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Blanco, L. P. etal. RNA externalized by neutrophil extracellular traps promo\ tes inflammatory pathways in endothelial cells. Arthritis Rheumatol. 73, \n2282 2292 \(2021\).\r:209)/F 4/H/N/Rect[221.519 686.855 229.454 674.444]/Subtype/Link/Type/Annot>> endobj 1402 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:101. Rahman, S. etal. Low-density granulocytes activate Tcells and demonstrate a\ non-suppressive role in systemic lupus erythematosus. Ann. Rheum. Dis. 78, 957 966 \(2019\).\r:210)/F 4/H/N/Rect[282.52 642.855 290.1 630.444]/Subtype/Link/Type/Annot>> endobj 1403 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:75. Villanueva, E. etal. Netting neutrophils induce endothelial damage, infiltr\ ate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J. 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A comprehensive evaluation \nof the relationship between d\ ifferent IgG and IgA anti-modified protein autoantibodies in rheumatoid arthritis. Front. Immunol. 12, 627986 \(2021\).\r:22\ 2)/F 4/H/N/Rect[293.23 290.855 300.789 278.444]/Subtype/Link/Type/Annot>> endobj 1415 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:107. Makrygiannakis, D. etal. Citrullination is an inflammation-dependent process\ . Ann. Rheum. Dis. 65, 1219 1222 \(2006\).\r:223)/F 4/H/N/Rect[334.199 268.855 341.858 256.444]/Subtype/Link/Type/Annot>> endobj 1416 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:108. Catrina, A., Krishnamurthy, A. & Rethi, B. Current view on the pathogenic rol\ e of anti-citrullinated protein antibodies in rheumatoid arthritis. RMD Open 7, e001228 \(2021\).\r:224)/F 4/H/N/Rect[307.822 213.855 315.591 201.444]/Subtype/Link/Type/Annot>> endobj 1417 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:109. Sokolove, J. etal. 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Dev\ el. 12, 616 627 \(2009\).\r:227)/F 4/H/N/Rect[287.232 147.855 294.81 135.444]/Subtype/Link/Type/Annot>> endobj 1420 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:113. Pillinger, M. H. & Abramson, S. B. The neutrophil in rheumatoid arthritis. R\ heum. Dis. Clin. North Am. 21, 691 714 \(1995\).\r:228)/F 4/H/N/Rect[286.781 114.855 294.36 102.444]/Subtype/Link/Type/Annot>> endobj 1421 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:114. Khandpur, R. etal. NETs are a source of citrullinated autoantigens and stimu\ late inflammatory responses \nin rheumatoid arthritis. Sci. Transl. Med. 5, 178ra140 \(2013\).\r:229)/F 4/H/N/Rect[295.535 114.855 303.113 102.444]/Subtype/Link/Type/Annot>> endobj 1422 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:114. Khandpur, R. etal. NETs are a source of citrullinated autoantigens and stim\ ulate inflammatory responses \nin rheumatoid arthritis. Sci. Transl. 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Rheumatoid arthritis and the mucosal origins hypothesis:\ protection turns to destruction. Nat. Rev. Rheumatol. 14, 542 557 \(2018\).\r:233)/F 4/H/N/Rect[435.076 675.855 442.655 663.444]/Subtype/Link/Type/Annot>> endobj 1426 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:118. Foulquier, C. etal. Peptidyl arginine deiminase type 2 \(PAD-2\) and PAD-4 bu\ t not PAD-1, PAD-3, and PAD-6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation. Art\ hritis Rheum. 56, 3541 3553 \(2007\).:234)/F 4/H/N/Rect[542.661 653.855 550.658 641.444]/Subtype/Link/Type/Annot>> endobj 1427 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:119. Romero, V. etal. Immune-mediated pore-forming pathways induce cellular hyper\ citrullination and generate citrullinated autoantigens in rheumatoid arthritis. Sci. Transl. 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Neutrophil-mediated carbamylation promotes articular dam\ age in rheumatoid arthritis. Sci. Adv. 6, eabd2688 \(2020\).\r:238)/F 4/H/N/Rect[418.499 356.855 423.569 344.444]/Subtype/Link/Type/Annot>> endobj 1431 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:122. Nakabo, S. etal. Activated neutrophil carbamylates albumin via the release o\ f myeloperoxidase and reactive oxygen species regardless of NETosis. \nMod. Rheumatol. 30, 345 349 \(2020\).\r:239)/F 4/H/N/Rect[424.752 356.855 432.356 344.444]/Subtype/Link/Type/Annot>> endobj 1432 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:123. Trouw, L. A., Rispens, T. & Toes, R. E. M. Beyond citrullination: other post-\ translational protein modifications in rheumatoid arthritis. Nat. Rev. Rheumatol. 13, 331 339 \(2017\).\r:240)/F 4/H/N/Rect[387.593 323.855 395.342 311.444]/Subtype/Link/Type/Annot>> endobj 1433 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:51. O Neil, L. J. etal. Neutrophil-mediated carbamylation promotes articular da\ mage in rheumatoid arthritis. Sci. Adv. 6, eabd2688 \(2020\).\r:241)/F 4/H/N/Rect[382.507 290.855 387.603 278.444]/Subtype/Link/Type/Annot>> endobj 1434 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:124. Wright, H. L., Makki, F. A., Moots, R. J. & \nEdwards, S. W. Low-density granu\ locytes: functionally distinct, immature neutrophils in rheumatoid arthritis with altered properties and defective TNF signalli\ ng. \nJ. Leukoc. Biol. 101, 599 611:242)/F 4/H/N/Rect[484.854 257.855 492.45 245.444]/Subtype/Link/Type/Annot>> endobj 1435 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:125. Ramanathan, K. etal. Neutrophil activation signature in juvenile idiopathic \ arthritis indicates the presence \nof low-density granulocytes. 