儿童自身炎症性疾病(autoinflammatory diseases，AID)通常是指一组由固有免疫参与介导的遗传性疾病，但近年来发现有些AID不具有明确的遗传史，受多种基因和环境因素共同作用[1]。儿童AID主要包括①遗传性周期热综合征：冷炎素相关周期热综合征(cryopyrin-associated periodic syndromes，CAPS，包括家族性寒冷性自身炎症综合征、Muckle-Wells综合征、新生儿期发病的多系统炎性疾病)，家族性地中海热(familial mediteranean fever，FMF)，高IgD伴周期热综合征，TNF受体相关周期热综合征[2]；②化脓性(非感染性)疾病：无菌性化脓性关节炎、坏疽性脓皮病、痤疮综合征(PAPA综合征)、Majeed综合征；③免疫介导的肉芽肿疾病：Blau综合征、克罗恩病；④特发性发热综合征：幼年特发性关节炎(juvenile idiopathic arthritis，JIA)、白塞综合征等[3]。该组疾病表现为反复的发热、皮疹、关节痛、关节炎等全身炎症反应，IL-1家族细胞因子(主要包括IL-1β和IL-18)水平升高[4]。NLRP3炎症小体是由受体蛋白(NLR蛋白)、接头蛋白[凋亡相关斑点样蛋白(apoptosis associated speck-like protein containing a caspase recruitment domain，ASC)]和效应蛋白(pro-caspase-1)构成的多蛋白复合物[5]，它通过激活半胱氨酸天冬氨酸特异性蛋白酶1(caspase-1)，促进IL-1β和IL-18的成熟和分泌，参与炎症反应[6]。近些年关于NLRP3炎症小体与AID关系的研究逐渐增多。已有研究显示，IL-1受体拮抗剂(Anakinra)和IL-1β单克隆抗体(Canakinumab)对儿童AID患者取有较好的疗效[7]。本文就NLRP3炎症小体参与儿童AID发病机制的研究进展作一综述。
1 NLRP3炎症小体与冷炎素相关周期热综合征CAPS为常染色体显性遗传病，系NLRP3基因获得性功能突变所致[8]。NLRP3基因定位于1号染色体短臂上(即1q44)，编码NLRP3蛋白(又称冷炎素，cryopyrin)[9]。目前NLRP3基因共有177种突变，多位于3号外显子或4号内含子上[10]。其中，T348M、D303N突变与CAPS病情严重程度相关[11]。有些患者生殖细胞中没有NLRP3突变，但是体细胞嵌合体中存在NLRP3突变[12]。家族性寒冷性自身炎症综合征患者外周血白细胞中NLRP3杂合突变使NLRP3炎症小体过度激活，进而起病[13]。Muckle-Wells综合征是由于NLRP3 NACHT结构域的错义突变导致NLRP3蛋白功能增强使NLRP3炎症小体持续活化。研究显示，NLRP3 T348M基因参与Muckle-Wells综合征的发生[14]。中国汉族一例Muckle-Wells综合征患者NLRP3中p.D31V基因突变促进NLRP3炎症小体的激活[15]。新生儿期发病的多系统炎性疾病患者脑脊液可检测到NLRP3基因突变，但其血清中未检测到。测序整个NLRP3基因发现外显子4(G755R、G755A)和外显子6(Y859C)的错义突变参与CAPS的发病[16]。此外，Yu等[17]发现NLRP3炎症小体缺陷小鼠模型IL-1产生过剩，导致CAPS炎症症状。
CAPS的诊断主要依据典型临床表现，基因检测有助于诊断。Anakinra治疗Muckle-Wells综合征和新生儿期发病的多系统炎性疾病疗效显著，但伴有关节严重破坏的CAPS患者对Anakinra应答不佳[18]；IL-1β单克隆抗体Canakinumab可使97%的CAPS患者症状改善[19]。
2 NLRP3炎症小体与家族性地中海热FMF是由编码Pyrin蛋白的MEFV基因突变引起的常染色体隐性遗传病[20]。Pyrin主要表达于中性粒细胞和单核细胞的细胞质中，其热蛋白结构域(PYD)可竞争性地与ASC分子PYD结合，从而减少NLRP3与ASC结合，抑制NLRP3炎症小体形成。MVEF突变系功能缺失性突变，可导致Pyrin数量减少或功能改变，致使NLRP3炎症小体过度活化。Repa等[21]发现，FMF患者新分离的白细胞中NLRP3和caspase-1表达水平较对照组下降。Mitroulis等[22]发现无症状FMF患者中性粒细胞NLRP3 mRNA水平降低。除MEFV基因突变外，Timerman等[23]在FMF样周期性发热综合征患者中还发现了NLRP3基因突变，猜测其为多基因遗传病。Chae等[24]的FMF动物模型也证实，单核细胞分泌IL-1β是通过NLRP3介导的。
基因检查有助于FMF的诊断。治疗首选秋水仙碱。但Manukyan等[25]发现使用秋水仙碱治疗一些难治性FMF时，NLRP3和MEFV的表达量较健康对照组增加，这可能是秋水仙碱疗效不佳的原因。此外，随机对照研究结果显示，Anakinra和Canakinumab治疗秋水仙碱抵抗的FMF患者安全、有效[26]。
