Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ii eitr,peoiatypotgadnD PD)adtecsluoree T4 T4adLTE4, and preformed LTD4 of LTC4, release cys-leukotrienes pathways the the major and and (PGD2) (SGs) three D2 granules through prostaglandin secretory heparin mediators predominantly of and mediators, releasing proteases exocytosis lipid is histamine, by as response react such rapid they mediators most receptors, The activating 1). trauma many (Figure and their injury of cell recognize one microbes to including MCs signals, for responses important “ IgE-mediated is regulating which as receptor, well peptides IL-33 as the cationic include other activation and MC of reactions products variety allergic eosinophil a pseudo secreted recognizing causing receptor ciprofloxacin) coupled icatibant, G-protein atracurium, a 3,4 (tubocurarine, (MRGPRX2), agents X2 pharmacologic receptor protein-coupled cell G progenitors mast related cell to mast leads Fc stimuli signaling of KIT development receptor, of in early diversity reduction KIT, for a a receptor, redundant to (SCF) as is factor cells, blood receptor cell mast peripheral the stem mature in The through on signaling receptors cells. in Yet, granulated critical absent highly most normally deficiency. as are the tissues MCs of all mature one almost progenitors, is in (MC) found cell mast while produce blood cells stem hematopoietic Although conditions. such treat to strategies development novel the of cell Introduction highlight development mast also into the We insights discuss new reactivity. and on and driven-diseases particularly heterogeneity cell focus recruitment, mast we development, review of this cell understanding that In clinical mast discoveries our many disease. years, in on in and recent focus resulted health have During a in models cells with animal cells. mast biology, using epithelial of experiments non-immune as function and and well the recognizing cells immune as decipher system, muscle cells both help human mast on smooth human the acting cells, on of mediators studies endothelial ingenious surveillance of experimental variety this fibroblasts, and and a of cells, homeostasis of roles nerve for release pathophysiological important including induce and which are cells, physiological agents, cells exogenous the Mast and but endogenous understood. diseases, both fully allergic not in still role are their cell for (in)famous are cells Mast Abstract 2020 28, October 5 4 3 2 1 Nilsson Gunnar and Dahlin Joakim cell mast into function insights and Contemporary behavior Cell: Mast Ingenious The e vvUiest ake aut fMedicine of Faculty Sackler University Aviv Tel Universitet Uppsala NIAID Charit´e Universit¨atsmedizin Berlin Institutet Karolinska RPX losre srcpo o usac ,cmoet fisc eo,atmcoilpeptides, antimicrobial venom, insect of components P, substance for receptor as serves also MRGPRX2 . ε I nte eetrta a eevdpriua teto uigrcn er steMas- the is years recent during attention particular received has that receptor Another RI. 1 acsMaurer Marcus , 1 C r qipdwt ra ubro eetr nbigte osneadreact and sense to them enabling receptors of number great a with equipped are MCs . 1 2 h otsuidrcpo htcue Catvto stehg-ffiiyIgE high-affinity the is activation MC causes that receptor studied most The . 11 hnMssnea noeoso xgnu gn hog idn to binding through agent exogenous or endogenous an sense MCs When . 2 enMetclafe Dean , 8-10 n atr eonto eetr PR)snig“danger sensing (PRRs) receptors recognition pattern and , 12 1 hsi copne ythe by accompanied is This . 5,6 3 unrPejler Gunnar , te eetr htidc IgE-independent induce that receptors Other . 4 oi Sagi-Eisenberg Ronit , enovo de isnhssof biosynthesis 5 , 7 Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. saso os oemro rgntr lovrfidta aohlM ieetaini lsl coupled closely is differentiation basophil/MC that experiments verified assay also fate progenitors single-cell erythropoiesis marrow in with bone recapitulated mouse is developmental of that trajectories MC assays finding basophil the a and that other single- population, each shows erythrocyte A to progenitor 2B). mouse close the particularly (Figure in to are cells adjacent hematopoiesis trajectories committed marrow positioned lineage bone is to of progenitors trajectory bipotent landscape of and transcriptional snapshot multi- cell a from capturing states, model on of hematopoietic based landscape delineating the is progenitors now of transcriptomics differentiating revision are single-cell single a with biology differentiation suggesting computational by hematopoietic and construct trajectory sequencing differentiation trajectory RNA MC unique branch single-cell the a either along high-throughput to differentiate in belong and Advances MCs – megakaryocyte- that cells the idea stem or the hematopoietic granulocyte-monocyte to supporting close Studies the as- with presented either However, topic. potential been controversial to 2A). lineage have a (Figure trajectory of is progenitors differentiation loss branch lineage-committed stepwise MC erythrocyte a to the assumes cells of hematopoiesis stem signment describes hematopoietic that from differentiation model tree-like classic The MCs landscapes differentiation re- tissue-type) to (connective mainly trees skin-resident MCs hematopoietic From marrow-derived depleted inflammation following bone reconstitute skin that can the show MCs populate also marrow-derived and Experiments bone postnatally as population MCs. waves MC all, mucosal not the but plenish marrow fraction, bone a the cells produce stem in hematopoietic cells produce con- wave stem mainly this potential waves during MC-forming two formed exhibit first Cells that MCs The region. serosal-type aorta-gonado-mesonephros progenitors. and the (CTMC) hematopoietic from MCs MCs definitive tissue first sac first connective The yolk to the extraembryonic tribute development. with the prenatal together in during appears progenitors waves MCs erythromyeloid distinct primitive temporally from several originate in arise cells Hematopoietic study cells to mast models recruit- of development, animal origin and and The origin possibilities, MC therapeutic regarding new findings disease, recent biology. most MC MC reactivity, the etc.) of and injury some heterogeneity (cell highlight ment, homeostasis, we body in review the role this within a In have from also or they etc.) that remember pathogens, many inflammation to (venoms, in acute important outside is implicated of it disease, initiation been of have the context the they in role, discussed are multifunctional their and MCs 23 allergy of beyond distribution diseases KIT, broad activated cells constitutively the other including Given to signature proteins MC mutant a the to of with proximal transfer exosomes either of enabling cells, levels other or by increased sites up have histology distant taken MC mastocytosis at (by be located can degranulation exosomes. that or including detectable RNA MC vesicles and secreting of extracellular enzymes, secrete absence proteins, also transfer the MCs can Finally, in exosomes mediators). cytokines granule and/or of interferons mediators measurement and lipid factors produce growth and 15-HETE chemokines, and cytokines, (TXA2) of novo A2 number thromboxane a like synthesize mediators to lipid other also but cancer , snhszdmdaoscntk lc ihu rcdn degranulation preceding without place take can mediators -synthesized 24 iwydiseases airway , 40 37-42 h obnto fsnl-eltasrpoisadlnaetaigpoie even provides tracing lineage and transcriptomics single-cell of combination The . 20-22 nadffrn nl,ohrivsiain rps htMsbac ffery– early off branch MCs that propose investigations other angle, different a On . o xml,rcn eiw ihih h oeo C ncrivsua diseases cardiovascular in MCs of role the highlight reviews recent example, For . 25 swl si ia,bceiladfna infections fungal and bacterial viral, in as well as , 35 46 oee,i snwcerta oemro eaooei tmcells stem hematopoietic marrow bone that clear now is it However, . 32 uhaayi eel htdffrnitn el rvreacontinuous a traverse cells differentiating that reveals analysis Such . twsfraln ieasmdta C eeo rmhematopoietic from develop MCs that assumed time long a for was It . 29 16-18 n ntepoeto gis agr hte tcmsfo the from comes it whether danger, against protection the in and wweoat.r)(iue1.Ntby ainswt systemic with patients Notably, 1). (Figure (www.exocarta.org) 36 47,48 . 32 oee,teei eudnyi h oeta fthe of potential the in redundancy a is there However, . 19 hc niae h rsneo ioetbasophil-MC bipotent a of presence the indicates which , . 2 32 h hr eaooei aeoriginates wave hematopoietic third The . 13 15 30 C lohv h capacity the have also MCs . hs C a eactivated be can MCs Thus, . 40,47 . 43,44 26-28 14 h Cadbasophil and MC The . . vni C commonly MCs if Even . 31-34 oal,rlaeof release Notably, . 45 eodwv of wave second A . h dat re- to idea The . 