自噬与自身免疫性甲状腺疾病

自噬是细胞的一个重要生物学过程,它对维持细胞存活和自身稳态发挥重要作用.大量研究表明,自噬及其相关蛋白参与调控淋巴细胞发育和免疫应答,在多种自身免疫性疾病中发挥着重要的调控作用.近年研究发现,细胞自噬与自身免疫性甲状腺疾病的发生、发展密切相关,结合近几年自身免疫性甲状腺疾病与自噬相关的报道,对自噬形成过程中的分子调控机制、自噬与自身免疫性甲状腺疾病的关系进行综述.     

Genetic susceptibility to autoimmune thyroid diseases in a Chinese Han population: Role of vitamin D receptor gene polymorphisms

Purpose

Previous studies have found that some immune-related genes were associated with autoimmune thyroid diseases (AITDs). A couple of studies have explored the association between vitamin D (1,25-dihydroxyvitamin D3) receptor (VDR) gene polymorphisms and susceptibility to AITDs in different populations and found conflicting results. This case-control study was designed to evaluate the role of polymorphisms of VDR gene in the predisposition of AITDs in a Chinese Han population.

Methods

A total of 417 patients with Graves’ disease (GD), 250 patients with Hashimoto's thyroiditis (HT) and 301 healthy subjects were enrolled. The Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometer (MALDI-TOF-MS) Platform was applied to detect four SNPs (rs1544410, rs2228570, rs731236 and rs7975232) in the VDR gene.

Results

In the rs7975232 allele A frequency showed a significant increase in GD patients (30.34% vs. 25.42% in controls; P = 0.041, OR = 1.278, 95%CI = 1.010–1.617). However, no relationship was found between clinical phenotypes and the four SNPs.

Conclusions

This result suggests that the VDR gene may be one susceptibility gene which contributes to the risk of GD.     

硒治疗自身免疫性甲状腺疾病的荟萃分析

目的 评价元素硒治疗自身免疫性甲状腺疾病(AITD)的有效性和安全性.方法 通过5个数据库(MEDLINE,Cochrane Central Register of Controlled Trials,中国期刊全文数据库,中国生物医学文献数据库和维普数据库)检索所有研究元素硒治疗AITD的随机对照试验(RCT).由两名研究者独立筛选文献、提取数据和进行结果的统计分析.将结果数据形式一致的同类临床试验的结果进行荟萃分析,对不能荟萃分析的数据进行描述性分析.共纳入30项RCT,涉及2 963例AITD患者.结果 (1)与对照组相比,硒治疗组桥本甲状腺炎患者甲状腺过氧化物酶抗体(TPOAb)和甲状腺球蛋白抗体(TgAb)水平明显下降[标准化均数差(SMD)=-1.35,95％ CI:-1.93～-0.67,P ＜0.000 01和SMD=-0.92,95％ CI:-1.53～-0.31,P＜0.01].(2)硒治疗组与对照组相比,Graves病患者促甲状腺激素受体抗体(TRAb)水平降低(均数差=-2.5,95％ CI:-2.99～-2.01,P＜0.000 01).(3)元素硒可以降低Graves病患者血清游离T3(FT3)和游离T4(FT4)水平(均数差=-1.57,95％ CI:-2.56～-0.58,P＜0.001和均数差=-3.74,95％ CI:-5.65～-1.82,P=0.000 01),但对桥本甲状腺炎患者FT3、FT4和促甲状腺激素的作用不明显(P均＞0.05).结论 对AITD患者使用200 μg∥d的元素硒治疗3～12个月,能够有效降低抗甲状腺自身抗体(TPOAb,TgAb和TRAb)的水平,并具有较好的安全性.     

Prevalence of autoimmune diseases in islet transplant candidates with severe hypoglycaemia and glycaemic lability: previously undiagnosed coeliac and autoimmune thyroid disease is identified by screening.

