Intranasal vaccination induced cross-protective secretory IgA antibodies against SARS-CoV-2 variants with reducing the potential risk of lung eosinophilic immunopathology

To control the coronavirus disease 2019 (COVID-19) pandemic, there is a need to develop vaccines to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. One candidate is a nasal vaccine capable of inducing secretory IgA antibodies in the mucosa of the upper respiratory tract, the initial site of infection. However, regarding the development of COVID-19 vaccines, there is concern about the potential risk of inducing lung eosinophilic immunopathology as a vaccine-associated enhanced respiratory disease as a result of the T helper 2 (Th2)-dominant adaptive immune response. In this study, we investigated the protective effect against virus infection induced by intranasal vaccination of recombinant trimeric spike protein derived from SARS-CoV-2 adjuvanted with CpG oligonucleotides, ODN2006, in mouse model. The intranasal vaccine combined with ODN2006 successfully induced not only systemic spike-specific IgG antibodies, but also secretory IgA antibodies in the nasal mucosa. Secretory IgA antibodies showed high protective ability against SARS-CoV-2 variants (Alpha, Beta and Gamma variants) compared to IgG antibodies in the serum. The nasal vaccine of this formulation induced a high number of IFN-γ-secreting cells in the draining cervical lymph nodes and a lower spike-specific IgG1/IgG2a ratio compared to that of subcutaneous vaccination with alum as a typical Th2 adjuvant. These features are consistent with the induction of the Th1 adaptive immune response. In addition, mice intranasally vaccinated with ODN2006 showed less lung eosinophilic immunopathology after viral challenge than mice subcutaneously vaccinated with alum adjuvant. Our findings indicate that intranasal vaccine adjuvanted with ODN2006 could be a candidate that can prevent the infection of antigenically different variant viruses, reducing the risk of vaccine-associated enhanced respiratory disease.     

滤泡辅助性T细胞及半乳糖缺乏的IgA1在儿童过敏性紫癜中的表达及意义

目的 探讨滤泡辅助性T（Tfh）细胞和半乳糖缺乏的IgA1（Gd-IgA1）在儿童过敏性紫癜（HSP）发病机制中的作用及两者之间的相关性。方法 选取初发HSP患儿36例，根据是否发生紫癜性肾炎（HSPN）分为HSPN组（11例）和非HSPN组（25例）。另选取15例门诊体检儿童作为健康对照组。采用流式细胞术检测外周血中Tfh细胞（CD4⁺CXCR5⁺ICOS⁺）比例。采用ELISA法检测外周血中IL-21、IL-6、血清IgA1、血清Gd-IgA1表达水平。采用Pearson相关分析法分析HSP组患儿血清Gd-IgA1浓度与Tfh细胞比例及其相关因子的相关性。结果 HSPN和非HSPN组患儿外周血Tfh细胞比例及IL-21、IL-6表达水平较健康对照组升高（P < 0.05），HSPN组上述指标较非HSPN组亦明显上升（P < 0.05）。HSPN和非HSPN组患儿血清中IgA1、Gd-IgA1表达水平较健康对照组升高（P < 0.05），HSPN组患儿血清IgA1和Gd-IgA1水平较非HSPN组亦明显升高（P < 0.05）。HSP组患儿血清Gd-IgA1水平与Tfh细胞比例及IL-21、IL-6水平均呈显著正相关关系（P < 0.05）。结论 Tfh细胞及其相关细胞因子和血清Gd-IgA1共同参与HSP/HSPN的发生。Tfh细胞可能介导了Gd-IgA1生成增加。     

占永立教授从咽论治IgA肾病的理论与实践探析

本文从理论与临床实践2方面总结了占永立教授从咽论治IgA肾病的经验。占教授将Ig A肾病分为3型进行辨证论治:1)肺气不足,热毒扰咽证; 2)脾气虚弱,热邪客咽证; 3)肾阴亏虚,余热留咽证。治疗上以清热解毒利咽为主,兼以扶正,根据病情灵活选方用药,取得较好的临床疗效。     

IgA Nephropathy-Associated Uveitis: A Case Presentation

ABSTRACT

Purpose: To describe a case of bilateral panuveitis in the setting of IgA nephropathy.

Methods: Retrospective review of clinical records, fundus, and optical coherence tomographic (OCT) images, and fluorescein angiography.

Results: A 36-year-old female presented with IgA nephropathy and contemporaneous ocular manifestations of one-year duration. Clinical exam demonstrated bilateral panuveitis, 3+ anterior chamber (AC) cell in the right eye (OD), and 0.5+ AC cell in the left eye (OS). Funduscopic exam demonstrated diffuse yellow drusenoid deposits bilaterally (OU), accentuated on fundus autofluorescence as focal areas of hyperautofluorescence. Deposits correlated with retinal pigment epithelium hyper-reflectivity on OCT, and choroidal hypo-fluorescence on fluorescein angiography. The patient was managed with oral prednisone.

