Pathophysiology of Immune-Mediated (Type 1) Diabetes Mellitus

Type 1 diabetes mellitus is a chronic T cell-mediated disease resulting from autoimmune destruction of pancreatic β-cells. This process leads to progressive and irreversible failure of insulin secretion. Development of the disease involves both genetic and environmental factors. Genetic predisposition is mainly connected with the human leucocyte antigen (HLA) region, which encodes structures responsible for antigen presentation. A comprehensive molecular understanding of the pathogenesis of the disease is essential for the design of rational and well tolerated means of prevention. This paper describes recent experimental and clinical findings and elucidates the current possibilities for immunotherapy of type 1 diabetes. The nature of breakdown of self-tolerance and the mechanisms involved in its recovery are discussed.     

PTPN22 Single-Nucleotide Polymorphisms in Iranian Patients with Type 1 Diabetes Mellitus

Background: PTPN22 plays a crucial role in regulating the function of various cells of the immune system, particularly T cells. Polymorphisms of the PTPN22 gene have been associated with many autoimmune diseases, including type 1 diabetes (T1D) which is a T-cell-mediated disease.

Objective: The present study was aimed at genotyping of an Iranian population for five polymorphisms of the PTPN22 gene.

Methods: The study population consisted of 99 T1D patients and 100 healthy controls. We genotyped five single-nucleotide polymorphisms (SNPs) (rs12760457, rs1310182, rs1217414, rs33996649, and rs2476601) of the PTPN22 gene.

Results: Regarding the variant rs2476601, genotypes AG and GG were increased and decreased in T1D patients compared with controls, respectively. Further, alleles G and A of this SNP were found to be decreased and increased in T1D patients, respectively (p value = 0.001). However, T1D and control groups did not differ on genotype distribution or allele frequency for other investigated SNPs.

Conclusions: The PTPN22 rs2476601 minor allele (A) was associated with T1D in Iran, accounting for its pathophysiology in autoimmune diseases.     

糖尿病伴发抑郁研究进展

概况 糖尿病是由于体内胰岛素缺乏或者胰岛素在靶细胞不能发挥正常生理作用而引起的糖、蛋白质及脂肪代谢紊乱的一种综合病症.其基本特征是长期的高血糖.随着病程延长,体内糖、蛋白质及脂肪代谢的紊乱可导致眼、肾、神经、血管及心脏等组织器官的慢性进行性病变;若得不到及时的、恰当的治疗,则会发生双目失明、下肢坏疽、尿毒症、脑血管病变或心脏病变,以致危及生命.     

A variant of the "DIDMOAD" syndrome: (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness)

A 29-year-old female with diabetes insipidus, deafness, a visual disorder and an abnormal glucose tolerance test, who gave birth to a healthy baby is described. Her male sibling is probably also similarly affected. These patients may represent previously unreported variants of the "DIDMOAD" (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness) syndrome. This is the first reported case of childbirth in an affected patient.     

Decreased Levels of CD54 (ICAM-1)-Positive Lymphocytes in the Peripheral Blood in Untreated Patients with Active Juvenile Dermatomyositis

Significant abnormalities are observed in the peripheral blood of juvenile dermatomyositis (JDM) patients with active disease. In this study, we confirm that there is a significant increase in the relative percentage of B lymphocytes in the peripheral blood of a group of untreated children with newly diagnosed active JDM compared to healthy children (P < 0.0001). In order to investigate if properties intrinsic to B cells contributed to their relative increase in JDM, the percentage of B cells expressing activation markers (CD23, CD25, CD54, and CD69) was measured and compared to pediatric controls. Compared to healthy children less than 10 years of age (not significantly different from the JDM group), the JDM patients had an increase in the proportion of lymphocytes expressing CD19 (B cells; P = 0.0017) and decreases in the percentage of lymphocytes that were CD3⁻ CD16⁺ and/or CD56⁺ (NK cells; P = 0.01) and CD3⁺ CD8⁺ (T suppressor/cytotoxic cells; P = 0.02). There were no significant differences in any of the B-cell activation markers assessed. Of note, the percentage of CD54⁺ non-B lymphocytes (i.e., T cells and NK cells expressing CD54) was significantly lower in the JDM patients (25% ± 5%) than in the “age-related” healthy control group (43% ± 4%; P = 0.013). These results suggest the following for untreated children with active JDM: (i) the increase in the percentage of peripheral blood B cells is not due to intrinsic B-cell activation, and (ii) CD54/ICAM-1⁺ non-B cells, CD8⁺ T cells, and NK cells are being removed from circulation and may be participating in the pathophysiology of the disease.     

