滤泡辅助性T细胞相关分子与类风湿性关节炎相关性研究进展

类风湿性关节炎(RA)患者体内滤泡辅助性T(Tfh)细胞异常表达,与RA的发生发展相关。目前, Tfh细胞调控RA发生机制的研究仍处于初级阶段。此外, Tfh细胞表面分子CXC趋化因子受体5(CXCR5)、诱导性共刺激分子(ICOS)和程序性死亡蛋白1(PD-1)及其分泌的白细胞介素21(IL-21)、 B细胞淋巴瘤因子6(BCL6)均被证实与RA的发生有关。我们主要从Tfh细胞表面分子及其分泌的因子的角度研究其调控RA发生的机制,分析与Tfh细胞相关的各分子对RA发生的作用,探讨各分子对RA临床诊断的意义和以各分子为靶点治疗RA的潜在途径。     

滤泡辅助性T细胞(T_(fh))的研究进展

T细胞辅助B细胞抗体的生成是体液免疫应答的中心环节.但直到最近,科学家们才对T细胞辅助B细胞的细胞及分子机制有了更清楚的认识.滤泡辅助性T细胞(T follicular helper cells,Tfh)是最近明确的一种新的CD4+T细胞亚群,其主要功能是辅助B细胞参与体液免疫.Tfh的表型和功能与其他CD4+T细胞亚群有所不同,包括趋化因子受体的表达(如CXCR5)、定位和迁移(Tfh存在于B细胞滤泡)及其辅助B细胞的功能.Tfh产生的细胞因子IL-21在Tfh功能中处于核心地位,通过与其受体IL-21R结合,可有效地刺激B细胞分化成抗体形成细胞.因此Tfh细胞相关分子(如ICOS或IL-21)的高表达或低表达,很可能与某些自身免疫性疾病或免疫缺陷疾病的发病有关.     

IL-21在滤泡辅助性T细胞分化发育及功能中的作用

抗原刺激B细胞产生抗体需要T细胞辅助,近年来人们逐渐认识到一个命名为滤泡辅助性T细胞(Tfh)的CD4+T细胞亚群在B细胞诱导的免疫应答中具有重要作用.Tfh细胞的主要特征包括表达趋化因子受体与(CXCR5),迁移定位于B细胞滤泡辅助B细胞产生抗体.Tfh细胞产生的细胞因子IL-21能够促进B细胞分化为抗体形成细胞,这种辅助性细胞因子在Tfh细胞的分化发育、效应发挥及Tfh细胞功能失调相关的疾病中具有重要意义.     

滤泡辅助性T细胞分化及其在HIV感染中的变化

T细胞辅助B细胞是适应性免疫和免疫记忆生成的基础.滤泡辅助性T细胞(Tfh)是辅助B细胞的主要T细胞亚群,其主要转录因子为Bcl6.Tfh细胞的明显特征为表达CXCR5、程序性死亡因子-1(PD-1)、IL-21和ICOS,同时Blimp-1表达下调.在HIV-1慢性感染过程中Tfh细胞累积增多,从而导致B细胞调节异常,发生功能性改变,这可能是HIV-1逃避体液免疫应答的根源.     

滤泡辅助T细胞的分化和功能及其在疾病中的作用

CD4~+辅助T(Th)细胞在抗原的刺激下会分化为不同的效应T细胞亚群。体液免疫应答具有很好的持久性,持久性的维持依赖于一群特殊的CD4~+T细胞提供辅助,即滤泡辅助性T(Tfh)细胞。树突状细胞(DC)提呈抗原并促进活化的Tfh前体细胞迁移到B细胞滤泡区域分化为成熟的Tfh细胞,辅助生发中心(GC)形成以及浆细胞和记忆性B细胞的分化,从而形成完整的体液免疫应答。Tfh细胞分化和功能上的失调均会导致多种疾病的发生。本文主要从Tfh细胞分化、功能以及在疾病中的作用三个方面对Tfh细胞的研究进展进行阐述。     

