趋化因子及其受体与自身免疫性甲状腺疾病

趋化因子及其受体是免疫系统的重要组成部分,其趋化活性可以介导免疫细胞的定向移动和活化。在自身免疫性甲状腺疾病（AITD）的形成过程中,趋化因子及其受体参与淋巴细胞在甲状腺组织的浸润、定位及活化,它们的表达是导致AITD发生的一个重要因素。     

Regulatory molecules required for nucleotide-sensing Toll-like receptors

Summary:  Toll-like receptors (TLRs) play an important role in innate immune responses against bacteria and viruses. TLRs localize either on the cell surface or in intracellular vesicular compartments. The cell-surface TLRs, including TLR1, TLR2, TLR4, and TLR6, recognize microbial membrane lipids, whereas TLR3, TLR7, TLR8, and TLR9 recognize pathogen-derived nucleotides in intracellular compartments. TLR7 and TLR9 respond to host-derived nucleotides as well, and they have been implicated in a variety of autoimmune diseases. Safety mechanisms are required to avoid detrimental autoimmune responses. TLR7 and TLR9 are sequestered in the endoplasmic reticulum (ER) in a resting state and traffic to endolysosomes upon ligand-induced stimulation. Sequestration in the ER is a mechanism controlling TLR7/9 responses. A chaperone, gp96, in the ER is reported to regulate TLR7/9 maturation. gp96 is associated with TLR9 and is required for ligand-induced activation of TLR7/9. Two molecules in the ER are reported to regulate TLR7/9 trafficking to endolysosomes. PRAT4A (a protein associated with TLR4 A) is associated with TLR9 and is required for ligand-induced trafficking of TLR9 to endolysosomes. UNC93B1 is specifically associated with TLR3, TLR7, TLR9, and TLR13 and regulates ligand-induced trafficking of TLR7 and TLR9 from the ER to endolysosomes. These molecules are potential therapeutic targets for controlling dysregulated TLR7/9 responses in autoimmune diseases.     

Th9细胞与自身免疫性疾病

Th1、Th2、Th17和调节性T细胞（Treg）亚群是CD4＋T细胞亚群中的重要成员,其参与了人类及动物自身免疫性疾病的发病过程.既往认为,IL-9是由CD4＋Th2细胞分泌的细胞因子,是机体免疫应答中重要的调节因子.最近研究表明,机体内可能存在着一群新型的具有分泌IL-9和IL-10能力的CD4＋Th细胞亚群,称之为＂Th9＂细胞.该细胞亚群与自身免疫性疾病的相关性尚不清楚.     

Celiac disease in North Italian patients with autoimmune thyroid diseases

Background: Patients with autoimmune thyroid diseases (AITDs) are prone to develop other autoimmune manifestations and to display autoimmune polyendocrine syndromes.

An increased prevalence of celiac disease (CD) was demonstrated in adult European and Italian patients with AITDs; conversely, an increased prevalence of AITDs was demonstrated in patients with CD. An IgA deficiency is the most frequent immunodeficiency in humans and, in general, high frequency of this disorder was demonstrated in those with autoimmune diseases.

Aim: To define the prevalence of both CD and IgA deficiency in North Italian patients with AITDs.

Methods: 276 Italian patients with AITD were enrolled (mean age 42.6 years range 12–89, 186 of whom had chronic thyroiditis and 90 had Graves' disease). The tissue transglutaminase autoantibodies of the IgA class (IgA-tTGAbs) were evaluated using an ELISA method in these patients. Furthermore, the serological levels of the IgA were determined.

Results: Five of the patients (1.8%) were affected by previously diagnosed CD and were on a gluten-free diet. Ten out of the remaining 271 patients (3.6%) were found to be positive for celiac-related autoantibodies. All of these patients agreed to undergo endoscopy and duodenal biopsies and silent CD was found in 5 of them but 5 had not histopathological signs of CD.

CD (clinical, silent or latent) was present in 15/276 (5.4%) of the North Italian patients with AITD; this prevalence is significantly higher with respect to the general population (p < 0.00001).

The genetic pattern of the 10 patients with both AITDs and CD was characterized by the presence of DQ2 in 8 patients and DQ8 in 2. An IgA deficiency was present in 2/276 of the patients (0.72%).

Conclusions: CD is significantly increased in patients with thyroid autoimmune disorders for this reason it is important to screen for CD in patients with AITDs.     

