Tag: mast cells

Longitudinal Cytokine and Multi-Modal Health Data of an Extremely Severe ME/CFS Patient with HSD Reveals Insights into Immunopathology, and Disease Severity

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) presents significant challenges in patient care due to its intricate multisystem nature, comorbidities, and global prevalence. To address these complexities, we employed a comprehensive approach, integrating longitudinal cytokine profiling with extensive clinical, health, textual, pharmaceutical, and nutraceutical data, and performed personalized analyses using AI.

Focusing on an exceptionally severe ME/CFS patient with hypermobility spectrum disorder (HSD) and marginal symptom improvements, our study highlights the dynamic nature of symptoms, severity, triggers, and modifying factors. As part of this study, we introduced an updated platform and two applications, ME-CFSTrackerApp, and LexiTime, facilitating real-time symptom tracking and enhancing physician-patient communication.

Our longitudinal cytokine profiling underscores the significance of Th2-type cytokines and synergistic activities between mast cells and eosinophils, leading to skewing of Th1 toward Th2 immune responses in ME/CFS pathogenesis, especially in cognitive impairment and sensorial intolerance. This suggests a potentially shared underlying mechanism with major comorbidities.

Additionally, our data reveal potential roles of BCL6 and TP53 pathways in ME/CFS etiology and emphasize the importance of investigating low-dose drugs with partial agonist activity in ME/CFS treatment. Our analyses underscore the patient-centered care approach for better healthcare management.

Source: Fereshteh Jahanbani1, Justin C. Sing, Rajan D. Maynard, Shaghayegh Jahanbani, Janet Dafoe, Whitney Dafoe, Nathan Jones, Kelvin J. Wallace, Azuravesta Rastan, Hannes Rost, Holden Maecker, Michael P. Snyder, Ronald W. Davis. Longitudinal Cytokine and Multi-Modal Health Data of an Extremely Severe ME/CFS Patient with HSD Reveals Insights into Immunopathology, and Disease Severity. Front. Immunol. Sec. Autoimmune and Autoinflammatory Disorders: Autoinflammatory Disorders. Volume 15 – 2024 | doi: 10.3389/fimmu.2024.1369295 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1369295/abstract

Mast Cells in the Autonomic Nervous System and Potential Role in Disorders with Dysautonomia and Neuroinflammation

Abstract:

Mast cells (MC) are ubiquitous in the body and are critical for allergic diseases, but also in immunity and inflammation, as well as potential involvement in the pathophysiology of dysautonomias and neuroinflammatory disorders. MC are located perivascularly close to nerve endings and sites such as the carotid bodies, heart, hypothalamus, the pineal and the adrenal glands that would allow them to regulate, but also be affected by the autonomic nervous system (ANS).

MC are stimulated not only by allergens, but also many other triggers including some from the ANS that can affect MC release of neurosensitizing, proinflammatory and vasoactive mediators. Hence MC may be able to regulate homeostatic functions that appear to be dysfunctional in many conditions, such as postural orthostatic hypertension syndrome (POTS), autism spectrum disorder (ASD), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long-COVID syndrome.

The evidence indicates that there is a possible association between these conditions and diseases associated with mast cell activation, There is no effective treatment for any form of these conditions other than minimizing symptoms. Given the many ways MC could be activated and the numerous mediators released, it would be important to develop ways to inhibit stimulation of MC and the release of ANS-relevant mediators.

Source: Theoharides TC, Twahir A, Kempuraj D. Mast Cells in the Autonomic Nervous System and Potential Role in Disorders with Dysautonomia and Neuroinflammation. Ann Allergy Asthma Immunol. 2023 Nov 9:S1081-1206(23)01397-2. doi: 10.1016/j.anai.2023.10.032. Epub ahead of print. PMID: 37951572. https://pubmed.ncbi.nlm.nih.gov/37951572/

Immunological dysfunction and mast cell activation syndrome in long COVID

Abstract:

At least 65 million people around the world suffer from long COVID, with the majority of cases occurring in the productive age (36–50 years old). Individuals with long COVID are confounded with multiple organ system dysfunctions, long-term organ injury sequelae, and a decreased quality of life. There is an overlapping of risk factors between long COVID and other postviral infection syndromes, so advances in research could also benefit other groups of patients.

Long COVID is the consequence of multiple immune system dysregulation, such as T-cell depletion, innate immune cell hyperactivity, lack of naive T and B cells, and elevated signature of pro-inflammatory cytokines, together with persistent SARS-CoV2 reservoir and other consequences of acute infection.

There is an activated condition of mast cells in long COVID, with abnormal granulation and excessive inflammatory cytokine release. A study by Weinstock et al. indicates that patients with long COVID suffer the same clinical syndrome as patients with mast cell activation syndrome (MCAS).

