doi:10.16138/j.1673-6087.2021.01.012

Abstract

CLC Number:

R543

Figures/Tables 2

模型	动物	建模方法	机制	模型特点	研究方向
ANCA相关EAV	WKY大鼠	hMPO免疫WKY大鼠	主动免疫MPO诱导抗MPO抗体反应	主动免疫打破了自身耐受,且无需其他干预措施;但使用该方法仅能在WKY大鼠品系中建模成功,且与人类疾病相比病理改变轻微	固有免疫在发病中的机制
抗GBM抗体激活的主动免疫性小鼠模型	C57BL/6小鼠	hMPO免疫C57BL/6小鼠后给予低于致肾炎剂量的羊抗鼠GBM抗体	主动免疫MPO诱导抗MPO抗体反应	主动免疫打破了自身免疫耐受,建模周期较短;但需要外源性免疫球蛋白（抗GBM抗体）的刺激以引发疾病,仅适用于AAV病程早期的相关研究	固有免疫在发病中的机制
基于MPO^-/-小鼠的MPO-ANCA被动转移模型	C57BL/6野生型或Rag2^-/- 小鼠	小鼠MPO免疫MPO^-/-小鼠获得MPO-ANCA,再将MPO-ANCA转移至野生型或Rag2^-/-小鼠体内	被动免疫MPO-ANCA与表达MPO的中性粒细胞相互作用	可用于研究ANCA的直接作用,且建模周期短,重复性好;但未打破免疫耐受,不属于真正意义上的自身免疫疾病	ANCA直接致病机制
基于MPO^-/-小鼠的抗MPO脾细胞被动转移模型	C57BL/6 Rag2^-/-小鼠	小鼠MPO免疫MPO^-/-小鼠获得抗MPO脾细胞,再将抗MPO脾细胞转移至野生型或Rag2^-/-小鼠体内	MPO特异性T细胞、B细胞介导损伤	病理改变较其他模型严重,更接近人类疾病;不属于真正意义上的自身免疫疾病,向免疫缺陷小鼠中转移的脾细胞出现异常增生,并导致肾小球中有免疫复合物沉积	免疫细胞（T、B、中性粒细胞）在ANCA相关性血管炎发病机制及作用
MPO^-/-小鼠辐照后MPO^+/+骨髓移植模型	C57BL/6 MPO^-/-小鼠辐照后接受MPO^+/+骨髓移植	小鼠MPO免疫MPO^-/-小鼠诱导MPO-ANCA,经辐照和骨髓移植引入MPO^+/+中性粒细胞	MPO-ANCA与MPO^+/+中性粒细胞相互作用	不必从小鼠血清中分离ANCA,实现了ANCA的持续产生,可用于研究ANCA的直接作用;但与ANCA相互作用的中性粒细胞来自异体,不属于真正意义上的自身免疫疾病,且建模方法复杂,周期长而病理改变轻微
MPO特异性T细胞转移模型	C57BL/6 Rag1^-/-小鼠	MPO或MPO T细胞表位免疫小鼠获得MPO特异性T细胞,再将其被动转移至Rag1^-/-小鼠体内后通过沉积MPO诱发疾病	MPO特异性T细胞识别肾小球中沉积的MPO介导疾病	可用于研究细胞免疫在AAV中的作用;不属于真正意义上的自身免疫疾病,建模方法复杂,未提及是否有免疫复合物形成,Rag1^-/-小鼠具有的免疫缺陷在AAV患者中并不存在