UNC93B1影响TLRs信号通路及其与疾发病机制关系的研究进展

UNC93B1存在于内质网上,具多次跨膜区域,它能与TLR(Toll-like receptors,TLRs)-3,-7,-9发生特异性结合并将它们从内质网上运输(trafficking)至溶酶体中。UNC93B1与TLRs相互作用并通过MyD88/TRIF途径进行着信号传递。TLRs通过识别相应的高度保守的病原相关分子模式(PAMPs),在介导防御外来微生物入侵的先天性免疫反应并桥连或触发获得性免疫反应中起重要作用。在3d(N-乙基-N-亚硝基脲诱导的染色体基因的隐性突变)小鼠中,UNC93B1上H412R位点的突变阻断了其和TLRs的结合,进而阻碍了TLRs信号的传递,这使得该小鼠易被各种病原体感染。另外,UNC93B1的突变阻止了小鼠体内抗原的交叉呈递途径,也降低了MHC-II类分子呈递途径。UNC93B1缺陷使得人体易受单纯疱疹病毒I型(HSV-1)病毒感染而引起单纯疱疹病毒1型脑炎(HSE)。此外,通过调节UNC93B1和TLR7/9的接触可控制或避免系统性红斑狼疮、关节炎等自身性免疫疾病的发生。     

The role of toll-like receptors in systemic lupus erythematosus

Systemic lupus erythematosus is an autoimmune disease characterized by the production of autoantibodies against a relatively limited range of nuclear antigens. These autoantibodies result in the formation of immune complexes that deposit in tissues and induce inflammation, thereby contributing to disease pathology. Growing evidence suggests that recognition of nucleic acid motifs by Toll-like receptors may play a role in both the activation of antinuclear B cells and in the subsequent disease progression after immune complex formation. The endosomal localization of the nucleic acid-sensing Toll-like receptors (TLRs), TLR3, 7, and 9, is believed to contribute to the distinction between endogenous nucleic acids and those of foreign origin. In this article we review recent work that suggests a role for the B-cell receptor and Fcγ receptors in delivering nuclear antigens to intracellular compartments allowing TLR activation by endogenous nucleic acids. A number of in vitro studies have presented evidence supporting a role for TLRs in SLE pathology. However, recent studies that have examined the contributions of individual TLRs to SLE by using TLR-deficient mice suggest that the situation is far more complicated in vivo. These studies show that under different circumstances TLR signaling may either exacerbate or protect against SLE-associated pathology. Further understanding of the role of TLRs in pathological autoreactivity of the adaptive immune system will likely lead to important insights into the etiopathogenesis of SLE and potential targets for novel therapies.     

The Chaperone UNC93B1 Regulates Toll-like Receptor Stability Independently of Endosomal TLR Transport

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Polymorphisms and expression of genes encoding Argonautes 1 and 2 in autoimmune thyroid diseases

The microRNA (miRNA) biogenesis pathway is regulated by specific proteins and enzymes, including Dicer, Drosha, DGCR8, Exportin 5 and the Argonaute (AGO) family. In this study, we investigated the AGO family, which is the primary component of RISC (RNA-induced silencing complex) and directly binds to microRNA. We examined the association of polymorphisms in AGO family genes with AGO expression and with the development and prognosis of autoimmune thyroid diseases. We genotyped AGO1 rs636832A/G, AGO2 rs7005286C/T, AGO2 rs11166985A/G and AGO2 rs2292779C/G polymorphisms in 184 Graves’ disease (GD) patients, 195 Hashimoto’s disease (HD) patients and 122 healthy volunteers using the polymerase chain reaction-restriction fragment length polymorphism method. We also examined the expression of AGO1 and AGO2 mRNAs in peripheral blood mononuclear cells (PBMC) obtained from 52 GD patients, 41?HD patients, and 25 healthy volunteers using quantitative RT-PCR methods. The G allele of AGO1 rs636832 and the A allele of AGO2 rs11166985 polymorphisms were significantly more frequent in GD patients than in healthy controls. The A allele of AGO2 rs11166985 was also significantly more frequent in intractable GD patients than in controls. The C carrier (CC?+?CG genotypes) and C allele of AGO2 rs2292779 polymorphism were significantly more frequent in intractable GD patients than in patients with GD in remission. Expression of AGO1 mRNA in PBMC was significantly higher in AITD patient than in controls, and that of AGO2 mRNA in PBMC was significantly higher in intractable GD patients than in patients with GD in remission. Furthermore, the expression levels of both the AGO1 and AGO2 genes were significantly correlated with the proportions of Th17 cells in PBMC. In conclusion, the polymorphisms of the AGO1 and AGO2 genes, the expression levels of which correlated with the proportion of Th17 cells, were associated with the development and prognosis of GD. The AGO2 rs2292779 C carrier and C allele were associated with the intractability of GD.     