Diagnosis and treatment of MCAS in patients with long COVID will provide further symptomatic relief, and manage mast cell-mediated hyperinflammation states, which could be useful in the long-term control and recovery of such patients.

Source: Sumantri, Stevent; Rengganis, Iris. Immunological dysfunction and mast cell activation syndrome in long COVID. Asia Pacific Allergy ():10.5415/apallergy.0000000000000022, March 30, 2023. | DOI: 10.5415/apallergy.0000000000000022 https://journals.lww.com/apallergy/Fulltext/9900/Immunological_dysfunction_and_mast_cell_activation.2.aspx (Full text)

Pathophysiology of Post-COVID syndromes: a new perspective

Abstract:

Most COVID-19 patients recovered with low mortality; however, some patients experienced long-term symptoms described as “long-COVID” or “Post-COVID syndrome” (PCS). Patients may have persisting symptoms for weeks after acute SARS-CoV-2 infection, including dyspnea, fatigue, myalgia, insomnia, cognitive and olfactory disorders. These symptoms may last for months in some patients.

PCS may progress in association with the development of mast cell activation syndrome (MCAS), which is a distinct kind of mast cell activation disorder, characterized by hyper-activation of mast cells with inappropriate and excessive release of chemical mediators. COVID-19 survivors, mainly women, and patients with persistent severe fatigue for 10 weeks after recovery with a history of neuropsychiatric disorders are more prone to develop PCS. High D-dimer levels and blood urea nitrogen were observed to be risk factors associated with pulmonary dysfunction in COVID-19 survivors 3 months post-hospital discharge with the development of PCS. PCS has systemic manifestations that resolve with time with no further complications. However, the final outcomes of PCS are chiefly unknown.

Persistence of inflammatory reactions, autoimmune mimicry, and reactivation of pathogens together with host microbiome alterations may contribute to the development of PCS. The deregulated release of inflammatory mediators in MCAS produces extraordinary symptoms in patients with PCS. The development of MCAS during the course of SARS-CoV-2 infection is correlated to COVID-19 severity and the development of PCS. Therefore, MCAS is treated by antihistamines, inhibition of synthesis of mediators, inhibition of mediator release, and inhibition of degranulation of mast cells.

Source: Batiha, G.ES., Al-kuraishy, H.M., Al-Gareeb, A.I. et al. Pathophysiology of Post-COVID syndromes: a new perspective. Virol J 19, 158 (2022). https://doi.org/10.1186/s12985-022-01891-2  https://virologyj.biomedcentral.com/articles/10.1186/s12985-022-01891-2 (Full text)

Mast cell activation syndrome and the link with long COVID

Abstract:

Mast cells are innate immune cells found in connective tissues throughout the body, most prevalent at tissue-environment interfaces. They possess multiple cell-surface receptors which react to various stimuli and, after activation, release many mediators including histamine, heparin, cytokines, prostaglandins, leukotrienes and proteases.

In mast cell activation syndrome, excessive amounts of inflammatory mediators are released in response to triggers such as foods, fragrances, stress, exercise, medications or temperature changes. Diagnostic markers may be difficult to assess because of their rapid degradation; these include urinary N-methyl histamine, urinary prostaglandins D2, DM and F2α and serum tryptase (which is stable) in the UK. Self-management techniques, medications and avoiding triggers may improve quality of life. Treatments include mast cell mediator blockers, mast cell stabilisers and anti-inflammatory agents. ‘Long COVID’ describes post-COVID-19 syndrome when symptoms persist for more than 12 weeks after initial infection with no alternative diagnosis.

Both mast cell activation syndrome and long COVID cause multiple symptoms. It is theorised that COVID-19 infection could lead to exaggeration of existing undiagnosed mast cell activation syndrome, or could activate normal mast cells owing to the persistence of viral particles. Other similarities include the relapse-remission cycle and improvements with similar treatments. Importantly, however, aside from mast cell disorders, long COVID could potentially be attributed to several other conditions.

Source: Arun S, Storan A, Myers B. Mast cell activation syndrome and the link with long COVID. Br J Hosp Med (Lond). 2022 Jul 2;83(7):1-10. doi: 10.12968/hmed.2022.0123. Epub 2022 Jul 26. PMID: 35938771. https://pubmed.ncbi.nlm.nih.gov/35938771/

Histamine production by the gut microbiota induces visceral hyperalgesia through histamine 4 receptor signaling in mice

Abstract:

The gut microbiota has been implicated in chronic pain disorders, including irritable bowel syndrome (IBS), yet specific pathophysiological mechanisms remain unclear. We showed that decreasing intake of fermentable carbohydrates improved abdominal pain in patients with IBS, and this was accompanied by changes in the gut microbiota and decreased urinary histamine concentrations.