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Med. 383, 2628 2638 \(2020\). \nThe first description of VEXAS syndrome, involving a somatic \ mutation that causes severe disease and:295)/F 4/H/N/Rect[485.389 576.855 493.563 564.444]/Subtype/Link/Type/Annot>> endobj 1496 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:160. Beck, D. B. etal. Somatic mutations in UBA1 and severe adult-onset autoinf\ lammatory disease. \nN. Engl. J. Med. 383, 2628 2638 \(2020\). \nThe first description of VEXAS syndrome, involving a somatic\ mutation that causes severe disease an:296)/F 4/H/N/Rect[390.833 477.974 398.682 465.444]/Subtype/Link/Type/Annot>> endobj 1497 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:160. Beck, D. B. etal. Somatic mutations in UBA1 and severe adult-onset autoin\ flammatory disease. \nN. Engl. J. Med. 383, 2628 2638 \(2020\). \nThe first description of VEXAS syndrome, involving a somati\ c mutation that causes severe disease a:297)/F 4/H/N/Rect[436.234 455.855 443.877 443.444]/Subtype/Link/Type/Annot>> endobj 1498 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:163. Lindor, N. M., Arsenault, T. M., Solomon, H., \nSeidman, C. E. & McEvoy, M. T.\ A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome. Mayo Clin. Pr\ oc. 72, 611 615 \(1997\).\r:298)/F 4/H/N/Rect[422.022 268.855 430.135 256.444]/Subtype/Link/Type/Annot>> endobj 1499 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:164. Wise, C. A. etal. Mutations in CD2BP1 disrupt binding to PTP PEST and are re\ sponsible for PAPA syndrome, an autoinflammatory disorder. Hum. Mol. Genet. 11, 961 969 \(2002\).\r:299)/F 4/H/N/Rect[431.488 268.855 439.601 256.444]/Subtype/Link/Type/Annot>> endobj 1500 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:165. Marzano, A. V., Borghi, A., Meroni, P. L. & Cugno, M. Pyoderma gangrenosum an\ d its syndromic forms: evidence for a link with autoinflammation. \nBr. J. Dermatol. 175, 882 891 \(2016\).\r:300)/F 4/H/N/Rect[462.476 202.855 470.548 190.444]/Subtype/Link/Type/Annot>> endobj 1501 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:166. Holzinger, D. & Roth, J. Alarming consequences - autoinflammatory disease spe\ ctrum due to mutations in proline-serine-threonine phosphatase-interacting protein 1. Curr. Opin. Rheumatol. 28, 550 559 \(2\ 016\).\r:301)/F 4/H/N/Rect[471.887 202.855 479.96 190.444]/Subtype/Link/Type/Annot>> endobj 1502 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:167. Mistry, P. etal. Dysregulated neutrophil responses \nand neutrophil extracell\ ular trap formation and degradation in PAPA syndrome. Ann. Rheum. Dis. 77, 1825 1833 \(2018\).\r:302)/F 4/H/N/Rect[412.855 59.8547 420.498 47.4439]/Subtype/Link/Type/Annot>> endobj 1503 0 obj <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/XObject<>>> endobj 1504 0 obj <>stream x}k#9?_GR+b׸]%2c;̖RU v|K2+CA2sookqzͿW77kc~kQoVu-n7߲ތrTKlU5ԵrշXY/SѬ_8ν/zgmQ,[Vr\<ժϭ]Q^ߨŋ(Vb_]<1TehX,U) t?~ ?A?bg>F?Xժ˧d$z_CQ/Dn z}-|U[9 Fֺw /]E)?}B^Tê~C;2;Gx[ za3yEjԚqO<9 xL# Nb?%\L69XcCm/ee;A{{TMSݽx:m>?VcWB_7JA.~TcV:X 5{d/Vcznz||-׶$gI῵,38d_nQ* 62Vml[U ߴeOmd1U4(U-VMYJeZZ!]]-Ze]ʉ2эrʯE5J-ʶ.n=!_js⴮ j,ea tR^3nTaK)$:=VEz1pJԺ~OoITʉעō ?{-l]AVCYgě~䨎eDx)񃠂Ŭ\jR 8c1ѐ'5~9 Xf, QFȏƭ1N'ӾJt=)*ryvbPKcVKUT6 D+↫ l1xQĠ4-z<&|4UzCq:;ah|+f#m꺑ZE+uT9j=h|5ۨ>߽foݙḃg{k)sޡaZsR cT nZ9tw s;h~+UE՚ٜt:ZtᨂAlc7#4Γ,Wm-`]BMl#ZZSN;ix'=LMicgz6HfUFCqYSˊ:z`]]rPkAFQ;TrNR\d!qEP)XZg3P֫twFiV[Ji+5w)nʾeINQ4~UGHr:#~!kSvVJ)g9B7WXáZ8EtV뉩/\M6?)S*_{5։WMu]=`ҊNKfߴnSʵ\@oyS { }Z!g-rb5a!=z᝱CiPVCzn~1^r\;ӌ`~$d"3`;_ Ìq&ު Gaf'Nô©I:˛d{~ {iԧZLD3m l߻I51*Q'%ދBD9]HN#v_QQ[}h]tdZ~BZ3AEF[fr6j|r:kkZޚ1LpJngPjIGbuXJٝ]0dXYWlLz|@ ~&/e8 g/e l KDS-a&o0[t <@o|'2vh{֏Q:fcwp9]KwVy Y;QĶpNɥ7)K j\f-)OhK] #!)/"Z㺬;m<\g[JC:UnGZheNw7:mG$(t#"A$R.e %*nc/sY6^jblxysO{9;Q2vBqn^I(U&lh)5ܤ#9R;]'H@pG.jD6ML{*Hsb^j-ehYD#hԴRSmC%S>Z0npa'jumjo^!&5j`w+&|LZQ 4[+_i:`x/&$7#^۽c #~.ާ }2-/^N"+Z[}Vow-YYLozqY+MǩT]ީMD&rm-x`:z6ƭ ɏ۰[eջ.^,͸8`V"Q`Sp&Y12lLC,GjFU,u7PTS>/v{09.'LGVKM;폄=RCڀG36'q,JΛҽgDm0[\Ϟ`DKa)ܝW^y5F psvZsոZe?V[K~\{)$/ѾTj26( *2D}^O{^ yJelYCRrl!0XX t<괴F$G2d^W-jlr L{) +xʒ3xX]Ak{TSpgy@CD`;Y 3B3bŵw<0.H[Q", FmG&!2|*K'モS[qseؓlŪzDٌ!mK-<%{)wNqz(8"uH+/b~~J=OmNyI%Z]h{>2\h7b56~-AuaLn?*CsmuB >YOLf!c3pY&hF$84kLuTBA9uw)>,P7Fڭeh%B Se؛slS{&BAOA 5"[QPpG~| ~Rȗ]Yѫ)1`pW$y:x;ovnk Mt/+ :*L ]},0eC |ޘmG^K^b E*,C(*:cXA<eي$KzϩK[ܴGT M/ByXZ|1g{9g4gÓEx!8I*8eh#>yq=dC-OJw8;&Ӥ)\t?0p)m Z4C³ܸ6QrggBQw'}♦H e,0G5'ER'_mzk!i%Ⱥ W];nյc̡BVM24vGZj ӳ_MTRXǹ4];T&\ILz<-Q,gu"[04a{3d W߲FHz&phSxbsI[@s ! =ԋ=8}fG0@ZJ.|f^ lĜ{EdShc.C- ]3Gr>Pp$"fOrF;-66 Si3e:=V;VjXTIIɅJ4ݦ!3^J>+j-V))& VMUqnWDhp`עm(oJR3}RIr;*d9%!V=*$^)5F0Zє= uS-=jf鉥1_T>/UY7oҸ- P:9&r૸Ċ$&QٍE/6_/ (ozN[BPr eAB%'A7c^mN6cH R i=b"f)FAqg eX-O\E5 "_V r ta >I#&zsS<:鮍zkCV]rt @ w %:A5&9Y2ZQxo7TS(gO*Td65I4"?SB~ Q*zo% 9"y%[8ZͻɹrYde1Ln8sߣENw.dخo= ~Qjym >M#v`t/nhJWWږӉjl_Ŏ Iԡ9jST- [%6/*&ɖ@R+"Pƒ$p gduR+yiH.x=2j 8 3+#uGH-Dhܹ->ӾE|W/VsZ6gJRa>'(Fy!T N`86Q\d` N/swc$[qC-r B^m}f4V!ԕ Y, <]|>rDUՌA'TYLc;m^Eu7SyQˁ/PdCt&> IYN犰XdU^SJQP+iŰ5 oa ?JE8t]jM}};6We/JoENyhtA0oS*뢄ݨ A zEtb4)mş'~ '|.q(RH9jt֜itx̋WƞBcȌg3|Ƨq:Xii&xK[-3g7ȷp?h<1WY~ y1 0h6리TJ1]υh <%#O DTRjM3YQO{嶔|r[tmXX\O"@[Y+NOoͣ46sWA jΉ4Zr:> G}{e14{MA'|wwxg ZaIDeS3b84)#g3fneGK' J@PP9;OGk<&| ࣮TՖ$)F^wVbzq*T~o1ggϔ`!|G3FZ6zHdu~?I!Q|/Xl(eKƓfS{Qn,y?ޏCT1 ڟFwrO&wr迤8ZR2)=+מg]ј\eqǙ|.BFp1t$B2xfEbCaל睡 aHal`3yӄ$=Ee*Ё2R f< lz 9)bWCߗ/EO4ȒϪ;bIr#бZ%إ-;m4H$ ]0+ KVEA3g3B"*A )Vvu# 0 [1=葳S^܇DJvÊ,m߰c3Ht&*('ۑ1-XO 59#^-2Y~EAFg}$'㨞-fd.kLI]w: t?5W6$QXjas@t*˫`:x6Y=/Nɯ^˙p+{-v䀐>@VO>%'fArS`A~RKNxHLKS0JeN;s C L ٴyxdJ8/p!QOH}BJt*Otn;j+V󝱹lfT;STUqX9W/< 86)bhȞW+qWu{&)Q1g,)9Ih@)Xև-7PP'5GnitW>mý駉2QFU |V5s׺?ì\Xz*T'QpW[0<-Z-^xScN{cB_ bD{lnK3btbūkFm.ei,M_H *F?W(啞B~=O M8~p?(QzT% a!*$U^u'Z$ƒx W$a'&S"mzE[Fvd Ńȧ0n^3Kᮞ HOXR$q:'U>I,nvqɒ3H@}^p]N<؁G.>:bspbU nxC){('&AuNe_DM ^32g\~ !ٓɶ#6Zuτ<]bΟC+)@_?"}YgAjh,Ǽ’A6[fuA%g9(F}LH8r?n6AM0N؟. bKÓҡ~?ìթ{Yn%#+ͳ뤀Al1oO213XڗEa JRmz1zTٶ^͞d4JtٴcIďEy̢̆<2^n9 6d?3O'YUIeȣl 1 I OjWG)^`k/_'Vr@ 1ݲV`! 6 iZ[7HN Fzs9lT:5fTҁ\GB}BGTP/IQUP?NIAUzh3(I,.yjD%:wѹhK&{/Y+2vr/j"2_9*C~b?, 4zjSge83t{27]Wxr_8Wk:䲤]_b,RD3\x#ײJ^MDT@yrݻm@憧_ 6R~%8ǁP352()BӱْMf Mqe) Fe~t}qv$_R$8‘',Rه9$PJzOٜ_ML \*_s-;G2T\eFr~E3p8 ?]kBG-0?1LO; "#M V2 Ć#Δ,%'dMg긏8ċjm1ؘ@ a5rE&B?