38,47-49 elfate Cell . de Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. iseweete opeetermtrto ne h nuneo oal rdcdfcos Surprisingly, factors. produced locally of influence the under maturation their CD34 complete as defined they humans in where blood, tissue the in circulating progenitors cycle MC life their during migration take might and cells and tissue. Homing heterogeneity mast same the MC that within into directions MCs insight behind among further Mechanisms differences give about will view This clearer a plasticity. provide and basophils) and heterogeneity eosinophils MC (neutrophils, decipher granulocytes the including lineages, immune distinct 67 among a MCs form of MCs identity that revealed cells cells immune tissues cells immune other across these heterogeneity other all in with from human proteases separated in tissues different well expression mouse the protease population different of of from prop- expression analysis MCs the histochemical detailed of in or and comparisons gradient plasticity, content great a protease a demonstrate their show MCs on MCs lung based simplistic. subpopulations rather different is into erties process. progenitor MCs this MC of into common separation insights a The and of In proof existence subpopulations progenitors? further the designated MC the provide suggested of likely all has results types will to different the that driven of addressed, rise heterogeneity recruitment population was the gives the is question progenitor that by words, this driven other one where it In is study is subtypes. or a there MC factors the if produced of any or locally into by mature circulation, and in differentiate described to was populations capacity clue progenitor one but MC enigmatic, different been above have mentioned subpopulations as MC different recently of lung development human and origin among The e.g., heterogeneity, mediator population. and considerable MC receptor the a their within is in there differ microenviron- responses organs tissue the matory different in single in changes a MCs on within dependent that MC probably clear also is is but latter It the expression, inflammation. above), (see an anti-tumorigenic MC during or the ment pro- of or def- anti-inflammatory, origin also or prenatal are pro- the there inducible, content, or protease MC2) constitutive or or either (MC1 localization two being their MCs on The of based initions subpopulations unstudied. into MCs virtually dividing and Besides secretagogues ignored to remained responsiveness and has content MCs mediator MC positive subpopulations, chymase-only MC of distinct (MC presence tryptase express the that born those and content; was (MC protease (MMCs) chymase their cells the by and mast and defined tryptase mucosal features, been and have staining (CTMCs) subpopulations histochemical cells MC in different mast differences by tissue other? mid-60s connective the each of in concept from differentiation described they first MC was are the heterogeneity different MC of how theories – new heterogeneity research. and cell future old Mast for unifies foundation hematopoiesis a of constitutes trajectories. differentiation and model granulocyte field landscape hematopoiesis basophil the of and summary, landscape erythrocyte overall In MC, an the reveals between data The association an differentiation. and MC of hematopoiesis understanding human our in olutionized fates proposed mouse been erythrocyte also barcoded and has individually MC progenitors Tracing between as differentiation. well MC during as on cells focus progenitor with hematopoietic hematopoiesis into insights deeper twl eitrsig hnsnl CRAsqecn aafo ua ise r vial,t further to available, are tissues human from data sequencing RNA MC single when interesting, be will It . T 62 utemr,tegn/rti xrsinwti hsMC this within expression gene/protein the Furthermore, . 24,60,61 63 usint drs si hs hne eaet ieetsbye raplasticity a or subtypes different to relate changes these if is address to question A . hl h iiinit osiuieadidcbesbouain ih erltdto related be might subpopulations inducible and constitutive into division the While . TC 66 33 n hms ny(MC only chymase and ) iial,poem nlsso ua knadftMscnre h unique the confirmed MCs fat and skin human of analysis proteome Similarly, . o eaooei nteaut h usinhsbe fteeaeseveral are there if been has question the adult, the in hematopoiesis For . T n MC and nvitro in 64 TC, oee,snl elRAsqecn n igecl cultures cell single and sequencing RNA cell single However, . 50 utr ofim opigbtenM n aohlfates basophil and MC between coupling a confirms culture swl steMCadCM,dffri hi localization, their in differ CTMC, and MMC the as well as ikbtenbspi/Cpoeiosaderythrocyte and progenitors basophil/MC between link A . 3 59 66 C ) . ihnteM ouainteewsasubstantial a was there population MC the Within . 57,58 51-54 h atrws o ogtm,controversial, time, long a for was, latter The . hs igecl N eunighsrev- has sequencing RNA single-cell Thus, . + T KIT , upplto hne uiginflam- during changes subpopulation + Fc , ε RI + cells 65 68 55,56 Transcriptome . ne specific a enter , nhumans, In . T ), Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. itdwt eonzdciia iessdet ffcso Cpoieainadsria,M eciiyor reactivity primary MC a survival, with and associated disease proliferation known MC widely asso- most on are the Some effects perhaps is to compartment. Mastocytosis due MC production. the diseases mediator affecting clinical MC I) aberrancies (Table recognized where “idiopathic” molecular with but MC thus characterized mediators ciated IgE-mediated well understood, MC well several and of not are release antigen-dependent is re- There the acquired recruitment of and through or and activated implicated activation formation inherited are are of to as MCs mechanism MCs due where such the where MCs conditions mechanism diseases clinical in condi- to to extrinsic defect These activation; compartment; primary an conditions. MC or inflammatory through the intrinsic of cruited within an number mutations with a and of associated polymorphisms perpetuation those and from initiation range the tions shed in involved will are studies MCs Future exocytosis. Diseases involved. of in entities Cells mode molecular Mast the the of be and inflammatory to selection to mechanisms recruitment beginning and these tissues, only on secretion destined are light to premature cycle homing of life MC prevention their ensure during that areas, mechanisms MCs include regulate They that biogenesis mechanisms clarified. their underlying both the during conclusion, fusion In exocytosis SG compound in role during a The fusion plays SG pattern. which degranulation for the essential defining for is critical which IKK as enzyme identified responses of the physiological been part is have unique factors first with only two associated or release level, are compound content; molecular and modes the by their membrane exocytic At different ii) release the the they content; with of which dynamics plasma fuse full and through the transiently their channel to only release a move content SGs and forming SGs their where other, membrane individual exocytosis” each i) the “kiss-and-run with ways: with iii) fuse different fuse SGs three and where in the dock exocytosis overrides place they phenotype take can actin where constraints This secretory membrane secretory the exocytosis. the secretagogue, undergo a relieving can degranulate encounter phenotype, to and actin how destination migratory is their question reach next MCs The As exocytosis? partial rearrangements or actin full center, these mDia1, Kiss-and-run, cell in formin, the player Diaphanous-related in key exocytosis. them be and trapping mobility to by supports appears granules phenotype secretory actin the secretory the immobilizes the in whereas phenotype SGs actin the basophil converge migratory and the the flattening Thus, from cell prevent differently that cytoskeleton center clusters actin cell cell pericentral the of accumulation to an linked revealed possibility are latter SGs some the MC as support requirement that challenging or a basophils, granules is to need This MCs opposed basophils 3). mature as of (Figure sites, degranulation degranulate inflamed degranulation induce yet at MC chemokines not destination MC but final the their migrate, of reaching to before regulated involve munitions be their also to of question may loss the inflammation avoid is To of that degranulate, sites to at tissue or accumulation migrate specific increased To a MC both within that of MCs consequence mature suggests of a MCs relocalization likely specific mature chemoattractants is tissue to and numbers response a in MC progenitors recruited is in progenitors their it increase of maturation that This as well except 72,73 asthma. as survival, unknown, and and proliferation mostly rhinitis allergic still in are as progenitors MC for process mechanisms homing the h atta oeceoiercpos uha C1 XR n XR,aeepesdo both on expressed are CXCR4, and CXCR2 CCR1, as such receptors, chemokine some that fact The . 69-71 77 80 akddffrne bevdbtenteatnseeo nmigrating in skeleton actin the between observed differences Marked . nadto oterbslhmn,M ubr lal nraea ie fiflmain such inflammation, of sites at increase clearly numbers MC homing, basal their to addition In . ycnrs,rdcini h ci ehdniycaatrzstesceoyatnphenotype. actin secretory the characterizes density mesh actin the in reduction contrast, By . 