KIT D816V and the cytokine storm in mastocytosis: production and role of interleukin-6

Valent, Peter

doi:10.3324/haematol.2019.234864

Cited by 13 publications

(17 citation statements)

References 24 publications

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“…In support of this, post-mortem lung biopsies of COVID-19 patients showed increased density of perivascular and septal MCs compared to controls ( 30 ). Recent evidence also indicates that MCs can play a role in initiating hyperinflammation or cytokine storm in multiple disease settings ( 18 , 49 , 50 ). Our findings also suggest systemic MC activation is associated with COVID-19 inflammation since we saw signatures of elevated proteases thought to be released from different MC populations.…”

Section: Discussionmentioning

confidence: 99%

Mast Cell and Eosinophil Activation Are Associated With COVID-19 and TLR-Mediated Viral Inflammation: Implications for an Anti-Siglec-8 Antibody

et al. 2021

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Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection represents a global health crisis. Immune cell activation via pattern recognition receptors has been implicated as a driver of the hyperinflammatory response seen in COVID-19. However, our understanding of the specific immune responses to SARS-CoV-2 remains limited. Mast cells (MCs) and eosinophils are innate immune cells that play pathogenic roles in many inflammatory responses. Here we report MC-derived proteases and eosinophil-associated mediators are elevated in COVID-19 patient sera and lung tissues. Stimulation of viral-sensing toll-like receptors in vitro and administration of synthetic viral RNA in vivo induced features of hyperinflammation, including cytokine elevation, immune cell airway infiltration, and MC-protease production—effects suppressed by an anti-Siglec-8 monoclonal antibody which selectively inhibits MCs and depletes eosinophils. Similarly, anti-Siglec-8 treatment reduced disease severity and airway inflammation in a respiratory viral infection model. These results suggest that MC and eosinophil activation are associated with COVID-19 inflammation and anti-Siglec-8 antibodies are a potential therapeutic approach for attenuating excessive inflammation during viral infections.

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Section: Discussionmentioning

confidence: 99%

Mast Cell and Eosinophil Activation Are Associated With COVID-19 and TLR-Mediated Viral Inflammation: Implications for an Anti-Siglec-8 Antibody

et al. 2021

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“…MCs are also a source of numerous cytokines, chemokines and growth factors. Furthermore, newly formed mediators produced during MC activation include lipids, such as prostaglandin D2 (PGD2), leukotriene C4 (LTC4), platelet-activating factor (PAF), and sphingosine-1-phosphate [ 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 ]. The precise role of all these MC mediators in the pathogenesis of CM and SM is not yet fully determined [ 69 ].…”

Section: Pathogenesismentioning

confidence: 99%

Molecular Background, Clinical Features and Management of Pediatric Mastocytosis: Status 2021

Lange

Hartmann

Carter

et al. 2021

IJMS

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Pediatric mastocytosis is a heterogeneous disease characterized by accumulation of mast cells in the skin and less frequently in other organs. Somatic or germline mutations in the KIT proto-oncogene are detected in most patients. Cutaneous mastocytosis is the most common form of the disease in children. In the majority of cases, skin lesions regress spontaneously around puberty. However, in few patients, mastocytosis is not a self-limiting disease, but persists into adulthood and can show signs of systemic involvement, especially when skin lesions are small-sized and monomorphic. Children with mastocytosis often suffer from mast cell mediator-related symptoms. Severe hypersensitivity reactions can also occur, mostly in patients with extensive skin lesions and blistering. In a substantial number of these cases, the triggering factor of anaphylaxis remains unidentified. Management of pediatric mastocytosis is mainly based on strict avoidance of triggers, treatment with H1 and H2 histamine receptor blockers, and equipment of patients and their families with epinephrine auto-injectors for use in severe anaphylactic reactions. Advanced systemic mastocytosis occurs occasionally. All children with mastocytosis require follow-up examinations. A bone marrow investigation is performed when advanced systemic mastocytosis is suspected and has an impact on therapy or when cutaneous disease persists into adulthood.

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“…Interleukin 6 (IL-6) is a multifunctional inflammatory cytokine that plays a role in the regulation of cell proliferation, hematopoiesis, immune response, and inflammation. Interleukin 6 is a major MC-derived mediator and is elevated in patients with mastocytosis [ 48 , 49 , 50 , 51 , 52 , 53 , 54 ].…”

Section: Studies Of the Common Germline Genetic Variants In Patienmentioning

confidence: 99%

“…Interleukin 6 may also act as an autocrine growth factor for neoplastic MC [ 53 , 54 ]. Brockow et al demonstrated that IL-6 plasma levels, but not sIL-6R levels, were elevated in patients with mastocytosis and correlated with BM pathology, organomegaly, and the extent of skin involvement.…”

Section: Studies Of the Common Germline Genetic Variants In Patienmentioning

confidence: 99%

“…TLR-1/2, TLR-2/6, TLR-4, and TLR-5 receptors activate P13K-AKT, MAPK, and increase production of eicosanoid and pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6 [ 55 , 56 , 57 ]. Several variants in TLR genes that affect these signaling pathways have been described [ 52 , 53 , 54 ]. In certain infectious, inflammatory, and allergic diseases, the missense variants TLR2 p.R753Q and TLR4 p.D299E, and the TLR9 promoter variant −1237C > T have been associated with increased signaling [ 58 , 59 , 60 , 61 ].…”

Section: Studies Of the Common Germline Genetic Variants In Patienmentioning

confidence: 99%

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Clinical Impact of Inherited and Acquired Genetic Variants in Mastocytosis

Nedoszytko

Arock

Lyons

et al. 2021

IJMS

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Mastocytosis is a rare and complex disease characterized by expansion of clonal mast cells (MC) in skin and/or various internal organ systems. Involvement of internal organs leads to the diagnosis of systemic mastocytosis (SM). The WHO classification divides SM into indolent SM, smoldering SM and advanced SM variants, including SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia. Historically, genetic analysis of individuals with pure cutaneous mastocytosis (CM) and SM have focused primarily on cohort studies of inherited single nucleotide variants and acquired pathogenic variants. The most prevalent pathogenic variant (mutation) in patients with SM is KIT p.D816V, which is detectable in most adult patients. Other somatic mutations have also been identified—especially in advanced SM—in TET2, SRSF2, ASXL1, RUNX1, CBL and JAK2, and shown to impact clinical and cellular phenotypes. Although only small patient cohorts have been analyzed, disease associations have also been identified in several germline variants within genes encoding certain cytokines or their receptors (IL13, IL6, IL6R, IL31, IL4R) and toll-like receptors. More recently, an increased prevalence of hereditary alpha-tryptasemia (HαT) caused by increased TPSAB1 copy number encoding alpha-tryptase has been described in patients with SM. Whereas HαT is found in 3–6% of general Western populations, it is identified in up to 17% of patients with SM. In the current manuscript we review the prevalence, functional role and clinical impact of various germline and somatic genetic variants in patients with mastocytosis.

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KIT D816V and the cytokine storm in mastocytosis: production and role of interleukin-6

Cited by 13 publications

References 24 publications

Mast Cell and Eosinophil Activation Are Associated With COVID-19 and TLR-Mediated Viral Inflammation: Implications for an Anti-Siglec-8 Antibody

Mast Cell and Eosinophil Activation Are Associated With COVID-19 and TLR-Mediated Viral Inflammation: Implications for an Anti-Siglec-8 Antibody

Molecular Background, Clinical Features and Management of Pediatric Mastocytosis: Status 2021

Clinical Impact of Inherited and Acquired Genetic Variants in Mastocytosis

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