3 NLRP3炎症小体与幼年特发性关节炎JIA是最常见的儿童风湿性疾病之一，共七个亚型，其中全身型JIA是最严重的亚型。NLRP3基因突变在全身型JIA的发生发展中具有调控作用[27]。Tadaki等[28]通过研究50例全身型JIA患者发现，NLRP基因19q13.42从头重复突变与全身型JIA相关。急性活动期全身型JIA患者单个核细胞微阵列分析结果提示IL-1β以及IL-1受体基因表达上调[29]。在日本发现一例3岁JIA患儿存在NLRP3 E378K位点基因突变，且血清IL-1β、IL-6和IL-18水平明显升高[30]。中国台湾的一项研究表明，携带NLRP3 rs4353135 G等位基因增加了少关节型或多关节型JIA发生的风险，该基因与高水平的CRP和红细胞沉降率正相关，而rs4353135、rs2043211单核苷酸多态性与全身型JIA患者易感性不相关[31]。Day等[32]研究结果显示，银屑病性关节炎与MEFV SNP rs224204(P=0.025)和NLRP3 SNP rs3806265(P=0.04)存在显著的相关性。Lamot等[33]研究结果表明，NLRP3和TLR4是全身性自身炎症性疾病最重要的基因，CXCR4和PTPN12共同参与附着点相关性关节炎的病理生理机制。随机双盲对照研究结果显示，Canakinumab治疗全身型JIA是安全、有效的，全身型JIA患者早期使用Anakinra或Canakinumab可延长疾病的稳定期[34]。
4 NLRP3炎性小体与Majeed综合征Majeed综合征是新生儿期常染色体隐性遗传病，为脂质2(LPIN2)基因突变所致，可编码LPIN2蛋白[35]。正常情况下，LPIN2通过抑制嘌呤能离子通道型受体7(P2X7R)来抑制NLRP3炎症小体的活化。Majeed综合征患者LPIN2基因突变，抑制作用减弱，炎症小体活化增强[35]。Scianaro等[36]的研究结果显示，慢性反复性多发性骨髓炎活动期NLRP3 mRNA表达水平较健康对照组和疾病缓解期组明显升高。治疗上，Herlin等[37]的研究结果显示，IL-1阻滞剂(Anakinra或Canakinumab)治疗Majeed综合征疗效显著，患者的临床症状及实验室检查结果明显改善。
5 NLRP3炎症小体与PAPA综合征PAPA综合征是罕见的常染色体显性遗传病，是由PSTPIPI基因突变所致，后者又称CD2结合蛋白1(CD2BP1)。PSTPIPI基因突变(A230T、E250Q)可致CD2BP1的过度磷酸化，增强Pyrin-CD2BP1的结合，干扰Pyrin对NLRP3炎症小体的负性抑制作用，导致促炎细胞因子过度产生，从而引起PAPA综合征[38]。伴有骨破坏的PAPA综合征患者经Anakinra治疗后临床症状改善，6个月后影像学表现明显改善[39]。
除上述AID外，NLRP3还参与其他AID的发病机制。如在自身炎症性神经系统疾病的家系中通过基因测序检测到NLRP3 c.864C>G(p.I288M)上存在突变[40]；也有报道儿童Schnitzler综合征患者出现NLRP3 V198M突变[41]。
综上所述，大量研究证实NLRP3炎症小体与多种AID相关，但发病机制尚未完全明确。NLRP3炎症通路上任何蛋白表达失调都会影响疾病的发生、发展。期待能有更多的研究来证实该炎症小体在AID中的作用，为AID的治疗提供新的方案。
| [1] | ÁLVAREZ-ERRICO D, VENTO-TORMO R, BALLESTAR E. Genetic and epigenetic determinants in autoinflammatory diseases[J]. Front Immunol, 2017, 8: 318. |
| [2] | PARK H, BOURLA A B, KASTNER D L, et al. Lighting the fires within:the cell biology of autoinflammatory diseases[J]. Nat Rev Immunol, 2012, 12(8): 570–580. doi:10.1038/nri3261 |
| [3] | 李冀, 宋红梅. 自身炎症性疾病分类[J]. 协和医学杂志, 2014, 5(4): 450–454. LI Ji, SONG Hongmei. Classification of inflammatory diseases[J]. Medical Journal of Peking Union Medical College Hospital, 2014, 5(4): 450–454. (in Chinese) |
| [4] | HOFFMAN H M, BRODERICK L. The role of the inflammasome in patients with autoinflammatory diseases[J]. J Allergy Clin Immunol, 2016, 138(1): 3–14. doi:10.1016/j.jaci.2016.05.001 |
| [5] | TONG Y, DING Z H, ZHAN F X, et al. The NLRP3 inflammasome and stroke[J]. Int J Clin Exp Med, 2015, 8(4): 4787–4794. |
| [6] | KANG M J, JO S G, KIM D J, et al. NLRP3 inflammasome mediates interleukin-1beta production in immune cells in response to Acinetobacter baumannii and contributes to pulmonary inflammation in mice[J]. Immunology, 2017, 150(4): 495–505. doi:10.1111/imm.2017.150.issue-4 |