81 hoigtemd feoyoi er hsooia infiac,a h itntfeatures distinct the as significance, physiological bears exocytosis of mode the Choosing . 78,79 hs twspooe htceoie a ihreii itntsgasi MCs, in signals distinct elicit either may chemokines that proposed was it Thus, . β, hs ciiyi eurdfrtepopoyaino h NR rti SNAP23, protein SNARE the of phosphorylation the for required is activity whose 80 nlsso ci eragmnsfloigceoiesiuaino MCs of stimulation chemokine following rearrangements actin of Analysis . 4 71-76 80 . 77 Fgr 3). (Figure 84 n yegz ihsceaoust potentiate to secretagogues with synergize and 81-83 n opudexocytosis compound and 80 C hnetrasaei hc they which in state a enter then MCs . h eodi h ml TaeRab5, GTPase small the is second The . versus 85 . ertn MCs secreting 82 Fgr 3). (Figure 86 . Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. uha uhn,utcra irha n heigivligtoo oeognsses hr h etiology the where symptoms systems, and organ more signs allergic-like or two episodic involving such has wheezing with MCAS) and present degran- (Idiopathic diarrhea, who MC syndrome urticaria, individuals activation of flushing, for MC evidence as diagnosis idiopathic or identifiable such a term release no The as mediator is I). applied MC there (Table been through involved. where documented tissues anaphylaxis is in and activation ulation angioedema MC urticaria, where which types includes but cell etiology, category responses circulating in MC of early or, influx idiopathic The an The reaction with leakage. flare associated vascular later and If hours extensive inflammation. weal permeability. reaction and further vascular phase a promote hypotension late in include a severe increase mechanism. into an include skin, activating transition be and may often to the may secretion, results localized on mucus Symptoms the muscle, if depending systemic, smooth chronic degranulation, MRGPRX2. airway com- of or MC through with contraction of sporadic airways, MCs associated effects disease of diseases resultant immediate activation diseases, and The with allergic frequent association in to primarily in infrequent occurs and activation activation, MC plement secondary association for this or risk to higher Extrinsic contribute have may and tryptases symptomatic, heterotetrameric more containing are alpha-tryptase serum, in levels anaphylaxis tryptase severe irritable higher to and show up flushing by duplications cutaneous reported include multiple Symptoms and release population. mediator general syndrome MC the of bowel of suggestive 5% are to patients these up of affect two-thirds may which levels tryptase serum basal of triplications and duplications alpha- germline encoding either number expresses in copy resulting locus TPSAB1 increased One by caused (TPSB2). is It modulation production. tryptase pain mediator in influencing role and (H a tissues. MC play tryptasemia dermal also through resident alpha may migrating both It Hereditary parasite alert healing. a may wound friction sense ADGRE2 induces and help to that injury and perhaps are responses potential mechanoreceptor combat and possibilities MC a to limited understood, as cells completely the functions immune not of and ADGRE2 relevance is Thus, this physiological individuals normal the In areas. histamine in Although affected in matrix. increase degranulation. the and extracellular degranulation MC from MC the cutaneous by blood evidenced from venous is stimulus proteins the vibratory dominant with in a local after interactions autosomal MCs a of facilitating in to activation reactivity. domain case, response present tyrosine MC in extracellular is to manifestations an increased cysteine (ADGRE2) systemic with to from and nature E2 hives substitution frictional lead receptor localized of missense that by stimulus protein-coupled A characterized conditions G (VU) urticaria. urticaria genetic adhesion physical vibratory a heritable the as of in manifested number (pC492Y) is suggested. growing example been such has a One significance now uncertain of are disorder There of MC monoclonal presence two term and/or or the expression one activation, of MC CD25 evidence morphology, (MMAS) by MC syndrome demonstrated activation aberrant as cutaneous MCs including without clonal mastocytosis or the has for with anaphylaxis recurrent criteria disease with systemic minor patients a of as group A or reasons. for only, unidentified threshold for disease lowered or cutaneous venom a Hymenoptera as manifestations and to present or MCs exposure complaints may following of gastrointestinal Mastocytosis occur pruritus, growth may flushing, unrestrained with that present anaphylaxis both may systemic to most mastocytosis is with leads Mastocytosis Individuals This MCs. activation. tissue activation. of expansion gain-of-function MC involving acquired disease independent an clonal a with is associated It commonly compartment. MC the in defect KIT 86 on uain ycness uhptet r urnl adt aemncoa MC monoclonal have to said currently are patients such consensus, By mutation. point D816V 90 h Ctyts oii uasmyencode may humans in loci tryptase MC The . α:β 87 rpaegn aiso :,13o : ndffrn niiul.Rcn tde ugs that suggest studies Recent individuals. different in 2:2 or 1:3 0:4, of ratios gene tryptase . 91 92,93 lorpre r oncietsu bomlte n yatnma niiul with Individuals dysautonomia. and abnormalities tissue connective are reported Also . eetmcaitcsuishv eosrtdta nqeezmtcpoete of properties enzymatic unique that demonstrated have studies mechanistic Recent . 89 88 DR2(D1)blnst ag aiyo deinGCsgenerally GPCRs adhesion of family large a to belongs (CD312) ADGRE2 . ftemro nig r bevdi h bec feiec fsystemic of evidence of absence the in observed are findings marrow the If . α )i edla eei ri htbasmnina nrni othe to intrinsic as mention bears that trait genetic Mendelian a is T) α α- or rpaeaelne osbet ihdmnnl neie elevated inherited dominantly with subjects to linked are tryptase β- rpae hl h te ou a xrs only express can locus other the while tryptase, 5 KIT .86 isnevrat eutn nligand- in resulting variant, missense p.D816V α or β rpae TSB)and (TPSAB1) tryptases 94 . β- β tryptases tryptase, Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. eanval,adcnla oM ciain ste fe oi otM-rvndiseases. MC-driven untouched, most are in pathways only do Other that often is cells they down. limitation mast as shut The silence activation, is MC that one. Treatments degranulation to only and lead than activation can rather from and MC mediators protects viable, MC of approach remain pathways all this of many that effects is of pathways the one and therefore, receptors, and, are include signals, release ligands) MC-activating the These as their targeting well inhibit CU of that as primarily diseases. benefit diseases, C5a compounds The MC-driven MC-driven complement (or of for and compounds degranulation development inhibitory IL-5, symptoms and clinical receptors, IL-4, and activation in these IL-33, currently signs the of (TSLP), all of to lymphopoietin For development contribute stromal MRGPRX2. thymic the to for held to clinical receptors thereby, are in the and, receptors are and MCs omalizumab, signals than of activating IgE other to Several affinity higher with GI-301, and wheals development itchy ligelizumab symptoms, and including signs anti-IgEs, of development the patients CSU drive most to in held in is Fc chain, angioedema, via alpha MCs and its skin to of autoantibodies activation by the treatmentor (CSU), the urticaria for spontaneous development chronic under In currently are CU. GSK2646264 with inhibitor Fc patients SYK via the of induced as MCs BTK well of human Inhibitors as of (SYK). the degranulation Remibrutinib, kinase for the tyrosine Examples associated inhibit spleen Fc release. SYK and IgE, mediator or (BTK) for and kinase receptors tyrosine degranulation receptor Bruton’s and into affinity include activation signals latter high activating receptor the of translating example, inhibition in involved the for signals at include, aim These therapeutically 4). MCs (Figure patients target to in attempts symptoms recent and More (acting activation signs mediators cell of different mast development many inhibit the diseases. that release to Treatments MC-mediated contribute MCs other to Activated and prevents held receptor. mastocytosis it are i.e., urticaria, or that limitation, with mediator inherent receptors) an MC more in with even one comes tested receptors on of was its of effects antibody one anti-tryptase the or an mediator only Recently MC with one diseases. protease, target to MC-driven MC However, and of specificity, major treatment affinity, the the binding and studies tryptase, results, primate for inhibit their promising preclinical developed to in shown approach MC have being ones receptor new currently individual generation 4 a are of histamine first effects the compounds to on such the act superior several inhibit that are Antihistamines that receptor drugs profiles. leukotrienes 1 risk/benefit of and histamine development prostaglandins the the by with on followed ago, histamine, pathogenesis years first be- their 70 mediators, in allergies, play than and MCs more mastocytosis, that (CU), started, role urticaria critical chronic the for of developed cause primarily are treatments treatment MC-targeted of targets as mediators a cell in treatments Mast resulting cell-targeted should defect re- mast MC search may of intrinsic the activation development an However, MC The or that stimulus findings. possibility environmental or the clinical phenotype. endogenous including the MC secondary identified disorders hyperactive and of yet-to-be idiopathic Primary a causes these episode. to possible of an late etiology as with the tryptase eliminated serum for be continue as such must activation, disorders MC of MC marker serum or urinary unknown is 102 95 n rvnsM ciainb euigtelvl ffe g n Fc and IgE free of levels the reducing by activation MC prevents and igotcciei nld epnet nimdao hrp n neeaini validated a in elevation an and therapy anti-mediator to response include criteria Diagnostic . 