长链非编码RNA H19和转录因子SIRT6在口腔鳞癌中的表达及其与预后的关系

目的研究长链非编码RNAH19(LncRNAH19)和转录因子去乙酰化酶6(SIRT6)在口腔鳞癌中的表达及临床意义。方法纳入2014年11月–2015年5月我院收治的89例口腔鳞癌患者作为研究对象,并以手术切除的口腔鳞癌组织为口腔鳞癌组,以癌旁组织作为正常组。采用实时定量PCR检测LncRNA H19与SIRT6表达水平,免疫组化法检测SIRT6蛋白表达,收集患者临床病理资料,根据口腔鳞癌组检测结果中位值将LncRNA H19分为高表达组与低表达组,观察LncRNAH19、SIRT6表达与患者临床病理特征的关系。采用Kaplan-Meier生存曲线、Log-Rank检验分析LncRNAH19与SIRT6相对表达量对患者预后的影响。结果与正常组相比,口腔鳞癌组LncRNA H19表达水平显著升高(P 0.05),而SIRT6 mRNA与蛋白表达显著降低(P 0.05);LncRNA H19、SIRT6均与淋巴结转移、TNM分期、分化程度显著相关(P 0.05);Kaplan-Meier分析结果显示,LncRNA H19低表达组无进展生存期、总体生存时间显著高于高表达组(P 0.05),SIRT6阳性表达组无进展生存期、总体生存时间显著高于阴性表达组(P 0.05)。结论口腔鳞癌组织中LncRNAH19高表达,而SIRT6低表达,两者均与口腔鳞癌的发生发展及预后有关,且均可成为临床早期诊断与治疗的潜在靶标。     

食管鳞癌中VEGF-C与CD44v6的表达及其与淋巴结转移的关系

目的研究食管鳞癌组织中血管内皮细胞生长因子-C(VEGF-C)与CD44v6的表达及其与淋巴结转移的关系。方法应用免疫组织化学方法对152例食管鳞癌组织进行VEGF-C与CD44v6蛋白检测结果VEGF-C与CD44v6蛋白在食管鳞癌的阳性表达为55.3%和71.7%,VEGF-C与CD44v6的表达与食管癌有无转移有显著差异(P<0.05)。结论VEGF-C与CD44v6与食管鳞癌淋巴结转移密切相关,可作为判断食管鳞癌预后的指标。     

人疱疹病毒6型感染与口腔鳞癌关系的初步研究

目的研究人疱疹病毒6型(HHV-6)感染与口腔鳞癌的关系。方法用间接免疫荧光试验及聚合酶链反应,分别检测口腔鳞癌和对照组患者血清中抗HHV-6 IgG及外周血单个核细胞中HHV-6 DNA序列;用免疫组化染色法检测口腔鳞癌组织标本中HHV-6抗原。结果16例口腔鳞癌患者和16例其他口腔疾病患者血清中抗HHV-6 IgG的阳性数分别为16例和12例,几何平均滴度分别为1:118和1:64,差异有显著意义(P<0.05)。上述两组患者HHV-6 DNA的检出数分别为10例和2例(P<0.05)。其中12例口腔鳞癌组织标本经免疫组化染色检测,9例(9/12)HHV-6抗原阳性,而8例对应癌旁组织中,阳性者仅有2例(2/8),两者间差异有显著意义(P<0.05)。结论HHV-6可能是口腔鳞癌发生的诱因,在肿瘤发生发展中起一定作用。     

口腔鳞癌患者淋巴细胞对人疱疹病毒6型增殖应答受损

目的研究口腔鳞癌患者淋巴细胞对人疱疹病毒6型（HHV-6）特异性增殖应答,初步探讨HHV-6在口腔鳞癌发病机制中的作用。方法间接免疫荧光法（IIF）检测血浆中抗HHV-6IgG;免疫微磁珠分离CD4^＋T及CD8^＋T细胞;3H-TdR法检测CD4^＋T和CD8^＋T细胞及PBMCs的增殖水平;FACS分析CD4^＋C25^＋调节性T细胞（Treg）的比例。结果口腔鳞癌组血浆中抗HHV-6IgG阳性数为8/8,正常对照组为12例（12/20）;口腔鳞癌组PBMCs及CD4^＋T细胞对HHV-6的增殖水平显著低于HHV-6潜伏感染组与未感染组（P〈0.05）;HHV-6潜伏感染组PBMCs及CD4^＋T细胞对HHV-6的增殖水平显著低于未感染组（P〈0.05）;口腔鳞癌组外周血中CD4^＋C25^＋Treg比例明显高于HHV-6潜伏感染组与未感染组（P〈0.05）。结论口腔鳞癌患者的HHV-6特异性CD4＋T细胞增殖应答减弱,可能在口腔鳞癌的发生发展中起一定作用。     

