本文报道1例 NLRC4基因变异导致的新生儿期发病的自身炎症反应伴婴幼儿小肠结肠炎（autoinflammation with infantile enterocolitis，AIFEC）患儿。患儿男，新生儿期发病，表现为反复发热、皮疹、肝脾大和小肠结肠炎，实验室检查显示铁蛋白、C-反应蛋白等升高，并发巨噬细胞活化综合征。抗感染治疗效果差。全外显子组测序提示 NLRC4基因c.1021G>C（p.Val341Leu）新发杂合变异，诊断AIFEC。AIFEC罕见，在新生儿期即可发病，可通过全外显子组测序明确诊断，该病目前尚无有效治疗方法。

抗体免疫缺陷病是一组由遗传缺陷引起的先天性疾病，影响机体免疫防御机制的发育和功能。患者可表现为反复感染、淋巴细胞增殖、自身免疫性疾病、自身炎症或恶性肿瘤。呼吸系统可表现为支气管扩张症、支气管哮喘、间质性肺疾病等。深入了解抗体免疫缺陷病将有助于将其从呼吸系统常见疾病中甄别出来。

目的:分析肺炎支原体诱导的皮疹和黏膜炎（MIRM）的临床特征及预后。方法:调阅中山大学附属第一医院2004年11月至2021年5月出院诊断为多形红斑/重症多形红斑或Stevens-Johnson综合征患者的资料，以MIRM诊断标准筛选出其中的MIRM患者，且排除了其他病因，分析其临床表现、实验室和辅助检查、治疗和预后。结果:8例符合MIRM诊断，其中男4例，女4例，发病年龄4 ~ 30（15.63 ± 9.16）岁。8例均有发热，其中5例有咳嗽、咽痛等上呼吸道前驱症状。所有患者均有口腔黏膜损害，其中5例有口唇血痂；7例有眼损害，表现为结膜充血及分泌物增多。所有患者均有皮损，表现为靶形损害5例、水疱4例。所有患者血清学肺炎支原体IgM均阳性。1例反复出现干咳等上呼吸道感染，每次发作与肺炎支原体感染密切相关，取外周血行全外显子测序显示，NLRC4和IRGM杂合突变。3例患者行皮损组织病理检查，符合多形红斑。7例系统使用糖皮质激素治疗，6例静脉注射免疫球蛋白，5例阿奇霉素，5例使用阿昔洛韦或伐昔洛韦或利巴韦林。平均随访2.9年，3例痊愈，1例失明，1例反复出现干咳和口腔溃疡及四肢皮疹，余3例分别出现眼睑板腺功能障碍、泪点狭窄及角膜上皮损害等眼部损害。结论:MIRM好发于儿童及年轻成人，多有发热、咽痛、咳嗽等前驱症状，黏膜损害明显，部分有皮肤靶形损害。多数患者单次发病后痊愈，个别反复发作者可能与自身炎症相关基因和感染相关基因突变有关。

Generalized pustular psoriasis (GPP) is a rare and life-threatening autoinflammatory skin disease characterized by recurrent and sudden episodes of widespread rashes with scattered sterile pustules. Clinical and genetic evidence indicates that the pathogenesis of GPP both overlaps and is separate from psoriasis vulgaris (PV). Interleukin (IL)-23/IL-17 immune pathway is well known to play a critical role in the immunopathogenesis of PV, while the inflammation of GPP is more inclined to involve the innate immune response via the IL-1/IL-36–chemokine pathway. Mutations in IL36RN, CARD13, AP1S3, MPO, TNIP1, SERPINA3, and SERPINA1 have been shown to be associated with GPP, among which loss-of-function mutation in IL36RN is the dominant mutation with the highest prevalence. Recent studies have shown that interaction of the IL-36 pathway and the IL-23/IL-17 axis underlies the immunological disturbances of GPP, indicating that innate and adaptive immune responses intertwine in the pathogenesis of GPP. With this deeper understanding of the pathogenesis of GPP, treatment by biologics targeting the IL-1/IL-36 pathway appears to be promising. IL-1 inhibitors, anakinra, canakinumab, and gevokizumab have reportedly been effective in some cases. Spesolimab and imsidolimab, which are antibodies to the IL-36 receptor, are undergoing investigation in a phase II trial and showing promising results. In the present review, we illustrate the current understanding of the pathogenesis of GPP based on recent updates on the molecular genetics and immunopathology of GPP and review recent clinical trials and case reports of novel biologics in the treatment of GPP.

肺间质疾病(interstitial lung disease，ILD)是一类在临床(氧合障碍)-影像(弥漫性病变)-病理(炎症和纤维化)上具有共同特征，而病因不同的异质性疾病的总称。儿童ILD的病因谱与成人存在明显差别，其中基因缺陷占有重要地位。常见的是肺表面活性物质代谢方面的基因缺陷，近年来，还发现肺发育、免疫/自身炎症、代谢方面的基因缺陷也可导致儿童ILD。随着基因检测技术的发展，越来越多的病因会被发现。

自身炎症和磷脂酶Cγ2(PLCγ2)相关的抗体缺乏和免疫失调(APLAID)是一种由PL-CG2基因突变引起的罕见自身炎症性疾病(AIDs),其临床特点复杂多样,多不具有特异性,发病机制尚未达成统一共识,临床工作中难以鉴别,明确诊断往往需要综合病史、临床表现和基因检测等多方面分析.本文就APLAID的发病机制与临床表型进行综述,以期为APLAID的诊断和治疗提供参考.