Hexokinase Domain Containing 1 (HKDC1) Gene Variants and their Association with Gestational Diabetes Mellitus in a South Indian Population

Hexokinase domain containing 1 (HKDC1), a novel human hexokinase gene, is known to affect glucose metabolism and was shown to have a strong association with 2‐h plasma glucose in pregnant women in a recent genome wide association study. This study aimed to evaluate the association of these regulatory variants of HKDC1 (rs1076224, rs4746822, rs2394529 and rs9645501) with gestational diabetes mellitus (GDM) in a South Indian population. The regulatory variants of HKDC1 were genotyped in unrelated 500 women with GDM and 510 non‐GDM individuals by using the MassARRAY system and by direct DNA sequencing. The minor alleles of the HKDC1 gene regulatory variants, namely rs10762264 and rs4746822, showed a significant association with GDM and these alleles conferred as much as 1.24 and 1.34 times higher risk for GDM, respectively. This is the first study to demonstrate the association of HKDC1 genetic variants with susceptibility to GDM.     

The role of anti-HSP70 autoantibody-forming V(H)1-J(H)1 B-1 cells in Toxoplasma gondii-infected mice

Anti-heat shock protein 70 (HSP70) autoantibody formation was induced by B-1 cells (CD5(+) B cells) in Toxoplasma gondii-infected mice. Here we report that V(H)1-J(H)1 B-1 cells from peritoneal exudate cells (PEC) of T. gondii-infected C57BL/6 mice (B6, a susceptible strain) increased predominantly. Moreover, the hybridoma lines producing anti-T. gondii HSP70 (TgHSP70) antibody cross-reactive with mouse HSP70 (mHSP70) expressed the V(H)1-J(H)1 gene, whereas the hybridoma lines producing anti-TgHSP70 antibody non-cross-reactive with mHSP70 expressed the V(H)11A-J(H)1 gene or V(H)12-J(H)1 gene. The avidity maturation of anti-TgHSP70 IgG antibody in the sera of BALB/c mice (a resistant strain) and that of anti-mHSP70 IgG autoantibody in the sera of B6 mice were observed 9 weeks after T. gondii infection. T. gondii numbers in the brains of T. gondii-infected B6 mice treated with anti-mHSP70 autoantibody were markedly higher than those in the brains of T. gondii-infected B6 mice treated with anti-TgHSP70 antibody. Furthermore, B-1 cells producing IL-10 down-regulated the IFN-gamma expression of PEC in T. gondii-infected mice. These results indicate that B-1 cells dominantly expressing V(H)1-J(H)1 mRNA, and producing anti-HSP70 autoantibody and IL-10 regulate susceptibility of mice to T. gondii infection.     

Intercellular adhesion molecule-1 (ICAM-1, CD 54) is associated with actin-filaments.

Intercellular adhesion molecule 1 (ICAM-1, CD 54) is a membrane associated glycoprotein involved in cell-cell interactions of the immune system. Detergent extraction of cultured human fibroblasts--stimulated with Interferon-gamma (IFN-gamma) for ICAM-1-expression--under conditions that stabilize actin in the filamentous (actin-F) form (NaF-buffer, phalloidine) resulted in greater retention of ICAM-1 in the detergent insoluble phase, containing the cytoskeletal matrix, compared to actin-F-destabilizing conditions (KCl-buffer). We further examined the in vitro ICAM-1 association with actin using immunoaffinity purified ICAM-1, prepared from either normal human tonsils or a spleen derived from a patient with Non-Hodgkin's lymphoma. ICAM-1 from both sources demonstrated binding to actin coated polystyrene surfaces. Our findings suggest that ICAM-1 interacts with actin-F and may use similar mechanisms described with other adhesion molecules for membrane-cytosol communication.     