ӌ6foFx͐n<ؐɐ#AQIӺ򻣥.F#9]t?aXo/IX&ЍO3O,J>"OOPHiڒ ٶy=B8ÝdH dmې$pO:DvުNFyL c}iB˓Ej#rC@LP䧌ǾD[8z/m"ڌZk+JqƪR}oWKӛU淯o߬+?g56:_mi_|w|xoޘPU[r**٭qrMe5̉^h,5jwJM/l6d'W;!,Qn\][ԪV?FVX}Yu _Oo~\Oux^ Pc[+κvH'Xà_}Ε%j\TCڌ endstream endobj 1505 0 obj <> endobj 1506 0 obj [1507 0 R 1508 0 R 1509 0 R 1510 0 R 1511 0 R 1512 0 R 1513 0 R 1514 0 R 1515 0 R 1516 0 R 1517 0 R 1518 0 R 1519 0 R 1520 0 R 1521 0 R 1522 0 R 1523 0 R 1524 0 R 1525 0 R 1526 0 R 1527 0 R 1528 0 R 1529 0 R 1530 0 R 1531 0 R 1532 0 R 1533 0 R 1534 0 R 1535 0 R 1536 0 R 1537 0 R 1538 0 R 1539 0 R 1540 0 R 1541 0 R 1542 0 R 1543 0 R 1544 0 R 1545 0 R 1546 0 R 1547 0 R] endobj 1507 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:168. Desai, J., Steiger, S. & Anders, H. J. Molecular pathophysiology of gout. Tr\ ends Mol. Med. 23, \n756 768 \(2017\).\r:303)/F 4/H/N/Rect[213.828 708.855 221.458 696.444]/Subtype/Link/Type/Annot>> endobj 1508 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:169. Dalbeth, N., Merriman, T. R. & Stamp, L. K. Gout. Lancet 388, 2039 2052 \(\ 2016\).\r:304)/F 4/H/N/Rect[222.649 708.855 230.279 696.444]/Subtype/Link/Type/Annot>> endobj 1509 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:168. Desai, J., Steiger, S. & Anders, H. J. Molecular pathophysiology of gout. T\ rends Mol. Med. 23, \n756 768 \(2017\).\r:305)/F 4/H/N/Rect[238.309 686.855 245.952 674.444]/Subtype/Link/Type/Annot>> endobj 1510 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:168. Desai, J., Steiger, S. & Anders, H. J. Molecular pathophysiology of gout. \ Trends Mol. Med. 23, \n756 768 \(2017\).\r:306)/F 4/H/N/Rect[261.661 631.855 269.443 619.444]/Subtype/Link/Type/Annot>> endobj 1511 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:55. Schauer, C. etal. Aggregated neutrophil extracellular traps limit inflammat\ ion by degrading cytokines and chemokines. Nat. Med. 20, 511 517 \(2014\). \nA description of aggregated NET formation contr\ ibuting to disease resolution.\r:307)/F 4/H/N/Rect[244.096 587.855 249.342 575.444]/Subtype/Link/Type/Annot>> endobj 1512 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:56. Hahn, J. etal. Aggregated neutrophil extracellular traps resolve inflammati\ on by proteolysis of cytokines and chemokines and protection from antiproteases. FASEB J. 33, 1401 1414 \(2019\).\r:308)/F 4/H/N/Rect[250.613 587.855 255.859 575.444]/Subtype/Link/Type/Annot>> endobj 1513 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:170. Taylor, P. C. etal. Reduction of chemokine levels and leukocyte traffic to j\ oints by tumor necrosis factor alpha blockade in patients with rheumatoid arthritis. Arthritis Rheum. 43, 38 47 \(2000\).\r:\ 309)/F 4/H/N/Rect[183.763 334.855 191.358 322.444]/Subtype/Link/Type/Annot>> endobj 1514 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:173. De Soyza, A. etal. A randomised, placebo-controlled study of the CXCR2 antag\ onist AZD5069 in bronchiectasis. Eur. Respir. J. 46, 1021 1032 \n\(2015\).\r:310)/F 4/H/N/Rect[194.104 334.855 201.699 322.444]/Subtype/Link/Type/Annot>> endobj 1515 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:58. Goldblatt, F. & O Neill, S. G. Clinical aspects of autoimmune rheumatic disea\ ses. Lancet 382, \n797 808 \(2013\).\r:311)/F 4/H/N/Rect[292.106 268.855 297.083 256.444]/Subtype/Link/Type/Annot>> endobj 1516 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:170. Taylor, P. C. etal. Reduction of chemokine levels and leukocyte traffic to \ joints by tumor necrosis factor alpha blockade in patients with rheumatoid arthritis. Arthritis Rheum. 43, 38 47 \(2000\).\r\ :312)/F 4/H/N/Rect[298.22 268.855 305.685 256.444]/Subtype/Link/Type/Annot>> endobj 1517 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:173. De Soyza, A. etal. A randomised, placebo-controlled study of the CXCR2 anta\ gonist AZD5069 in bronchiectasis. Eur. Respir. J. 46, 1021 1032 \n\(2015\).\r:313)/F 4/H/N/Rect[306.822 268.855 314.288 256.444]/Subtype/Link/Type/Annot>> endobj 1518 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:174. Catella-Lawson, F. etal. Cyclooxygenase inhibitors and the antiplatelet effe\ cts of aspirin. N. Engl. J. Med. 345, 1809 1817 \(2001\).\r:314)/F 4/H/N/Rect[315.424 268.855 322.89 256.444]/Subtype/Link/Type/Annot>> endobj 1519 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:Fig. 2 | Targeting neutrophil extracellular traps. The formation of neutrop\ hil extracellular traps \(NETs\) can be triggered by various stimuli through engagement of surface receptors such as cytokine rec\ eptors, Fc receptors \(FcRs\), Toll-li:315)/F 4/H/N/Rect[230.756 246.855 235.291 234.444]/Subtype/Link/Type/Annot>> endobj 1520 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:120. Carmona-Rivera, C. etal. Synovial fibroblast-\nneutrophil interactions promo\ te pathogenic adaptive immunity in rheumatoid arthritis. Sci. Immunol. 2, eaag3358 \(2017\).\r:316)/F 4/H/N/Rect[238.136 202.855 245.731 190.444]/Subtype/Link/Type/Annot>> endobj 1521 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:175. Smith, C. K. etal. Neutrophil extracellular trap-derived enzymes oxidize hig\ h-density lipoprotein: an additional proatherogenic mechanism in systemic lupus erythematosus. Arthritis Rheumatol. 66, \n25\ 32 2544 \(2014\).\r:317)/F 4/H/N/Rect[246.911 202.855 254.506 190.444]/Subtype/Link/Type/Annot>> endobj 1522 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:7. Mutua, V. & Gershwin, L. J. A review of neutrophil extracellular traps \(NETs\)\ in disease: potential anti-NETs therapeutics. Clin. Rev. Allergy Immunol. \n61, 194 211 \(2021\).\r:318)/F 4/H/N/Rect[194.821 125.855 197.419 113.444]/Subtype/Link/Type/Annot>> endobj 1523 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:176. Silvestre-Roig, C. etal. Externalized histone H4 orchestrates chronic inflam\ mation by inducing lytic \ncell death. Nature 569, 236 240 \(2019\).\r:319)/F 4/H/N/Rect[196.564 81.8547 204.175 69.4439]/Subtype/Link/Type/Annot>> endobj 1524 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:177. Hsieh, I. N., Deluna, X., White, M. R. & Hartshorn, K. L. Histone H4 directly\ stimulates neutrophil activation through membrane permeabilization. J. Leukoc. Biol. 109, 763 775 \(2021\).