目的 探讨伴皮肤症状的原发性免疫缺陷病(PIDs)患儿的临床特征及基因特点.方法 回顾分析2014年1月至2017年3月收治的15例伴皮肤症状的PIDs患儿的临床资料.结果 15例患儿的中位起病年龄为4个月(新生儿期至11岁8个月),均出现明显的皮肤症状,包括湿疹或冻疮样皮疹、脓疱型银屑病、皮肤感染、皮下出血点或皮肤瘀斑、鱼鳞样红皮病、早老外观及其他皮肤血管炎表现等,伴随症状包括反复感染、自身炎症、自身免疫、生长发育迟缓或淋巴增殖,有脑、肺、肾脏等重要器官功能受损.15例患儿中,5例嗜酸性粒细胞计数增多,5例IgE水平升高,其中4例同时存在两项指标异常.基因检测显示WAS、RNASEH2C、NLRP12、IL36RN、NRAS、PIK3CD、STAT1、FOXP3、STAT3、DOCK8、TYK2、SPINK5、NBAS或ITGB2基因变异.2例患儿死于多器官功能障碍综合征,1例失访,其余12例存活,并在个体化治疗中.结论 多种PIDs可出现皮肤症状,当伴有反复感染、自身炎症、自身免疫、生长发育迟缓或淋巴增殖等表现时,需警惕PIDs可能,基因检测有助于诊断.

Objective:To investigate immune-related genetic background in intractable Meniere's disease (MD)and the immediate results of a novel therapy by delivering steroids to the surface of the intact endolymphatic sac (ES) and incus in a sustainable manner.Case report and methods:Candidate genes involved in immune regulation were sequenced using a nextgeneration sequencing method in a patient with intractable MD.Mutations were confirmed using the Sanger sequencing method.The ES was exposed,and gelatin sponge particles were immersed in high-dose methylprednisolone solution and placed onto the surface of ES."L"-shaped gelatin sponge strips were immersed in dexamethasone solution and served as a guiding device for the steroids by touching the incus and gelatin sponge particles on the surface of the ES.Gelatin sponge particles immersed in dexamethasone solution were placed around the gelatin sponge strips and sealed using fibrin glue.Results:Autoinflammation in the refractory MD case was indicated by genotype,including novel heterozygous mutations of PRF1,UNC13D,SLC29A3,ITCH,and JAK3,as well as phenotype.The vertigo was fully relieved immediately after operation.Tinnitus and aural fullness were resolved 3 weeks after operation,whereas hearing improved in 2 mon postoperation.No recurrence was noted during the 5-monfollow-up,and the final MRI supported the novel therapeutic hypothesis.Conclusion:Autoinflammation was involved in a refractory MD.This novel therapy,which involves the delivery of steroids to the surface of the intact ES and incus,is effective in relieving vertigo and tinnitus and improves hearing function of refractory MD.

The etiology and underlying mechanism of Meniere's disease(MD)development are still unknown,although inflammation and autoimmunity have been implicated as underlying mechanisms.The human endolymphatic sac(ES)has been reported to have innate and adaptive immune capacity in local immune reactions.In vivo demonstration of inflammation of the ES in patients with MD is missing in the liter-ature.We report the case of a 47-year-old female patient diagnosed with unilateral MD with genetic variants and cytokine markers indicating inflammation and vascular congestion of the ES.Endolymphatic hydrops in the right cochlea(grade 2)and vestibulum(grade 3)were detected using MRI.She carried heterozygous variants in MEFV(c.442G＞C),IRF8(c.1157G＞T),ADA(c.445C＞T),PEPD(c.151G＞A),NBAS(c.4049T＞C),CSF2RB(c.2222C＞T),HPS6(c.277G＞T),IL2RB(c.1109C＞T),IL12RB1(c.1384G＞T),IL17RC(c.260_271del GCAAGAGC TGGG),LIG1(c.746G＞A),RAG1(c.650C＞A),and SLX4(c.1258G＞C,c.5072A＞G).In the serum,the levels of granulocyte colony-stimulating factor(G-CSF),macrophage inflammatory protein 1α,and IL7 were significantly elevated,and the level of IL2Rα was reduced.Intratympanic administration of dexamethasone temporarily alleviated her hearing loss.Her vertigo was significantly relieved but remained slight after ES administration of corticosteroids.

Dear Editor,Necroptosis,a form of caspase-independent cell death,is tightly regulated to maintain tissue homeostasis.The execution of necroptosis depends on receptor interacting protein kinase 3(RIP3)-activated mixed lineage kinase domain-like protein(MLKL).MLKL is phosphorylated by RIP3,which releases MLKL autoinhibi-tion and drives its self-oligomerization.1-3 Oligomerized MLKL translocates to cellular membranes,where it disrupts membrane integrity causing necroptotic cell death.