Low FCMR mRNA expression in leukocytes of patients with Kawasaki disease six months after disease onset.
川崎病患者发病后 6 个月白细胞 FCMR mRNA 低表达。
- 作者列表："Ling-Sai C","Guo MM","Yan JH","Huang YH","Lo MH","Kuo HC
BACKGROUND:Immunoglobulin (Ig) M plays an important role in immune regulation. FCMR-encoded FcμR is a receptor of IgM. Previous research has suggested that Ig M levels may be involved in the coronary artery lesions of Kawasaki syndrome (KD). In this study, we aimed to explore the roles of mRNA expressions of IgM receptors, particularly FCMR, in KD patients. METHODS:We enrolled 60 KD patients and 55 non-KD controls. Whole blood leukocytes were isolated and the mRNA expression for FCMR was determined. Each mRNA consisted of a sample taken before intravenous immunoglobulin (IVIG) was administered (acute, KD1) and those taken at three weeks, six months, and one year later (KD3, KD4, KD5). Paired KD subjects were analyzed from both the acute and convalescent phase (n = 28). RESULTS:After six months and one year of treatment, KD patients still apparently have lower FCMR compared with controls (p = 0.004). FCMR expressions were down-regulated in male patients with KD prior to IVIG administration (p = 0.044). The FCMR of paired KD patients who received IVIG treatments after six months was significantly lower than before undergoing IVIG treatment (p= 0.044). Expressions in the polymorphonuclear leukocytes were similar to those in the peripheral blood mononuclear cells. CONCLUSION:The unique data supported that FCMR is expressed by granulocytes at RNA levels in humans and demonstrated lower FCMR six months after the onset of KD. The findings remind us of the need to track the health of children with KD over the long term, even if we think patients have fully recovered.
背景: 免疫球蛋白 (Ig) M 在免疫调节中起重要作用。FCMR 编码的 fc μ r 是 IgM 的受体。既往研究提示 Ig M 水平可能参与了川崎综合征 (KD) 的冠状动脉病变。在这项研究中，我们旨在探讨 IgM 受体，特别是 FCMR 的 mRNA 表达在 KD 患者中的作用。 方法: 我们入组了 60 例 KD 患者和 55 例非 KD 对照。分离全血白细胞，测定 FCMR 的 mRNA 表达。每个 mRNA 由静脉注射免疫球蛋白 (IVIG) 给药前 (急性，KD1) 和一年后 (KD3，KD4, KD5)。从急性期和恢复期 (n = 28) 分析配对 KD 受试者。 结果: 川崎病患者治疗 6 个月、 1 年时，其 FCMR 仍明显低于对照组 (p = 0.004)。给予 IVIG 前 KD 男性患者 FCMR 表达下调 (p = 0.044)。6 个月后接受 IVIG 治疗的配对 KD 患者的 FCMR 显著低于接受 IVIG 治疗前 (p = 0.044)。多形核白细胞的表达与外周血单个核细胞相似。 结论: 独特的数据支持 FCMR 在人类粒细胞 RNA 水平表达，并在 KD 发病后 6 个月表现出较低的 FCMR。这些发现提醒我们有必要长期跟踪 KD 儿童的健康状况，即使我们认为患者已经完全康复。
METHODS:Novel interventions that do not rely on daily adherence to ART are needed to achieve sustained viral remission for perinatally infected children, who currently rely on lifelong ART. Considering the risks and expense associated with ART interruption trials, the identification of biomarkers of viral rebound will prioritize promising therapeutic intervention strategies, including anti-HIV Env protein therapeutics. However, comprehensive studies to identify those biomarkers are logistically challenging in human infants, demanding the need for relevant nonhuman primate models of HIV rebound. In this study, we developed an infant RM model of oral infection with simian-human immunodeficiency virus expressing clade C HIV Env and short-term ART followed by ATI, longitudinally characterizing the immune responses to viral infection during ART and after ATI. Additionally, we compared this infant RM model to an analogous adult RM rebound model and identified virologic and immunologic correlates of the time to viral rebound after ATI.To achieve long-term viral remission in human immunodeficiency virus (HIV)-infected children, novel strategies beyond early antiretroviral therapy (ART) will be necessary. Identifying clinical predictors of the time to viral rebound upon ART interruption will streamline the development of novel therapeutic strategies and accelerate their evaluation in clinical trials. However, identification of these biomarkers is logistically challenging in infants, due to sampling limitations and the potential risks of treatment interruption. To facilitate the identification of biomarkers predicting viral rebound, we have developed an infant rhesus macaque (RM) model of oral simian-human immunodeficiency virus (SHIV) SHIV.CH505.375H.dCT challenge and analytical treatment interruption (ATI) after short-term ART. We used this model to characterize SHIV replication kinetics and virus-specific immune responses during short-term ART or after ATI and demonstrated plasma viral rebound in 5 out of 6 (83%) infants. We observed a decline in humoral immune responses and partial dampening of systemic immune activation upon initiation of ART in these infants. Furthermore, we monitored SHIV replication and rebound kinetics in infant and adult RMs and found that both infants and adults demonstrated equally potent virus-specific humoral immune responses. Finally, we validated our models by confirming a well-established correlate of the time to viral rebound, namely, the pre-ART plasma viral load, as well as identified additional potential humoral immune correlates. Thus, this model of infant ART and viral rebound can be used and further optimized to define biomarkers of viral rebound following long-term ART as well as to preclinically assess novel therapies to achieve a pediatric HIV functional cure.