\r:320)/F 4/H/N/Rect[205.36 81.8547 212.971 69.4439]/Subtype/Link/Type/Annot>> endobj 1525 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:49. Sollberger, G. etal. Gasdermin D plays a vital role \nin the generation of neu\ trophil extracellular traps. \nSci. Immunol. 3, eaar6689 \(2018\).\r:321)/F 4/H/N/Rect[260.781 59.8547 265.904 47.4439]/Subtype/Link/Type/Annot>> endobj 1526 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:50. Chen, K. W. etal. Noncanonical inflammasome signaling elicits gasdermin D-de\ pendent neutrophil extracellular traps. Sci. Immunol. 3, eaar6676 \n\(2018\).\r:322)/F 4/H/N/Rect[267.114 59.8547 272.238 47.4439]/Subtype/Link/Type/Annot>> endobj 1527 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:178. Silva, C. M. S. etal. Gasdermin D inhibition prevents multiple organ dysfunc\ tion during sepsis by blocking NET formation. Blood 138, 2702 2713 \(2021\).\r:323)/F 4/H/N/Rect[273.448 59.8547 281.133 47.4439]/Subtype/Link/Type/Annot>> endobj 1528 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:179. Wang, X. etal. Effects of Gasdermin D in modulating murine lupus and its ass\ ociated organ damage. Arthritis Rheumatol. 72, 2118 2129 \(2020\).\r:324)/F 4/H/N/Rect[442.936 686.855 450.547 674.444]/Subtype/Link/Type/Annot>> endobj 1529 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:7. Mutua, V. & Gershwin, L. J. A review of neutrophil extracellular traps \(NETs\)\ in disease: potential anti-NETs therapeutics. Clin. Rev. Allergy Immunol. \n61, 194 211 \(2021\).\r:325)/F 4/H/N/Rect[511.103 642.855 513.64 630.444]/Subtype/Link/Type/Annot>> endobj 1530 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:114. Khandpur, R. etal. NETs are a source of citrullinated autoantigens and sti\ mulate inflammatory responses \nin rheumatoid arthritis. Sci. Transl. Med. 5, 178ra140 \(2013\).\r:326)/F 4/H/N/Rect[514.826 642.855 522.436 630.444]/Subtype/Link/Type/Annot>> endobj 1531 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:180. Willis, V. C. etal. N-alpha-benzoyl-N5-\(2-chloro-1-iminoethyl\)-L-ornithine \ amide, a protein arginine deiminase inhibitor, reduces the severity of murine collagen-induced arthritis. J. Immunol. 186, \n\ 4396 4404 \(2011\).\r:327)/F 4/H/N/Rect[523.622 642.855 531.233 630.444]/Subtype/Link/Type/Annot>> endobj 1532 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:181. Martinod, K. etal. PAD4-deficiency does not \naffect bacteremia in polymicrob\ ial sepsis and ameliorates endotoxemic shock. Blood 125, \n1948 1956 \(2015\).\r:328)/F 4/H/N/Rect[455.868 587.855 463.672 575.444]/Subtype/Link/Type/Annot>> endobj 1533 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:182. Sulem, P. etal. Identification of a large set of rare complete human knockou\ ts. Nat. Genet. 47, \n448 452 \(2015\).\r:329)/F 4/H/N/Rect[497.516 532.855 505.196 520.444]/Subtype/Link/Type/Annot>> endobj 1534 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:183. Sorensen, O. E. etal. Papillon-Lefevre syndrome patient reveals species-depe\ ndent requirements for neutrophil defenses. J. Clin. Invest. 124, 4539 4548 \(2014\).\r:330)/F 4/H/N/Rect[506.405 532.855 514.085 520.444]/Subtype/Link/Type/Annot>> endobj 1535 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:184. Zavada, J. etal. Cyclosporine A or intravenous cyclophosphamide for lupus ne\ phritis: the Cyclofa-Lune study. Lupus 19, 1281 1289 \(2010\).\r:331)/F 4/H/N/Rect[533.996 433.855 541.716 421.444]/Subtype/Link/Type/Annot>> endobj 1536 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:185. Lee, Y. H., Lee, H. S., Choi, S. J., Dai Ji, J. & \nSong, G. G. Efficacy and s\ afety of tacrolimus therapy for lupus nephritis: a systematic review of clinical trials. Lupus 20, 636 640 \(2011\).\r:332)/F 4/H/N/Rect[542.938 433.855 550.658 421.444]/Subtype/Link/Type/Annot>> endobj 1537 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:121. Carmona-Rivera, C. etal. Neutrophil extracellular traps mediate articular c\ artilage damage and enhance cartilage component immunogenicity in rheumatoid arthritis. JCI Insight 5, e139388 \(2020\).\r:3\ 33)/F 4/H/N/Rect[382.727 389.855 390.466 377.444]/Subtype/Link/Type/Annot>> endobj 1538 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:186. Macanovic, M. etal. The treatment of systemic \nlupus erythematosus \(SLE\) in\ NZB/W F1 hybrid mice; studies with recombinant murine DNase and with dexamethasone. Clin. Exp. Immunol. 106, 243 252 \(1996\ \).\r:334)/F 4/H/N/Rect[381.553 345.855 389.374 333.444]/Subtype/Link/Type/Annot>> endobj 1539 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:187. Davis, J. C. Jr. etal. Recombinant human Dnase I \(rhDNase\) in patients with\ lupus nephritis. Lupus 8, 68 76 \(1999\).\r:335)/F 4/H/N/Rect[426.529 323.855 434.207 311.444]/Subtype/Link/Type/Annot>> endobj 1540 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:90. Al-Mayouf, S. M. etal. Loss-of-function variant \nin DNASE1L3 causes a famili\ al form of systemic \nlupus erythematosus. Nat. Genet. 43, 1186 1188 \(2011\).\r:336)/F 4/H/N/Rect[460.742 268.855 465.838 256.444]/Subtype/Link/Type/Annot>> endobj 1541 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:93. Sisirak, V. etal. Digestion of chromatin in apoptotic cell microparticles pr\ events autoimmunity. Cell 166, 88 101 \(2016\).\r:337)/F 4/H/N/Rect[467.034 268.855 472.129 256.444]/Subtype/Link/Type/Annot>> endobj 1542 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:45. Lood, C. etal. Neutrophil extracellular traps enriched in oxidized mi\ tochondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, \n146 153 \(2016\). \nThis paper descr\ ibes mitochondrial products and nucleic:338)/F 4/H/N/Rect[405.274 191.855 410.359 179.444]/Subtype/Link/Type/Annot>> endobj 1543 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:188. Nelander, K. etal. Early clinical experience with AZD4831, a novel myelopero\ xidase inhibitor, developed for patients with heart failure with preserved ejection fraction. Clin. Transl. Sci. 14, \n812 8\ 19 \(2021\).