1型糖尿病基因治疗研究进展

1型糖尿病自身免疫发病机制涉及到免疫耐受、自身抗原提呈、T细胞活化以及细胞凋亡等异常。转染β细胞特异性抗原基因可诱导免疫耐受,转染前炎性因子受体拮抗蛋白基因及干扰协同刺激信号可阻止抗原提呈细胞及T细胞活人,可通过抑制细胞凋亡来阻断针对胰岛的自身免疫反应,最终达到治疗糖尿病的目的。此外,通过转基因技术可使非胰岛β细胞获得合成分泌胰岛素的能力,用于治疗胰岛素缺乏所致糖尿病亦将成为可能。     

1型糖尿病基因治疗研究进展

1型糖尿病自身免疫发病机制涉及到免疫耐受、自身抗原提呈、T细胞活化以及细胞凋亡等异常。转染 β细胞特异性抗原基因可诱导免疫耐受 ,转染前炎性因子受体拮抗蛋白基因及干扰协同刺激信号可阻止抗原提呈细胞及T细胞活化 ,并可通过抑制细胞凋亡来阻断针对胰岛的自身免疫反应 ,最终达到治疗糖尿病的目的。此外 ,通过转基因技术可使非胰岛 β细胞获得合成分泌胰岛素的能力 ,用于治疗胰岛素缺乏所致糖尿病亦将成为可能。     

耗竭T细胞对1型糖尿病的研究进展

T1DM是遗传和环境因素共同作用导致的自身免疫性疾病。由于自身免疫攻击，CD8T细胞持续性破坏胰岛β细胞，胰岛β细胞血糖调节功能降低直至丧失，患者需终身依赖胰岛素治疗。免疫反应诱导免疫耐受，中断自身免疫攻击。耗竭T细胞（Tex）是外周免疫耐受的组成部分，在T细胞效应阶段发挥调节作用和胰岛β细胞功能保护相关。本文综述Tex对T1DM的研究进展。     

树突状细胞与1型糖尿病的关系

1型糖尿病是一种T淋巴细胞介导的器官特异性自身免疫性疾病,表现为胰岛β细胞的选择性破坏.树突状细胞(DCs)作为体内最重要的专职性抗原递呈细胞,在1型糖尿病的发病机制中具有极其重要的作用.DCs具有功能上的可塑性,不同类型DCs、不同成熟状态的DCs以及DCs所处微环境的不同,都将诱导其产生不同的功能状态.通过调节DCs的不同功能状态促进中枢或外周免疫耐受、扩展胰岛特异性调节性T细胞(CD4~+ CD25~+ Treg cell)、以及介导辅助性T(Th)细胞发生Th1/Tk2细胞的免疫偏离,可诱导免疫耐受,预防1型糖尿病的发生.     

1型糖尿病免疫学研究进展

1型糖尿病是一种器官特异性自身免疫性疾病.其发病机制复杂,在遗传、环境、免疫等诸多因素的共同作用下,自身抗原免疫耐受丧失,免疫调节失衡,导致针对胰岛β细胞的自身免疫性破坏,导致糖尿病的发生.但其具体病因目前尚不明确,再生基因家族、胰-十二指肠同源盒因子1、嗜铬粒蛋白A、辅助性T细胞(Th)17及胰岛稳态蛋白等均参与1型糖尿病发病的不同环节,同时这些新的免疫学因子的发现,为1型糖尿病的诊断及治疗提供了新的靶点.     

胰岛β细胞自身免疫的分子机制

根据美国糖尿病学会(ADA,1997)和世界卫生组织(WHO,1999)糖尿病分型诊断的新建议,1型糖尿病可分为免疫介导性和特发性两种亚型。遗传易感因素[如人白细胞抗原(HLA)DQ/DR、胰岛素基因的可变串联重复序列(INS VNTR)和细胞毒性T淋巴细胞抗原(CTLA)4等]与环境因素(如病毒感染、饮食成分及化学毒素等)相互作用,致使免疫调节失衡[如辅助性T细胞(Th)1功能亢进,Th2功能减弱等],胰岛β细胞的免疫耐受性丧失而遭受免疫攻击,发生自身免疫性糖尿病。换言之,免疫介导性1型糖尿病系由自身免疫选择性破坏胰岛β细胞,引起胰岛素分泌缺乏所致。胰…     

胰岛β细胞自身免疫的分子机制

根据美国糖尿病学会(ADA，1997)和世界卫生组织(WHO，1999)糖尿病分型诊断的新建议，1型糖尿病可分为免疫介导性和特发性两种亚型。遗传易感因素[如人白细胞抗原(HLA)-DQ／DR、胰岛素基因的可变串联重复序列(INS-VNTR)和细胞毒性T淋巴细胞抗原(CTLA)-4等]与环境因素(如病毒感染、饮食成分及化学毒素等)相互作用，致使免疫调节失衡[如辅助性T细胞(Th)1功能亢进，Th2功能减弱等]，胰岛β细胞的免疫耐受性丧失而遭受免疫攻击，发生自身免疫性糖尿病。换言之，免疫介导性1型糖尿病系由自身免疫选择性破坏胰岛β细胞，引起胰岛素分泌缺乏所致。     