类风湿性关节炎患者外周血CD3~+CD8~+效应记忆T细胞和滤泡辅助性T细胞ICOS、 PD-1表达上调且与病情相关

目的研究类风湿性关节炎(RA)患者外周血T淋巴细胞程序性死亡蛋白1(PD-1)和可诱导共刺激分子(ICOS)的表达,并确定其与疾病活动度之间的关系。方法募集RA患者30例、健康对照26例。流式细胞术检测外周血CD3~+CD8~+的效应记忆T细胞(Tem)和滤泡辅助性T(Tfh)细胞比例,而后检测淋巴细胞亚群中PD-1和ICOS阳性的细胞比例;通过Spearman相关性分析评估其与28个关节疾病活动度评分(DAS28)之间的相关性。结果与健康对照组相比, RA组患者外周血Tem和Tfh细胞绝对数增高, Tem和Tfh细胞的ICOS与PD-1表达增加; RA组患者外周血CD3~+CD8~+ Tem和Tfh细胞ICOS和PD-1表达水平与DAS28之间呈正相关。结论外周血CD3~+CD8~+ Tem和Tfh细胞PD-1和ICOS可能参与RA的发生发展,并可能作为RA活动度的评价指标。     

滤泡辅助性T细胞是系统性红斑狼疮潜在的治疗靶标

系统性红斑狼疮(systemic lupus erythematosus,SLE)是一种慢性自身免疫性疾病,其特征是B细胞过度活化产生致病性自身抗体,因而减少抗体产生是治疗SLE疾病的一种方式。滤泡辅助性T细胞(follicular T helper cells,Tfh)是CD4~+T细胞的一个亚群,辅助B细胞分化成长寿命浆细胞产生自身抗核抗体促发SLE疾病。本文就Tfh细胞参与SLE疾病的发展、参与Tfh细胞形成的因素以及Tfh细胞作为SLE强有力的治疗靶标进行概述。     

滤泡辅助性T细胞与自身免疫病

滤泡辅助性T细胞(Tfh)是近年来被确认的新的CD4~+辅助性T细胞亚群,主要功能是刺激B细胞增殖、分化和辅助B细胞产生相应抗体以及诱导生发中心(GC)形成。Tfh发育或功能异常会诱发异常的体液免疫引起自身免疫病发生。     

滤泡辅助性T细胞在HIV感染及疫苗免疫中的作用及机制

滤泡辅助性T细胞( follicular helper T cell, Tfh )是近期发现的具有B细胞辅助功能的CD4+T淋巴细胞亚群, 对于生发中心形成、亲和力成熟、高亲和力抗体产生和记忆B细胞的发育至关重要。Tfh与艾滋病(acquired immunodeficiency syndrome, AIDS)发展进程密切相关。在人类免疫缺陷病毒(human immunodeficiency virus, HIV)感染过程中, Tfh细胞数量、功能、病毒潜伏、Tfh/滤泡调节T细胞(follicular regulatory T cell, Tfr)比例平衡、中和抗体产生等方面均发生变化。文章综述Tfh在HIV感染及疫苗免疫后抗体应答中的作用及机制, 旨在为HIV疫苗的设计与免疫策略制定提供参考。     

IL-21在滤泡辅助性T细胞分化发育及功能中的作用

抗原刺激B细胞产生抗体需要T细胞辅助,近年来人们逐渐认识到一个命名为滤泡辅助性T细胞（Tfh）的CD4^＋T细胞亚群在B细胞诱导的免疫应答中具有重要作用。Tfh细胞的主要特征包括表达趋化因子受体与（CXCR5）,迁移定位于B细胞滤泡辅助B细胞产生抗体。Tfh细胞产生的细胞因子IL-21能够促进B细胞分化为抗体形成细胞,这种辅助性细胞因子在Tfh细胞的分化发育、效应发挥及Tfh细胞功能失调相关的疾病中具有重要意义。     

Opportunities and challenges in the prevention and control of cancer and other chronic diseases: children's diet and nutrition and weight and physical activity