\r:339)/F 4/H/N/Rect[411.549 191.855 419.175 179.444]/Subtype/Link/Type/Annot>> endobj 1544 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:189. Zheng, W. etal. PF-1355, a mechanism-based myeloperoxidase inhibitor, preven\ ts immune complex vasculitis and anti-glomerular basement membrane glomerulonephritis. J. Pharmacol. Exp. Ther. 353, 288 298\ \(2015\).\r:340)/F 4/H/N/Rect[420.366 191.855 427.992 179.444]/Subtype/Link/Type/Annot>> endobj 1545 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:190. Blanco, L. P. etal. Improved mitochondrial metabolism and reduced inflammati\ on following attenuation of murine lupus with coenzyme Q10 analog idebenone. Arthritis Rheumatol. 72, 454 464 \(2020\).\r:34\ 1)/F 4/H/N/Rect[462.893 125.855 470.397 113.444]/Subtype/Link/Type/Annot>> endobj 1546 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:191. Fortner, K. A. etal. Targeting mitochondrial oxidative stress with MitoQ red\ uces NET formation and kidney disease in lupus-prone MRL-lpr mice. Lupus Sci. Med. 7, e000387 \(2020\).\r:342)/F 4/H/N/Rect[471.547 125.855 479.051 113.444]/Subtype/Link/Type/Annot>> endobj 1547 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:192. Kim, J. etal. VDAC oligomers form mitochondrial pores to release mtDNA fragm\ ents and promote lupus-like disease. Science 366, 1531 1536 \n\(2019\).\r:343)/F 4/H/N/Rect[370.873 70.8547 378.541 58.4439]/Subtype/Link/Type/Annot>> endobj 1548 0 obj <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/XObject<>>> endobj 1549 0 obj <>stream x}r#upDmԽ*pDkz.HJazcdyHb觰j"Z<7_}Z|Z{|7|Z6;Z_Zrkqycӛ~N*|ʫbU}We)"_uJϋex1׋rZw$( S z);ܚF:HVs,/*l͖n \WkQqw#[hIC/wdE/OZlLMͧ ,a>\[n6UVU?hZEl׆lY[qMՋP72$WrMx<?czfN7f2Gv|=] 0.LϽșV&DtuVpB&P4 I />kn줥{܈pS/7ӇXYOv8`7[/+0)MަWu[G6> eq1I)CZnA<,ͬgF^&m%>Sp˘.~UUeKC6[Dong7LvLpP{F zWZտc.]~) fztܐH$$\#i(M(m(@'$Q(+Zk҄Vüd1u0:5ށ4v'h4k†^Ȩt~H v%%^A? {5l)SP&8>hF݊[${{P*%ϑdY\G EtT.G4R*dgfA*8A׌^vN.hoq>sS !N~ 2.6!4 ¯/APzfW`vŃ%C/8Gݿ(qf<ѳElݎUI:iŻ?'`ėf̲RJ#jW)/gs%ևZ&řy^-/]-KQg.;Q>[;2sh;Z)=cwg^D[N:ÍvHZ <3wF7*?6Su]>cCؤmhpV&AiLΗ1쯜$:&pݘ2XފX4Mz0=cE.~cn:.,ĤAȁ L/7x3kKS?l6V7$뒻˔A17 jc&%Wv7.!9>+]r/yh1M@hP-ўmg42aohmN-E'}-|u ZڮTz#OOʆ{V #mf޶wD}'ZRʤ3Ezېl#tߘ$Ъ6&=A-CnOJ׳B`\&ԓC| fs@3lPGJl`B!8L&.e,Ms-kf 1_Jd5{b6"C")SO' ɛVǃ^nFI+qD`>s%,']FF_{{\ts;D-H?2lORp16vv hF`b5dy{:<Gf5a 8(jܑH$"#_}-K[u Xq-(\Qב!iRo}Ŕ;&σK}Z[ehB́~(9.ay3ˀèe~g7cv;]60w-l#x{2csf*~~$>6M+=˻#\ [3Q>"16Ђ~ q|(܊5aj ?MMu|@t&:%U0w:!, ^g$do92,&s6ZS ^k&2cQrD}R4I m>jӌmlP>Oi|0nk}-]p5T}rmVԎv2_DrcStSKFF2!Uv)kQVT ut_-(uYQ s=f>Le[eaӓl ]XC IMI6ӫka amNjmZ Ғ@xC, NSjX$Ҁ2hK\APQv7kBD N8\8}Kk\GJpM@6ĥ&Fzǃ [9n9&ih:Ƶc D|vP\+^^caW|t _7\;m( o9Xo]\ʛ$ts2-[ *N(04@ X[ag aRH3FOKM =G6Ѓ|{/⁈;:ju$ÁlW]hi*AE ݸ;Ds5H5;>y8joCZmzR}g BGk]y'ASt}ٴ,:ҭN!*]k23ȜU_̌Lsχ[jR,j,$u>ݟԒȹjE;7[t;zNMrRj N"%9a($yՍX6 7>M ,vk}}LiP4N5k>/1Z{¹`3 ;MGJսqb_jKD/zCq[)EcЛٻNX4[$ o?R2|FѺ!`݀Q<\HyrcTv$A_?d_jW%MPn񀑰[ʩѣRɸGe܉XqLMc 4t٦wkrJ2Ŧ:Fl?OnR:ek/ pomIۖ=lYx@s0D1oFZ i~%BTB`9[z¯ih,r",K&WY6i~yzLWtZ-Č%*q3!ҙ>n,u]WM%彎(wԑS1F3ﯔz$9yu_tf֚jL1$Q# Ac^ =`J";7|/=+w *UY\;.hMI[AY}Vd,L$#HazݬBkul%߭;kʮj}n*2 ^=HCURGojDx*cAXh"pD"D̚{4OYO$^*C*9'82(rXIHݼDԓz}Bxsᢚt7͓0R{&m IO1efz{GhboL"Y<^DI7(J *F{+&Ӹ\`m":75hhDhwfQ*Kݮ>LA|$Fb(hE4ܰ_b;znٴ_$VH9G\ `R\jX(Cy:7 **#]سdc`.6k*=;Ryg(谆DTYcEh3Fq(A00&N!~S8ڮw 3qC0/I`IAA0qhY)bE(!`{ =j)3 X @U͆UYe&30C]^4[a]ׄ ^/QJASESmRD32T%u`Bj#`4.v:qdI,DJa ŖHs*.q虠 Rg/X?I2y@:UӁ RDaMm)<EƉS5vS:O_Q-htKg.-j3KgxǪŪLFUd0cXtxL Ԡbe߈\R\"e}Tء tV$OlF {_Hu0BWZ$9Էwͯ0;s*fN P=w6Tp{r >ka !h) [3']b9I^*&@1˜Эi\8>lYC߰D|wcɌޭ֩G৒U$(cuX XXx`e3n͠l7X%x_ŤJq]X2ߩ]?Z bhTSN- Kn4/p$G SL&ob.f&OJci-24w>kt}

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Wang, H., Li, T., Chen, S., Gu, Y. & Ye, S. \nNeutrophil extracellular trap mi\ tochondrial DNA and its autoantibody in systemic lupus erythematosus \nand a proof-of-concept trial of metformin. 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Dinauer, M. C. Inflammatory consequences of inherited disorders affecting neut\ rophil function. Blood 133, 2130 2139 \(2019\).\r:125)/F 4/H/N/Rect[235.396 532.855 240.492 520.444]/Subtype/Link/Type/Annot>> endobj 339 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:39. Dinauer, M. C. Disorders of neutrophil function: \nan overview. Methods Mol. B\ iol. 412, 489 504 \(2007\).\r:126)/F 4/H/N/Rect[241.688 532.855 246.783 520.444]/Subtype/Link/Type/Annot>> endobj 340 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:40. Burgener, S. S. & Schroder, K. Neutrophil extracellular traps in host defense.\ Cold Spring Harb. Perspect. Biol. 12, a037028 \(2020\).\r:127)/F 4/H/N/Rect[243.831 345.855 249.135 333.444]/Subtype/Link/Type/Annot>> endobj 341 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:41. Brinkmann, V. etal. Neutrophil extracellular traps kill bacteria. Science \ 303, 1532 1535 \(2004\). \nThe first description of NETs.\r:128)/F 4/H/N/Rect[250.435 345.855 255.739 333.444]/Subtype/Link/Type/Annot>> endobj 342 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:41. Brinkmann, V. etal. Neutrophil extracellular traps kill bacteria. Science \ 303, 1532 1535 \(2004\). \nThe first description of NETs.\r:129)/F 4/H/N/Rect[249.947 301.855 255.271 289.444]/Subtype/Link/Type/Annot>> endobj 343 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:42. Yipp, B. G. etal. Infection-induced NETosis is a dynamic process involving ne\ utrophil multitasking invivo. Nat. Med. 18, 1386 1393 \(2012\).\r:130)/F 4/H/N/Rect[256.581 301.855 261.905 289.444]/Subtype/Link/Type/Annot>> endobj 344 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:34. Hidalgo, A. etal. Neutrophil extracellular traps: from physiology to patholo\ gy. Cardiovasc. Res. https://\ndoi.org/10.1093/cvr/cvab329 \(2021\).