血清糖化血红蛋白及脂蛋白-(a)水平变化与糖尿病并发冠心病的关系

目的:探讨血清糖化血红蛋白(HbAlc)及脂蛋白-a[Lp(a)]水平变化与糖尿病并发冠心病的关系。方法:单纯2型糖尿病患者54例(糖尿病组)和2型糖尿病并发冠心病患者128例(糖尿病并发冠心病组),测定各组血清HbAlc和Lp(a)水平,通过Logistic回归和ROC曲线分析血清HbAlc和Lp(a)水平变化对糖尿病并发冠心病的相对危险性预测价值。结果:糖尿病合并冠心病组HbAlc(7.5±1.4)%和Lp(a)(0.25±0.19)g/L明显高于单纯糖尿病组[(6.9±1.4)%和(0.19±0.16)g/L,均P<0.05]。Logistic回归分析显示,血清高水平HbAlc和Lp(a)分别是糖尿病并发冠心病的独立危险因素(OR值2.28,95%CI1.12～4.63,P<0.05)及(OR值2.3,95%CI1.11～4.79,P<0.05)。Logistic回归模型的ROC曲线下面积为0.73(P<0.01)。最佳切点0.7对判断糖尿病患者并发冠心病的敏感性和特异性分别为70%和65%。结论:血清HbAlc和Lp-(a)水平是糖尿病患者并发冠心病的独立危险因素,对评估糖尿病并发冠心病的相对危险性具有临床价值。     

VCAM-1、AOPP、HbA1c和FBG在二甲双胍治疗妊娠期糖尿病患者中的意义

目的 研究VCAM-1、AOPP、HbA1c和FBG对二甲双胍治疗GDM患者分娩结局的预测价值.方法 125例GDM患者接受二甲双胍治疗,于治疗前、分娩前后测定VCAM-1、AOPP、HbA1c和FBG,将分娩前指标与分娩结局正常与否进行ROC分析,研究其在分娩结局预测中的价值.结果 分娩前的FBG、HbA1c、VCMA-1和AOPP指标显著低于治疗前(P＜0.05),分娩前后差异无统计学意义(P＞0.05).分娩前,当VCAM-1取截点为40.87 ng/mL时,其预测灵敏度为89.3％,特异性为72.5％,均较高;当AOPP取截点为23.25ng/mL时,其预测灵敏度为82.1％,特异性为67.5％,均较高.VCAM-1和AOPP联合应用于分娩结局预测的灵敏度为90.6％,特异性为70.0％,阳性预测值为90.63％,阴性预测值为70.00％.结论 VCAM-1和AOPP可以有效预测二甲双胍治疗GDM分娩结局.     

Der(22)t(11;22) resulting from a paternal de novo translocation, adjacent 1 segregation, and maternal heterodisomy of chromosome 22.

The t(11;22) (q23;q11) translocation is the most frequently identified familial reciprocal translocation in humans. In translocation carriers, 3:1 meiotic segregation with tertiary trisomy can occur resulting in abnormal progeny with the der(22) as the supernumary chromosome. Affected children have a distinct phenotype with multiple anomalies and severe mental retardation. We have identified a child with developmental delay and multiple anomalies consistent with the der(22) phenotype. Cytogenetic analysis showed an abnormal chromosome complement of 47,XX,+der(22)t(11;22)(q23; q11) in all 50 cells analysed. FISH analysis using chromosome 11 and 22 painting probes showed a pattern consistent with a reciprocal translocation of the distal bands 11q23 and 22q11 respectively. Parental karyotypes were normal. RFLP analysis of locus D22S43, which maps above the t(11;22) breakpoint, showed that the der(22) was paternal in origin and indicated that the normal chromosomes 22 were the probable result of maternal heterodisomy. RFLP analysis of locus D22S94, which maps below the t(11;22) breakpoint, also suggested that both normal chromosomes 22 of the child represented the two maternal homologues. Non-paternity was excluded through the analysis of 10 microsatellite markers distributed on 10 different chromosomes and three VNTRs on three different chromosomes. To the best of our knowledge, this is the first reported case of a patient with an abnormal karyotype resulting from a de novo translocation in the paternal germline with probable unbalanced adjacent 1 segregation and maternal non-disjunction of chromosome 22 in meiosis I.     