| [7] | CUSH J J. Autoinflammatory syndromes[J]. Dermatol Clin, 2013, 31(3): 471–480. doi:10.1016/j.det.2013.05.001 |
| [8] | AKSENTIJEVICH I, NOWAK M, MALLAH M, et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory dis-ease (NOMID):a new member of the expanding family of pyrin-associated autoinflammatory diseases[J]. Arthritis Rheum, 2012, 46(12): 3340–3348. |
| [9] | EROGLU F K, KASAPCOPUR O, BEŞBAŞN, et al. Genetic and clinical features of cryopyrin-associated periodic syndromes in Turkish children[J]. Clin Exp Rheumatol, 2016, 34(6 Suppl 102): S115–S120. |
| [10] | SARRABAY G, GRANDEMANGE S, TOUITOU I. Diagnosis of cryopyrin-associated periodic syndrome:challenges, recommendations and emerging concepts[J]. Expert Rev Clin Immunol, 2015, 11(7): 827–835. doi:10.1586/1744666X.2015.1047765 |
| [11] | NAKAGAWA K, GONZALEZ-ROCA E, SOUTO A, et al. Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes[J]. Ann Rheum Dis, 2015, 74(3): 603–610. doi:10.1136/annrheumdis-2013-204361 |
| [12] | MENSA-VILARO A, TERESA B M, MAGRI G, et al. Brief report:late-onset cryopyrin-associated periodic syndrome due to myeloid-restricted somatic NLRP3 mosaicism[J]. Arthritis Rheumatol, 2016, 68(12): 3035–3041. doi:10.1002/art.39770 |
| [13] | BRODERICK L, DE NARDO D, FRANKLIN B S, et al. The inflammasomes and autoinflammatory syndromes[J]. Annu Rev Pathol, 2015, 10: 395–424. doi:10.1146/annurev-pathol-012414-040431 |
| [14] | NAZ V E, CARO G D, PINEDOi M F, et al. Muckle-Wells syndrome:a case report with an NLRP3 T348M mutation[J]. Pediatr Dermatol, 2016, 33(5): e311–e314. doi:10.1111/pde.2016.33.issue-5 |
| [15] | HU J, ZHU Y, ZHANG J Z, et al. A novel mutation in the pyrin domain of the NOD-like receptor family pyrin domain containing protein 3 in Muckle-Wells syndrome[J]. Chin Med J (Engl), 2017, 130(5): 586–593. doi:10.4103/0366-6999.200537 |
| [16] | STOJANOV S, WEISS M, LOHSE P, et al. A novel CIAS1 mutation and plasma/cerebrospinal fluid cytokine profile in a German patient with neonatal-onset multisystem inflammatory disease responsive to methotrexate therapy[J]. Pediatrics, 2004, 114(1): e124–e127. doi:10.1542/peds.114.1.e124 |
| [17] | YU J R, LESLIE K S. Cryopyrin-associated periodic syndrome:an update on diagnosis and treatment response[J]. Curr Allergy Asthma Rep, 2011, 11(1): 12–20. doi:10.1007/s11882-010-0160-9 |