103 . 98 h hrpui rai ntal eeeatm hr C r implicated are MCs where asthma severe initially is area therapeutic The . 100,101 ramn ihoaiua,a niIEatbd,i effective is antibody, anti-IgE an omalizumab, with Treatment . 6 65,96 ε h vlto fM-agtdtreatments MC-targeted of evolution The . I w T niios eertnband Fenebrutinib inhibitors, BTK Two RI. 104 97 ε oenathsaie htact that antihistamines Modern . . I ihrb g oautoallergens to IgE by either RI, ε I swl steintracellular the as well as RI, ε Iepeso.Newer expression. RI 99 . Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ute,i a endmntae htMshv eeca oei otoln atra laac and clearance bacterial controlling in role beneficial a have MCs that demonstrated been has it Further, osteoarthritis dissemination inflammation responses melanoma fracture-associated in allergic bone role in a MCs have can of MCs role of use essential the Cre the expected, expressing confirmed As by obtained. been generated has was vivoMCs affected) in these not MCs/basophils using were visualize By (CTMCs to baboon- for the MMCs tool of coding of elegant control gene numbers an the the under reduced as into with also genes line and protein mouse basophils fluorescent td-Tomato and red MCs element bright of enhancer and but IL-4 receptor MCs MC-specific DT of a the the absence of insert of complete control also essentially deletion to the was an under was for expressed to promoter used was led was Cpa3 basophils gene This system in receptor The Mcl-1. reduction recombination factor major Cre-LoxP Cpa3. a anti-apoptotic the in of to the which latter also levels for in the coding low strain basophils, gene mouse express of the a reduction basophils generate substantial that of to a showing depletion exploited to studies conditional also MCs to but with by genotoxicity, lead predominantly agreement Cre-mediated thus expressed to will gene due DT a apparently with Cpa3, mice for these promoter of treatment receptor; MCs DT Cre the strategy, of one expression In promoters. (DT) toxin MC-specific diphtheria with of that crossed control be ascertain for the promoter then under to the by expression challenging driven recombinase was been recombinase Cre therefore by driven has is it in of and (reviewed independent types, populations deficiency, cell other on other effects of number of a consequences by in expressed defects in MC-deficiency mutations also MCs, models, various such for to outline of due to factor generation was years first growth rat the the and throughout In utilized mouse settings. the pathological been have diverse in in mouse, MCs the of in contribution primarily the models, animal of function types cell Numerous KIT- mast oral levels. in study of tryptase efficacy to MC show serum development models systemic which and/or the Animal of MCs of for all in indicative Avapritinib, reductions Examples tryptase, and to CU. Midostaurin, linked plasma KIT, for Nilotinib, mastocytosis of of Imatinib, development suppression include domain under are treatments sustained dimerization currently SCF targeted and extracellular or is KIT profound the CDX-0159 target binds induce ablation. that specifically to Compounds mastocytosis which shown and numbers. CU CDX-0159, was MC including antibody reduced diseases MC-driven and the in apoptosis development inhibition example, clinical The MC survival. the to and for proliferation explored leads migration, currently SCF differentiation, MC or of KIT driver key of the is receptor CU. KIT The for development numbers under cell also mast reduce is LY3454738 that Treatments antibody urticaria, CD200Ra-targeted treatment cholinergic The the mastocytosis. dermographism, in anti- systemic results symptomatic Siglec-8-targeted promising and The CSU, showed and 4). omalizumab-refractory eosinophils) (Figure therapeutic omalizumab-na¨ıve depletes and CU and (and of activation for CD200Ra, development MC and inhibits under AK002 Siglec-8 currently body are including them receptors, engage MC that Inhibitory antibodies MCs. silencing thereby receptors ulation, inhibitory several express MCs β 109 hi fFc of chain naohrapoc,M ecec a copihdb netn r ne h oto fthe of control the under Cre inserting by accomplished was deficiency MC approach, another In . 121 Kit Kit ε n a eit h ermna mato mk opnnso shai features asthmatic on components smoke of impact detrimental the mediate can and I hc sepesdb aohl n C.Ti prahcnb sdfrdepletion for used be can approach This MCs. and basophils by expressed is which RI, idpnetmdl fM ecec,ipratisgtit h ilgclfnto of function biological the into insight important deficiency, MC of models -independent eet r nedepandb nipc nteM ih sopsdt off-target to opposed as niche MC the on impact an by explained indeed are defects R26 109 lentvl,temc a ecosdwt the with crossed be can mice the Alternatively, . DTA Kit ie edn ocntttv Cdfiinydet Cseicepeso of expression MC-specific to due deficiency MC constitutive to leading mice, aebe eeoe Tbe2.Teeicuemc hr Cdeficiency MC where mice include These 2). (Table developed been have , α- hms ee n rsigteet iewt oe leeo Mcl-1 of allele floxed a with mice to these crossing and gene, chymase Kit 111 119 euti nesnilycmlt bec fMs oee,KTis KIT However, MCs. of absence complete essentially an in result Cdpeinhsas enacmlse namdlweeteDT the where model a in accomplished been also has depletion MC . 105 n oehealing bone and 107,108 Mcpt5 hi iadeggmn niisM ciainaddegran- and activation MC inhibits engagement ligand Their . Kit 116 .T con o hs sus e os oeso MC- of models mouse new issues, these for account To ). eeseiclyepesdb TC.Teemc can mice These CTMCs. by expressed specifically gene a , uaeu lymphoma cutaneous , idpnetmuemdl o Cdfiinyhsfirmly has MC-deficiency for models mouse -independent Kit 7 ..tercpo o C.SneSFi nessential an is SCF Since SCF. for receptor the i.e. , 110,115 120 twsas eosrtdta C aggravate MCs that demonstrated also was It . 110 oevr eetsuishv hw that shown have studies recent Moreover, . hslast osiuieM depletion, MC constitutive to leads This . 117 iDTR olgnidcdarthritis collagen-induced , ie edn oMC-specific to leading line, 113 112 oercnl,a recently, More . nte strategy Another . 106 For . 118 122 114 , . . Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ct-r;RDACeepeso ne h oto fteMp5pooe;Cedie xrsino TCMsNo CTMCs DT of expression Cre-driven promoter; Mcpt5 the of control the under expression Cre Principle R-DTA Mcpt5-Cre; Constitutive designation Model, only 2 identified examples Table is diseases, stimulus cell-associated inciting mast no human When on # is Focus explanation. for MCAS) text (Idiopathic *See syndrome activation cell mast Idiopathic d. Urticaria c. Angioedema b. Anaphylaxis a. C5a) Idiopathic# (C3a, 3. activation complement with associated Diseases d. (CD64) receptor reactions IgG mediated affinity MRGPRX2 high c. the through activation cell Mast b. (Fc disorders Allergic a. (Extrinsic) Secondary 2. (HaT) tryptasemia alpha Hereditary d. (VU) urticaria vibratory dominant Autosomal (MMAS) c. syndrome activation cell mast Monoclonal b. Mastocytosis a. potential the diseases* (Intrinsic) has mediated Primary function. model cell MC 1. humanized mast human this study of Clearly, to Classification reactions tool mice. 1. valuable drug these Table highly cutaneous of a and marrow as anaphylaxis used bone inhibitor in BTK be the MCs a to NSG-SGM3), from of using e.g., developed or role therapies, the be “humice” new study of could (denoted evaluation to the mice used in also these been Fc but mainly In and human far of transplanting KIT so IL-3. by generation (co-expressing have accomplished and the MCs was GM-CSF in human This SCF, resulted mature MCs. have human human efforts IL2R- expressing by NOD-scid recent populated plasmids into above, is cells niche describe stem MC models hematopoietic the mouse which various in the mice to addition In example, For emerging. implied. challenged diseases has been autoimmune MCs deficiency has for of MC pathologies models for various models certain in mouse MCs in novel on of these based contribution of findings a use recent where the findings that previous note to some important is it However, by infection skin in seen was after healing wound promoting 118 I-needn osiuieadidcbemuemdl fM deficiency. MC of models mouse inducible and constitutive KIT-independent . ec,amr une iwo o C r novdi ahlgclstig scurrently is settings pathological in involved are MCs how of view nuanced more a Hence, . ε Kit Imediated) RI idpnetmuemdl o Cdfiinyhv usindterl fMCs of role the questioned have deficiency MC for models mouse -independent prtrxschenckii Sporothrix suooa aeruginosa Pseudomonas 110 γ -/- n obesity and ε 124 ie n hnpooigM rwhb administrating by growth MC promoting then and mice, I eedtce nmlil ise.Tee“humice” These tissues. multiple in detected were RI) 8 . infection 125 swl stepooe duatactivities adjuvant proposed the as well as , 123 hra ermna mato MCs of impact detrimental a whereas , 129 oevr ucinlhmnMCs human functional Moreover, . 