About the Author
Theoharis C. Theoharides MS MPhil MD PhD
Dr. Theoharides is Professor of Pharmacology and Internal Medicine, and Director of Molecular Immunopharmacology and Drug Discovery at Tufts University School of Medicine, Boston. He received his degrees (BA cum laude, MS, MPhil, PhD, MD) from Yale University and was awarded the Winternitz Prize in Pathology. He trained in internal medicine at New England Medical Center and received the Oliver Smith Award “recognizing excellence, compassion and service.” He received a Certificate in Global Leadership from the Tufts Fletcher School of Law and Diplomacy and a Fellowship at the Harvard Kennedy School of Government. He was awarded the Distinguished Faculty Recognition Award twice, the Excellence in Teaching ten times and the Alumni Award for Faculty Excellence. He first showed that mast cells, known for allergic reactions, are critical for neuroinflammatory conditions. He has published 470 scientific papers with over 40,000 citations and was listed in the world’s top 2% most cited scientists. He has received 37 patents and trademarks. He was inducted into the Alpha Omega Alpha National Medical Honor Society, the Rare Diseases Hall of Fame, and the World Academy of Sciences. He has been recognized with the 2018 Albert Nelson Marquis Lifetime Achievement and the Distinguished Humanitarian Awards.
Mast Cells in Atopic Diseases: More Than Just Histamine
Mast cells are present in all tissues and are able to release multiple mediators in response to allergic, autoimmune, environmental, neurohormonal and pathogenic triggers. Histamine has received most of the attention in terms of pathophysiology and drug development, while tryptase remains to this date with no clear function and no known inhibitor. Mast cells can also release pro-inflammatory and pruritogenic molecules, such as IL-6 and IL-31, selectively without degranulation. One such critical molecule is platelet activating factor (PAF), which is vasoactive, can cause wheal and flare on its own, but can also stimulate eosinophils and mast cells that are critical in the pathogenesis of chronic spontaneous urticaria (CSU) and rhinitis. Mast cell-derived cytokines and PAF have also been implicated in inflammatory processes including COVID-19. Among the second generation histamine-1 receptor antagonists, rupatadine is more effective overall, it has potent anti-PAF activity, and also inhibits activation of human mast cells and eosinophils. Rupatadine could, therefore, serve as a first-line drug for CSU and rhinitis, but may also be used, especially for patients resistant to antihistamines.
Biology of Mast Cells
Mast cells1-5 derive from hematopoietic precursors,6 travel in the circulation as precursor cells and proliferate in response to stem cell factor (SCF), the ligand of the surface tyrosine kinase receptor CD117 (C-KIT).7 Mast cells mature and are located perivascularly8-10 in all tissues11 under the influence of local micro-environmental factors12, 40 resulting in different phenotypes.13 Mast cells are present in the brain,14,15 including the meninges,16,17 and the median eminence16,18,19 where they are located perivascularly in close proximity to neurons20 that are positive for corticotropin releasing hormone (CRH).16 Brain mast cells are the richest source of histamine,21 which is involved in neurodevelopment.22 Furthermore, histamine may serve as an alert signal in the brain when high attention or a strong wake-drive is needed, such as during exploration, learning and motivation.23 Brain mast cells have been associated with memory consolidation and retrieval,24-26 as well as arousal27,28 and motivation.29,30
Mast cells are typically activated by allergens crosslinking specific immunoglobulin E (IgE) bound to high affinity surface Fc epsilon receptor 1 (FcεRI).31,32 Even though mature mast cells reside in the tissues, they probe the blood vessel lumen by extending filopodia through endothelial gaps, capturing IgE from the circulation, and sensing circulating antigens.33 Contrary to early research, fetal mast cells can bind maternal circulating IgE and contribute to postnatal allergic responses.34 Quite surprisingly, prenatal stressful events have been reported to increase cord blood IgE.35