AIMS: Autoimmune diseases such as Addison's or coeliac disease can contribute to hypoglycaemia or malabsorption and are more common in Type 1 diabetes (T1DM). This brief report describes the prevalence of known and newly detected autoimmune disease in clinical islet transplant candidates with longstanding T1DM and severe hypoglycaemia and/or glycaemic lability who are routinely screened for coexisting autoimmune disease. METHODS: One hundred and twenty-four C-peptide negative T1DM subjects [77 (62%) female, mean age 44 +/- 9 years, diabetes duration 28 +/- 11 years, body mass index 24.9 +/- 3.5 kg/m(2)] with indications for clinical islet transplantation at the University of Alberta were screened for autoimmune disease by history and measurement of anti-transglutaminase antibodies (positive > 10 U/ml), 09.00 h cortisol (followed by adrenocorticotrophic hormone-stimulation if < 495 nmol/l) and thyroid-stimulating hormone to determine the prevalence of coeliac disease, Addison's disease and autoimmune thyroid disease, respectively. RESULTS: Forty per cent of subjects had one or more coexisting autoimmune disease. The prevalence of autoimmune disease was 35%, coeliac disease 8% and Addison's disease 1.6%. In 11 individuals (9%), one or more autoimmune disease were newly detected (seven coeliac disease and five thyroid disease). Seven of 10 cases of coeliac disease were newly detected. A gluten-free diet in individuals with newly diagnosed coeliac disease reduced gastrointestinal symptoms, but indications for clinical islet cell transplantation persisted. CONCLUSIONS: Coexisting autoimmune disease is common in candidates for clinical islet cell transplantation. Screening in this group identified a substantial number of previously unrecognized cases. Clinicians should consider the presence of autoimmune disease even in the absence of classical symptoms.     

Influence of thyroid autoantibodies on thyroid cellular growth in vitro

Porcine thyroid follicle cells, cultured in suspension, were employed to investigate the effects of immunoglobulin preparations from patients with colloid goitre, Graves' disease or Hashimoto's thyroiditis on thyroid growth in vitro. Epidermal growth factor (EGF, 19 ng/ml) was used as a reference for maximum growth stimulation and produced a 9-fold increase in [3H]thymidine incorporation. Immunoglobulins (1000 micrograms/ml) were found to increase [3H]thymidine incorporation compared to control: from 10 normal individuals 32 +/- 4% (mean +/- SEM, % of EGF response), from 10 patients with colloid goitre 26 +/- 4% (not significantly different from normal), from 10 patients with Graves' disease 19 +/- 3% (P less than 0.05) and from 15 patients with Hashimoto's thyroiditis 11 +/- 2% (P less than 0.001). No patient immunoglobulin preparation showed activity greater than that of normal individuals. The lower growth stimulatory activity in Graves' disease and Hashimoto's thyroiditis remained after heat inactivation of serum and is thought to reflect surface binding of thyroid autoantibodies.     

FcRL3基因多态性与自身免疫性甲状腺疾病相关

运用PCR-RFLP对506例Grayes病(GD)患者,80例桥本甲状腺炎(HT)患者和261名正常对照者的可结晶片段受体样因子3(FcRL3)基因外显子4进行多态性研究,结果提示FcRL3基因外显子4等位基因82G可能为重庆地区汉族GD男性患者的易感基因.     

Lack of association between interleukin-4 gene polymorphisms and autoimmune thyroid diseases amongst Taiwanese Chinese

Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) are both common autoimmune diseases of the thyroid gland (AITD). The IL-4 is involved in both humoral and cellular immunity. The aim of this study was to test whether the IL-4 gene could be used as a genetic marker to predict the development of AITD amongst the Chinese population of Taiwan. For this study, a normal control group of 105 healthy subjects and two experimental groups featuring individuals afflicted with either GD (104 patients) or HT (109 patients) were examined. Polymerase chain reaction (PCR) was used to analyze the variable number of tandem repeats (VNTRs) polymorphism for the IL-4 gene intron 3 and PCR-based restriction analysis using endonuclease BsmFI was undertaken for the same gene at the promoter −590 position. We found no significant difference in the frequencies of presence of genotype and allelic variants for the IL-4 gene at both the intron 3 and the promoter regions between the normal control group and each of the two patient groups. These findings suggest that the IL-4 gene polymorphisms that arise at either intron 3 or promoter −590 positions are not suitable genetic markers for AITD among Taiwanese Chinese.     