126-128 , yeo CaetdBspisaetdRef affected Basophils affected MC of Type 109 Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. si osseti elhaddisease? lineages. and myeloerythroid other health and in trajectory consistent MC functions. the it distinct between Is relationship exhibit developmental waves the hematopoietic determine To different * from MCs if determine To * perspectives research cells Future mast 2 of Box development prenatal reactions the pseudoallergic into causing Insight receptor 2018 a venoms as and MRGPRX2 peptides of endogenous Identification detoxify 2015 proteases cell cells Mast mast 2006 human & for 2004 factor D816V maturation the and of growth Identification main 1995 the is SCF that Demonstration SCF 1992 of characterization and reactivity cloning cell Identification, mast 1990 affects system nervous central The 1989 IgE-receptor high-affinity the of cytokines Characterization secrete 1989 and express cells can mast cells from Mast released 1987 be to protease shown cell D2 mast Prostaglandin predominant 1982 the as tryptase demon- of cells was Identification marrow leukotrienes, 1981 bone be from to develop shown cells Mast later activation 1977 (SRS-A), IgE-receptor cells anaphylaxis after mast released of tissue be substance connective to reacting and strated Slow cells 1972 mast mucosal & i.e, 1970 heterogeneity, cell anaphylaxis mast in of cells Description mast 1966 of involvement the of Demonstration 1956 histamine contain cells Mast 1953 mastocytosis systemic of Description cells 1949 mast in Ehrlich present Paul is by Heparin cells 1937 different mast of from description tissues and connective Identification unstained 1878 in biology cells cell granulated mast identify of species Recklinghausen field von the Friedrich MC in 1863 mucosal-type discoveries MMC, milestone MC; tissue-type Major connective 1 CTMC, Box toxin; diphtheria DT, determined; not ND, Principle Mcl-1 Chm-Cre; Mcl-1 Cpa3-Cre; Cpa3 designation Model, ct-r;iT Trcpo xrse ne h oto fteMp5pooe TC No CTMCs administration DT after days 12 populations basophil of recovery depletion; Transient determined not MMCs CTMCs; element enhancer IL-4 MC-specific promoter a Mcpt5 of the control of the control under the expressed under receptor expressed DT receptor DT the control the under expressed protein fluorescent td-Tomato red bright and receptor DT mouse (RMB) basophil and cell mast Red iDTR Mcpt5-Cre; Mas-TRECK Inducible Cre+ “r-atr)Ceepeso ne h oto fteCa rmtrCMs+MC e ˜0 reduction) (˜60% Yes MMCs + CTMCs promoter Cpa3 the of control the under expression Cre (“Cre-Master”) fl/fl fl/fl “el it” c- eeinudrtecnrlo h p3pooe TC MsYs(6-0 reduction) (˜60-80% Yes MMCs + CTMCs promoter Cpa3 the of control the under deletion Mcl-1 Kitty”) (“Hello KIT 134 131,132 uaini ytmcmastocytosis systemic in mutation 133 c- eeinudrtecnrlo h baboon- the of control the under deletion Mcl-1 35 141,142 136,137 9 143,144 146 31,32 145 140 130 135 138,139 151 152,153 3 α- hms eeMC eue;CMsnra o determined Not normal CTMCs reduced; MMCs gene chymase 147-150 55,56 β hi fFc of chain ε I(sa)CMs Msntdtrie rnin elto;rcvr fbspi ouain 2dy fe Tadministration DT after days 12 populations basophil of recovery depletion; Transient determined not MMCs CTMCs; (Ms4a2) RI yeo CaetdBspisaetdRef affected Basophils affected MC of Type 111 110 113 109 112 114 Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. .MNi D udrP ekrS ta.Ietfiaino atcl-pcfi eetrcuilfrpseudo- for crucial receptor mast-cell-specific a of Identification al. et S, progenitor disease. Meeker reactions. cell and P, drug health mast Pundir allergic in human BD, importance McNeil for their 3. signal dispensable cells is Mast signaling DD. Metcalfe KIT Immunol MA, Clin Beaven al. A, Olivera et 2. J, Grootens M, signaling Ekoff their JS, development. or Dahlin receptors / 1. signals activating cell depletion. REFERENCES mast cell mast mediators, or cell receptors, either inhibitory development. mast modes, molecules, under target possible to have treatments three that cells in MC-targeted development the degranulate exocytosis. process can kiss-and-run 4: this by MCs During Figure or (3) (2). exocytosis tissue tissue compound the the exocytosis, into In full recruited by are (2). cell. and mast degranulation stream the premature blood of avoid Neu, the life granulocyte, entering monocyte, the Gr, are Mo, in (1) erythrocyte, decisions megakaryocyte; Fate Ery, hematopoietic MK, 3. eosinophil; represents from cell; Figure Eo, mast model paths MC, basophil; multiple landscape Ba, lymphocyte; are hematopoietic Ly, there The point. cell; neutrophil. which entry (B) stem lineage’s in hematopoietic controversial. each HSC, progenitors, is to of differentiating cells position model single The stem this of defined cells. in at continuum lineage-committed lost branch to a is cell potential cells lineage stem mast cell which hematopoietic the in from events, differentiation branching of along hematopoiesis. series checkpoints in 4) strict differentiation a interferons; as cell and proteins. hematopoiesis mast represents and representing factors mRNA Models growth miRNA, chemokines, 2. containing Figure cytokines, exosomes, synthesized TXA2 e.g., LTC4/D4/E4, novo vesicles, PGD2, sets de extracellular as such of of different mediators mediators release release heparin, release lipid releasing histamine, synthesized 3) by e.g., and newly 15-HETE; containing react of granules products and cells release of 2) mast release exogenous and cytokines; recognition degranulation and and Upon 1) proteases endogenous pathways: involved. several mediators. receptor recognize or one the of can through on release that dependent and mediators receptors pathways of of activation palette cell a Mast 1. to rat, contributions Figure and as functions such MC species which in legends other investigated. diseases), Figure also specifically specific be but for can better (mouse, disease be models and might deficient that health pig MC guinea KIT-independent and ferret new of MCs. Development target * selectively that drugs diagnosed be of and it Development can diseases * How MC mechanisms? the primary are beyond What (MCAS). treated? diseases syndrome and activation in cell mast mediators understand To their * and MCs of contribution mediators. allergy. the MC decipher of that To release mechanisms differential the * for define mechanisms to the and understand tissues To different * in heterogeneity MC of plasticity. understanding progenitor MC survival better MC regulate proliferation, a drive local get factors To chemotactic inflammation: * What of site inflammation? a of vivo? at site in MCs the recruitment in to increase recruitment an progenitor behind and/or mechanisms identify To * Blood 08 4() 381-93. 142(2): 2018; 07 3(6:1785-94. 130(16): 2017; Nature 05 1(52:237-41. 519(7542): 2015; 10 atcl rgntr Mp ntebn marrow bone the in (MCp) progenitors cell Mast xmlso ramnscretyunder currently treatments of Examples atclsaeedwdwith endowed are cells Mast A h relk model tree-like The (A) Allergy J Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 2 al J adni ,Ta .Ms el nIflmainadDsae eetPors n Ongoing and Progress Recent Disease: and maturity. Inflammation to in Cells infancy Mast From M. disorders: Tsai cell N, Concerns. Gaudenzio Mast and SJ, PD. Galli Disease Arkwright 22. of S, Drivers Bulfone-Paus as R, Cells Bahri Mast Allergy M. A, Maurer Wilcock BF, 21. Gibbs SC, Bischoff FA, Targets. cell Redegeld Therapeutic mast activation. F, a their Siebenhaar exhibit promote vesicles 20. and extracellular cells, Mastocytosis-derived al. stellate E10692-E701. et to 115(45): HD, KIT Komarow transfer YE, cells. signature, Cho mRNAs between of exchange DK, transfer genetic Kim Exosome-mediated of JO. 19. by Lotvall mechanism JJ, mediated novel Lee is a M, activation is Sjostrand lymphocyte microRNAs A, T Bossios of and and K, Modulation Ekstrom B H, cell-dependent the Valadi Mast 18. in exosomes. al. active et Signaling immunologically I, FcepsilonRI of Villa secretion S, R. Panse the Paolini Le A, D, Skokos Exosomes. Santoni 17. Cell-Derived ND, Mast Milito of Role R, pathways Response: Molfetta secretory Allergic the M, and Lecce release differential 16. their factors. mediators: growth cell and Mast chemokines, M. Kulka cytokines, involved. AD, of Befus sources TC, as Moon cells 15. Mast SJ. Galli H, Saito Rev M, Immunol regulation. Tsai autocrine K, and Mukai paracrine 14. reciprocal of system a mediators: Rev eicosanoid and Immunol cells battle. Mast for JA. Boyce armed 13. granules: secretory Products. cell Pathogen Mast and G. Viruses 478-94. Pejler to S, Responses Wernersson Cell 12. Mast Sci E. Mol Leong Exposure J 33 L, Interleukin Int Portales-Cervantes Prolonged JS, and Acute Marshall allergy. of 11. Effects in Divergent Functions. al. IgE-Mediated Interleukin-33 et Cell C, S. Mast Ceriol Nakae on A, Ghaib K, E, Matsumoto Ronnberg 10. K, Mast Arae Skin Human H, in Morita 1203-14. IL-33 T, of Yin-Yang Ohno Activation. T. 9. p38 Zuberbier through M, Synthesis Artuc Histamine S, Reco- Augmented Guhl the matol but K, through Degranulation, Franke Injury Reduced Z, Cell Cells: Wang to M, Respond Babina Cells 8. Mast G. Nilsson IL-33. M, of gnition Enoksson C, Lunderius-Andersson cell- 7. mast on X2 receptor allergies. dermatological protein-coupled diseases. G K inflammatory Mas-related chronic 6. of and from Roles Insights reactions, H. drug Hypersensitivity: Ali pseudoallergic Drug Immunol K, defense, Immediate Gupta host and H, MRGPRX2 mediated Subramanian al. et 5. MA, Faber Cells. V, Mast Human Sabato Cultured J, Elst 4. h ,KlhrP aiaM ta.MsrltdGpoenculdrcpo 2adisatvtr in activators its and X2 receptor protein-coupled G Mas-related al. et M, Babina P, Kolkhir K, uhn ¨ 09 3() 562 e3. 