References 48

[1]	Kitching AR, Anders HJ, Basu N, et al. ANCA-associated vasculitis[J]. Nat Rev Dis Primers, 2020, 6(1): 71. doi: 10.1038/s41572-020-0204-y pmid: 32855422
[2]	Kronbichler A, Shin JI, Lee KH, et al. Clinical associations of renal involvement in ANCA-associated vasculitis[J]. Autoimmun Rev, 2020, 19(4):102495. doi: 10.1016/j.autrev.2020.102495 URL
[3]	Centenera MM, Scott JS, Machiels J, et al. ELOVL5 is a critical and targetable fatty acid elongase in prostate cancer[J]. Cancer Res, 2021. [Epub ahead of print].
[4]	陈楠, 陈永熙. ANCA相关性小血管炎的肾外表现[J]. 临床肾脏病杂志, 2008, 28(5): 203-205.
[5]	Chen YX, Yu HJ, Zhang W, et al. Analyzing fatal cases of Chinese patients with primary antineutrophil cytoplasmic antibodies-associated renal vasculitis: a 10-year retrospective study[J]. Kidney Blood Press Res, 2008, 31(5): 343-349. doi: 10.1159/000165117 URL
[6]	Chen YX, Chen N. Pathogenesis of rapidly progressive glomerulonephritis: what do we learn[J]?. Contrib Nephrol, 2013, 181: 207-215.
[7]	Chen YX, Chen XN. Antineutrophil cytoplasmic antibodies-associated glomerulonephritis: From bench to bedside[J]. Chronic Dis Transl Med, 2018, 4(3): 187-191.
[8]	Chen YX, Xu J, Pan XX, et al. Histopathological classification and renal outcome in patients with antineutrophil cytoplasmic antibodies-associated renal vasculitis: a study of 186 patients and metaanalysis[J]. J Rheumatol, 2017, 44(3): 304-313. doi: 10.3899/jrheum.160866 URL
[9]	Chen YX, Yu HJ, Ni LY, et al. Propylthiouracil-associated antineutrophil cytoplasmic autoantibody-positive vasculitis: retrospective study of 19 cases[J]. J Rheumatol, 2007, 34(12): 2451-2456.
[10]	Chen YX, Zhang W, Chen XN, et al. Propylthiouracil-induced antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis versus primary ANCA-associated renal vasculitis: a comparative study[J]. J Rheumatol, 2012, 39(3): 558-563. doi: 10.3899/jrheum.110931 URL
[11]	Ramponi G, Folci M, De Santis M, et al. The biology, pathogenetic role, clinical implications, and open issues of serum anti-neutrophil cytoplasmic antibodies[J]. Autoimmun Rev, 2021. [Epub ahead of print].
[12]	Nakazawa D, Masuda S, Tomaru U, et al. Pathogenesis and therapeutic interventions for ANCA-associated vasculitis[J]. Nat Rev Rheumatol, 2019, 15(2): 91-101. doi: 10.1038/s41584-018-0145-y pmid: 30542206
[13]	Esnault VL, Mathieson PW, Thiru S, et al. Autoantibodies to myeloperoxidase in brown Norway rats treated with mercuric chloride[J]. Lab Invest, 1992, 67(1): 114-120. pmid: 1320710
[14]	Kinjoh K, Kyogoku M, Good RA. Genetic selection for crescent formation yields mouse strain with rapidly progressive glomerulonephritis and small vessel vasculitis[J]. Proc Natl Acad Sci U S A, 1993, 90(8): 3413-3417. pmid: 8475090
[15]	Kobayashi K, Shibata T, Sugisaki T. Aggravation of rat nephrotoxic serum nephritis by anti-myeloperoxidase antibodies[J]. Kidney Int, 1995, 47(2): 454-463. pmid: 7723233
[16]	Heeringa P, Brouwer E, Klok PA, et al. Autoantibodies to myeloperoxidase aggravate mild anti-glomerular-basement-membrane-mediated glomerular injury in the rat[J]. Am J Pathol, 1996, 149(5): 1695-1706. pmid: 8909258
[17]	Brouwer E, Huitema MG, Klok PA, et al. Antimyeloperoxidase-associated proliferative glomerulonephritis: an animal model[J]. J Exp Med, 1993, 177(4): 905-914. doi: 10.1084/jem.177.4.905 pmid: 8384653
[18]	Hutton HL, Holdsworth SR, Kitching AR. ANCA-associated vasculitis: pathogenesis, models, and preclinical testing[J]. Semin Nephrol, 2017, 37(5):418-435. doi: S0270-9295(17)30055-4 pmid: 28863790
[19]	Little MA, Smyth CL, Yadav R, et al. Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte-microvascular interactions in vivo[J]. Blood, 2005, 106(6): 2050-2058. doi: 10.1182/blood-2005-03-0921 pmid: 15933057
[20]	Ruth AJ, Kitching AR, Kwan RY, et al. Anti-neutrophil cytoplasmic antibodies and effector CD4⁺ cells play nonredundant roles in anti-myeloperoxidase crescentic glomerulonephritis[J]. J Am Soc Nephrol, 2006, 17(7):1940-1949. doi: 10.1681/ASN.2006020108 URL
[21]	Chang J, Eggenhuizen P, O’sullivan KM, et al. CD8⁺ T cells effect glomerular injury in experimental anti-myeloperoxidase GN[J]. J Am Soc Nephrol, 2017, 28(1): 47-55. doi: 10.1681/ASN.2015121356 URL
[22]	Gan PY, O’sullivan KM, Ooi JD, et al. Mast cell stabilization ameliorates autoimmune anti-myeloperoxidase glomerulonephritis[J]. J Am Soc Nephrol, 2016, 27(5): 1321-1233. doi: 10.1681/ASN.2014090906 URL
[23]	Odobasic D, Oudin V, Ito K, et al. Tolerogenic dendritic cells attenuate experimental autoimmune antimyeloperoxidase glomerulonephritis[J]. J Am Soc Nephrol, 2019, 30(11): 2140-2157. doi: 10.1681/ASN.2019030236 pmid: 31444274
[24]	Gan PY, Chan A, Ooi JD, et al. Biologicals targeting T helper cell subset differentiating cytokines are effective in the treatment of murine anti-myeloperoxidase glomerulonephritis[J]. Kidney Int, 2019, 96(5): 1121-1133. doi: 10.1016/j.kint.2019.05.012 URL
[25]	Ooi JD, Jiang JH, Eggenhuizen PJ, et al. A plasmid-encoded peptide from Staphylococcus aureus induces anti-myeloperoxidase nephritogenic autoimmunity[J]. Nat Commun, 2019, 10(1): 3392. doi: 10.1038/s41467-019-11255-0 URL