METHODS:There is a pressing need for next-generation influenza vaccine strategies that are better able to manage antigenic drift and the cocirculation of multiple drift variants and that consistently improve vaccine effectiveness. Influenza virus NA is a key target antigen as a component of a next-generation vaccine in the influenza field, with evidence for a role in protective immunity in humans. However, mechanisms of protection provided by antibodies directed to NA remain largely unexplored. Herein, we show that antibody Fc interaction with Fcγ receptors (FcγRs) expressed on effector cells contributes to viral control in a murine model of influenza. Importantly, a chimeric mouse-human IgG1 with no direct antiviral activity was demonstrated to solely rely on FcγRs to protect mice from disease. Therefore, antibodies without NA enzymatic inhibitory activity may also play a role in controlling influenza viruses and should be of consideration when designing NA-based vaccines and assessing immunogenicity.Influenza virus neuraminidase (NA) has been under intense study recently as a vaccine antigen, yet there remain unanswered questions regarding the immune response directed toward NA. Antibodies (Abs) that can inhibit NA activity have been shown to aid in the control of disease caused by influenza virus infection in humans and animal models, yet how and if interactions between the Fc portion of anti-NA Abs and Fcγ receptors (FcγR) contribute to protection has not yet been extensively studied. Herein, we show that poly- and monoclonal anti-NA IgG antibodies with NA inhibitory activity can control A(H1N1)pdm09 infection in the absence of FcγRs, but FcγR interaction aided in viral clearance from the lungs. In contrast, a mouse-human chimeric anti-NA IgG1 that was incapable of mediating NA inhibition (NI) solely relied on FcγR interaction to protect transgenic mice (with a humanized FcγR compartment) against A(H1N1)pdm09 infection. As such, this study suggests that NA-specific antibodies contribute to protection against influenza A virus infection even in the absence of NI activity and supports protection through multiple effector mechanisms.
METHODS:Maternal primary and non-primary cytomegalovirus (CMV) infection during pregnancy can result in in utero transmission to the developing fetus. Congenital CMV (cCMV) can result in significant morbidity, mortality or long-term sequelae, including sensorineural hearing loss, the most common sequela. As a leading cause of congenital infections worldwide, cCMV infection meets many of the criteria for screening. However, currently there are no universal programs that offer maternal or neonatal screening to identify infected mothers and infants, no vaccines to prevent infection, and no efficacious and safe therapies available for the treatment of maternal or fetal CMV infection. Data has shown that there are several maternal and neonatal screening strategies, and diagnostic methodologies, that allow the identification of those at risk of developing sequelae and adequately detect cCMV. Nevertheless, many questions remain unanswered in this field. Well-designed clinical trials to address several facets of CMV treatment (in pregnant women, CMV-infected fetuses and both symptomatic and asymptomatic neonates and children) are required. Prevention (vaccines), biology and transmission factors associated with non-primary CMV, and the cost-effectiveness of universal screening, all demand further exploration to fully realize the ultimate goal of preventing cCMV. In the meantime, prevention of primary infection during pregnancy should be championed to all by means of hygiene education.