/10.1016/j.anai.2020.04.012

At the time of this writing, April 7, 2020, more than 1.2 million people worldwide are infected and more than 68,000 have died because of coronavirus disease 2019 (COVID-19) induced by the novel severe acute respiratory syndrome coronavirus 2 infection, and this figure will surely multiply in the next few weeks according to Dr Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases.

Severe acute respiratory syndrome coronavirus 2 uses angiotensin-converting enzyme-2 (ACE-2) (a type I transmembrane metallocarboxypeptidase) as its preferred entry receptor. The expression of ACE-2 is high in alveolar and epithelial tissues in the lungs and the gastrointestinal tract. Drugs which affect the expression of ACE-2 (such as ACE inhibitors and angiotensin receptor blockers) are being investigated as possible risk factors for the severity of coronavirus disease 2019. Nonsteroidal anti-inflammatory drugs are being similarly investigated.

Clinical trials with azithromycin and hydroxychloroquine, antiretroviral drugs, and anti–interleukin-6 are ongoing in an attempt to improve disease outcomes before a vaccine can be available. This provides a glimpse of the complexities of this disease and reveals the importance of identifying candidate drugs for clinical trials that may save lives. It follows in importance to identify patients with allergy who are at risk, if treated, and who may need desensitization. Understanding the mechanisms of drug allergy is key, given that the classification of drug hypersensitivity continues to expand.

Cytokine storm–like reactions with elevated interleukin-6 can be seen in patients treated with chemotherapy and monoclonal antibodies
and are now part of a broader definition of anaphylaxis, allowing for better management and treatment options.

https://www.annallergy.org/article/S1081-1206(20)30240-4/fulltext?dgcid=raven_jbs_etoc_email

https://medcraveonline.com/MOJI/the-mast-cell-activation-syndrome-a-mini-review.html

Implanted synthetic mesh mast cell response.

Reactions to mesh implants

Characterization of the Foreign Body Response to Common Surgical Biomaterials in a Murine Model Mohamed Ibrahim, MD1, Jennifer Bond, PhD1, Manuel A. Medina, MD1, Lei Chen, MD3, Carlos Quiles, MD1, et.al.

https://dukespace.lib.duke.edu › …PDF
Characterization of the Foreign Body Response to Common

Research Preprint

COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms

RW Malone MD LLC, Madison, VA https://orcid.org/0000-0003-0340-7490

Philip Tisdall Medical School Companion LLC, Marco Island, FL
Philip Fremont-Smith MIT Lincoln Laboratory, Lexington, MA
Yongfeng Liu Department of Pharmacology, University of North Carolina, Chapel Hill, Chapel Hill, NC
Xi-Ping Huang Department of Pharmacology, University of North Carolina, Chapel Hill, Chapel Hill, NC
Kris M. White Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY
et.al.

SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We explore several plausible avenues of activity including antiviral and host-mediated actions. We propose that the principal famotidine mechanism of action for COVID-19 involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release.

Early clinical data from a variety of sources indicate that famotidine treatment may reduce morbidity and mortality associated with COVID-19.

A retrospective cohort study of 1,620 hospitalized COVID-19 patients indicates that 84 propensity score matched patients receiving famotidine during hospitalization (oral or IV, 20mg or 40mg daily) had a statistically signicant reduced risk for death or intubation (adjusted hazard ratio (aHR) 0.42, 95% CI 0.21-0.85) and also a reduced risk for death alone (aHR 0.30, 95% CI 0.110.80) 20.

In contrast, proton pump inhibitor use was not associated with reduced risk for these outcomes. A preceding anecdotal report from Wuhan, China is purported to have indicated that famotidine may be partially protective for COVID-19, but that neither cimetidine nor proton pump inhibitors were protective 21.

Together, these data have been interpreted as indicating that this increased survival pattern is due to an off-target, non-histamine receptor-mediated property of famotidine that is not shared with cimetidine.

Famotidine is currently being tested under an IND waiver for treating COVID-19 in a double blind randomized clinical trial at high intravenous doses in combination with either hydroxychloroquine or remdesivir (ClinicalTrials.gov Identier: NCT04370262).