[26]	Ooi JD, Gan PY, Chen T, et al. FcγRIIB regulates T-cell autoreactivity, ANCA production, and neutrophil activation to suppress anti-myeloperoxidase glomerulonephritis[J]. Kidney Int, 2014, 86(6): 1140-1149. doi: 10.1038/ki.2014.189 URL
[27]	Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice[J]. J Clin Invest, 2002, 110(7): 955-963. doi: 10.1172/JCI0215918 URL
[28]	安晓宁, 陈永熙. 单核-巨噬细胞在抗中性粒细胞胞浆抗体相关性血管炎中作用的研究进展[J]. 上海交通大学学报(医学版), 2020, 40(1): 123-127.
[29]	Rousselle A, Kettritz R, Schreiber A. Monocytes promote crescent formation in anti-myeloperoxidase antibody-induced glomerulonephritis[J]. Am J Pathol, 2017, 187(9): 1908-1915. doi: S0002-9440(17)30018-4 pmid: 28667835
[30]	Hu P, Su H, Xiao H, et al. Kinin B1 receptor is important in the pathogenesis of myeloperoxidase-specific ANCA GN[J]. J Am Soc Nephrol, 2020, 31(2):297-307. doi: 10.1681/ASN.2019010032 URL
[31]	Choi M, Schreiber A, Eulenberg-Gustavus C, et al. Endothelial NF-κB blockade abrogates ANCA-induced GN[J]. J Am Soc Nephrol, 2017, 28(11): 3191-3204. doi: 10.1681/ASN.2016060690 URL
[32]	Wang Q, van Timmeren MM, Petersen AH, et al. Age-determined severity of anti-myeloperoxidase autoantibody-mediated glomerulonephritis in mice[J]. Nephrol Dial Transplant, 2017, 32(2): 254-264.
[33]	Xiao H, Ciavatta D, Aylor DL, et al. Genetically determined severity of anti-myeloperoxidase glomerulonephritis[J]. Am J Pathol, 2013, 182(4): 1219-1226. doi: 10.1016/j.ajpath.2012.12.006 URL
[34]	Schreiber A, Xiao H, Falk RJ, et al. Bone marrow-derived cells are sufficient and necessary targets to mediate glomerulonephritis and vasculitis induced by anti-myeloperoxidase antibodies[J]. J Am Soc Nephrol, 2006, 17(12): 3355-3364. pmid: 17108314
[35]	Ooi JD, Chang J, Hickey MJ, et al. The immunodominant myeloperoxidase T-cell epitope induces local cell-mediated injury in antimyeloperoxidase glomerulonephritis[J]. Proc Natl Acad Sci U S A, 2012, 109(39): E2615-E2624.
[36]	Gan PY, Holdsworth SR, Kitching AR, et al. Myeloperoxidase (MPO)-specific CD4⁺ T cells contribute to MPO-anti-neutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis[J]. Cell Immunol, 2013, 282(1): 21-27. doi: 10.1016/j.cellimm.2013.04.007 URL
[37]	Pfister H, Ollert M, Fröhlich LF, et al. Antineutrophil cytoplasmic autoantibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo[J]. Blood, 2004, 104(5): 1411-1418. doi: 10.1182/blood-2004-01-0267 pmid: 15150076
[38]	van Der Geld YM, Hellmark T, Selga D, et al. Rats and mice immunised with chimeric human/mouse proteinase 3 produce autoantibodies to mouse Pr3 and rat granulocytes[J]. Ann Rheum Dis, 2007, 66(12): 1679-1682. doi: 10.1136/ard.2006.064626 URL
[39]	Primo VC, Marusic S, Franklin CC, et al. Anti-PR3 immune responses induce segmental and necrotizing glomerulonephritis[J]. Clin Exp Immunol, 2010, 159(3): 327-337. doi: 10.1111/j.1365-2249.2009.04072.x pmid: 20015271
[40]	Little MA, Al-Ani B, Ren S, et al. Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system[J]. PLoS One, 2012, 7(1): e28626. doi: 10.1371/journal.pone.0028626 URL
[41]	Li N, Zhu B, Zhu Q, et al. Serum lysosomal-associated membrane protein-2 levels are increased in small and medium-vessel vasculitis, especially in polyarteritis nodosa[J]. Clin Exp Rheumatol, 2019, 37 Suppl 117(2):79-85.
[42]	Tang S, Zhang Y, Yin SW, et al. Neutrophil extracellular trap formation is associated with autophagy-related signalling in ANCA-associated vasculitis[J]. Clin Exp Immunol, 2015, 180(3): 408-418. doi: 10.1111/cei.12589 pmid: 25644394
[43]	Sangaletti S, Tripodo C, Chiodoni C, et al. Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity[J]. Blood, 2012, 120(15): 3007-3018. doi: 10.1182/blood-2012-03-416156 pmid: 22932797
[44]	Nakazawa D, Tomaru U, Suzuki A, et al. Abnormal conformation and impaired degradation of propylthiouracil-induced neutrophil extracellular traps: implications of disordered neutrophil extracellular traps in a rat model of myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis[J]. Arthritis Rheum, 2012, 64(11): 3779-3787. doi: 10.1002/art.34619 URL
[45]	Martin KR, Pederzoli-Ribeil M, Pacreau E, et al. Transgenic mice expressing human proteinase 3 exhibit sustained neutrophil-associated peritonitis[J]. J Immunol, 2017, 199(11): 3914-3924. doi: 10.4049/jimmunol.1601522 URL
[46]	Merkel PA, Xie G, Monach PA, et al. Identification of functional and expression polymorphisms associated with risk for antineutrophil cytoplasmic autoantibody-associated vasculitis[J]. Arthritis Rheumatol, 2017, 69(5):1054-1066. doi: 10.1002/art.40034 URL
[47]	Nusser A, Nuber N, Wirz OF, et al. The development of autoimmune features in aging mice is closely associated with alterations of the peripheral CD4⁺ T-cell compartment[J]. Eur J Immunol, 2014, 44(10): 2893-2902. doi: 10.1002/eji.201344408 pmid: 25044476
[48]	Tao L, Reese TA. Making mouse models that reflect human immune responses[J]. Trends Immunol, 2017, 38(3):181-193. doi: 10.1016/j.it.2016.12.007 URL