Here, we used germ-free mice colonized with fecal microbiota from patients with IBS to investigate the role of gut bacteria and the neuroactive mediator histamine in visceral hypersensitivity. Germ-free mice colonized with the fecal microbiota of patients with IBS who had high but not low urinary histamine developed visceral hyperalgesia and mast cell activation. When these mice were fed a diet with reduced fermentable carbohydrates, the animals showed a decrease in visceral hypersensitivity and mast cell accumulation in the colon. We observed that the fecal microbiota from patients with IBS with high but not low urinary histamine produced large amounts of histamine in vitro.

We identified Klebsiella aerogenes, carrying a histidine decarboxylase gene variant, as a major producer of this histamine. This bacterial strain was highly abundant in the fecal microbiota of three independent cohorts of patients with IBS compared with healthy individuals. Pharmacological blockade of the histamine 4 receptor in vivo inhibited visceral hypersensitivity and decreased mast cell accumulation in the colon of germ-free mice colonized with the high histamine-producing IBS fecal microbiota. These results suggest that therapeutic strategies directed against bacterial histamine could help treat visceral hyperalgesia in a subset of patients with IBS with chronic abdominal pain.

Source: De Palma G, Shimbori C, Reed DE, Yu Y, Rabbia V, Lu J, Jimenez-Vargas N, Sessenwein J, Lopez-Lopez C, Pigrau M, Jaramillo-Polanco J, Zhang Y, Baerg L, Manzar A, Pujo J, Bai X, Pinto-Sanchez MI, Caminero A, Madsen K, Surette MG, Beyak M, Lomax AE, Verdu EF, Collins SM, Vanner SJ, Bercik P. Histamine production by the gut microbiota induces visceral hyperalgesia through histamine 4 receptor signaling in mice. Sci Transl Med. 2022 Jul 27;14(655):eabj1895. doi: 10.1126/scitranslmed.abj1895. Epub 2022 Jul 27. PMID: 35895832. https://pubmed.ncbi.nlm.nih.gov/35895832/

Histamine-producing gut bacteria can trigger chronic abdominal pain

Press Release: Hamilton, ON (July 27, 2022) – Researchers from McMaster University and Queen’s University have discovered a gut bacterial ‘super-producer’ of histamine that can cause pain flare-ups in some patients with irritable bowel syndrome (IBS).

The culprit is what has now been named Klebsiella aerogenes, the McMaster-Queen (MQ) strain, identified in up to 25 per cent of gut microbiota samples from patients with IBS. Researchers examined stool microbiota samples from both Canadian and American patient cohorts.

“We followed up these patients for several months and found high levels of stool histamine at the time when the patients reported severe pain, and low stool histamine when they were pain-free,” said senior author Premysl Bercik, professor of medicine of McMaster’s Michael G. DeGroote School of Medicine and a gastroenterologist.

The McMaster-Queen’s research team pinpointed the bacterium Klebsiella aerogenes as the key histamine producer by studying germ-free mice colonized with gut microbiota from patients with IBS. They also colonized some mice with gut microbiota from healthy volunteers as a control group.

The study found that the bacterium Klebsiella aerogenes converts dietary histidine, an essential amino acid present in animal and plant protein, into histamine, a known mediator of pain.

The bacterial histamine then activates the gut immune system through histamine-4 receptor, which draws immune mast cells into the intestines. These activated mast cells produce even more histamine and other pain-signalling mediators, triggering inflammation and pain.

“Now that we know how the histamine is produced in the gut, we can identify and develop therapies that target the histamine producing bacteria,” said first author Giada de Palma, assistant professor of medicine at McMaster.

The study found that when the mice colonized with histamine producing bacteria were fed a diet low in fermentable carbohydrates, bacterial histamine production dramatically decreased. This was due to change in bacterial fermentation and acidity within the gut, which inhibited the bacterial enzyme responsible for histamine production.

Bercik said that these results explain the beneficial effects of a low fermentable diet observed in patients with IBS.

It is known that patients with IBS have more mast cells in their intestines, and that some of them improve with treatments targeting mast cells or histamine, such as mast cell stabilizers or antihistamines.

“Although mast cell treatment in IBS has been explored, a novel approach based on our research would be targeting the bacterial histamine production or H4R pathways,” Bercik said.

The McMaster-Queen’s study explains why increased mast cells are found in IBS and suggests that H4 receptor pathway plays a major role in this process.

“If we block the H4 receptors, then we can prevent recruitment of mast cells to the colon and subsequently the development of abdominal pain,” said senior co-author Stephen Vanner, professor of medicine at Queen’s University.