Mast cells are also triggered by non-IgE stimuli36-38 and by additional ligands,39 including neuropeptides,40 such as CRH,41 neurotensin (NT),42 substance P (SP)43 and somatostatin44,45 via high affinity receptors (Table 1), as well as by many cationic compounds through the low affinity G-coupled receptor MRGPRX2.46 This process is distinct from that utilizing the FcεRI and may lead to release of different mediators. Allergic stimulation of mast cells leads to secretion of the SP-related peptide Hemokinin-1, which augments IgE-mediated allergic responses by binding with low affinity to the SP receptor (NK1) on mast cells.47 CRH augmented release from human mast cells stimulated by IgE/anti-IgE of vascular endothelial growth factor (VEGF), which is also vasodilatory, could contribute to edema and has been shown to be increased in lesional skin in CSU.48 Mast cells are also triggered by pathogens including fungi,49 toxins,50 as well as viruses51,52 including SARS-CoV-2.53,54 Mast cells express multiple receptors for a variety of stimuli (Table 1),40,55 including receptors for sex hormones.56 In addition, mast cells can synthesize hormones57 and neuropeptides such as CRH,58 as well as the peptide neurotensin (NT),59 which can sensitize sensory nerve endings and mediate the effect of stress. Mast cells in the pineal and the hypothalamus may also be involved in circadian rhythms.60-63
Upon stimulation, mast cells rapidly secrete via degranulation multiple mediators that include the preformed, granule-stored such as heparin, histamine, tryptase and TNF.3 Histamine has been the main mediator associated with mast cells,64,65 but is also released from basophils.66 Interestingly, mast cells can also generate a histamine-releasing peptide from albumin,67 meaning that once stimulated mast cells can release enzymes that can act on albumin and produce a peptide that can further stimulate mast cells. Mast cells also secrete newly synthesized mediators 6-24 hours after stimulation (late-phase reaction); these include prostaglandin D2 (PGD2),68 cytokines (IL-5, IL-6, IL-31, IL-33 and TNF) and chemokines (CCL2, CCL5 and CXCL8), 4,5,69 as well as platelet activating factor (PAF),70 which has been implicated in inflammation71 and microthromboses.71,72 PAF has many potent biological effects on almost all tissues and organs, leading to inflammation and microthromboses.71 PAF is the most potent trigger of platelet aggregation known. It was discovered in 1972.73 Its structure was elucidated in 1979 by Demopoulos and colleagues as a glyceryl-ether lipid (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine).74 PAF is produced by many prokaryotic and eukaryotic cells, but it is extremely short-lived making its routine measurement in biologic fluids difficult.75
Selective release of mediators
Mast cells can release specific mediators, such as serotonin,76 IL-677 and VEGF78 without degranulation, but rather via intragranular changes associated with release of mediators without release of histamine or tryptase.79 In addition, the “alarmin” IL-3380-82 stimulates mast cells via activation of its own specific surface receptor, ST2, significantly increasing the ability of SP to stimulate release of VEGF,43,83 IL-31,84 TNF85 and IL-1β,86 as well as CCL2 and CCXL887 and other newly synthesized mediators.82 IL-33 also augments release of IL-31 from human mast cells stimulated either by SP or IgE/anti-IgE.84 Mast cells can release IL-33, themselves.88 Mast cell-derived IL-1β or histamine-induced release of IL-1β from macrophages89 can then stimulate mast cells to release IL-6 selectively without degranulation.77,90 IL-6 is elevated in systemic mastocytosis and correlated with disease severity,91-93 and is also elevated in COVID-19.94,95 In fact, IL-6 promotes an increase in mast cell numbers,96 and is constitutively released in the presence of the D816V-KIT mutation.97 IL-6 and other mast cell-derived molecules, such as bradykinin, IL-31, matrix metalloproteinase-9 (MMP-9) and PAF are quite pruritogenic (Table 2).