雌激素及其受体与自身免疫性疾病

自身免疫性疾病有明显的性别差异,女性的发病率显著高于男性,表明雌激素影响这类疾病的发生。雌激素及其代谢产物水平、雌激素受体基因多态性、雌激素受体介导的信号通路等方面与自身免疫性疾病密切相关,雌激素及其受体在自身免疫性疾病治疗中发挥重要作用。     

Thyroglobulin polymorphisms in Tunisian patients with autoimmune thyroid diseases (AITD)

The thyroglobulin (Tg) gene was reported to be linked and/or associated to autoimmune thyroid diseases (AITD) development in European Caucasian populations. Here, we attempt to replicate this finding and to evaluate the contribution of the Tg gene in the genetic susceptibility of AITD in the Tunisian population. We examined the genomic region (11.5cM) containing the Tg gene by genotyping seven microsatellite markers and four SNPs located respectively at exon 10 (Ser715Ala), exon 12 (Met1009Val), exon 21 (Ala1483Ala) and exon 33 (Arg1980Trp) in 15 Tunisian multiplex families affected with AITD including Graves' disease (GD) and Hashimoto's thyroiditis (HT) (members: 87; patients: 27 GD and 16 HT). A case-control study was performed by genotyping the Tgms2 intragenic microsatellite marker (intron 27) and four intragenic SNPs on 108 unrelated patients affected with GD and 169 normal controls. Analysis of family data did not show linkage of the thyroglobulin gene with AITD nor did analysis of case-control data show association of Tgms2 or SNPs with GD. In contrast to the European Caucasian population, we failed to detect any contribution of Tg gene in the genetic component of Tunisian AITD.     

Functional TSH receptor antibodies in children with autoimmune thyroid diseases

Introduction: The diagnostic value of the level of TSH receptor antibodies (TSHR-Ab) in the population of children with autoimmune thyroid diseases (AITDs) is still unknown. The aim of this cross-sectional study was to investigate the prevalence of TSHR-Ab in a paediatric cohort with AITD and healthy controls.

Materials and methods: A total of 240 serum samples were obtained from 205 patients with AITD, type 1 diabetes (T1D), juvenile arthritis (JA), and healthy controls (C). TSHR stimulating (TSI) and -blocking (TBI) immunoglobulins were measured in cell-based bioassays using CHO cells expressing a chimeric TSHR and a c-AMP response-element-dependent luciferase. TSI was reported as percentage of specimen-to-reference ratio (cutoff 140SRR%). Blocking activity was defined as percent inhibition of luciferase expression relative to induction with bovine TSH alone (40% inhibition).

Results: C as well as children with JA and T1D were both TSI and TBI negative. In contrast, children with Graves’ disease (GD) were positive for TSI in 47/53 samples (88.7%) while those with thyroidal and orbital GD showed TSI positivity in 95.8% (23/24 samples). Serum TSI levels were SRR% 320?±?157 and 417?±?135 in GD and GD?+?orbitopathy, respectively (p?=?.02). Children with Hashimoto’s thyroiditis (HT) were TSI positive in 4/83 (4.8%) samples, including two with orbital involvement. TSI levels were increased in HT children with vs. those without eye disease (SRR% 177 vs. 51, p?Conclusions: In conclusion, TSI is prevalent in children with GD while the highest serum TSI levels were noted in children with AITD and orbitopathy.     

巨噬细胞活化与自身免疫病

巨噬细胞“活化”在免疫反应、机体自稳、疾病的发生发展与预后中发挥重要作用,与多种自身免疫病的发生发展密切相关.但目前对其活化的定义、分类、鉴定等尚未有统一的标准,因此研究巨噬细胞活化的定义、分类、表面标记的改变、更清楚地了解巨噬细胞活化在自身免疫病中发挥的重要作用很有必要.     