Australia Antigen: Persistence of Immunological Markers (d, y, w) in Antigen Carriers

It is important to establish the stability of Australia antigen subtypes in chronic carriers in order to evaluate the validity of using immunological determinants as long-term epidemiological markers. In this study sequential blood samples containing Australia antigen from 31 chronic carriers were typed for determinants d, y, and w. The subjects included asymptomatic carriers from Rongelap Atoll in the Marshall Islands, Down's syndrome patients, and renal patients receiving hemodialysis treatment. The period of time between blood samples extended from 3 months to 11 years. In no case did the subtype change within any individual. It appears from these data that the Australia antigen subtypes are good long-term markers for epidemiological studies.     

A New HLA-B Antigen (HOK-1) Found in the Japanese

The HLA-B8 antigen is one of the characteristic antigens associated with organ specific autoimmune diseases among Caucasians. Among the Japanese, HLA-B8 positives have been assumed to be extremely rare. By using some HLA-B8 typing sera, a new HLA-B antigen, HLA-Bw4 positive, was found in the Japanese. This new HLA-B antigen, tentatively called HOK-1, showed a phenotype frequency of 3.7% and a gene frequency of 1.9 +/- 0.6%. This antigen has a strong linkage disequilibrium with HLA-Cw1 among the Japanese.     

MALA-2, mouse homologue of human adhesion molecule ICAM-1 (CD54)

In humans, lymphocyte adhesion to cells is mediated by the protein heterodimer CD11a/CD18 (Leu-CAMa, LFA-1) and its ligand CD54 (ICAM-1). Although the murine CD11a/CD18 is well characterized, the mouse homologue of human ICAM-1 has not been identified. In the present study a rat monoclonal antibody to the murine lymphocyte activation antigen MALA-2 was found to inhibit in a dose-dependent manner the phorbol ester-enhanced aggregation of mouse lymphoblasts, an adhesion-specific assay, and hence to define an adhesion molecule. By immunofluorescence flow cytometry the antigen expression was low on spleen cells but it largely increased after stimulation with mitogens. The antigen was expressed by some, but not all, lymphoid cell lines, and myelomonocytic and mastocytoma cells were also positive. In frozen tissue sections MALA-2 was mainly detected on germinal center B cells, dendritic cells, macrophages and vascular endothelium, including high endothelial venules. Cell surface labeling followed by immunoprecipitation and gel electrophoresis indicated that the antigen is a sialoglycoprotein which has a relative molecular mass of 95 kDa and displays a faster electrophoretic mobility under non-reducing conditions. The function, cellular distribution and molecular properties of MALA-2 are indistinguishable from those of human ICAM-1.     

IL-1、hs-CRP和亚临床甲减与妊娠期糖尿病的相关性研究

目的 探讨亚临床甲减、IL-1及hsCRP对妊娠期糖尿病的影响及其相关性.方法 选取2014年5月至2016年3月在唐山市协和医院妇产科检查的SCH合并GDM孕中期孕妇138例为观察组,根据促甲状腺素(TSH)的值,将其分为轻度亚临床甲减A组82例(TSH 2.5~4.22 mIU/L),重度亚临床甲减B组56例(TSH≥4.22 mIU/L).另选同期甲状腺功能正常的GDM孕妇50例为对照组.采用罗氏Cobas e601化学发光分析仪检测促甲状腺素(TSH)、甲状腺过氧化物酶抗体(TPOAb)、空腹胰岛素(FINS);ELISA法检测血清白细胞介素1(IL-1);运用贝克曼DXC800全自动生化分析仪检测超敏C反应蛋白(hs-CRP),空腹血糖(FBS),糖化血红蛋白(HbA1c),计算胰岛素抵抗指数(HoMA-IRII),对结果进行分析比较.结果 研究B、A组TPOAb 、HoMA-IRI、IL-1、hsCRP水平高于对照组,研究B组IL-1、hsCRP高于研究A组,差异有统计学意义(P< 0.05);研究B组IRI高于研究A组和对照组,差异有统计学意义(P<0.05).研究A、B组TSH、IL-1、hsCRP与HoMA-IRI呈正相关,IL-1、hsCRP与TSH呈正相关,差异有统计学意义(P<0.05).结论 IL-1、hsCRP可能在SCH合并GDM的发生发展过程中起重要作用,SCH与GDM发生有一定相关性.     