\r:131)/F 4/H/N/Rect[322.07 268.855 327.313 256.444]/Subtype/Link/Type/Annot>> endobj 345 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:43. Clark, S. R. etal. Platelet TLR4 activates neutrophil extracellular traps to \ ensnare bacteria in septic blood. Nat. Med. 13, 463 469 \(2007\).\r:132)/F 4/H/N/Rect[328.583 268.855 333.826 256.444]/Subtype/Link/Type/Annot>> endobj 346 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:45. Lood, C. etal. Neutrophil extracellular traps enriched in oxidized mitochon\ drial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, \n146 153 \(2016\). \nThis paper describes m\ itochondrial products and nucleic acid :133)/F 4/H/N/Rect[336.662 268.855 341.858 256.444]/Subtype/Link/Type/Annot>> endobj 347 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:Fig. 2 | Targeting neutrophil extracellular traps. The formation of neutroph\ il extracellular traps \(NETs\) can be triggered by various stimuli through engagement of surface receptors such as cytokine rece\ ptors, Fc receptors \(FcRs\), Toll-lik:134)/F 4/H/N/Rect[158.344 257.855 162.74 245.444]/Subtype/Link/Type/Annot>> endobj 348 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:46. Amulic, B. etal. Cell-cycle proteins control production of neutrophil extrace\ llular traps. Dev. Cell 43, \n449 462.e5 \(2017\).\r:135)/F 4/H/N/Rect[314.849 158.855 320.112 146.444]/Subtype/Link/Type/Annot>> endobj 349 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:47. Metzler, K. D., Goosmann, C., Lubojemska, A., Zychlinsky, A. & Papayannopoulos\ , V. \nA myeloperoxidase-containing complex regulates neutrophil elastase release and actin dynamics \nduring NETosis. Cell Rep.\ 8, 883 896 \(2014\).\r:136)/F 4/H/N/Rect[195.614 81.8547 200.954 69.4439]/Subtype/Link/Type/Annot>> endobj 350 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:50. Chen, K. W. etal. Noncanonical inflammasome signaling elicits gasdermin D-dep\ endent neutrophil extracellular traps. Sci. Immunol. 3, eaar6676 \n\(2018\).\r:137)/F 4/H/N/Rect[203.838 81.8547 209.178 69.4439]/Subtype/Link/Type/Annot>> endobj 351 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:51. O Neil, L. J. etal. Neutrophil-mediated carbamylation promotes articular dama\ ge in rheumatoid arthritis. Sci. Adv. 6, eabd2688 \(2020\).\r:138)/F 4/H/N/Rect[437.757 730.855 442.843 718.444]/Subtype/Link/Type/Annot>> endobj 352 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:52. Li, P. etal. PAD4 is essential for antibacterial innate immunity mediated by \ neutrophil extracellular traps. J. Exp. Med. 207, 1853 1862 \(2010\).\r:139)/F 4/H/N/Rect[391.742 653.855 396.917 641.444]/Subtype/Link/Type/Annot>> endobj 353 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:53. Liu, Y. etal. Peptidylarginine deiminases 2 and 4 modulate innate and adapti\ ve immune responses \nin TLR-7-dependent lupus. JCI Insight 3, e124729 \(2018\).\r:140)/F 4/H/N/Rect[427.716 587.855 432.813 575.444]/Subtype/Link/Type/Annot>> endobj 354 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:54. Tsourouktsoglou, T. D. etal. Histones, DNA, and citrullination promote neutro\ phil extracellular \ntrap inflammation by regulating the localization \nand activation of TLR4. Cell Rep. 31, 107602 \n\(2020\)\ .\r:141)/F 4/H/N/Rect[434.01 587.855 439.107 575.444]/Subtype/Link/Type/Annot>> endobj 355 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:55. Schauer, C. etal. Aggregated neutrophil extracellular traps limit inflammati\ on by degrading cytokines and chemokines. Nat. Med. 20, 511 517 \(2014\). \nA description of aggregated NET formation contri\ buting to disease resolution.\r:142)/F 4/H/N/Rect[445.308 521.855 450.382 509.444]/Subtype/Link/Type/Annot>> endobj 356 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:56. Hahn, J. etal. Aggregated neutrophil extracellular traps resolve inflammatio\ n by proteolysis of cytokines and chemokines and protection from antiproteases. FASEB J. 33, 1401 1414 \(2019\).\r:143)/F 4/H/N/Rect[451.568 521.855 456.642 509.444]/Subtype/Link/Type/Annot>> endobj 357 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:Fig. 3 | Organ-specific effects of neutrophils in autoimmune and autoinflammator\ y diseases. a | In some autoimmune conditions, such as systemic lupus erythematosus and antineutrophil cytoplasmic antibod\ y-associated vasculitis, glomerulonep:144)/F 4/H/N/Rect[518.671 433.855 523.27 421.444]/Subtype/Link/Type/Annot>> endobj 358 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:1. Nauseef, W. M. & Borregaard, N. Neutrophils at work. Nat. Immunol. 15, 602 \ 611 \(2014\).\r:145)/F 4/H/N/Rect[516.911 279.855 519.591 267.444]/Subtype/Link/Type/Annot>> endobj 359 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:57. Catrina, A. I., Svensson, C. I., Malmstrom, V., Schett, G. & Klareskog, L. Mec\ hanisms leading from systemic autoimmunity to joint-specific disease in rheumatoid arthritis. Nat. Rev. Rheumatol. 13, 79 86\ \(2017\).\r:146)/F 4/H/N/Rect[520.919 279.855 526.279 267.444]/Subtype/Link/Type/Annot>> endobj 360 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:58. Goldblatt, F. & O Neill, S. G. Clinical aspects of autoimmune rheumatic diseas\ es. Lancet 382, \n797 808 \(2013\).\r:147)/F 4/H/N/Rect[381.404 158.855 386.499 146.444]/Subtype/Link/Type/Annot>> endobj 361 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:59. Herrada, A. A. etal. Innate immune cells  contribution to systemic lupus eryt\ hematosus. Front. Immunol. 10, 772 \(2019\).\r:148)/F 4/H/N/Rect[491.992 92.8547 497.102 80.4439]/Subtype/Link/Type/Annot>> endobj 362 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:61. Arts, R. J. W., Joosten, L. A. B. & Netea, M. G. The potential role of trained\ immunity in autoimmune and autoinflammatory disorders. Front. Immunol. 9, 298 \(2018\).\r:149)/F 4/H/N/Rect[499.872 92.8547 504.982 80.4439]/Subtype/Link/Type/Annot>> endobj 363 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:194. Boeltz, S. etal. To NET or not to NET:current opinions and state of the scie\ nce regarding the formation of neutrophil extracellular traps. Cell Death Differ. 