Roles of toll-like receptors in natural interferon-producing cells as sensors in immune surveillance

Natural IFN-alpha/beta producing cells (IPCs) play a central role in innate immunity against microbial infections. In primary immune responses, toll-like receptors (TLRs), as major pattern-recognition receptors, are essential for IPCs as well as other antigen presenting cell (APC) subsets to recognize microbes. IPCs unequivocally express TLR7 and TLR9, and can respond to the respective ligand to produce IFN-alpha/beta and to rapidly differentiate into dendritic cells (DCs). Thereby, IPCs can not only activate innate immune system but also provoke T cell responses. Thus, IPCs link innate and adaptive immunity through TLR system. In addition, recent work has revealed the regulatory system of DC subsets in response to microbial invasion. In this context, by the different but complementary expression profile of TLRs, IPCs together with myeloid APC subsets constitute a rational system of immune surveillance that can cover a wide variety of pathogens and enlarge immune adjuvant effects.     

白细胞介素-37与自身免疫性疾病

白细胞介素(interleukin,IL)-37是新近发现的IL-1家族细胞因子,对固有免疫和适应性免疫均有抑制作用.IL-37主要表达于中性粒细胞、淋巴细胞、巨噬细胞、单核细胞、组织上皮细胞、角质形成细胞和树突状细胞.最近大量研究显示,IL-37在许多自身免疫性疾病患者或动物模型中表达异常并发挥关键作用,如系统性红斑狼疮、炎症性肠病、强直性脊柱炎、支气管哮喘、银屑病、Graves病以及类风湿性关节炎等.深入研究IL-37的生物学功能、信号转导途径及作用机制将为IL-37在自身免疫性疾病的治疗提供新思路和靶点.     

DICER and DROSHA gene expression and polymorphisms in autoimmune thyroid diseases

Dicer and Drosha are RNase III enzymes that are necessary for the biogenesis of most miRNAs. However, there are no reports on the association of Dicer and Drosha with the pathogenesis of autoimmune thyroid disease (AITD). We genotyped DICER rs3742330A/G and rs1057035T/C as well as DROSHA rs644236C/T and rs10719C/T polymorphisms in 255?Hashimoto's disease (HD) patients, in 255 Graves' disease (GD) patients and in 128 healthy controls by the polymerase chain reaction (PCR)- restriction fragment length polymorphism (RFLP) method. We also examined the expression of DICER and DROSHA gene in peripheral blood mononuclear cells (PBMCs) by quantitative RT-PCR (qRT-PCR) methods. The TT genotype of the DICER rs1057035 polymorphism was less frequent in GD patients (p?=?0.0098) than in healthy subjects. The CC genotype of DROSHA rs644236 polymorphism were more frequent in GD patients than in HD patients (p?=?0.0171). The gene expression of DICER was lower in patients with AITD compared with that in control subjects (p?=?0.0064) and was lower in patients with GD in remission than in patients with intractable GD (p?=?0.0213). In addition, the expression of DROSHA was lower in patients with AITD than that in control subjects (p?p?=?0.0440). In conclusion, the DICER rs1057035 TT genotype and DROSHA rs644236?CC genotype were associated with the development of GD and the differentiation between GD and HD, respectively. The expression levels of DICER and DROSHA genes were low in AITD and differed depending on the intractability of GD and the severity of HD, respectively.     

Nucleic acid-sensing TLRs and autoimmunity: novel insights from structural and cell biology

Invasion of pathogenic microorganisms or tissue damage activates innate immune signaling receptors that sample subcellular locations for foreign molecular structures, altered host molecules, or signs of compartment breaches. Upon engagement of innate immune receptors an acute but transient inflammatory response is initiated, aimed at the clearance of pathogens and cellular debris. Among the molecules that are sensed are nucleic acids, which activate several members of the transmembrane Toll-like receptor (TLR) family. Inappropriate recognition of nucleic acids by TLRs can cause inflammatory pathologies and autoimmunity. Here, we review the mechanisms involved in triggering nucleic acid-sensing TLRs and indicate checkpoints that restrict their activation to endolysosomal compartments. These mechanisms are crucial to sample the content of endosomes for nucleic acids in the context of infection or tissue damage, yet prevent accidental activation by host nucleic acids under physiological conditions. Decoding the molecular mechanisms that regulate nucleic acid recognition by TLRs is central to understand pathologies linked to unrestricted nucleic acid sensing and to develop novel therapeutic strategies.     