Clinical significance of immunohistochemistry to detect BRAF V600E mutant protein in thyroid tissues

This study investigated the feasibility of using immunohistochemistry (IHC) instead of PCR to detect BRAF V600E mutant protein in papillary thyroid carcinoma (PTC), and to determine the value of using preoperative BRAF V600E mutant protein by IHC to assist in the diagnosis of thyroid nodule patients with Hashimoto''s thyroiditis (HT).The expression of BRAFV600E mutant protein was measured in 23 cases of HT+PTC, 31 cases of PTC, and 28 cases of HT by IHC, followed by PCR in the same samples for validation. SPSS 19.0 software was used for statistical analysis.The sensitivity and specificity of IHC to detect BRAF V600E mutation were 100% and 42.86%, respectively. In addition, the mutation rate of BRAF V600E protein in the HT+PTC group (34.78%, 8/23) was lower than that in the PTC group (80.65%, 25/31).The application of IHC to detect BRAF V600E mutant protein has good sensitivity but not specificity to diagnose PTC. IHC can be used as a preliminary screening method to detect BRAF V600E mutation. The strongly positive (+++) staining of IHC potently indicated BRAF V600E gene mutation. For suspicious thyroid nodules combined with HT, the detection of BRAF V600E mutant protein with IHC alone is not of great significance for differentiating benign and malignant nodules.     

甲状腺球蛋白基因多态性与甲状腺球蛋白抗体的相关性

分析陕西地区汉族自身免疫性甲状腺疾病(AITD)患者体内甲状腺球蛋白(Tg)外显子10、12及33的单核苷酸多态性与甲状腺球蛋白抗体(TgAb)产生的相关性.对222例AITD患者依据TgAb滴度进行分组,采用PCR-RFLP方法 检测甲状腺球蛋白基因外显子10、12和33的单核苷酸多态性,并对其进行单体型分析.4个位点的等位基因及基因型在TgAb阳性组和TgAb阴性组两组分布频率差异无统计学意义;但单体型分析结果提示:在TgAb阳性组中,单体型G-C-A-C所占频率明显增高(P=0.028,OR=3.34),而单体型G-C-G-C的频率明显降低(P=0.048,OR=0.62),提示单体型G-C-A-C增多与单体型 G-C-G-C 的减少可能与AITD患者体内TgAb的产生有关.甲状腺球蛋白的基因多态性可能是导致TgAb产生的重要机制之一.

Abstract：

To identify association between the presence of previously reported four single nucleotide polymorphisms(SNPs) at exon 10, 12 and 33 of thyroglobulin(Tg) gene with autoimmune thyroid disease(AITD) patients whose TgAb is positive. In this case-control association study, the Tg gene polymorphisms at exon 10, 12, and 33 were determined by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)method in 222 patients with AITD. According to the titers of the Tg autoantibodies(TgAb) in serum, they were divided into two subgroups: TgAb positive group and TgAb negtive group. And a haplotype case-control analysis was also done in two groups.The difference of their frequencies was analyzed by Chi-square test. No differences in alleles and genotypes frequencies were observed in all patients whose TgAb iseither positive or negative(P＞0.05). But there was a significant association of G-C-A-C haplotype with the patients whose TgAb was positive(P=0.028,OR=3.34). There is association of thyroglobulin gene polymorphisms with TgAb in patients with AITD.     

Case of idiopathic portal hypertension complicated with autoimmune hepatitis

We report a case of idiopathic portal hypertension (IPH) complicated with autoimmune hepatitis. A 60‐year‐old woman was admitted to our hospital with esophageal and gastric varices in February 2010. Abdominal ultrasonography and computed tomography showed splenomegaly and collateral veins without evidence of liver cirrhosis. Laboratory examinations and liver biopsy indicated that the esophageal and gastric varices were caused by IPH. She underwent endoscopic injection sclerotherapy and partial splenic embolization. Two years after these therapies, laboratory examinations showed liver dysfunction with elevated levels of aspartate aminotransferase (180 IU/L), alanine aminotransferase (190 IU/L), γ‐glutamyl transpeptidase (159 IU/L) and immunoglobulin G (2609 mg/dL). The titer of antinuclear antibodies was 1:320 and its pattern was homogeneous and speckled. Histological examination revealed plasma cell/lymphocyte infiltration and interface hepatitis in the portal tract. Based on these findings, a diagnosis of autoimmune hepatitis accompanied by IPH was made. After treatment with prednisolone (20 mg/day), liver functions were normalized immediately. Overlapping of IPH and AIH is extremely rare, but the present case is interesting considering the etiology of IPH because an autoimmune mechanism is thought to be involved in the pathogenesis of IPH.     

Long-term outcome of interferon-alpha-induced autoimmune thyroid disorders in chronic hepatitis C.