“Many but not all IBS patients will benefit from therapies targeting this histamine driven pathway,” said co-first author David Reed, assistant professor of medicine at Queen’s. Reed said that one or more biomarkers of this pathway could be used to find the patients most likely to benefit.

The McMaster-Queens study was funded by the Canadian Institutes of Health Research.

The study was published in the journal Science Translational Medicine on July 27.

Click HERE to read the study.

 

Stress, inflammation and natural treatments

Abstract:

Stress and inflammation have become the curses of our times and are the main pathogenetic factors in multiple diseases that are often comorbid and include allergies and asthma, eczema and psoriasis, fibromyalgia syndrome, mast cell activation syndrome, irritable bowel syndrome, myalgic encephalomyelitis/chronic fatigue syndrome and autism spectrum disorder (ASD). Unfortunately, there are no effective drugs.

Cross-talk between mast cells and microglia in the hypothalamus and amygdala could explain stress-induced inflammation. We recently showed that the “alarmin” IL-33 could play a major role through its synergistic action with the neuropeptide substance P to stimulate human mast cell secretion of the pro-inflammatory molecules IL-1β, TNF and VEGF. A new formulation using pure luteolin with Ashwagandha has now been developed and could be of significant benefit to patients suffering from these diseases.

Source: Theoharides TC, Kavalioti M. Stress, inflammation and natural treatments. J Biol Regul Homeost Agents. 2018 Nov-Dec;32(6):1345-1347. https://www.ncbi.nlm.nih.gov/pubmed/30574737

Tetramethoxyluteolin for the treatment of neurodegenerative diseases

Abstract:

Background: Most neurodegenerative and other brain disorders, especially Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and autism spectrum disorder (ASD) continue to elude objective biomarkers and effective treatments. Increasing evidence indicates that such diseases involve focal inflammation of the brain.

Objective: To review the role of cytokine-neuropeptide interactions in the pathogenesis of inflammation of the brain and the beneficial role of natural flavonoids.

Method: Medline search was conducted (2000-2017) for articles using the terms allergy, amygdala, atopy, autism, brain, chemokines, cytokines, hypothalamus, immunity, inflammation, mast cells, microglia, neurotensin, peptides, substance P, TNF.

Results: Neuropeptides and cytokine stimulation of mast cells and microglia can results in focal inflammation in the hypothalamus and amygdala, thus explaining most of the symptoms at least in ME/CFS and ASD. Some of the triggers may be corticotropin-releasing hormone (CRH), neurotensin (NT), and substance P (SP), which has synergistic action with IL-33. The natural flavonoids luteolin and tetramethoxyluteolin inhibit these processes and have neuroprotective actions. Tetramethoxyluteolin is also more metabolically stable and has greater oral absorption.

Conclusion: Inhibition of inflammatory processes unique to the brain with intranasal formulations of tetramethoxyluteolin could provide new possibilities for the understanding and treatment of neurodegenerative diseases.

Source: Theoharides TC, Tsilioni I. Tetramethoxyluteolin for the treatment of neurodegenerative diseases. Curr Top Med Chem. 2018 Nov 19. doi: 10.2174/1568026617666181119154247. [Epub ahead of print]  https://www.ncbi.nlm.nih.gov/pubmed/30451113

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis?

Abstract:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease characterized by debilitating fatigue, lasting for at least 6 months, with severe impairment of daily functioning and associated symptoms. A significant percentage of ME/CFS patients remains undiagnosed, mainly due to the complexity of the disease and the lack of reliable objective biomarkers. ME/CFS patients display decreased metabolism and the severity of symptoms appears to be directly correlated to the degree of metabolic reduction that may be unique to each individual patient. However, the precise pathogenesis is still unknown preventing the development of effective treatments. The ME/CFS phenotype has been associated with abnormalities in energy metabolism, mostly with mitochondrial dysfunction, resulting in reduced oxidative metabolism. Mitochondrial dysfunction may be further contributing to the ME/CSF symptomatology by extracellular secretion of mitochondrial DNA, which could create an “innate” inflammatory state in the hypothalamus, thus disrupting normal homeostasis. We propose that stimulation of hypothalamic mast cells activates microglia leading to focal inflammation in the brain and disturbed homeostasis.

Source: Hatziagelaki E, Adamaki M, Tsilioni I, Dimitriadis G, Theoharides TC. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis? J Pharmacol Exp Ther. 2018 Aug 3. pii: jpet.118.250845. doi: 10.1124/jpet.118.250845. [Epub ahead of print]   http://jpet.aspetjournals.org/content/early/2018/08/03/jpet.118.250845.long (Full article)