ANO1在口腔鳞癌中的表达及临床分析

 目的 探讨ANO1基因及蛋白在口腔鳞癌中的表达及其临床意义。方法 应用免疫组化SP法及Northern blot检测81例口腔鳞癌组织及相应正常组织的ANO1基因及蛋白的表达进行检测,并结合临床病理资料和基因蛋白表达特征对比作差异显著性检验及相关分析。利用western blot检测ANO1在多株鳞癌细胞株的表达。结果 ANO1在口腔鳞癌组织中的阳性表达明显高于正常组织,有显著性差异( P <0.05);有淋巴结转移的口腔鳞癌组织ANO1阳性表达高于无转移的口腔鳞癌组织。有显著性差异( P <0.05);随着口腔鳞癌临床分期的升高,ANO1的阳性表达率升高(P＜0.05);而ANO1的阳性表达率与病理分级,年龄和性别暂无关(P＞0.05)。Hep-2的内源性ANO1表达最低, 而SCC-25细胞株的内源性ANO1表达最高。 结论 ANO1可能在口腔鳞癌的发生和进展过程中起到重要作用。     

PDCD5和Smac在口腔鳞癌中的表达及临床意义

目的研究凋亡相关新基因PDCD5与Smac蛋白在口腔正常黏膜、口腔鳞癌中表达的相关性及其意义。方法采用免疫组化方法检测68例口腔鳞癌组织和43例癌旁正常黏膜组织中PDCD5和Smac的表达,并分析两者的表达与临床病理的关系以及两者之间相互关系。结果正常口腔黏膜组PDCD5染色阳性率为80.2%(P0.05),口腔鳞癌组PDCD5阳性率为29%(P0.05),明显低于癌旁组织,并且表达与TNM分期、淋巴结转移相关性有统计学意义(P0.05)。Smac在正常口腔黏膜组染色阳性率为41.2%(P0.05),明显高于口腔鳞癌组织11.7%(P0.05),且与肿瘤的分化程度、TNM分期、淋巴结转移的相关性均有统计学意义(P0.05)。PDCD5和Smac蛋白呈明显正相关(r=0.892,P0.05)。结论PDCD5和Smac蛋白在口腔鳞癌中表达下调,提示PDCD5与Smac蛋白的改变可能与口腔鳞癌的发生、发展相关,这两项指标可作为辅助口腔黏膜癌变的基因标志物。     

CCR7和VEGF-C蛋白与乳腺癌预后之间的关系

目的:探讨趋化因子受体7(CCR7)及血管内皮生长因子C(VEGF-C)蛋白在乳腺癌组织中的表达水平,并分析二者与乳腺癌预后的关系。方法:采用免疫组织化学技术,联合检测CCR7和VEGF-C蛋白分别在乳腺癌组织及正常乳腺组织中的表达差异情况,并分析二者与乳腺癌各相关临床病理特征之间的关系。采用Kaplan-Meier法来评估CCR7及VEGF-C蛋白的异常表达与乳腺癌患者生存期之间的关系。结果:CCR7蛋白在乳腺癌组织(68%)中的阳性表达率高于正常乳腺组织(30%),差异有统计学显著性(P0.01);而VEGF-C蛋白在乳腺癌组织(71%)中的阳性表达率也明显高于正常乳腺组织(24%),差异也有统计学显著性(P0.01)。且在乳腺癌组织中,CCR7与VEGF-C蛋白的表达呈正相关关系(r=0.613,P0.01)。CCR7和VEGF-C蛋白的高表达均与淋巴结转移和TNM分期有关(P0.05),而与年龄、肿瘤大小、雌激素受体和孕激素受体均无关。CCR7及VEGFC蛋白阳性表达者的生存期低于阴性表达者,两组比较差异有统计学显著性(P0.05)。结论:CCR7与VEGF-C的异常高表达可能与乳腺癌预后关系密切,二者可作为判断乳腺癌预后不良的重要指标之一。     