1516-25 139(7): 2019; 09 41:53-63. 74(1): 2019; rn Immunol Front 06 3() 700-10. 138(3): 2016; nuRvImmunol Rev Annu 08 8() 121-50. 282(1): 2018; 168-85. 217: 2007; 09 20(17). 2019; rn Immunol Front rnsImmunol Trends leg lnImmunol Clin Allergy J 04 :569. 5: 2014; ora fivsiainlalrooy&ciia immunology clinical & allergology investigational of Journal 00 8 49-77. 38: 2020; 02 :120-30. 3: 2012; rn Immunol Front 08 92:151-62. 39(2): 2018; 00 c 5 pbaedo print. of ahead Epub 15, Oct 2020; Immunol J 11 09 0 1361. 10: 2019; n o Sci Mol J Int 01 6() 868-76. 166(2): 2001; 00 21(15). 2020; a elBiol Cell Nat rcNt cdSiUSA S U Sci Acad Natl Proc a e Immunol Rev Nat Allergy 07 () 654-9. 9(6): 2007; 00 0. 2020: leg Clin Allergy J netDer- Invest J 02 67(10): 2012; 04 14(7): 2014; 2018; Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 2 isebu S o P eeeT otrB ct M ecleD.Dmntainta human aminopeptidase that expresses and Demonstration c-kit(+), DD. CD34(+), Metcalfe is LM, that Scott population granulocyte cell B, and progenitor Foster (CD13). cell a T, N from mast Semere arise Distinguishing JP, cells SJ. Goff mast AS, Galli Kirshenbaum IL, 42. Weissman M, level. single-cell Drukker the CC, at Chen differentiation erythroid and CB, haematopoietic Franco early 41. predict snapshots Population al. et C, cell. Weinreb hierarchies. precursor SL, Wolock cell/erythrocyte BK, Tusi mast 40. erythro- bipotent and a mastocytosis e1008579. by spiralis-induced Trichinella 16(5): supported al. 2020; lineages et simultaneously EK, cell are Henry basophil/mast CM, poiesis the Hernandez of JM, checkpoints Inclan-Rico Developmental 39. al. Hematopoietic et Reveals hematopoiesis. MF, Mouse murine Gurish Reporter adult H, Protein in GATA2 Iwasaki Novel Y, A Arinobu Stable al. 38. Occupy et Cells PS, Mast Types. Hoppe A. Cell L, Roers Progenitor Kunz A, N, Gerbaulet Ahmed T, 37. Skin. Zerjatke Steady-State A, Adult Dudeck marrow in bone Territories R, grafted Clonal Naumann from A, cells mice. Weitzmann mast of 36. of Development sac Y. yolk mice. Miyano the irradiated K, Hatanaka in in M, cells precursors Shimada cell Y, mast Kitamura of 35. Presence Erythro- Y. cells. Late Kitamura 89-94. mast 97(1): C, from of 1983; Hayashi origin Originate the T, Cells into Sonoda Mast insights 34. New Tissue-Resident JS. Connective Dahlin Adult G, al. Nilsson 33. et J, Xu S, Progenitors. Developmental Liu Myeloid Dual Reveals Z, Mapping Li Fate Endothelial 32. Hemogenic al. health. Cells. et of Mast G, of protectors Hoeffel Origin C, as Ghigo cells R, Mast Gentek al. 31. et O, infections. Goldmann S4-S18. fungal 144(4S): M, in 2019; Koberle cells A, mast inflammation. Dudeck of in 30. role control complex of The Points C. M. Nathan Maurer 29. Z, Zhao J, Immunity. Scheffel Infection Y, Fungal Dermatol Luo and Q, Bacterial, Jiao Viral, infections. 28. in Cells viral Mast Sci during NJ. Mol cells Shubin J mast M, Int Acharya for AM, roles Piliponsky pathogenic 27. and disease. Protective lung AL. in Immunol John activation Opin St their AP, and Rathore cells 26. Mast P. Biology. Bradding Cell G, Mast Arthur 60-76. in H, Needs Future Virk SJ. 25. Galli G, Cardio- Marone in A, Cells Paulis 20(18). Immune de Underappreciated G, Varricchi Cells: 24. Mast Cardiac Disease. PT. and Kovanen Homeostasis G, vascular Marone G, Varricchi 23. 09 87:749-55. 28(7): 2019; Blood Nature 09 20(12). 2019; 00 6 74-81. 66: 2020; 99 47:2333-42. 94(7): 1999; 08 5(64:54-60. 555(7694): 2018; Immunity Immunity tmCl Reports Cell Stem Nature rcNt cdSiUSA S U Sci Acad Natl Proc 97 6(69:442-3. 268(5619): 1977; 08 94:605 e5. 640-53 49(4): 2018; 08 86:16-1e5. 1160-71 48(6): 2018; rnsImmunol Trends elSe Cell Stem Cell 00 52:326-39. 15(2): 2020; netDermatol Invest J Nature 00 18:734-46. 41(8): 2020; 00 () 361-8. 6(4): 2010; 12 02 2:846-52. 420: 2002; 05 0(0:18105-10. 102(50): 2005; 2020. Allergy 09 44:844-5. 74(4): 2019; leg lnImmunol Clin Allergy J rnlRes Transl n o Sci Mol J Int LSpathogens PLoS 06 174: 2016; e Biol Dev 2019; Curr Exp Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 2 neso K oiM jre ,LfalC,Ejfl S oe ieSeicMs elSubpopulations Cell Mast Site-Specific Novel JS. Lung. Erjefalt CG, Human Lofdahl the L, in mucosal Bjermer to M, Mori progenitors mice. CK, cell Andersson in mast 62. of inflammation Maturation pulmonary MF. allergic Gurish during KF, Austen cells AY, constitutive mast Liu and DF, Dwyer inducible and LG, of Bankova IgE-dependent regulation 61. inflammation. to Lineage-specific airway al. response allergic et in in N, release cells Hallen colon Histamine mast SK, and Samuchiwal heterogeneity: T, tonsils, cell Derakhshan adenoids, 60. mast lung Human skin, MK. from Church stimuli. dispersed RC, nonimmunologic Benyon cells PH, mast Rees from MA, cells Lowman mast normal have59. of that characterization cells sites. immunohistochemical mast body and human multiple Ultrastructural of at KF. types Austen Two N, Weidner LB. Schwartz 58. G, DeBlois compositions. SS, protease Craig neutral NM, distinct Schechter AA, Irani 57. Scand Microbiol Pathol Acta Enerb 56. 289-302. 66: 1966; haematopoiesis. liver Enerb fetal 55. human Decoding al. resolution. et E, single-cell 365-71. Stephenson at 574(7778): RA, development Botting macrophage DM, human Popescu Deciphering 54. al. et T, Huang Y, Nature Gong Z, human Bian of pathways 53. distinct two of Identification C. Nerlov distinguishes K, Theilgaard-Monch myelopoiesis. CD203c S, JS. Thongjuea R, marrow Dahlin Drissen bone 52. G, FcepsilonRI(+) Nilsson human K, among Levedahl trajectories differentiation Hamberg cell-basophil progenitors. C, mast Wu and JS, erythroid the Ungerstedt J, Grootens and 51. C/EBPalpha landscapes differentiation. transcriptional factors during on fate tracing transcription Lineage to the AM. state Klein by FD, links Camargo regulation A, Rodriguez-Fraticelli Antagonistic C, Weinreb fates. al. 50. cell et mast L, and map Chaves basophil high-resolution J, specifies a Hong MITF provides X, profiling lineage Qi molecular 8 Single-cell 49. development. al. resolves cell et landscape mast I, and hematopoietic Kucinski basophil WWY, single-cell of Lau A FK, al. Hamey mice. et 48. mutant B, Kit in Pijuan-Sala defects FK, and landscapes. Hamey trajectories differentiation JS, complex Dahlin to 47. cells stem haematopoietic 418-26. From hema- 553(7689): B. from 2018; Gottgens trajectory E, differentiation Laurenti the 46. Deciphering cells. JS. mast Dahlin to in G, cells progenitors Nilsson stem cell JS, topoietic mast Ungerstedt of J, Identification Grootens deep-CAGE SJ. 45. by Galli transcriptome IL, Weissman cell M, mast Tsai mice. human MA, adult the Grimbaldeston of CC, Redefinition Chen 44. al. et Y, Ishizu S, sequencing. Guhl E, Motakis 43. 00 8(83:571-6. 582(7813): 2020; c .Ms el nrtgsritsia uoa .Eet ffixation. of Effects I. mucosa. gastrointestinal rat in cells Mast L. ¨ ack c .Ms el nrtgsritsia uoa I y-idn n eahoai properties. metachromatic and Dye-binding II. mucosa. gastrointestinal rat in cells Mast L. ¨ ack rcNt cdSiUSA S U Sci Acad Natl Proc Blood Allergy c Immunol Sci 04 2(7:e58-67. 123(17): 2014; 00 51:211-4. 75(1): 2020; Thorax netDermatol Invest J leg lnImmunol Clin Allergy J 09 4(35). 2019; 09 4 297-305. 64: 2009; 96 6 302-12. 66: 1966; lo Adv Blood rcNt cdSiUSA Sci Acad Natl Proc 05 0(2:11408-13. 102(32): 2005; Allergy Science 91 63Spl:2S3S icsinS1,60S-5S. S-1S, discussion 26S-30S; Suppl): 96(3 1991; x Med Exp J 08 (7:2273-81. 2(17): 2018; Blood Immunity 00 c 0 pbaedo print. of ahead Epub 30, Oct 2020; 00 367(6479). 2020; 98 150:590-7. 81(590): 1988; 08 3(1:e1-e11. 131(21): 2018; 13 01 218(1). 2021; 03 91:97-110. 39(1): 2013; uoa Immunol Mucosal 96 346) 4464-8. 83(4464): 1986; 05 () 596-606. 8(3): 2015; caPto irbo Scand Microbiol Pathol Acta Nature Nature 2019; Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 1 ikt A dado M opudeoyoi:mcaim n ucinlsignificance. functional and mechanisms exocytosis: 109-16. Compound 7(2): JM. Edwardson JA, Pickett (mDia1) activity.81. 