| [18] | FINETTI M, OMENETTI A, FEDERICI S, et al. Chronic infantile neurological cutaneous and articular (CINCA) syndrome:a review[J]. Orphanet J Rare Dis, 2016, 11(1): 167–177. doi:10.1186/s13023-016-0542-8 |
| [19] | NEVEN B, PRIEUR A M, QUARTIER DIT MAIRE P. Cryopyrinopathies:update on pathogenesis and treatment[J]. Nat Clin Pract Rheumatol, 2008, 4(9): 481–489. doi:10.1038/ncprheum0874 |
| [20] | ALGHAMDI M. Familial Mediterranean fever, review of the literature[J]. Clin Rheumatol, 2017, 36(8): 1707–1713. doi:10.1007/s10067-017-3715-5 |
| [21] | REPA A, BERTSIAS G K, PETRAKI E, et al. Dysregulated production of interleukin-1beta upon activation of the NLRP3 inflammasome in patients with familial Mediterranean fever[J]. Hum Immunol, 2015, 76(7): 488–495. doi:10.1016/j.humimm.2015.06.007 |
| [22] | MITROULIS I, KOURTZELIS I, KAMBAS K, et al. Evidence for the involvement of mTOR inhibition and basal autophagy in familial Mediterranean fever phenotype[J]. Hum Immunol, 2011, 72(2): 135–138. doi:10.1016/j.humimm.2010.11.006 |
| [23] | TIMERMAN D, FRANK N Y. Novel double heterozygous mutations in MEFV and NLRP3 genes in a patient with familial Mediterranean fever[J]. J Clin Rheumatol, 2013, 19(8): 452–453. doi:10.1097/RHU.0000000000000044 |
| [24] | CHAE J J, CHO Y H, LEE G S, et al. Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1β activation and severe autoinflammation in mice[J]. Immunity, 2011, 34(5): 755–768. doi:10.1016/j.immuni.2011.02.020 |
| [25] | MANUKYAN G, PETREK M, NAVRATILOVA Z, et al. Transcriptional activity of neutrophils exposed to high doses of colchicine:short communication[J]. J Biol Regul Homeost Agents, 2015, 29(1): 125–130. |
| [26] | BEN-ZVI I, KUKUY O, GIAT E, et al. Anakinra for colchicine-resistant familial mediterranean fever:a randomized, double-blind, placebo-controlled trial[J]. Arthritis Rheumatol, 2017, 69(4): 854–862. doi:10.1002/art.v69.4 |
| [27] | HERSH A O, PRAHALAD S. Immunogenetics of juvenile idiopathic arthritis:a com prehensive review[J]. J Autoimmun, 2015, 64(1): 113–124. |
| [28] | TADAKI H, SAITSU H, NISHIMURA-TDAKI A, et al. De novo 19q13.42 duplications involving NLRP gene cluster in a patient with systemic-onset juvenile idiopathic arthritis[J]. J Hum Genet, 2011, 56(5): 343–347. doi:10.1038/jhg.2011.16 |
| [29] | HAYEM F, HAYEM G. Still's disease and the mitochondrion:the other face of an old friend?[J]. Med Hypotheses, 2012, 79(2): 136–137. doi:10.1016/j.mehy.2012.04.009 |