Herein we aim to investigate how famotidine may act to relieve early phase COVID-19 clinical symptoms.

The most likely mechanisms of actions include: via antiviral activity, via novel human targets, or via the on-target mechanism described in the current FDA market authorization – famotidine is a histamine receptor H2 antagonist (and inverse agonist).

A total of 62 patients (72%) were on JAK inhibitors or biologics at baseline, including 38 (44%) on tumor necrosis factor inhibitors.

Overall, 14 patients (16%) were hospitalized with COVID-19, which is consistent the 26% hospitalization rate among the general population in New York City.

Baseline biologic and JAK inhibitor use was actually lower among hospitalized patients than among those who weren’t hospitalized (50% vs. 76%), and the hospitalization rate was only 11% among 62 subjects who had been on the agents long term, more than a year among most.

I had discussions with a former colleague this morning about our concerns relative to the anti inflammatory usages of cromolyn, quercetin, famotidine and others common Mast Cell medications for fighting Covid 19 symptoms.

He assured me that in discussions with major pharmaceutical and FDA sources, they were aware of the supply chain issues and were stepping up production to address concerns.

There may also be a new study unique to patients in our community, in that, we are so well documented from a bloodwork standpoint, and already the highest volume users of these anti inflammatory and H2 medications, much before the virus propagated world wide.

In a twist of irony, we actually may be the key to development of a safe and effective symptom control cocktail until a efficacious vaccine can be put through trials.

More later.

The US FDA has apparently just relaxed food labeling requirements, duentonsupply chain issue ls related to Covid as its justification.

This allows companies to substitute a new ingredient for an old one without listing this change on the label.

While the substitution cannot be one of the main allergens, there are some loopholes. See article included in this post.

This of course could be quite dangerous and scary for our Mast Cell community. We have sensitivities that go way beyond the “usual” allergens and that of course can have fatal consequences.

Because of the emergency nature of the declaration, it appears that a public comment period is not required.

Idiopathic Mast Cell Activation Syndrome and Radiation Therapy: A Case Study, Literature Review, and Discussion of Mast Cell Disorders and Radiotherapy

Robin E Landy et al. Radiat Oncol. 2019.

Authors

Robin E Landy 1, William C Stross 2, Jackson M May 3, Tasneem A Kaleem 3, Timothy D Malouff 3, Mark R Waddle 3, Laura A Vallow 3

Affiliations
1Florida State University College of Medicine, 1115 W Call St, Tallahassee, FL, 32304, USA.2Department of Radiation Oncology, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL, 32224, USA. stross.william@mayo.edu.3Department of Radiation Oncology, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL, 32224, USA.

PMID: 31818306
PMCID: PMC6902562
DOI: 10.1186/s13014-019-1434-6

Mast Cell Activation Syndrome (MCAS) is classified as an idiopathic mast cell disorder where inconsistent or unknown triggers release inflammatory mediators and cause a constellation of symptoms.

Studies demonstrate mast cells increase histamine, tryptase, and inflammatory cytokine expression following ionizing radiation.

Additionally, there are cases of cutaneous mastocytosis developing within the initial radiation field suggesting mast cells play a role in local tissue reactions.

Literature is sparse on radiation induced toxicity in patients with mast cell disorders.

Mayo Clinic Program for the Study of Mast Cell and Eosinophil Disorders Cell and Serum Bank

ABOUT THIS STUDY

This study is being done to store blood cells, genetic material, blood serum and tissue biopsies so that they can be used in laboratory studies now and in the future to find causes of the rare disorder of mast cells and/or eosinophils and factors that may contribute to disease progression and treatment response.

Management Strategies Of Idiopathic Anaphylaxis In The Emergency Room: Current Perspectives

In conclusion, few studies have evaluated the diagnosis and management strategies of true IA. Future studies are needed to optimize treatment regimens for IA in both children and adults.

Health care providers should be aware of the potential differential diagnosis and underlying causes in order to develop an appropriate management strategy.

Omalizumab is a promising therapeutic option for IA as a novel approach to prophylactic treatment. We recommend conducting large-scale studies on the use of omalizumab in IA and a shift in treatment paradigm that will prioritize omalizumab over glucocorticoids as an efficacious and safe second-line prophylactic treatment.