环孢菌素A与自身免疫性糖尿病胰岛β细胞凋亡

自身免疫性糖尿病是由抗原特异性T淋巴细胞对胰岛β细胞的选择性破坏,凋亡是β细胞破坏的基本过程。凋亡的β细胞所产生的自身抗原通过树突状细胞递呈给幼稚的T淋巴细胞使之活化、进入循环、激发胰岛炎,并通过细胞毒性T细胞再次诱导β细胞凋亡,由此形成恶性循环,导致β细胞强烈而特异性的破坏。环孢菌素A通过对钙调磷酸酶的特异性抑制,下调T淋巴细胞某些早期基因的转录,抑制其活化与增殖,打断β细胞凋亡-T淋巴细胞激活-β细胞凋亡链;环孢菌素A还可能通过阻断钙调磷酸酶介导的线粒体膜通透性转运孔的开放,直接抑制胰岛β细胞凋亡。     

胰岛素依赖性糖尿病患者抑制性T细胞缺乏用单克隆抗体进行分析

胰岛素-依赖性糖尿病的特征是葡萄糖-诱导胰岛素分泌缺乏和胰岛β-细胞进行性丧失,并导致内源性胰岛素产生障碍。虽然本病的病因学尚未清楚,而大量证据指出免疫系统在该病的发病中起重要作用。Doberson等报告在胰岛素依赖性糖尿病患者血清中有针对胰岛β-细胞的细胞毒自身抗体。胰岛素依赖糖尿病有各种器官和组织的自身抗体并伴随自身免疫疾病提示该病存在免疫调节的紊乱。近年来利用小鼠单克隆抗体(McAb)鉴定T细胞     

胰岛β细胞损伤的分子机制探讨

1型糖尿病的病理生理机制为自身免疫T细胞特异性破坏胰岛β细胞[1].越来越多的研究显示,胰岛β细胞的破坏同样在2型糖尿病的发生发展中发挥重要作用.2型糖尿病胰岛β细胞损伤的可能机制包括内质网应激、氧化应激、淀粉样物质沉着、脂毒性和糖毒性等[2].这些机制导致的炎症反应开始时可能促进胰岛β细胞的修复和再生,但持续存在的炎...     

The immunoneuroendocrine role of melatonin

Abstract: A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MHO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as -γ-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.     

Response of rat pineal melatonin to calcium, magnesium, and lithium is circadian stage dependent

Abstract: Herein we documented the response of pineal melatonin production to electrolytes known to be effective on pineal function in view of a possible circadian stage dependence. We studied the release of melatonin by perifused rat pineal glands at 2 different circadian stages corresponding to the middle of the light and dark periods, i.e., respectively, 7 and 19 HALO (Hours After Light Onset, L:D = 12:12). The initial efflux rates were, as expected, much higher in the perifusates of glands removed from rats sacrificed during the dark phase than of those removed during the light phase. After 3 hr of perifusion, melatonin release reached similar levels which were found constant up to the 8th hr of perifusion, whatever the circadian stage. Perifusion of the glands with physiological concentrations for the rat of calcium (5.2 mmol/1) and magnesium (1.34 mmol/1) resulted in a stimulatory effect on the pineal glands removed from rats sacrificed in the middle of the dark period (19 HALO), whereas no effects were observed on the pineal glands removed from rats sacrificed during the light (7 HALO). Lithium (0.28 and 0.55 mmol/1) was ineffective on melatonin release in pineal glands removed 7 and 19 HALO. Our results show differences in the initial efflux rates of melatonin and in the response of perifused pineal glands to calcium and magnesium according to the circadian stage.     

Changes in connexin43, the gap junction protein of astrocytes, during development of the rat pineal gland

Abstract: The abundance of gap junctions between rat pineal astrocytes formed by connexin43 (Cx43) was studied during development. Levels and distribution of Cx43 were measured by immunoblotting and indirect immunofluorescence, respectively. The amount of Cx43 in cells located within the gland was low until about the 7th postnatal day and increased to adult values between the 14th and 21st days postpartum. Although astrocytes, recognized by their vimentin immunoreactivity, were scarce before birth, they were abundant by the 7th postnatal day suggesting that the low levels of Cx43 found at this age corresponded to a low expression of this protein. Localization of the immunoreactivity to Cx43 and vimentin showed a close correlation, indicating that mature or immature pineal astrocytes form gap junctions made of Cx43. Since Cx43 levels attained their adult values at about the time the innervation and the functional state of the gland reached maturity (2–3 weeks after birth), it is proposed that astrocyte gap junctions are involved in the function of the adult rat pineal gland.     