脂多糖通过NF-κB途径调节大鼠星形胶质细胞Toll样受体表达

目的 研究脂多糖（LPS）对大鼠星形胶质细胞Toll样受体表达的影响及其机制。方法 在原代培养的第3代星形胶质细胞中加入不同浓度的LPS作用24h,通过免疫荧光、western blot观察星形胶质细胞 Toll样受体的表达和NF-κB p65的表达,同时研究NF-κB通路抑制剂对其的影响。结果 在正常状况下,星形胶质细胞胞浆和胞膜表达大量的TLR3受体,很少的TLR4受体。在LPS的刺激下,星形胶质细胞的TLR3表达保持不变,TLR4受体的表达随予以LPS的量增加而增高。LPS可刺激星形胶质细胞NF-κB的表达升高,抑制NF-κB通路活化抑制TLR4受体的上调。 结论 星形胶质细胞Toll样受体的表达是不同源的,TLR4受体随环境的变化而改变,其分子机制可能与NF-κB信号途径有关。     

口服耐受机制和对自身免疫性疾病治疗的研究进展

ｅｌｌｓ等 ( 1 91 1 ) [1 ] 首次描述了口服耐受现象 ,他们发现预先给豚鼠口服鸡蛋白可防止后来对该蛋白的全身性过敏反应。Ｃｈａｓｅ( 1 946) [2 ] 发现预先给豚鼠口服接触性致敏原二硝基氯苯 (ｄｉｎｉｔｒｏｃｈｌｏｒｏ-ｂｅｎｚｅｎｅ) ,可使动物减少对其皮肤接触性过敏反应。Ｎａｇｌｅｒ-Ａｎｄｅｒｓｏｎ等[3] 和Ｔｈｏｍｐｓｏｎ等[4] ( 1 986)首次将口服耐受用于自身免疫性疾病的实验研究。针对自身抗原的免疫无反应状态称为自然耐受 (ｎａｔｕｒａｌｔｏｌｅｒａｎｃｅ)或自身耐受 (ｓｅｌｆ-ｔｏｌｅｒａｎｃｅ) ;针对外源性…     

感染因素与自身免疫性疾病发病相关性的研究进展

自身免疫病(AID)是指自身免疫出现异常,自身抗体和/或自身反应性淋巴细胞攻击表达靶抗原的细胞和组织,导致组织器官损伤和功能障碍所引起的一大类疾病.自身免疫病的发病机制是目前研究的热点之一.最近的研究表明感染因素与自身免疫病的发生密切相关,细菌或病毒等通过诱发自身免疫而致病.自身免疫病的种类很多,发病机制亦相当复杂,确切病因尚不十分清楚,国内外研究者做了多方面深入研究提出了包括分子模拟、自身抗原或表位扩展的提呈、病毒或细菌的超抗原、旁路激活和淋巴细胞感染等多种机制.文中就感染因素致自身免疫病的机制及两者的相关性进行综述.     

Association studies of the IL-23R gene in autoimmune thyroid disease in the Japanese population

Autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are caused by interplays of genetic factors and environmental triggers. Interleukin-23 and its receptor (IL-23R) guide T cells towards the Th17 phenotype. IL-23R single nucleotide polymorphisms (SNPs) have been shown to be associated with several autoimmune diseases, including Crohn's disease and rheumatoid arthritis, and Graves' ophthalmopathy (GO) in Caucasians. To determine whether variants in the IL-23R gene are associated with AITDs in Japanese, 464 Japanese AITD patients (290 with GD, 174 with HT) and 179 matched Japanese control subjects were genotyped for four SNPs spanning the IL-23R gene. SNPs rs11209026 and rs7530511 were genotyped using TaqMan allelic discrimination assays and SNPs rs2201841 and rs10889677 were genotyped using a fluorescent-based restriction fragment length polymorphism method. Case-control association studies were performed using the χ² and Fisher's exact tests with Yates correction. Of the four SNPs rs11209026 was non-polymorphic in our dataset. The other three SNPs were not associated with GD or GO or HT in our Japanese population. These results suggest that the IL-23R gene is associated with AITDs only in a specific ethnic group.