| [30] | OHNISHI H, TERAMOTO T, IWATA H, et al. Characterization of NLRP3 variants in Japanese cryopyrin-associated periodic syndrome patients[J]. J Clin Immunol, 2012, 32(2): 221–229. doi:10.1007/s10875-011-9629-0 |
| [31] | YANG C A, HUANG S T, CHANG B L. Association of NLRP3 and CARD8 genetic polymorphisms with juvenile idiopathic arthritis in a Taiwanese population[J]. Scand J Rheumatol, 2014, 43(2): 146–152. doi:10.3109/03009742.2013.834962 |
| [32] | DAY T G, RAMANAN A V, HINKS A, et al. Autoinflammatory genes and susceptibility to psoriatic juvenile idiopathic arthritis[J]. Arthritis Rheum, 2008, 58(7): 2142–2146. doi:10.1002/(ISSN)1529-0131 |
| [33] | LAMOT L, BOROVECKI F, TAMBIC B L, et al. Aberrant expression of shared master-key genes contributes to the immunopathogenesis in patients with juvenile spondyloarthritis[J]. PLoS One, 2014, 9(12): e115416. doi:10.1371/journal.pone.0115416 |
| [34] | HORNEFF G, PEITZ J, KEKOW J, et al. Canakinumab for first line steroid-free treatment in a child with systemic-onset juvenile idiopathic arthritis[J]. Scand J Rheumatol, 2017: 1–2. |
| [35] | LORDEN G, GARCIA S I, PABLO N, et al. Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation[J]. Exp Med, 2017, 214(2): 511–528. doi:10.1084/jem.20161452 |
| [36] | SCIANARO R, INSALACO A, LAUDIERO L B, et al. Deregulation of the IL-1β axis in chronic recurrent multifocal osteomyelitis[J]. Pediatr Rheumatol, 2014, 12(30): 1–6. |
| [37] | HERLIN T, FⅡGAARD B, BJERRE M, et al. Efficacy of anti-IL-1 treatment in Majeed syndrome[J]. Ann Rheum Dis, 2013, 72(3): 410–413. doi:10.1136/annrheumdis-2012-201818 |
| [38] | SHOHAM N G, CENTOLA M, MANSFIELD E, et al. Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway[J]. Proc Natl Acad Sci U S A, 2003, 100(23): 13501–13506. doi:10.1073/pnas.2135380100 |
| [39] | CAORSI R, PICCO P, BUONCOMPAGNI A, et al. Osteolytic lesion in PAPA syndrome responding to anti-interleukin 1 treatment[J]. J Rheumatol, 2014, 41(11): 2333–2334. doi:10.3899/jrheum.140060 |
| [40] | SALSANOL E, RIZZO A, BEDINI G, et al. An autoinflammatory neurological disease due to interleukin 6 hypersecretion[J]. J Neuroinflammation, 2013, 10(1): 29–36. |
| [41] | LOOCK J, LAMPRECHT P, TIMMANN C, et al. Genetic predisposition (NLRP3 V198M mutation) for IL-1-mediated inflammation in a patient with Schnitzler syndrome[J]. J Allergy Clin Immunol, 2010, 125(2): 500–502. doi:10.1016/j.jaci.2009.10.066 |