BACKGROUND: Autoimmune thyroid disorders are among the well-known adverse effects of interferon-alpha (IFN-alpha) therapy in patients with chronic hepatitis C. However, there are few reports regarding the long-term outcome of this complication. We aimed to evaluate the natural history of IFN-alpha-induced autoimmune thyroid disorders with long-term follow-up. METHODS: Four hundred and thirty-nine patients with chronic hepatitis C were treated with IFN-alpha for 24 weeks between March 1993 and April 1998. Seventeen of 439 (3.9%) patients developed symptomatic autoimmune thyroid disorders including nine cases of hyperthyroidism and eight cases of hypothyroidism. The patients with hypothyroidism were all women. These 17 patients were followed up for 71.1 +/- 17.8 months (48-120 months) and were evaluated for long-term outcome. RESULTS: Eight patients could discontinue the thyroid medication (2-36 months, median 10 months). Nine patients needed the thyroid medication at the follow-up period. The patients with hyperthyroidism who needed long-term thyroid medication had a significantly high titer of TSH receptor antibody on onset compared with the patients who could discontinue the thyroid medication. There were no significant differences in age, type of IFN, duration from IFN administration to onset, cessation of IFN, genotype of hepatitis C virus and thyroid hormone levels on onset between the patients who needed long-term thyroid medication and the patients who could discontinue the thyroid medication. CONCLUSION: All patients with IFN-alpha-induced thyroid disorders could be controlled with medication. However, the IFN-alpha-induced thyroid disorders are not always reversible. One must be careful about not only the development of autoimmune thyroid disorders during IFN-alpha therapy but also the outcome of the thyroid disease.     

Association of autoimmune disease-related gene polymorphisms with chronic graft-versus-host disease

Chronic graft-versus-host disease (GVHD) is the most common cause of poor outcomes after haematopoietic stem cell transplantation (HSCT), while the pathophysiology of chronic GVHD remains poorly understood. As both chronic GVHD and autoimmune disease share clinical features, we speculated that autoimmune disease-related genes might be candidate chronic GVHD-related genes. Recent large-scale cohort studies showed that Fc receptor-like 3 gene (FCRL3) single nucleotide polymorphism (SNP) and peptidylarginine deiminases citrullinating enzymes 4 gene (PADI4) haplotype were associated with autoimmune disease. The present study investigated the association between polymorphisms of these two genes and the incidence of chronic GVHD. We analysed 123 cases of Japanese human leucocyte antigen-matched sibling recipients and their donors who underwent HSCT. Although PADI4, which is the rheumatoid arthritis-specific related gene, was not associated with the occurrence of chronic GVHD, the recipient FCRL3-169C/C genotype was significantly less frequent in chronic GVHD patients than in those without chronic GVHD (P = 0.0086). There was no relationship between FCRL3 polymorphism and acute GVHD. As FCRL3 is expressed by B cells and might have an important role in immunoregulation, this significant protective genetic effect raises the question of whether FCRL3 might also be involved in the pathogenesis of chronic GVHD.     

Association of the thyroglobulin gene polymorphism with autoimmune thyroid disease in Chinese population

Objective This study was performed to identify the presence of previously reported thyroglobulin (Tg) gene single nucleotide polymorphisms (SNPs) in Han Chinese Asians, and to investigate their potential relation to autoimmune thyroid disease (AITD). Methods Polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP) in 228 Chinese patients with AITD (146 with Graves’ disease and 82 with Hashimoto’s thyroiditis) and 131 healthy Chinese controls. Results (1) The occurrence of four common Tg gene SNPs (E10SNP24 T/G and E10SNP158 T/C in exon 10, E12SNP A/G in exon 12, and E33SNP C/T in exon 33) was confirmed in this Chinese population. No differences in allele and genotype frequencies were found between AITD patients and control subjects, or between male and female individuals in any group. Neither were differences in allele frequencies observed when Graves’ disease (GD) or Hashimoto’s thyroiditis (HT) patients were analyzed separately. (2) Haplotype analysis of these four SNPs revealed that the G-C-A-C haplotype was significantly associated with HT (P < 0.01, OR = 3.06, OR 95% CI [1.326–7.089]) and with serum anti-Tg antibody (Tg-Ab) positive AITD patients (P = 0.028, OR = 3.34). Conclusion Our study confirms the existence of four SNPs among Han Chinese. In addition, the association of one SNP haplotype with HT suggests that Tg may be an AITD susceptibility gene.