We had called brain mast cells the “immune gate to the brain”14 and the “immunoendocrine master player.”98 Restraint stress in rodents increased blood-brain barrier (BBB) permeability18,99,100 via CRH-stimulating mast cells.99,101,102 Mast cell-derived mediators, such as cytokines,103,104 increased BBB permeability not only to small molecules,18,99 but also to mammary adenocarcinoma brain metastases in mice.101 This process could worsen with stress, including psychological stress acting via CRH stimulation of mast cells99,101 leading to increased dura vascular permeability105— an effect that was absent in mast cell-deficient mice.106 Allergic stimulation of nasal mast cells resulted in stimulation of the hypothalamic-pituitary-adrenal (HPA) axis,41, 107-109 possibly via mast cell release of histamine,110 IL-6111 and CRH.58 The regulation of mast cells by neuropeptide and neurotransmitters was reviewed recently.40,112,113
The mode and extent of mast cell responsiveness ultimately depends on the interplay between stimulatory and inhibitory signaling pathways. Mast cell responsiveness may be regulated not only by the neuroimmune stimuli, but also by the effects of the different receptors involved. For instance, mast cells express high affinity NK-1 receptors for SP.85,114 Moreover, SP115 and NT116 induced the expression of CRHR-1 in human mast cells. Secretion of mediators can occur utilizing different signaling117-120 and secretory117,121 pathways. The diagnosis of atopic diseases rests on clinical symptoms and the measurement of a number of molecules in the blood and urine (Table 3). However, there are no specific mast cell markers;122 histamine is degraded within a few minutes, while tryptase reflects the mast cell volume rather than its activation. Moreover, mast cells are also implicated in both health and disease,38,123,120,124 especially immunity125,126 and inflammation.38,127,128
Pathophysiology of Chronic Spontaneous Urticaria (CSU)
CSU is a common skin condition characterized by wheals and flares, but also intense itching, with or without angioedema129,130 and constitutes a major global health burden.131
Mast cells are a necessary component in the pathogenesis of CSU,132 but so are eosinophils.133
CSU is a clinical diagnosis. In spite of proposals for potential blood biomarkers, to date there is no consensus of specific biomarkers for CSU.134,135 Elevations of D-Dimer, eosinophil cationic protein (ECP), IL-6, matrix metalloproteinase-9 (MMP-9), PAF, TNF and vitamin D3 are the most useful markers for the diagnosis of CSU (Table 4). In addition, the presence of dermatographia and a positive anti-FcεRI IgG (basophil activation test) are commonly present in such patients (Table 4). Elevated mean serum IgE levels and blood eosinophils, along with the presence of positive skin prick tests to aeroallergens, correlates with the presence of anti-FcεRI IgG and anti-IgE IgG.136 It was recently shown that elevated serum levels of the non-specific mast cell surface receptor MMRGPRX2 correlated with disease severity in CSU.137 These findings may explain why as many as 30% of patients with CSU are resistant to antihistamines (Table 4).131,138
Elevated PAF levels had been strongly associated with severe anaphylaxis,139,140 more so than histamine or tryptase.141 Moreover, combination treatment blocking both PAF and histamine markedly reduces the severity of peanut-induced anaphylaxis.142 PAF is also reported to be involved in allergies in general,143 and more specifically in allergic rhinitis,144,145 immediate and late cutaneous reactions,146 as well as CSU.147
With respect to allergic rhinitis,145 PAF has been identified in nasal polyps and eosinophils,144 and has been shown to stimulate eosinophils,148,149 especially superoxide ion generation.150 More specifically, PAF is believed to be more potent than histamine in increasing nasal airway resistance.151 PAF appears to have a bidirectional association with cytokines. For instance, IL-6 stimulates production of PAF, 152,153 while PAF induces IL-6 production.154-156 Elevated blood PAF levels have been reported in patients refractory to treatment with antihistamines.147 Additionally, PAF-induced wheal and flare reactions on their own, are independent from histamine.157 These findings indicate that PAF plays a major role in CSU by having a direct effect on the skin independent of histamine, but also stimulating mast cells to release other pruritogenic molecules.
A key aspect of CSU is pruritus .158, 159 As mentioned earlier, a number of mast cell-derived molecules are involved in pruritus (Table 3), especially IL-31,160-162 which has been reported to be elevated in CSU.163 Research has demonstrated that human mast cells can release IL-31 in response to allergic and non-allergic triggers, especially IL-33.84 Unfortunately, IL-31 is not yet measured in clinical laboratories.
Pruritus in general,164 and in CSU specifically,165 worsens with stress. Pruritus is mediated by neuroimmune circuits,166 especially the interactions between peripheral nerves, mast cells and eosinophils.167 In this context, it may be relevant that PAF stimulates expression of histamine-1 receptors in trigeminal ganglia,168 implying that it may have a similar action on cutaneous sensory nerves resulting in increased sensitivity to histamine.