Conclusion: IgA nephropathy is a systemic autoimmune disease that may be associated with uveitis. Immunosuppression with corticosteroids appears to be an effective therapy.     

Induction of mucosal and systemic immune responses against the common O78 antigen of an oral inactivated ETEC vaccine in Bangladeshi children and infants

We tested an oral enterotoxigenic Escherichia coli (ETEC) vaccine, ETVAX, consisting of inactivated E. coli overexpressing the most prevalent ETEC colonization factors (CFs) and a toxoid (LCTBA), in Bangladeshi children for capacity to induce mucosal and plasma immune responses against O78 lipopolysaccharide (LPS) expressed on the vaccine strains. The vaccine was given ± double-mutant heat-labile toxin (dmLT) adjuvant. We evaluated the impact of dmLT on anti-O78 LPS immune responses and whether such responses can predict responses against the CFs as a marker for vaccine “take”. Two fractionated doses of ETVAX ± different amounts of dmLT were administered biweekly to groups of children 24–59 (n = 125), 12–23 (n = 97) and 6–11 (n = 158) months of age. Immune responses were evaluated in antibody in lymphocyte supernatants (ALS), fecal extracts and plasma. ALS IgA responses against O78 LPS were induced in 44–49% of the children aged 12–59 months. The magnitudes of the ALS responses were significantly higher in children receiving a half-dose (5 × 10¹⁰ bacteria) of ETVAX ± dmLT than in placebo recipients. <10% of the vaccinees aged 6–11 months mounted ALS responses against O78 LPS. However, 49% of the infants developed fecal secretory IgA responses which were significantly more frequent in those receiving a quarter-dose (2.5 × 10¹⁰ bacteria) of vaccine + dmLT (62%) compared to a quarter-dose alone (36%). Plasma IgA antibody responses were induced in 80% of older children and 36% of infants. The frequencies of O78 LPS responses in plasma and feces were comparable or higher than against the vaccine CFs in infants. Our findings show that ETVAX induced mucosal and systemic immune responses against O78 LPS in all age groups and that dmLT improved intestinal immune responses among infants. These observations may have implications for more successful use of other oral vaccines based on O antigens in children.     

阿霉素肾病小鼠病理机制中白细胞介素-18水平分析

目的探讨白细胞介素-18(IL-18)在阿霉素肾病模型(微小病变型肾病,MCN)小鼠病程中的免疫失调作用。方法采用阿霉素单次尾静脉注射昆明种小鼠,诱导形成微小病变型肾病模型,设置模型组、生理盐水对照组和IL-18mAb抗体中和实验组(mAb)。测定3组小鼠第1、2、4、6周24h尿蛋白(24hUPQ)水平;于第42天时心脏采血法留取血清,检测模型组与对照组血清总蛋白(TP)、清蛋白(ALB)、尿素氮(BUN)、肌酐(Cr)、三酰甘油(TG)、总胆固醇(Tch)的水平;取单侧肾做病理检测,同时制备脾淋巴细胞悬液、肾组织匀浆液检测3组IL-18、γ干扰素(IFN-γ)、肿瘤坏死因子-α(TNF-α)及IL-4水平。结果模型组小鼠从注射阿霉素第2周起,24hUPQ值均高于对照组,差异均有统计学意义(P0.01);血清TP、ALB、BUN、Cr、Tch、TG结果和病理诊断结果显示,模型小鼠出现低蛋白血症、高脂血症等类肾病综合征症状。检测显示模型组小鼠血清、肾组织匀浆上清液、脾淋巴细胞培养上清液IL-18、INF-γ、TNF-α水平均高于对照组,而IL-4水平均低于对照组,组间比较差异均有统计学意义(P0.01)。mAb组小鼠24hUPQ及IL-18、IFN-γ、TNF-α水平均低于模型组,组间比较差异有统计学意义(P0.01)。结论模型小鼠病程中,Th1类细胞因子分泌增强,Th2类因子受抑制,且IL-18mAb起到部分中和内源性IL-18的作用,表明IL-18是小鼠MCN病程中重要的免疫失调因子。     

