Pivotal role of mast cells in pruritogenesis in patients with myeloproliferative disorders

Ishii, Takefumi; Wang, Jiapeng; Zhang, Wei; Mascarenhas, John; Hoffman, Ronald; Dai, Ying; Wisch, Nathaniel; Xu, Mingjiang

doi:10.1182/blood-2008-09-179416

Cited by 76 publications

(81 citation statements)

References 46 publications

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“…In this regard, there is recent evidence that an increased output of CD34 + cell-derived mast cells in patients with myeloproliferative neoplasms plays a role in the etiogenesis of pruritus, possibly through the release of prostaglandin D2 and increased levels of IL-31. 43 Overall, the results of this study indicate that PV basophils are constitutively activated and hypersensitive to IL-3, favoring a direct role of JAK2V617F mutation. They also lend support to the hypothesis that activated basophils contribute to pruritus in PV patients and that JAK2 inhibitors might be effective in countering this agonizing and usually treatment-insensitive symptom.…”

Section: Discussionmentioning

confidence: 55%

The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils from patients with polycythemia vera

Pieri¹,

Bogani²,

Guglielmelli³

et al. 2009

Haematologica

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BackgroundThe JAK2V617F mutation has been associated with constitutive and enhanced activation of neutrophils, while no information is available concerning other leukocyte subtypes. Design and MethodsWe evaluated correlations between JAK2V617F mutation and the count of circulating basophils, the number of activated CD63 + basophils, their response in vitro to agonists as well as the effects of a JAK2 inhibitor. ResultsWe found that basophil count was increased in patients with JAK2V617F -positive myeloproliferative neoplasms, particularly in those with polycythemia vera, and was correlated with the V617F burden. The burden of V617F allele was similar in neutrophils and basophils from patients with polycythemia vera, while total JAK2 mRNA content was remarkably greater in the basophils; however, the content of JAK2 protein in basophils was not increased. The number of CD63 + basophils was higher in patients with polycythemia vera than in healthy subjects or patients with essential thrombocythemia or primary myelofibrosis and was correlated with the V617F burden. Ultrastructurally, basophils from patients with polycythemia vera contained an increased number of granules, most of which were empty suggesting cell degranulation in vivo. Ex vivo experiments revealed that basophils from patients with polycythemia vera were hypersensitive to the priming effect of interleukin-3 and to f-MLP-induced activation; pre-treatment with a JAK2 inhibitor reduced polycythemia vera basophil activation. Finally, we found that the number of circulating CD63 + basophils was significantly greater in patients suffering from aquagenic pruritus, who also showed a higher V617F allele burden. ConclusionsThese data indicate that the number of constitutively activated and hypersensitive circulating basophils is increased in polycythemia vera, underscoring a role of JAK2V617F in these cells' abnormal function and, putatively, in the pathogenesis of pruritus.Key words: JAK2V617F mutation, basophil, polycythemia vera, pruritus.Citation: Pieri L, Bogani C, Guglielmelli P, Zingariello M, Rana RA, Bartalucci N, Bosi A, and Vannucchi AM. The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils from patients with polycythemia vera. Haematologica 2009; 94:1537-1545. doi:10.3324/haematol.2009 This is an open-access paper.The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils from patients with polycythemia vera

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Section: Discussionmentioning

confidence: 55%

The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils from patients with polycythemia vera

Pieri¹,

Bogani²,

Guglielmelli³

et al. 2009

Haematologica

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“…In this sense, it has recently been shown that mast cells are also involved in the malignant process of patients with myeloproliferative neoplasms and that they have an increased state of activation and release greater levels of pruritogenic factors, which might contribute to the pruritus. 27,28 In addition, there is now accumulating evidence that mast cells may play a role in atherothrombosis. 29 The observation by Pieri et al lends additional support to the notion that the JAK2 mutation promotes the activation, and not only the accumulation, of normally functional mature blood cells.…”

Section: 21mentioning

confidence: 99%

Blood cell activation in myeloproliferative neoplasms

Cervantes¹,

Arellano‐Rodrigo²,

Alvarez‐Larrán³

2009

Haematologica

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“…Intriguingly, this action in missing from epidermal keratinocytes of AD patients where TLR-2 expression is impaired [152]. Finally, it should be mentioned that in pruritic myeloproliferative disorders, mast cells release higher amount of IL-31 and other pruritogenic mediators [153].…”

Section: Inflammatory Mediators As Peripheral Itch Sensitizersmentioning

confidence: 99%

TRP Channels and Pruritus

Tóth¹,

Bı́ró²

2013

TOPAINJ

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Itch (pruritus) is one of the most often seen sensory phenomena in clinical practice. Recent neurophysiological findings proposed the existence of a novel pruriceptive system which includes a multitude of pruritogenic (itch-inducing) peripheral mediators, itch-selective pruriceptors, sensory afferent networks, spinal cord neurons, and certain central nervous system regions. In this review, we first introduce major features of the pruriceptive system. We then focus on defining the roles of transient receptor potential (TRP) ion channels in skin-coupled itch and provide compelling evidence that certain thermosensitive TRP channels (especially TRPV1, TRPV3, TRPV4, and TRPA1) are indeed key players in pruritus pathogenesis. Finally, we propose TRP-centered future experimental directions towards the therapeutic targeting of TRP channels in the clinical management of itch.

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Pivotal role of mast cells in pruritogenesis in patients with myeloproliferative disorders

Abstract: Pruritus is a common symptom in patients with Philadelphia chromosomenegative myeloproliferative disorders (MPDs).

Cited by 76 publications

References 46 publications

The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils from patients with polycythemia vera

The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils from patients with polycythemia vera

Blood cell activation in myeloproliferative neoplasms

TRP Channels and Pruritus

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