Role of mast cells and PAF in COVID-19
The pathogenesis of most patients with COVID-19 is significant for the presence of perivascular inflammation and microthrombi169-171 that could involve PAF.71,72,172
The mediators involved could be released from mast cells.72,89,173-177 Mast cell degranulation associated with interstitial edema and immunothrombosis has been reported in the alveolar septa of deceased patients with COVID-19.54 In fact, mast cell-derived chymase was shown to be elevated in the serum of patients with COVID-19178,179 as have been eosinophil-related mediators.179 Another study reported increased number of eosinophils in the blood of patients with COVID-19.180 Interestingly, many COVID-19 patients also develop urticaria.181,72, 89,173-177
Many patients (30-50%) infected with SARS-CoV-2 develop a post-acute syndrome a few months after the initial infection182-186 known as post-acute COVID or “long-COVID.”183,187-189 Long COVID is particularly associated with persistent fatigue190 and cognitive dysfunction, known as brain fog.183,188,189,191-197 Symptoms experienced by COVID patients, especially cognitive dysfunction,198-200 are similar174,175 to those present in patients with mast cell activation syndrome (MCAS).201,202 Mast cells in such patients can be stimulated by environmental and stress triggers11 and viruses52 including SARS-CoV-2.53,176,203
There are still no clinically effective mast cell inhibitors.204, 205 A number of inhibitors of the tyrosine kinase c-kit receptor that block mast cell proliferation have been developed,206,207 but most of them do not inhibit mast cell activation.208 Disodium cromoglycate (cromolyn), known as a “mast cell stabilizer,” had originally been shown to inhibit rat peritoneal mast cell histamine release.209 However, cromolyn does not effectively inhibit either murine mast cells210 or human mast cells.212-214 The first generation histamine-1 receptor antagonist ketotifen has been promoted as a mast cell inhibitor, but the only such evidence is from a few studies using conjuctival mast cells, and it is very sedating. New approaches address new histamine receptors,211 such as the putative inhibitory receptor (Siglec-8).138,212,213
Avoidance of potential triggers (Table 5) is self-evident. Supplementation with the main histamine metabolizing enzyme, diamine oxidase214 and Vitamin D3,215 which has been shown to modulate immune responses216 and suppresses the production of VEGF from mast cells in CSU217 may be helpful.
The initial treatment approach is the use of second-generation, non-sedating histamine-1 receptor antagonists up to 4 times the recommended doses as tolerated (Table 5).129,218-221 One of these, the histamine-1 receptor antagonist rupatadine, was specifically developed to have potent anti-PAF activity.222 The relative potency of rupatadine for blocking the histamine-1 receptor using histamine-induced guinea pig ileum contraction was shown to be about 24x greater than cetirizine and 75x greater than loratadine.223 Rupatadine at 40 mg/day is well tolerated and inhibits histamine- and PAF-induced flares and ex vivo platelet aggregation in normal male subjects.224 When compared to other non-sedating antihistamines in chronic urticaria, 20 mg/day of rupatadine showed the greatest efficacy in the treatment of CSU (71.6%) as compared to 80 mg/day of bilastine (60%), 20 mg/day of desloratadine (50%), 240 mg b.i.d. of fexofenadine (56%), and 20 mg/day of levocetirizine (21.7%).225 In a network meta-analysis comparing the efficacy of second-generation antihistamines in CSU, rupatadine was superior to other antihistamines including bilastine with respect to change from baseline in pruritus and wheal scores.226
Notably, rupatadine also inhibited histamine and TNF release from human mast cells in response to PAF,36 and the release of histamine and IL-6 from human mast cells stimulated by different triggers.227 In another study comparing rupatadine to desloratadine and levocetirizine, rupatadine was shown to be superior at inhibiting PAF-induced release of histamine from human mast cells.228
As discussed earlier, many patients with CSU do not respond to antihistamines (Table 4). For such patients, the anti-IgE omalizumab may be an appropriate treatment option.229
Mast cells have useful physiologic functions,231 and play a critical role in atopic diseases,11 especially allergies38 and anaphylactic reactions,2,4,11,231 as well as inflammation.2,128,230,232,233 Given the multiple pathways involved in CSU, the possession of potent anti-PAF, anti-eosinophilic and mast cell inhibitory properties by rupatadine, makes it an excellent first-line drug for this debilitating condition.
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