模型	动物	建模方法	机制	模型特点	研究方向
重组小鼠PR3-ANCA被动转移模型	129/SvEv小鼠	重组mPR3免疫mPR3/mNE双基因敲除小鼠获得PR3-ANCA,再将PR3-ANCA转移至野生型小鼠体内	PR3-ANCA与中性粒细胞相互作用	仅加重了TNF-α诱发的局部炎症反应,并未引起血管炎	中性粒细胞在疾病发病中机制及作用
PR3免疫的NOD小鼠脾细胞被动转移至NOD/SCID小鼠模型	NOD/SCID小鼠	mPR3免疫NOD小鼠获得抗PR3脾细胞,再将抗PR3脾细胞转移至NOD/SCID小鼠体内	PR3特异性T细胞、B细胞介导损伤	出现了新月体性肾小球肾炎相关症状;不属于真正意义上的自身免疫,仅有肾脏症状而缺乏人类PR3-AAV的肺部症状,且小鼠的免疫缺陷状态与人类患者不相符	T、B细胞在疾病发病中作用及机制
PR3-ANCA被动转移至人源化嵌合小鼠模型	人源化NOD/SCID/IL-2R^-/-小鼠	将人造血干细胞注射到受辐照的NOD/SCID/IL-2R^-/-小鼠体内建立人源化小鼠,然后接受人类患者PR3-ANCA	人PR3-ANCA与来自人造血干细胞的中性粒细胞和单核细胞相互作用	可用于研究PR3-ANCA的直接作用,出现了与人类疾病相似的肺部和肾脏症状;但建模过程复杂而疾病症状较为轻微,小鼠的免疫缺陷状态与人类患者亦不相符	中性粒细胞和单核细胞在疾病发病中作用及机制

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