OBJECTIVE: The purpose of this article is to review the role of behavioral research in disease prevention and control, with a particular emphasis on lifestyle- and behavior-related cancer and chronic disease risk factors--specifically, relationships among diet and nutrition and weight and physical activity with adult cancer, and tracking developmental origins of these health-promoting and health-compromising behaviors from childhood into adulthood. METHOD: After reviewing the background of the field of cancer prevention and control and establishing plausibility for the role of child health behavior in adult cancer risk, studies selected from the pediatric published literature are reviewed. Articles were retrieved, selected, and summarized to illustrate that results from separate but related fields of study are combinable to yield insights into the prevention and control of cancer and other chronic diseases in adulthood through the conduct of nonintervention and intervention research with children in clinical, public health, and other contexts. RESULTS: As illustrated by the evidence presented in this review, there are numerous reasons (biological, psychological, and social), opportunities (school and community, health care, and family settings), and approaches (nonintervention and intervention) to understand and impact behavior change in children's diet and nutrition and weight and physical activity. CONCLUSIONS: Further development and evaluation of behavioral science intervention protocols conducted with children are necessary to understand the efficacy of these approaches and their public health impact on proximal and distal cancer, cancer-related, and chronic disease outcomes before diffusion. It is clear that more attention should be paid to early life and early developmental phases in cancer prevention.     

Pain and Effusion and Quadriceps Activation and Strength

Context:

Quadriceps dysfunction is a common consequence of knee joint injury and disease, yet its causes remain elusive.

Objective:

To determine the effects of pain on quadriceps strength and activation and to learn if simultaneous pain and knee joint effusion affect the magnitude of quadriceps dysfunction.

Design:

Crossover study.

Setting:

University research laboratory.

Patients or Other Participants:

Fourteen (8 men, 6 women; age = 23.6 ± 4.8 years, height = 170.3 ± 9.16 cm, mass = 72.9 ± 11.84 kg) healthy volunteers.

Intervention(s):

All participants were tested under 4 randomized conditions: normal knee, effused knee, painful knee, and effused and painful knee.

Main Outcome Measure(s):

Quadriceps strength (Nm/kg) and activation (central activation ratio) were assessed after each condition was induced.

Results:

Quadriceps strength and activation were highest under the normal knee condition and differed from the 3 experimental knee conditions (P < .05). No differences were noted among the 3 experimental knee conditions for either variable (P > .05).

Conclusions:

Both pain and effusion led to quadriceps dysfunction, but the interaction of the 2 stimuli did not increase the magnitude of the strength or activation deficits. Therefore, pain and effusion can be considered equally potent in eliciting quadriceps inhibition. Given that pain and effusion accompany numerous knee conditions, the prevalence of quadriceps dysfunction is likely high.Key Words: arthrogenic muscle inhibition, central activation failure, voluntary activation, muscles

Key Points

• Knee pain and effusion resulted in arthrogenic muscle inhibition and weakness of the quadriceps.
• The simultaneous presence of pain and effusion did not increase the magnitude of quadriceps dysfunction.
• To reduce arthrogenic muscle inhibition and improve muscle strength, clinicians should employ interventions that target removing both pain and effusion.