1 actin-nucleating formin its diaphanous-related through 1074-90. Mammalian secretion 144(4): al. and prostaglandin 2019; et migration for P, cell required Lazki-Hagenbach mast mechanisms RA, coordinates signaling Krier-Burris production. O, and IL-6 Klein Receptors and 80. 1 al. degranulation receptor et cell chemokine LP, mast CC Audoly of not and regulation M, FceRI E2-mediated do Solle of M, but engagement Nguyen of migrate, 79. Impact motility. cells al. and mast et activation T, murine cell Nakamura mast marrow-derived M, on Bone Dawson M, al. Toda et 78. N, chemokines. to Inamura response in- J, in through Dastych degranulate, migration D, cell Taub mast CCR4. 77. CCL5/RANTES-induced and Selective CCR1 G. receptors Nilsson chemokine with N, chemotaxin. teractions cell Olsson mast M, a Juremalm is as CXCR4 76. acts receptor SDF-1a chemokine ligand The its G. 3614-22. and Nilsson 30: lineage K, Nilsson 2000; cell I, mast Harvima the through N, within mediated Olsson expressed is M, IL-8 Hjertson to M, response Juremalm migratory 75. cell CXC-2/IL-8RB. Mast DD. receptor Taub chemokine DD, with Metcalfe interaction J, Mikovits G, Nilsson cells. 74. mast by expression receptor Chemokine G. 130-44. Nilsson M, pathways. signaling Juremalm and 73. chemoattractants and - CCR1 chemotaxis cell of Mast P. Expression Draber Immunol Localization-Specific L, Draberova J. I, Halova Hallgren 72. J, Progenitors. Ungerstedt Cell Mast JS, by Dahlin CCR5 M, maturation. Salomonsson and 71. trafficking progenitor cell biology (alpha4beta7 Mast and CD49dbeta7 MF. dicine require Gurish progenitors J, cell Hallgren mast 70. Intestinal al. et homing. JP, tissue-specific Abonia for blood H, integrin) human Tao in MF, cells progenitors. Gurish FcepsilonRI+ cell CD117int/hi 69. mast CD34hi of Lin- al. population et rare H, a Ohrvik Proteome constitute A, Cell Malinovschi Mast JS, Dahlin Human Ablation. 68. HR. Cell Rodewald for TB, Basis Feyerabend Structural e5. J, and Functions, Krijgsveld 404-16 consti- Putative M, of Lineage, Rettel Unique profiling system. X, Reveals immune Expression Wang the T, C. within Plum Project identity 67. Genome unique Immunological a KF, reveals cells Austen mast NA, tutive Barrett DF, Wallenberg from Dwyer Marcus Highlights (EMBRN)-A function: 66. Network basophil Research and Basophil cell and mast Cell of Mast aspects European Novel Symposium. the al. of et meeting M, 9th Maurer the L, progenitor. Hellman circulating J, common Hallgren a 65. from populations arise cell cells Immunol mast mast Clin Human lung Allergy PT. Kovanen in J J, Alterations Lappalainen JS. K, Maaninka Erjefalt disease. 64. CG, pulmonary Lofdahl obstructive chronic L, with Bjermer patients M, in Mori CK, Andersson 63. 02 :119. 3: 2012; Allergy 01 1:14-28. 716: 2011; 00 53:707-8. 75(3): 2020; 03 3() 6- e3. 463-9 132(2): 2013; rn Immunol Front x Med Exp J h ora fbooia chemistry biological of Journal The Immunol J 01 9() 1243-52. 194(9): 2001; 00 1 321. 11: 2020; 95 5:2393-402. 154: 1995; 14 Blood Blood ice ipy e Commun Res Biophys Biochem mJRsi rtCr Med Care Crit Respir J Am 99 3 2791-7. 93: 1999; 06 2() 383-91. 127(4): 2016; a Immunol Nat 04 7(6:48443-8. 279(46): 2004; Immunol J hmImnlAllergy Immunol Chem dacsi xeietlme- experimental in Advances leg lnImmunol Clin Allergy J 02 6() 4586-93. 169(8): 2002; 06 77:878-87. 17(7): 2016; Immunity 00 8() 206-17. 181(3): 2010; 02 9() 480-5. 297(3): 2002; u Immunol J Eur Traffic 00 52(2): 2020; 05 87: 2005; Front 2006; Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 0.Atihe ,ZmeiV lrc ,ZagK hrhM,Mue .IMadIAi diinto addition in IgA and IgM M. Maurer chronic of MK, markers Church disease with K, associated Zhang and urticaria. frequent A, spontaneous are Ellrich FcvarepsilonRIalpha against V, autoantibodies Zampeli IgG S, Altrichter Update (CIA) 101. Allergologicum Internationale Collegium Urticaria: al. asthma. of et in Treatment S, 2020. proteases Eyerich the K, cell Eyerich for mast M, Maurer of Antibody 100. role Anti-tryptase emerging Allosteric The An G. Pejler al. 99. et DF, Asthma. Choy Severe novel JK, Cell-Mediated for Jackman Mast basophils HR, and Maun cells 98. mast Antihistamines. M. on Maurer targets MK, Molecular Church al. 97. et P, Draber F, Mast therapies. Suspected Levi-Schaffer with IT, Patients Harvima for Algorithm 96. Diagnostic Proposed al. heterote- et Syndrome. P, alpha/beta-tryptase Activation Bonadonna human Cell for C, forming Akin biomarker naturally P, Valent of genetic alpha-tryptasemia. 95. Impact hereditary valid al. of a et pathogenesis is AN, the Naranjo tryptasemia in JJ, tramers alpha Lyons Hereditary QT, Le al. 94. et mastocytosis. A, in Gorska symptoms B, mediator-related Sprinzl severe G, Greiner 93. increased with associated TPSAB1. anaphylaxis severe at for print. number risk Heritable copy al. germline et disorder MP, in alpha-tryptase-encoding Variability O’Connell multisystem J, and Chovanec Prevalence JJ, a UK Lyons Alpha-Tryptasemia: 92. identifies Hereditary tryptase al. et serum H, basal Expression. Bonin A, Disease Elevated Wilcock al. RC, Robey et 91. number. JD, copy Hughes TPSAB1 increased X, with Yu ADGRE2. associated in eds. JJ, Variant Missense al., Lyons a with et 90. Associated FR, Urticaria Med Vibratory Applebaum al. J DA, et Engl G, Arber Cruse N A, JP, 1793-808. Desai 2019: Greer SE, Boyden Kluwer Mastocytosis: In: Wolters 89. of Philadelphia: mastocytosis. Treatment edition Systemic Fourteenth and Hematology, J. Classification Clinical Gotlib Wintrobe’s the DD, in Metcalfe Advances Future. al. 88. the et toward K, Outlook and Hartmann criteria. Status C, Current diagnostic Akin during Proposed P, fusion syndrome: Valent activation granule-granule 87. cell regulated Mast SNAP23 DD. for Metcalfe Immunol critical P, Clin Valent is C, Rab5 on Akin al. impact 86. et granules: secretory N, cell Zur mast A, exocytosis. of Roded compound regulator novel O, a Klein is 85. Rab5 al. et exocytosis. A, and Efergan cargo, N, size, Zur SNAP-23 NP, of Azouz Phosphorylation PA. 84. Roche SW, cells. Whiteheart degra- mast GL, cell from Crawford mast AC, exocytosis Hohenstein distinct regulates N, induce Puri signals R, activation Hepp 83. Different al. et T, Marichal strategies. R, nulation Sibilano N, Gaudenzio 82. n rhAlryImmunol Allergy Arch Int leg lnImmunol Clin Allergy J 00 2() 0914e4. 1099-104 126(6): 2010; 06 7() 656-63. 374(7): 2016; lnInvest Clin J leg lnImnlPract Immunol Clin Allergy J c Rep Sci Allergy leg lnImnlPract Immunol Clin Allergy J Immunol J 00 oln ha fprint). of ahead (online 2020; 07 () 15315. 7(1): 2017; 00 8() 321-33. 181(5): 2020; 06 2(0:3981-98. 126(10): 2016; 04 3() 530-44. 134(3): 2014; Cell h ora fbooia chemistry biological of Journal The 04 9() 4043-53. 192(9): 2014; 09 7() 1-1e19. 417-31 179(2): 2019; hmImnlAllergy Immunol Chem acrRes Cancer a Genet Nat 2020. Blood 15 09 () 153 e1. 1125-33 7(4): 2019; 2020. 07 76:1261-70. 77(6): 2017; leg lnImmunol Clin Allergy J 06 81) 1564-9. 48(12): 2016; x Med Exp J u eprJ Respir Eur 04 0:302-10. 100: 2014; 05 8() 6610-20. 280(8): 2005; 09 1(0:2348-61. 216(10): 2019; 09 54(4). 2019; 00 nieaedof ahead online 2020; Allergy J Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 2.Wn ,LpsC,RguH ta.IEmdae atcl ciainpooe namto and inflammation promotes activation cell-deficient cell mast mast IgE-mediated in al. repair et bone H, osteoarthritis. Raghu Defective in CM, destruction al. cartilage Lepus et Q, Wang R, 121. Fracture-Induced Samberg Bone of D, Regulators Chan mice. Critical Cpa3Cre/+ JL, Are Cells Ramirez-GarciaLuna Mast 120. arthritis al. Activity. et antigen-induced and Formation J, cell-driven Osteoclast Kemmler T and A, Inflammation of Kovtun bypassed. J, promotion are Kroner cells cell 119. T Mast which al. in arthritis et 903-13. cuta- 67(4): P, antibody-induced primary 2015; for Liu in dispensable J, role being protumorigenic Dudeck despite a N, play Schubert cells Mast 118. lungs. al. of et colonization LC, Heukamp melanoma lymphoma. M, promote the neous Schlaak cells initiate A, Mast cells Rabenhorst al. 117. Mast et A. I, Dudeck Waern 68990-9001. M, S, 7(42): 2016; Grujic Drube H, J, stress. Ohrvik Dudeck cell 116. sensing HJ, by Mucosal allergens Edler of contact Numbers K, to Reduced response Katsoulis-Dimitriou vascular Exhibit A, Mice Mcl-1(fl/fl) Hoppe Chymase-Cre; 115. al. et Q, macrophage Jiao Cells. peritoneal N, inhibiting Mast Meyer by Y, sepsis aggravate Luo cells 114. dendritic Mast al. skin et and T, cells Attout mast G, phagocytosis. between Gautier interaction A, of Dahdah Requirement 113. al. hypersensitivity. et Cpa3-Cre; contact T, in establish Honda function to M, and cells numbers Kubo basophil A, and Otsuka cell 112. mast Reduced al. in et contribution K, mice. Mukai cell Mcl-1fl/fl CC, mast Chen contests JN, ablation Lilla autoimmunity. cell 111. cell-mediated Cre-mediated T the al. and mediate et that antibody- A, allergy of Tietz contact models A, of Weiser promoters TB, key Feyerabend are 110. cells Mast al. haptens. et of J, vivo. effects Scholten in adjuvant J, functions Dudeck cell A, mast Dudeck fiction? analyzing 109. for or models fact New 613-25. SJ. cells: 33(12): Galli mast T, 2012; Marichal of LL, Reber functions From 108. system: immunological cell Widespread and TB. lineage Feyerabend hematologic in Immunity unique HR, CD30 a Rodewald of cells, relevance Mast 107. vivo al. medicine. In et precision P. K, to Fabbri Hartmann Ehrlich A, C, Paul Amedei Akin P, M, Valent Carli urticaria. 