祛风除湿法治疗IgA肾病的Meta分析

目的:IgA肾病是以系膜区IgA沉积为主要特征的原发性肾小球疾病,异常IgA1的免疫复合物沉积及RAAS系统激活与其发病关系密切。目前主要使用ACEI或ARB类药物及糖皮质激素或联合免疫抑制剂治疗。近年来中医药在IgA肾病的防治中发挥了巨大的作用,其中祛风除湿法治疗IgA肾病成为关注的焦点,在西医治疗基础上联用祛风除湿的中药在提高临床疗效、减少蛋白尿、减轻血尿、保护肾功能方面效果显著,同时也可减轻激素及免疫抑制剂所产生的不良反应,逐渐被临床认可。但由于目前现有的研究样本量小,文献质量较低,很难被广泛接受,迫切需要科学的研究方法为临床提供充分的证据支持,所以本研究拟通过Meta分析,综合分析祛风除湿法治疗IgA肾病的临床疗效及安全性评估。方法:检索中文数据库包括中国知网、万方、维普及英文数据库包括PubMed、Cochrane Library及手工检索相关领域期刊杂志中关于祛风除湿法治疗风湿内扰型IgA肾病的随机对照试验。采用Cochrane协助网提供的RevMan 5.3软件进行Meta分析,主要研究指标为有效率、24 h尿蛋白定量、血肌酐、血清白蛋白、肾小球滤过率、中医证候积分评估及不良反应发生率。结果:通过计算机检索中英文数据库及手工检索中医肾病相关领域期刊杂志,共检索出197篇文献,然后逐一阅读题目及摘要、泛读及精读全文后排除主题不相关文献,排除回顾性研究、假随机、半随机、重复文献、会议论文、不符合纳入标准文献,最后纳入8篇随机对照试验,共826例患者进行研究。Meta分析结果显示在西医治疗基础上联合祛风除湿的方药比单纯西医治疗在提高临床疗效(OR=3.35,95%CI［2.20,5.10］,P<0.000 01)、降低24 h尿蛋白定量(MD=-0.46,95%CI［-0.76,-0.17］,P=0.002)、提高白蛋白(MD=4.95,95%CI［3.62,6.28］,P<0.000 01),减少不良反应发生率方面(OR=0.42,95%CI［0.22,0.80］,P=0.008)效果显著,差异均有统计学意义。而血肌酐(MD=-4.82,95%CI［-12.27,2.63］,P=0.20)、肾小球滤过率(MD=-0.63,95%CI［-4.26,2.99］,P=0.73)、中医证候积分方面(MD=-1.96,95%CI［-3.98,0.05］,P=0.06)差异均无统计学意义。结论:在西医基础上联合祛风除湿的方药治疗IgA肾病比单纯西医治疗,在提高临床有效率、降低蛋白尿、提高白蛋白、减少不良反应的发生方面效果显著,差异均有统计学意义。但此次纳入文献样本量小,文献质量均不高,未来需要更科学可靠的循证医学方法进一步完善祛风除湿法治疗IgA肾病的临床研究。     

凉血散瘀方对肾虚血瘀型 IgA 肾病患者的疗效观察

〔摘 要〕 目的：分析凉血散瘀方加减辅助雷公藤多苷、醋酸泼尼松片治疗肾虚血瘀型 IgA 肾病患者的临床效果。 方法：选取三明市中西医结合医院 2019 年 6 月至 2020 年 6 月期间收治的 70 例肾虚血瘀型 IgA 肾病患者，依照治疗方案不同分为 观察组与对照组，各35例。对照组给予西药治疗；观察组在对照组基础上加用凉血散瘀方加减治疗。比较两组治疗效果。 结果：观察组患者治疗总有效率为 91.43 %，高于对照组的 71.43 %，差异具有统计学意义（P ＜ 0.05）。治疗前两组患者的尿红细 胞个数、血清肌酐（Scr）、血尿酸（SUA）、24 h 尿蛋白定量、Ⅳ 型胶原（C–Ⅳ）、基质金属蛋白酶组织抑制物 –1（TIMP–1） 及层粘连蛋白（LN）比较，差异无统计学意义（P ＞ 0.05）；治疗后两组患者的尿红细胞个数、Scr、SUA、24 h 尿蛋白 定量、C–Ⅳ、TIMP–1 及 LN 均低于治疗前，且观察组患者的尿红细胞个数、Scr、SUA、24 h 尿蛋白定量、C–Ⅳ、TIMP–1 及 LN 均低于对照组，差异具有统计学意义（P ＜ 0.05）。观察组患者不良反应发生率为 2.86 %，与对照组的 8.57 % 比较，差异无统计学意义（P ＞ 0.05）。 结论：凉血散瘀方联合雷公藤多苷、醋酸泼尼松片治疗肾虚血瘀型 IgA 肾病患者， 可进一步改善患者病情，调节血脂水平，改善肾脏纤维化，且安全性不受影响。