Quadriceps weakness is a common consequence of traumatic knee joint injury^1,2 and chronic degenerative knee joint conditions.^3,4 Arthrogenic muscle inhibition (AMI), a neurologic decline in muscle activation, results in quadriceps weakness and hinders rehabilitation by preventing gains in strength.⁵ The inability to reverse AMI and restore muscle function can lead to decreased physical abilities,⁶ biomechanical deficits,⁷ and possibly reinjury.⁵ Furthermore, researchers^8,9 have suggested that quadriceps weakness resulting from AMI may place patients at risk for developing osteoarthritis in the knee. In light of the substantial influence of quadriceps AMI on these clinically relevant outcomes, we need to improve our understanding of the factors that contribute to this neurologic decline in muscle activity so efforts to target and reverse it can be implemented and gains in strength can be achieved more easily.Joint injury and disease are accompanied by numerous sequelae (ie, pain, swelling, tissue damage, inflammation), so ascertaining which one ultimately leads to neurologic muscle dysfunction is difficult. Whereas a joint effusion can result in AMI,^10–12 the effects of pain are less understood despite many clinicians attributing AMI to pain. Using techniques that introduce knee pain without accompanying injury may provide insights into the role of pain in eliciting AMI.The degree of knee joint damage may play a role in the quantity of AMI that manifests. Hurley et al^13,14 demonstrated that quadriceps AMI, measured using an interpolated-twitch technique, was greater in patients with extensive traumatic knee injury (eg, fractured tibial plateau, ruptured medial collateral ligament, and medial meniscectomy) than patients with isolated joint trauma (ie, isolated anterior cruciate ligament [ACL] rupture). Similarly, patients with more knee joint symptoms (ie, greater number of symptoms and increased severity of symptoms) may present with greater magnitudes of quadriceps inhibition. Recently, investigators¹⁵ have suggested that patients with more pain display less quadriceps strength, supporting this tenet. Given that effusion and pain often present simultaneously with joint injuries and diseases, such as ACL injury and osteoarthritis, examining both the isolated and cumulative effects of these sequelae appears warranted to determine if they influence the magnitude of muscle inhibition.Experimental joint-effusion and pain models are safe and effective experimental methods that allow for the isolated examination of their effects on muscle function. The effusion model, whereby sterile saline is injected directly into the knee joint capsule,⁷ produces a clinically relevant magnitude of the joint effusion that may be present with traumatic injury. Effusion is thought to activate group II afferents responding to stretch or pressure,^16–18 which in turn may facilitate group Ib interneurons and result in quadriceps AMI.⁵ The pain model involves injecting hypertonic saline into the infrapatellar fat pad to produce anteromedial knee pain similar to that described in patients with patellofemoral pain syndrome.¹⁹ Pain is considered to initiate AMI through activation of group III and IV afferents that act as nocioceptors to signal damage or potential damage to joint structures.^16–18 The firing of these afferents then may lead to facilitation of group Ib interneurons, the flexion reflex, or the gamma loop, ultimately resulting in quadriceps inhibition.²⁰ Thus, these models allow us to create symptoms that are associated with knee injury and have the added benefit of providing a way to examine their effects in isolation.Therefore, the purpose of our study was to determine the effects of pain on quadriceps strength and activation and to learn if simultaneous pain and knee joint effusion would affect the magnitude of quadriceps dysfunction. We hypothesized that pain alone would result in quadriceps inhibition and that the magnitude of inhibition would be greater when effusion and pain were present simultaneously.     

Postinfectious immunodeficiency and autoimmunity: pathogenic and clinical values and implications

Autoimmunity is still a mystery of clinical immunology and medicine as a whole. The etiology and pathogenesis of autoimmune disorders remain unclear and, thus, are assessed as a balance between hereditary predisposition, triggering factors and the appearance of autoantibodies and/or self-reactive T cells. Among the immunological armamentarium, molecular mimicry, based on self-reactive T- and B-cell activation by cross-reactive epitopes of infectious agents, is of special value. Hypotheses regarding the possible involvement of molecular mimicry in the development of postinfectious autoimmunity are currently very intriguing. They provide new approaches for identifying etiological agents that are associated with postinfectious autoimmunity, paired microbial- and tissue-linked epitopes targeted for autoimmune reaction determination, postinfectious autoimmunity pathogenesis recognition and specific prevention, and therapy for autoimmune disorder development.     