26, 395 408 \(2019\).\r:71)/F 4/H/N/Rect[177.413 679.298 184.54 670.032]/Subtype/Link/Type/Annot>> endobj 364 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:53. Liu, Y. etal. Peptidylarginine deiminases 2 and 4 modulate innate and adaptiv\ e immune responses \nin TLR-7-dependent lupus. JCI Insight 3, e124729 \(2018\).\r:72)/F 4/H/N/Rect[258.849 599.298 263.601 590.032]/Subtype/Link/Type/Annot>> endobj 365 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:195. Kienhofer, D. etal. Experimental lupus is aggravated in mouse strains with i\ mpaired induction of neutrophil extracellular traps. JCI Insight 2, e92920 \(2017\).\r:73)/F 4/H/N/Rect[264.581 599.298 271.709 590.032]/Subtype/Link/Type/Annot>> endobj 366 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:197. Hanata, N. etal. Peptidylarginine deiminase 4 promotes the renal infiltratio\ n of neutrophils and exacerbates the TLR7 agonist-induced lupus mice. Front. Immunol. 11, 1095 \(2020\).\r:74)/F 4/H/N/Rect[273.836 599.298 280.61 590.032]/Subtype/Link/Type/Annot>> endobj 367 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:55. Schauer, C. etal. Aggregated neutrophil extracellular traps limit inflammatio\ n by degrading cytokines and chemokines. Nat. 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Zhao, J. etal. A missense variant in NCF1 is associated with susceptibility t\ o multiple autoimmune diseases. Nat. Genet. 49, 433 437 \(2017\).\r:152)/F 4/H/N/Rect[328.133 664.855 333.325 652.444]/Subtype/Link/Type/Annot>> endobj 376 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:63. Gateva, V. etal. A large-scale replication study identifies TNIP1, PRDM1, JAZ\ F1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat. Genet. 41, 1228 1233 \(2009\).\r:153)/F 4/H/N/Rect[334.569 664.855 339.761 652.444]/Subtype/Link/Type/Annot>> endobj 377 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:29. Mistry, P. etal. Transcriptomic, epigenetic, and functional analyses implic\ ate neutrophil diversity in the pathogenesis of systemic lupus erythematosus. Proc. Natl Acad. Sci. 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Curr. Opin\ . Rheumatol. 26, 482 492 \(2014\).\r:166)/F 4/H/N/Rect[545.364 510.855 550.658 498.444]/Subtype/Link/Type/Annot>> endobj 390 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:73. Garcia-Romo, G. S. etal. Netting neutrophils are major inducers of type I IFN\ production in pediatric systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra20 \(2011\).\r:167)/F 4/H/N/Rect[405.05 488.855 410.146 476.444]/Subtype/Link/Type/Annot>> endobj 391 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:75. Villanueva, E. etal. Netting neutrophils induce endothelial damage, infiltrat\ e tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J. Immunol. 187, 538 552 \(2011\).\r:168)/F 4/H/N/Rect[411.342 488.855 416.437 476.444]/Subtype/Link/Type/Annot>> endobj 392 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:78. Bruschi, M. etal. Neutrophil extracellular traps profiles in patients with in\ cident systemic lupus erythematosus and lupus nephritis. J. Rheumatol. 47, 377 386 \(2020\).\r:169)/F 4/H/N/Rect[419.199 488.855 424.295 476.444]/Subtype/Link/Type/Annot>> endobj 393 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:79. Banchereau, R. etal. Personalized immunomonitoring uncovers molecular network\ s that stratify lupus patients. Cell 165, 551 565 \(2016\).\r:170)/F 4/H/N/Rect[422.144 444.855 427.375 432.444]/Subtype/Link/Type/Annot>> endobj 394 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:45. Lood, C. etal. Neutrophil extracellular traps enriched in oxidized mitocho\ ndrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, \n146 153 \(2016\). \nThis paper describes \ mitochondrial products and nucleic acid:171)/F 4/H/N/Rect[530.484 422.855 535.812 410.444]/Subtype/Link/Type/Annot>> endobj 395 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:80. Donnelly, S. etal. Impaired recognition of apoptotic neutrophils by the C1q/c\ alreticulin and CD91 pathway in systemic lupus erythematosus. Arthritis Rheum. 54, 1543 1556 \(2006\).\r:172)/F 4/H/N/Rect[537.124 422.855 542.452 410.444]/Subtype/Link/Type/Annot>> endobj 396 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:82. Alves, C. M. etal. Superoxide anion production \nby neutrophils is associated \ with prevalent clinical manifestations in systemic lupus erythematosus. \nClin. Rheumatol. 27, 701 708 \(2008\).\r:173)/F 4/H/N/Rect[545.33 422.855 550.658 410.444]/Subtype/Link/Type/Annot>> endobj 397 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:30. Carlucci, P. M. etal. Neutrophil subsets and their gene signature associate \ with vascular inflammation and coronary atherosclerosis in lupus. JCI Insight 3, e99276 \(2018\).\r:174)/F 4/H/N/Rect[460.264 367.855 465.32 355.444]/Subtype/Link/Type/Annot>> endobj 398 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:83. vander Linden, M. etal. Neutrophil extracellular trap release is associated \ with antinuclear antibodies in systemic lupus erythematosus and anti-phospholipid syndrome. Rheumatology 57, 1228 1234 \(201\ 8\).\r:175)/F 4/H/N/Rect[466.497 367.855 471.553 355.444]/Subtype/Link/Type/Annot>> endobj 399 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:84. Midgley, A. & Beresford, M. W. Increased expression of low density granulocyte\ s in juvenile-onset systemic lupus erythematosus patients correlates with disease activity. Lupus 25, 407 411 \(2016\).\r:17\ 6)/F 4/H/N/Rect[472.73 367.855 477.786 355.444]/Subtype/Link/Type/Annot>> endobj 400 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:73. Garcia-Romo, G. S. etal. Netting neutrophils are major inducers of type I IF\ N production in pediatric systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra20 \(2011\).