106. De chronic MM, for D’Elios treatments B, dermatitis. New atopic Bianchi M. M, Maurer Caproni T, 105. Hawro M, Munoz Immunol S, Asthma Urticaria. Allergy Altrichter Spontaneous P, Chronic for Kolkhir Ligelizumab 104. al. et G, Med Sussman J AM, spontaneous Engl Gimenez-Arnau or idiopathic M, chronic Maurer of treatment 103. the for Omalizumab al. et HJ, Hsieh urticaria. K, Rosen M, Maurer 102. nlJMed J Engl N 02 71:13-24. 37(1): 2012; rn Immunol Front 09 8(4:1321-32. 381(14): 2019; lnInvest Clin J Blood Blood lSone PloS Allergy 01 1(6:6930-8. 118(26): 2011; 02 2(0:2042-54. 120(10): 2012; 03 6(0:924-35. 368(10): 2013; 00 2() 2-12. 124(1): 2020; 97 2 1063-70. 52: 1997; 09 0 2399. 10: 2019; 04 2(0:4577-89. 124(10): 2014; Immunity 07 23:e0174396. 12(3): 2017; Theranostics Elife 01 46:973-84. 34(6): 2011; lSone PloS 09 8. 2019; 00 02) 10743-68. 10(23): 2020; 01 () e25538. 6(9): 2011; 16 oeMnrRes Miner Bone J Immunity leg lnImmunol Clin Allergy J 01 55:832-44. 35(5): 2011; 07 21) 2431-44. 32(12): 2017; 00 4() 469e3. 1476-9 145(5): 2020; rhii Rheumatol Arthritis rnsImmunol Trends Oncotarget Ann N Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 4.BonM,Pec H asnC,FloJ heJ,Pu E elsiuaoyfactor-1/interleukin-4 stimulatory cells. cell B mast WE. transformed Paul and JN, normal Ihle by J, Falco expressed CJ, is Watson mRNA JH, anti-IgE. Pierce generation with MA, D2 cells Prostaglandin Brown mast 2nd. 141. LJ, human Roberts and JA, rat Oates KF, of of Austen activation granules PT, after Diamond secretory NA, from Soter tryptase RA, Lewis and 140. hydrolases and Acid cells. Purification KF. mast cells: Austen lung D, mast human Seldin dispersed pulmonary RA, Lewis human LB, from Schwartz 139. Tryptase anaphylaxis KF. of Austen substance RA, reacting Lewis characterization. slow LB, and cells. Schwartz histamine mast 138. of monkey Release on reactions H. Tomioka IgE-anti-IgE by K, (SRS-A) Ishizaka T, Ishizaka lung. 137. monkey from the (SRS-A) mediate anaphylaxis to guinea of E the immunoglobulin substance 335-43. human reacting of 104(2): of slow capacity cells and The mast histamine KF. of Austen the RP, release on Orange K, 48/80 Ishizaka T, compound Ishizaka and 136. shock anaphylactic of Effects lung. cells. I. pig mast Vugman tissue I, in Mota histamine of 135. autopsy. presence The with GB. case West a JF, mastzellen of Riley lichschen report 134. - a ehr pigmentosa; Urticaria der JM. funktion Ellis und 133. chemie in der und kenntnis Forsch gefasswanden zur -anat den Beitrag mikr in O. Ztschr Wilander heparin van H, vorkommen Holmgren 132. das Ueber O. Wilander augen. H, den Holmgren JE, Jorpes 131. tyrosine1878. Beitr Bruton’s P. BS. Ehrlich Bochner 130. PA, anaphylaxis. Robida IgE-mediated BJ, human Undem against 4759-70. KD, protects mouse Chhiba effectively humanized RA, inhibition A Krier-Burris kinase HC. MC, Oettgen LB, Dispenza Schwartz 129. KJ, cuta- allergy. Koleoglou passive peanut JM, anaphylactic cell-mediated Tamayo of mast AJ, model of Stranks model OT, mouse Burton Humanized 128. anaphylaxis. al. systemic mediated et passive cells LL, and mast Kenney anaphylaxis study R, neous to Falahati model PJ, mouse Bryce humanized 127. A al. reactions. et KSM, drug Yong adverse M, cutaneous Gunawan Resistance. A, Deficiency, Insulin Mencarelli Kit and 126. Obesity Hematopoietic from HR. Mice Infection. Rodewald Protects schenckii S, Cells, Sporothrix Herzig Mast 678-91. to of TB, Lack Feyerabend Contribute than S, Cells rather Muralidhar Mast DA, Skin the Gutierrez al. controlling 125. et for J, critical Scheffel are Y, cells Luo Immunol Mast Q, wounds. Jiao al. infected 124. et of VA, healing the Gimenez-Rivera model and D, asthma burden mouse Troeltzsch bacterial a C, exacerbate can Zimmermann component 123. smoke Thirdhand SJ. Galli cells. M, mast Tsai through K, Mukai M, Yu 122. Nature 00 1 469. 11: 2020; tcrmk aa Forsch -anat mikr Ztschr 96 7(55:427-9. 177(4505): 1956; ilChem Biol J leg lnImmunol Clin Allergy J g u hoi n rxsdrHsooice F Histologischen der Praxis und Theorie zur ¨ age 97 2 242-78. 42: 1937; 91 5(13) 11939-43. 256(11939): 1981; Immunol J ekcBiol Leukoc J 97 2 279-301. 42: 1937; leg lnImmunol Clin Allergy J 08 4() 682 e9. 1618-27 142(5): 2018; 91 2:1290-4. 126: 1981; 00 0() 797-807. 107(5): 2020; 17 rcNt cdSiUSA S U Sci Acad Natl Proc leg lnImmunol Clin Allergy J Immunol J Immunol J Cell 07 3() 1-2e9. 314-22 139(1): 2017; 97 0 809-18. 50: 1987; rhPto (Chic) Pathol Arch hso (London) Physiol J 92 0() 513-20. 108(2): 1972; rug epi:LizgUniversity; Leipzig Leipzig: ¨ arbung. 92 2() 1627-31. 129(4): 1982; 06 3() 769-79. 138(3): 2016; lnInvest Clin J 09 1(1:20500-4. 116(41): 2019; elMetab Cell 99 85:426-35. 48(5): 1949; 93 2:528-37. 120: 1953; Immunol J 00 130(9): 2020; 05 21(5): 2015; Front 1970; Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 5.Mt ,Plpnk M hnC,e l atclscnehnerssac osaeadhoneybee and snake to resistance enhance can cells Mast endothelin-1- al. limiting et by CC, homeostasis Chen promote AM, cells Piliponsky venoms. Mast M, al. Metz et 153. of an domain M, with catalytic Metz mastocytosis the J, toxicity. have in Wedemeyer induced who mutation M, patients point Maurer of a 152. cells of mononuclear Identification blood blood al. disorder. cord peripheral et hematologic umbilical in associated CK, from c-kit Oh cells protooncogene AS, mast Worobec the human H, of Nagata ligand. Development c-kit 151. al. murine et and AM, human recombinant Dvorak long- by T, in cells Furitsu factor/kit-ligand H, cell Mitsui stem 150. human recombinant by cells culture. mononuclear cells. term blood progenitor stem peripheral pluripotent and and CD34+ IL-3 marrow from Spanbl of P, cells Effect Valent mast DD. 149. and Metcalfe basophils KM, human Zsebo of JM, apperance Mican Immunol the SW, on Kessler factor differentiation JP, stimulates cell Goff factor cells. AS, cell liver Kirshenbaum stem fetal human 148. human Recombinant dispersed al. from et U, cells Miettinen mast G, of factor. mucosal Nilsson growth rat AA, multipotent of Irani new 147. conditioning defines Pavlovian locus J. Steel II. ON. Bienenstock protease Witte S, cell 146. mast Siegel rat M, secrete Perdue to immunoglobulin J, cells human Marshall mast of G, binding high-affinity MacQueen of trans- 145. Expression in JP. expression Kinet cells. and H, transfected structure Metzger by Complete U, E JP. Blank Kinet L, H, Miller receptor. Metzger 144. IgE K, affinity White high L, of Miller cells C, fected Ra of factor. U, characterization Blank necrosis and 143. tumor purification, to Identification, SJ. related Galli factor ZA, cytolytic 9175-9. Cohn cell-associated G, Butler mast C-C, a Liu J-E, Young 142. Science 92 4:772-7. 148: 1992; Blood 06 1(76:526-30. 313(5786): 2006; Nature 92 023) 2237-45. 80(2237): 1992; clE pr R ta.Idcino ieetaino ua atclsfo bone from cells mast human of differentiation of Induction al. et WR, Sperr E, ¨ ochl Science 04 3(06:512-6. 432(7016): 2004; 99 4(92:334-7. 244(4902): 1989; rcNt cdSiUSA Sci Acad Natl Proc Nature Science 99 3(23:187-9. 337(6203): 1989; Blood 18 rcNt cdSiUSA Sci Acad Natl Proc 99 4(87:83-5. 243(4887): 1989; 95 2 10560-4. 92: 1995; 92 030) 3009-21. 80(3009): 1992; Cell 90 31:5-6. 63(1): 1990; rcNt cdSiUSA Sci Acad Natl Proc 93 075:735-9. 90(735): 1993; 97 84: 1987; J Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. eitr,eg e.g. Mediators, gaue . . μm) 0.8 - 0.2 (granules Degranulation 1. Cytokines Tryptase Heparin Histamine .D oolpdboytei,eg e.g. biosynthesis, lipid novo De 2. 15-HETE TXA2 LTC4/D4/E4 PGD2 MC 19 .D oopoensnhss e.g. synthesis, protein novo De 3. .Etaellrvsce,eg e.g. vesicles, Extracellular 4. nefrn INβ IFN-γ) (IFN-β, Interferons (VEGF) factors Growth CCL2) (CXCL8, Chemokines GM-CSF) IL-13, (IL-4, Cytokines miRNA mRNA Proteins nm) 150 - (30 Exosomes iue1Nlsne al. et 1_Nilsson Figure Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. A MC ? rMo Gr relk model Tree-like MK HSC Ery Ly B Ery MK 20 MC eaooei adcp model landscape Hematopoietic Ba HSC Eo Neu Ly Mo Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 1 MC MCp MCp MCp mDia1 2 exocytosis 21 Full MC Compound exocytosis iue3Nlsne al. et 3_Nilsson Figure Kiss-and-run exocytosis 3 Posted on Authorea 28 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160390266.66559016/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. atcell Mast atcell Mast atcell Mast cell Mast Th2 cell B Avdoralimab IL-17 C5Rα1 C5a Secukinumab Dupilumab IL-4Rα IL-17 IL-4 GI-301 FcεRI IgE Ligelizumab LY3454738 CD200 CD200R Th17 f-ae biologicals Off-label e biologicals New Eosinophil Eosinophil 22 SIGLEC-8 AK-002 Mepolizumab Tezepelumab Benralizumab TSLPR TSLP IL-5Rα IL-5Rα IL-5 IL-5 Reslizumab CDX-0159 SCF KIT iue4Nlsne al. et 4_Nilsson Figure receptor receptor Epithelial ligand cell Th2 Th2 MC MC

Soluble targets Cellular targets Soluble targets Cellular targets