2型糖尿病患者胰岛素抵抗与脂联素、瘦素关系的探讨

目的:通过对2型糖尿病患者血清脂联素、瘦素水平检测及二者之间的比值分析,探讨DM2胰岛素抵抗发生的机理,为临床诊断治疗提供依据。方法:用酶联免疫分析和放射免疫分析对87例DM2,25例DM1患者和30例正常对照者及52例DM2经一年治疗前后脂联素、瘦素水平进行检测分析。结果:DM2患者脂联素水平明显低于DM1和正常对照组(P<0.01);瘦素水平DM1、DM2均高于正常对照组,DM2明显高于DM1(P<0.01);脂联素/瘦素的比值DM1>1(1.183),DM2<1(0.211),DM1与DM2比值比较有显著性差异(P<0.001);52例DM2治疗前后比较,脂联素、瘦素及二者比值有显著差异(P<0.01),脂联素与瘦素比较呈负相关。结论:2型糖尿病胰岛素抵抗的发生与脂联素、瘦素密切相关,二者的比值变化对糖尿病分型具有重要意义。     

HLA-B22 diversity including a novel B54 variant (B*5507) in the Korean population.

Diversity in the HLA-B22 group was investigated in the Korean population using PCR-SSOP and DNA sequencing analyses. Allelic typing of the B22 gene was performed by gene amplification of the polymorphic exons 2 and 3 of the HLA-B genes from 91 B22 positive individuals followed by a hybridization assay using 63 digoxigenin-labelled probes. Five different SSOP patterns including an unexpected pattern were identified and correlated well with the observed serologic types and with data obtained from DNA sequencing analyses. Novel allele, B*5507, was identified from two unrelated individuals who exhibited standard B54 serologic reactivity but an unexpected SSOP pattern. The DNA sequence of B*5507 is identical to B*5502 in exons 2 and 3 except for a single nucleotide substitution at codon 45 (GAG-->GGG) altering glutamic acid to glycine. Among the already known B molecules, this substitution has been observed only in the B54 molecule encoded by B*5401 allele. This is the evidence that Gly-45 is a crucial site forming the B54 serologic epitope. Interestingly, both alleles (B*5401 and B*5507) exhibit strong association with Cw*0102. Along with previous data, B22 appears to be a very diverse group in the Korean population consisting of at least seven different alleles. B*5401, B*5502, and B*5601 are the most frequent alleles. B*5507, B*5501, B*5504, and B*5604 appear at lower frequencies. Data obtained from this study will be useful in hematopoietic stem cell donor searches as well as in determination of a typing strategy for the HLA-B22 types in this population.     

Soluble Intercellular Adhesion Molecule-1 (ICAM-1) Antigen in Patients with Rheumatoid Arthritis

Intercellular adhesion molecule-1 (ICAM-1), a member of the immunoglobulin supergene family, is known to play an important role in inflammatory diseases. Using a previously developed enzyme-linked immunosorbent assay (ELISA) with two monoclonal antibodies (MoAbs) against human ICAM-1, levels of soluble ICAM-1 (sICAM-1) were measured in sera from patients with collagen diseases and in synovial fluids (SF) from patients with rheumatoid arthritis (RA). Although the results did not demonstrate that RA and other collagen diseases, as a group, had significantly higher levels of sICAM-1 in sera as compared with healthy controls, 21 of 138 cases (15%) with collagen diseases and 11 out of 57 patients (19%) with RA clearly showed higher levels of sICAM-1 in the sera. Comparisons between RA patients of radiological stages I and II and between stage I and other stages showed significantly higher levels of sICAM-1 in the sera of patients in the latter stages. RA patients with vasculitis and/or pneumonitis showed significantly higher levels of sICAM-1 than those without vasculitis or pneumonitis. Significant correlations were demonstrated between sICAM-1 and the factors IgG-RF, IgM-RF, erythrocyte sedimentation rate (ESR) and TNF-α in sera of RA patients. In addition, it was noted that the levels of sICAM-1 in SF were as high as those in the sera of patients with RA.     

替米沙坦对高血压合并糖尿病患者血浆APN及IR的影响

目的:探讨替米沙坦对高血压合并2型糖尿病(DM2)患者脂联素(adiponectin,APN)及胰岛素抵抗(IR)的影响.方法:选择150例高血压合并DM2患者,随机分为替米沙坦组和对照组,每组75例.两组均予以降血糖治疗.同时,替米沙坦组给予替米沙坦80mg口服,1次/d;对照组给予培哚普利4mg口服,1次/d.若4...