\r:177)/F 4/H/N/Rect[540.804 334.855 546.168 322.444]/Subtype/Link/Type/Annot>> endobj 401 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:85. Gestermann, N. etal. Netting neutrophils activate autoreactive B cells in lup\ us. J. Immunol. 200, \n3364 3371 \(2018\).\r:178)/F 4/H/N/Rect[547.499 334.855 552.756 322.444]/Subtype/Link/Type/Annot>> endobj 402 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:29. Mistry, P. etal. Transcriptomic, epigenetic, and functional analyses impli\ cate neutrophil diversity in the pathogenesis of systemic lupus erythematosus. Proc. Natl Acad. Sci. 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Lood, C. etal. Neutrophil extracellular traps enriched in oxidized mitoch\ ondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, \n146 153 \(2016\). \nThis paper describes\ mitochondrial products and nucleic aci:185)/F 4/H/N/Rect[227.863 202.855 233.071 190.444]/Subtype/Link/Type/Annot>> endobj 420 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:83. vander Linden, M. etal. Neutrophil extracellular trap release is associated\ with antinuclear antibodies in systemic lupus erythematosus and anti-phospholipid syndrome. Rheumatology 57, 1228 1234 \(20\ 18\).\r:186)/F 4/H/N/Rect[234.323 202.855 239.531 190.444]/Subtype/Link/Type/Annot>> endobj 421 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:88. Yu, Y. & Su, K. Neutrophil extracellular traps and systemic lupus erythematosu\ s. J. Clin. 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Netting neutrophils induce endothelial damage, infiltra\ te tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J. Immunol. 187, 538 552 \(2011\).\r:190)/F 4/H/N/Rect[303.99 158.855 309.295 146.444]/Subtype/Link/Type/Annot>> endobj 425 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:76. Hakkim, A. etal. Impairment of neutrophil extracellular trap degradation is a\ ssociated with lupus nephritis. Proc. Natl Acad. Sci. USA 107, 9813 9818 \(2010\).\r:191)/F 4/H/N/Rect[539.274 169.855 544.368 157.444]/Subtype/Link/Type/Annot>> endobj 426 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:89. Jimenez-Alcazar, M. etal. Host DNases prevent vascular occlusion by neutrophi\ l extracellular traps. Science 358, 1202 1206 \(2017\).\r:192)/F 4/H/N/Rect[545.564 169.855 550.658 157.444]/Subtype/Link/Type/Annot>> endobj 427 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:90. Al-Mayouf, S. M. etal. 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Lood, C. etal. Neutrophil extracellular traps enriched in oxidized mito\ chondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, \n146 153 \(2016\). \nThis paper describ\ es mitochondrial products and nucleic a:198)/F 4/H/N/Rect[197.305 719.855 202.54 707.444]/Subtype/Link/Type/Annot>> endobj 614 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:77. Leffler, J. etal. Neutrophil extracellular traps that \nare not degraded in sy\ stemic lupus erythematosus activate complement exacerbating the disease. \nJ. Immunol. 188, 3522 3531 \(2012\).\r:199)/F 4/H/N/Rect[203.805 719.855 209.04 707.444]/Subtype/Link/Type/Annot>> endobj 615 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:94. Gehrke, N. etal. Oxidative damage of DNA confers resistance to cytosolic nucl\ ease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity 39, 482 495 \(2013\).\r:200)/F 4/H/N/Rect[210.305 719.855 215.54 707.444]/Subtype/Link/Type/Annot>> endobj 616 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:96. Antiochos, B. etal. The DNA sensors AIM2 and IFI16 are SLE autoantigens that \ bind neutrophil extracellular traps. eLife 11, e72103 \(2022\).\r:201)/F 4/H/N/Rect[218.372 719.855 223.606 707.444]/Subtype/Link/Type/Annot>> endobj 617 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:97. Apel, F. etal. The cytosolic DNA sensor cGAS recognizes neutrophil extracellu\ lar traps. Sci. Signal. 14, eaax7942 \(2021\).\r:202)/F 4/H/N/Rect[307.672 697.855 312.692 685.444]/Subtype/Link/Type/Annot>> endobj 618 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:45. Lood, C. etal. Neutrophil extracellular traps enriched in oxidized mit\ ochondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, \n146 153 \(2016\). \nThis paper descri\ bes mitochondrial products and nucleic :203)/F 4/H/N/Rect[234.093 642.855 239.019 630.444]/Subtype/Link/Type/Annot>> endobj 619 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:98. Tumurkhuu, G. etal. Oxidative DNA damage accelerates skin inflammation in pri\ stane-induced lupus model. Front. Immunol. 11, 554725 \(2020\).\r:204)/F 4/H/N/Rect[292.761 620.855 297.781 608.444]/Subtype/Link/Type/Annot>> endobj 620 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:72. Lande, R. etal. Neutrophils activate plasmacytoid dendritic cells by releasi\ ng self-DNA-peptide complexes in systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra19 \(2011\).\r:205)/F 4/H/N/Rect[475.059 642.855 480.423 630.444]/Subtype/Link/Type/Annot>> endobj 621 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:73. Garcia-Romo, G. S. etal. Netting neutrophils are major inducers of type I \ IFN production in pediatric systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra20 \(2011\).\r:206)/F 4/H/N/Rect[481.753 642.855 487.117 630.444]/Subtype/Link/Type/Annot>> endobj 622 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:85. Gestermann, N. etal. Netting neutrophils activate autoreactive B cells in lu\ pus. J. Immunol. 200, \n3364 3371 \(2018\).\r:207)/F 4/H/N/Rect[488.447 642.855 493.811 630.444]/Subtype/Link/Type/Annot>> endobj 623 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_787.indd:99. Georgakis, S. etal. NETs decorated with bioactive IL-33 infiltrate inflamed t\ issues and induce IFN-alpha production in patients with SLE. 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