Conservative management of perforated duodenal diverticulum： A case report and review of the literature

Duodenal diverticula are a relatively common condition. They are asymptomatic, unless they become complicated, with perforation being the rarest but most severe complication. Surgical treatment is the most frequently performed approach. We report the case of a patient with a perforated duodenal diverticulum, which was diagnosed early and treated conservatively with antibiotics and percutaneous drainage of secondary retroperitoneal abscesses. We suggest this method could be an acceptable option for the management of similar cases, provided that the patient is in good general condition and without septic signs.     

Presence of immunoreactive growth hormone and prolactin in the ovine pineal gland

Abstract: The use of antisera raised against bovine growth hormone (GH) and ovine prolactin (PRL) enabled the detection of related immunoreactive (ir) sequences of proteins in ovine pineal tissue. The isolation of PRL-like ir-material was accomplished using a 0.25 M ammonium sulphate (pH 5.5) extraction followed by ethanol precipitation, whereas the resulting 2.0 M ammonium sulphate (pH 7.0) precipitate contained a GH-like immunoreactivity. Gel chromatography of the GH-like immunoreactivity (Sephadex G-100) indicated the presence of several GH-like fragments ranging in the M_r range of 7,000 to 55,000. Analyses of the PRL-like ir-material found in pineal tissue on HPLC using a TSK 545-DEAE column led to the resolution into a single peak of immunoreactivity. A single peak of activity was also observed following chromatofocusing and hydrophobic interaction chromatography of the ir-peak from the TSK 545-DEAE column. The PRL-like ir-material inhibited the binding of [¹²⁵I]ovine PRL-S14 to anti-ovine PRL antibodies without showing an affinity for binding to anti-rat PRL or anti-bovine GH antibodies. Scatchard analysis of the binding of pineal PRL-like ir-material and pituitary ovine PRL-S14 to liver membranes from day-20 pregnant rats revealed similar affinity constants (K_a of 4.7 ± 0.2 × 10⁹ M^-1). In addition, the replication of Nb 2 Node rat lymphoma cells was stimulated by pineal PRL-like ir-material, an effect known to be specific for lactogenic hormones. The pineal PRL-like immunoreactivity appeared on sodium dodecyl sulfate polyacrylamide gels as a single major band of M_r 24,000. The functional status of PRL-and GH-like ir-material in the ovine pineal remains to be determined, but evidence is presented that the overall protein synthesis rate of the rat pineal responded to circulating concentrations of PRL.     

Microbiology of human immunodeficiency virus anorectal disease

PURPOSE: Individuals who are seropositive for the human immunodeficiency virus are at high risk for opportunistic infection and anorectal disorders. Little prospective information is available regarding anorectal pathogens in these patients. METHODS: One hundred sixty-three HIV-seropositive patients presented to the colorectal clinic between 1989 and 1992. Forty-seven (29 percent) patients were thought to have an infectious process and were prospectively studied using a standardized multiculture protocol. RESULTS: Mean age was 33 (range, 19–59) years. All were male; high-risk behavior accounted for 87 percent of HIV transmissions. Presenting complaints included anorectal pain (79 percent), pus per anum (28 percent), and blood per anum (26 percent). Examination revealed perianal tenderness (60 percent), condyloma (38 percent), perianal ulcers (38 percent), and anal fissures (34 percent). Sixty-six sets of cultures were performed; 28 patients had one set, 15 had two sets, and 4 had three sets. Thirty-two of these 47 patients (68 percent) had positive cultures including herpes (50 percent), cytomegalovirus (25 percent),Neisseria gonorrhoeae (16 percent), chlamydia (16 percent), acidfast bacilli (2 percent), and others (9 percent). Six of 32 patients with positive cultures had more than one organism cultured. Sixteen (50 percent) patients with positive cultures were treated medically, 8 (25 percent) were treated surgically and 8 (25 percent) were treated with both modalities. Sixty-one procedures were performed on 17 patients for condylomata. Eighteen patients had 20 procedures for abscesses, 50 percent of whom had positive cultures for other than common bowel flora; all improved. Fourteen patients underwent 33 procedures for perianal fistulas.Mycobacterium fortuitum was cultured from one patient who required 13 procedures for abscesses and fistulas. Forty-five (96 percent) patients were followed for an average of 12.5 months ±2.9 SEM (range, 1–94 months). Symptoms were improved or resolved in 22 of 32 (69 percent) patients with positive cultures and in 11 of 13 (84 percent) with negative cultures. CONCLUSIONS: Specific pathogens may often be identified in human immunodeficiency virus-seropositive patients with anorectal disorders if aggressively sought. Although patients without specific pathogens identified may be expected to improve with planned empiric treatment, positive identification allows more directed therapy.