Beta-endorphin and drug-induced reward and reinforcement

Although drugs of abuse have different acute mechanisms of action, their brain pathways of reward exhibit common functional effects upon both acute and chronic administration. Long known for its analgesic effect, the opioid beta-endorphin is now shown to induce euphoria, and to have rewarding and reinforcing properties. In this review, we will summarize the present neurobiological and behavioral evidences that support involvement of beta-endorphin in drug-induced reward and reinforcement. Currently, evidence supports a prominent role for beta-endorphin in the reward pathways of cocaine and alcohol. The existing information indicating the importance of beta-endorphin neurotransmission in mediating the reward pathways of nicotine and THC, is thus far circumstantial. The studies described herein employed diverse techniques, such as biochemical measurements of beta-endorphin in various brain sites and plasma, and behavioral measurements, conducted following elimination (via administration of anti-beta-endorphin antibodies or using mutant mice) or augmentation (by intracerebral administration) of beta-endorphin. We suggest that the reward pathways for different addictive drugs converge to a common pathway in which beta-endorphin is a modulating element. beta-Endorphin is involved also with distress. However, reviewing the data collected so far implies a discrete role, beyond that of a stress response, for beta-endorphin in mediating the substance of abuse reward pathway. This may occur via interacting with the mesolimbic dopaminergic system and also by its interesting effects on learning and memory. The functional meaning of beta-endorphin in the process of drug-seeking behavior is discussed.     

PTEN与信号转导及肿瘤

ＴＥＮ[1] (ｐｈｏｓｐｈａｔａｓｅａｎｄｔｅｎｓｉｎｈｏｍｏｌｏｇｙｄｅｌｅｔｅｄｏｎｃｈｒｏｍｏｓｏｍｅｔｅｎ)又名ＭＭＡＣ1 [2 ] (ｍｕｔａｔｅｄｉｎｍｕｔｉｐｌｙａｄａｎｃｅｄｃａｎｃｅｒ 1 )和ＴＥＰ1 [3 ] (ＴＧＦ -βｒｅｇｕｌａｔｅｄａｎｄｅｐｉｔｈｅｌｉａｌｃｅｌｌ -ｒｉｃｈｅｄｐｈｏｓｐｈａｔａｓｅ 1 ) (以下均称为ＰＴＥＮ) ,是 1 997年由 3个研究小组先后发现的一个具有双特异磷酸酶活性的抑癌基因。ＰＴＥＮ基因异常广泛存在于人类多种恶性肿瘤 ,如恶性神经胶质瘤、前列腺癌、子宫内膜癌、黑色素瘤等…     

Tobacco and alcohol and the risk of head and neck cancer

Summary We carried out two case-control studies on the relative risk of head and neck cancer in association with tobacco and alcohol consumption. The first study carried out at the ENT Department of the University hospitals of Heidelberg and Giessen (FRG) comprised 200 male patients with squamous cell cancer of the head and neck and 800 control subjects matched for sex, age, and residential area (1:4 matching design). Of the tumour patients, 4.5% had never smoked, in contrast to 29.5% of the control group. The average tobacco and alcohol consumption of the patients was approximately twice as high as in the control subjects. The highest alcohol and tobacco consumption was observed in patients suffering from oropharyngeal cancer. Tobacco and alcohol increased the risk of head and neck cancer in a dose-dependent fashion and acted as independent risk factors. In heavy smokers (> 60 pack-years) a relative risk of 23.4 (alcohol adjusted) was calculated. Combined alcohol and tobacco consumption showed a synergistic effect. The risk ratio increased more in a multiplicative than in an additive manner. Oral and laryngeal cancer were associated with the highest tobacco-associated risk values. The highest ethanol-associated risk values were associated with oropharyngeal and laryngeal cancer. The second study was carried out at the ENT Department of the University of Heidelberg on 164 males with squamous cell carcinoma of the larynx and 656 control subjects matched for sex, age and residential area (1:4 matching design). Of the cases, 4.2% had never smoked, compared with 28.5% of the control subjects. The risk of laryngeal cancer by tobacco consumption was dose dependent, reaching a maximum value of 9.1 (adjusted for alcohol) for a consumption of more than 50 tobacco-years (TY). The relative risk of laryngeal cancer associated with alcohol intake was also dose dependent, reaching a value of 9.0 (adjusted for tobacco) for a mean daily consumption of more than 75 g alcohol. An analysis of subsite specific risks showed that heavy smokers (> 50 TY) carried a nearly ten times higher risk of supraglottic cancer than of glottic cancer. The risk of supraglottic cancer from alcohol consumption was also higher than that of glottic cancer.     