miR-429在食管鳞癌中的表达及对细胞增殖迁移的影响

目的探讨微小RNA-429(miR-429)在食管鳞癌(ESCC)中的表达及其对细胞增殖及迁移的影响。方法选取本院45例ESCC患者手术切除的癌组织(ESCC组)及癌旁组织(正常组)标本为研究对象,并采用实时荧光定量(q RT-PCR)检测两组miR-429表达水平。体外培养ESCC癌细胞株系ECa109及人正常食管上皮细胞株Het-1A,将转染试剂、miR-429阴性对照质粒、miR-429mimic质粒分别转染ECa109细胞,命名为空白组、阴性转染组、miR-429过表达组,同时应用生物信息学工具预测miR-429的靶基因为CTl0激酶调节子样蛋白(CRKL),荧光素酶活性检测miR-429与CRKL的靶向调控关系。采用qRT-PCR法检测细胞中miR-429与CRKLmRNA表达水平,蛋白免疫印迹法检测细胞中CRKL蛋白表达。MTT法检测细胞增殖情况,Transwell检测细胞迁移能力。结果与正常组相比,ESCC组miR-429表达水平显著降低(P0.05);荧光素酶活性测定显示3'UTR-Wt细胞中miR-429过表达组荧光素酶活性显著低于阴性对照组(P 0.05),3'UTR-Mut细胞中miR-429阴性转染组与过表达组比较差异无统计学意义(P 0.05);与Het-1A细胞相比,ECa109细胞中miR-429表达水平显著降低(P0.05),而CRKL mRNA及蛋白表达水平显著升高(P 0.05);与空白组、阴性转染组相比,miR-429过表达组miR-429表达水平显著升高(P 0.05),而CRKL mRNA及蛋白表达水平显著降低(P 0.05);与空白组、阴性转染组相比,miR-429过表达组细胞增殖率及迁移数量均显著降低(P 0.05)。结论 ESCC中miR-429呈低表达,其可通过下调CRKL表达进而抑制ESCC细胞增殖及迁移。     

口腔鳞癌中survivin、cyclinD1和p53基因的表达及其相关性

目的:探讨survivin、cyclinD1和p53基因蛋白在口腔鳞癌中的表达及其相互关系.方法:应用免疫组化SP法检测95例口腔鳞癌组织和50例正常口腔黏膜组织中survivin、cyclinD1和p53蛋白的表达.结果:survivin、cyclinD1和p53在口腔鳞癌与正常口腔黏膜组织之间的差异均有统计学意义(P<0.05);在口腔鳞癌中,Survivin和CyclinD1蛋白的过表达均与临床分期及淋巴结转移有关(P<0.05或P<0.01),p53过表达与组织分化程度及临床分期有关(P<0.05或P<0.01);survivin的过表达与cyelin D1及p53蛋白表达均呈正相关(r=0.628,0.829),cyclin D1蛋白的过表达与p53蛋白表达也呈正相关.结论:survivin、cyclinD1和p53基因在口腔鳞癌的发生、发展中起着不同程度的作?三者之间可能具有协同作用.     

口腔鳞癌组织中p15和p21的表达分析

目的 探讨p15和p21基因的蛋白产物在口腔鳞癌中的表达及意义。 方法 采用免疫组化P-V法检测108例口腔鳞癌和10例正常口腔黏膜组织中p15和p21蛋白的表达，并将结果与临床病理指标进行统计分析。 结果 口腔鳞癌组织中p15蛋白的阳性表达率低于正常口腔黏膜组织(P<0.05)，而p21蛋白的阳性表达率两组间无明显差异(P>0.05)；口腔鳞癌中，III、IV期口腔鳞癌p15蛋白的阳性表达率明显低于I、II期口腔鳞癌的表达率（P<0.01），无颈淋巴结转移组p15蛋白表达水平比有转移组高（P<0.05）；p21阳性表达率在不同性别组中的表达差异具有统计学意义(P<0.05)。 结论 p15蛋白的表达与口腔鳞癌的临床分期及淋巴结转移有关，p15蛋白表达水平可作为临床评估口腔鳞癌恶性程度、转移和预后的参考指标。     

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.     

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.     

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.     

类赖氨酰氧化酶2与肿瘤转移和发生

类赖氨酰氧化酶2(lysyl oxidase-like 2,LOXL2)是赖氨酰氧化酶(lysyl oxidase,LOX)基因家族的成员之一,其表达产物能促进胶原沉积.LOXL2的过表达能促进纤维化,并与肿瘤侵袭、转移及不良预后有关.目前大部分学者认为LOXL2是一种转移促进基因,也有实验支持其是一种肿瘤抑制基因.研究发现LOXL2可以通过激活Snail/Ecadherin通路或Src/FAK通路促进转移.LOXL2有望作为肿瘤生物标志物,用于预后判断,成为一个新的治疗靶点.     

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.