Muscle strength and serum testosterone,cortisol and SHBG concentrations in middle-aged and elderly men and women

Forty healthy males (M) and females (F) divided into two different age groups i.e. M50 years (range 44–57; n= 9), F50 years (range 43–54; n= 9), M70 years (range 64–73; n= 11) and F70 years (range 63–73; n= 11) volunteered as subjects for examination of muscle cross-sectional area (CSA) and maximal voluntary isometric force production characteristics of the leg extensor muscles and serum androgen and sex hormone binding globulin (SHBG) concentrations. The CSA in the male groups was greatly larger (P < 0.01) than in the female groups and both elderly groups demonstrated slightly (n.s.) smaller values in the CSA than the two middle-aged groups. Maximal force of 2854 ± 452 N in M50 was greater (P < 0.05) than that of 2627 ± 752 N recorded for F50 as well as the force of 2787 ± 843 in M70 was greater (P < 0.001) than that of 1849 ± 295 recorded for F70. The force between F50 and F70 differed significantly (P < 0.05) from each other. The maximal rate of force production in M50 was greater (P < 0.01) than in F50 as well as in M70 greater (P < 0.001) than in F70. Both middle-aged groups demonstrated greater (P < 0.05) values than the respective elderly groups of the same sex. The individual values in the CSA correlated with the values in maximal force both in the middle-aged subjects (r= 0.66; P < 0.01) and in the elderly subjects (r= 0.69; P < 0.01). The mean concentration of serum testosterone in M50 was slightly (n.s.) greater than in M70 and in F50 significantly (P < 0.05) greater than in F70. Serum SHBG levels were lower in the males (P < 0.01) than in the females and serum testosterone/SHBG ratio in M70 and in F70 were lower (P < 0.05) than in M50 and in F50, respectively. In the females significant positive correlations were observed between the individual values in serum testosterone concentration and the values both in the CSA (r= 0.46; P < 0.05) and in maximal force (r= 0.62; P < 0.01) as well as between serum testosterone/SHBG ratio and both the CSA (r= 0.55; P < 0.05) and maximal force (r= 0.68; P < 0.01). The present results imply that the decreasing basal level of blood testosterone over the years in aging people, especially in females, may lead to decreasing anabolic effects on muscles thus having an association with age-related declines in the maximal voluntary neuromuscular performance capacity in aging people.     

Platelet-activating factor receptor and respiratory and metabolic responses to hypoxia and hypercapnia

Activation of the platelet-activating factor receptor (PAFR) regulates neural transmission. A PAFR blocker reduced the peak hypoxic (pHVR) but not hypercapnic ventilatory (HCVR) responses in rats [Am. J. Physiol. 275 (1998) R604]. To further examine the role of PAFR in respiratory control, genotype-verified PAFR -/- and PAFR +/+ adult male mice underwent hypoxic and hypercapnic challenges. HCVR was similar in the two groups (p-NS). However, pHVR was significantly reduced in PAFR -/- mice (38 +/- 13% baseline [S.D.]) compared to PAFR +/+ mice (78 +/- 16% baseline; P < 0.001, ANOVA), with reduced tidal volume recruitments during pHVR. In addition, hypoxic ventilatory depression was attenuated in PAFR -/- mice (P < 0.01), and was primarily due to attenuation of the time-dependent decreases in oxygen consumption during sustained hypoxia (P < 0.01). Thus, PAFR expression/function modulates components of the acute ventilatory and metabolic adaptations to hypoxia but not to hypercapnia. Imbalances in PAFR activity may lead to maladaptive regulation of the tightly controlled metabolic-ventilatory relationships during hypoxia.